Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:19]([O-])=O)=[CH:4][C:5]2[O:9][C:8]([N:10]3[CH2:16][CH2:15][CH2:14][N:13]([CH3:17])[CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:18]=1.Cl.[H][H]>CO.[Pd]>[Cl:1][C:2]1[C:3]([NH2:19])=[CH:4][C:5]2[O:9][C:8]([N:10]3[CH2:16][CH2:15][CH2:14][N:13]([CH3:17])[CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:18]=1
Reactant: [H][H]
Reactant: CN1CCCN(c2nc3cc(Cl)c([N+](=O)[O-])cc3o2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN1CCCN(c2nc3cc(Cl)c(N)cc3o2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A 50 mg portion of 5-chloro-6-nitro-2-(4-methyl-1-homopiperazinyl)benzoxazole was dissolved in 15 ml of methanol, and the resulting solution was mixed with 5 ml of 1 N hydrochloric acid aqueous solution and 30 mg of Pd/C catalyst and, after replacing the atmosphere in the reaction container by hydrogen gas, stirred at room temperature for 15 hours. The catalyst was removed by filtration and the solvent was concentrated under a reduced pressure. The thus remained oily matter was mixed with 5 ml of 1 N hydrochloric acid and washed with ethyl acetate. This was adjusted to pH 8 by adding saturated sodium bicarbonate, and the thus precipitated crystals were collected by filtration to obtain the title compound (16 mg).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:14]=[C:13]([CH3:15])[C:6]2[NH:7][CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:5]=2[CH:4]=1.CC1CCCO1.O.C([O-])([O-])=O.[Na+].[Na+].Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].Cl>>[CH3:2][C:3]1[CH:14]=[C:13]([CH3:15])[C:6]2[N:7]([C:30]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])[CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:5]=2[CH:4]=1
Reactant: Cc1cc(C)c2c(c1)C(=O)CCCN2
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC1CCCO1
Product: Cc1cc(C)c2c(c1)C(=O)CCCN2C(=O)OCc1ccccc1
Temperature: 10 °C
Reaction time: 50 h
Yield: 91.9 %

Procedure:
Charge a 22 L flask with an overhead stirrer, thermocouple, 3 L addition funnel, baffle, cooling bath and N2 purge and 7,9-dimethyl-3,4-dihydro-1H-benzo[b]azepin-5(2H)-one hydrochloride (1,000 g, 4.43 moles). Add 2-methyltetrahydrofuran (6.44 kg, 7.5 L, 74.5 moles) and agitate the off-white slurry. Cool to 5-15° C. Add water 2.5 L, 138.8 moles and Na2CO3 (1.12 kg, 3 moles) to the addition funnel then slowly add to the reaction mixture at a fast drip over about 25 m. Charge a 2 L addition funnel with benzyl chloroformate (91.59 kg, 8.86 moles) add dropwise to the reaction, while maintaining the reaction mixture below about 15° C. Transfer the resulting mixture to a flask equipped with a condenser and heat to 25-25° C. and stir for about 50 h. Cool to about 15° C., add HCl (5 M, until the pH is about 5). Separate the layers. Extract the aqueous layer with methyltetrahydrofuran (4 L); combine the organic layers and wash with water (4 l). Concentrate the organic layer at about 40° C. Add IPA (4 L) and then concentrate to 2 L. Transfer to a 12 L flask equipped with an overhead stirrer, thermocouple, heating mantle condenser, 2 L addition funnel and N2 purge. Heat the flask contents to about 70-80° C. and add heptane (5 L). Slowly cool to RT overnight; seed the mixture if necessary to induce crystallization of the titled compound. Cool and collect the solid; rinse the solid with cold heptane and dry in a vacuum at 50° C. to provide 1,316 g of the title compound.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[C:6]([O:10][C:11]([NH:13][C@H:14]1[CH2:18][C:17](C(O)=O)=[CH:16][C@H:15]1[OH:22])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C.C[O-].[Na+]>CO>[CH3:5][O:4][C:2]([C:17]1[CH2:18][C@H:14]([NH:13][C:11]([O:10][C:6]([CH3:8])([CH3:7])[CH3:9])=[O:12])[C@H:15]([OH:22])[CH:16]=1)=[O:3]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CC(C(=O)O)=C[C@H]1O
Agent: C[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)C1=C[C@@H](O)[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
Methyl chloroformate (29 /ml, 0.37 mol) was added dropwise to a cooled solution (0° C.) of (3R,4S)-4-tert-butoxycarbonylamino-3-hydroxycyclopent-1-enecarboxylic acid (83 g, 0.34 mol) and triethylamine (52 ml, 0.37 mol) in methanol (600 ml). The reaction was stirred for 1 h at 0° C. and then allowed to warm to room temperature. After stirring for 14 h, it was apparent that the reaction was incomplete. After cooling to 0° C., triethylamine (30 ml, 0.22 mol) was added, and then methyl chloroformate (15 ml, 0.19 mol) was added dropwise. The reaction was complete after a further 2 h. The reaction mixture was concentrated under vacuum and the residue redissolved in dichloromethane (400 ml). The organic solution was washed sequentially with 1M potassium hydrogen sulfate (aq) (2×200 ml), saturated hydrogen carbonate (2×200 ml) and brine (200 ml) before drying over magnesium sulfate. Following filtration, the solvent was removed to yield an orange oil which was redissolved in methanol (300 ml) and cooled to 5° C. Sodium methoxide (0.25 ml, 25% wt solution in methanol, 3 mol %) was then added and the reaction mixture cooled and stirred for 4 h. The reaction was quenched with glacial acetic acid and concentrated under vacuum, and the residue was redissolved in dichlormethane (300 ml). The organic solution was washed with saturated sodium hydrogen carbonate (100 ml) then brine (100 ml) and dried over magnesium sulfate. Following filtration, the solvent was removed under vacuum to yield the title compound as an orange oil (76 g, 87%).
Reaction SMILES: C([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([NH:37][CH:38]([CH3:40])[CH3:39])[C:14]([N:16]2[CH:25]([C:26]3[NH:27][CH:28]=[C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:30]=3)[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17]2)=[O:15])=[CH:8][CH:7]=1)(C)(C)C.FC(F)(F)C(O)=O>>[OH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([NH:37][CH:38]([CH3:40])[CH3:39])[C:14]([N:16]2[CH:25]([C:26]3[NH:27][CH:28]=[C:29]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:30]=3)[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17]2)=[O:15])=[CH:8][CH:7]=1
Reactant: CC(C)NC(Cc1ccc(OC(C)(C)C)cc1)C(=O)N1Cc2ccccc2CC1c1nc(-c2ccccc2)c[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(Cc1ccc(O)cc1)C(=O)N1Cc2ccccc2CC1c1nc(-c2ccccc2)c[nH]1

Procedure:
3-(4-tert-Butoxy-phenyl)-2-isopropylamino-1-[3-(4-phenyl-1H-imidazol-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-propan-1-one (0.086 g, 0.16 mmol) was added to ice cooled trifluoroacetic acid (3 mL). After 1.5 hour the reaction was concentrated under reduced pressure to give a clear oil. This material was purified via a Gilson preparative HPLC resulting in the isolation of desired product 3-(4-hydroxy-phenyl)-2-isopropylamino-1-[3-(4-phenyl-1H-imidazol-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-propan-1-one as a white solid after lyophilization, which proved 100% pure by HPLC at 254 and 214 nm, (LC/MS; Measured MW (MH+): 481).
Reaction SMILES: [H-].[Na+].O[CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.[C:22]([O:25][CH2:26][CH3:27])(=[O:24])[CH3:23]>COCCOC>[CH2:14]([N:5]1[C:6](=[O:13])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:4]1[CH2:23][C:22]([O:25][CH2:26][CH3:27])=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(C)=O
Reactant: O=C1c2ccccc2C(O)N1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)CC1c2ccccc2C(=O)N1Cc1ccccc1
Temperature: 20 °C

Procedure:
Ethyl (2-benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate is prepared as described in Example 2, starting with 3.2 g of 60% sodium hydride in 200 cm3 of 1,2-dimethoxyethane, 16.4 cm3 of triethyl phosphonoacetate and 9.5 g of 3-hydroxy-2-benzyl-2,3-dihydroisoindol-1-one. The mixture is refluxed for 18 hours and is then cooled to a temperature in the region of 20° C. The reaction mixture is treated with 100 cm3 of water and then with 100 cm3 of ethyl acetate. After separation of the phases by settling, the aqueous phase is extracted twice with 100 cm3 of ethyl acetate. The organic extracts are combined, washed with 50 cm3 of brine, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is purified by chromatography under argon pressure (60 kPa) on a column of silica gel (particle size 15-40 μm), eluting with successive mixtures of cyclohexane/ethyl acetate (75/25 and then 67/33 by volume). The fractions comprising the expected product are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 8.7 g of ethyl (2-benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate are thus obtained in the form of a viscous yellow oil. (Rf=0.35, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (75/25 by volume)).
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[O:7])=[CH:15][CH:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)c2ccc(F)cc2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccc(F)cc1)c1ccc(CBr)cc1
Yield: 43 %

Procedure:
A mixture of 2.0 g (9.9 mmol) of 4-methyl-4′-fluorobenzophenone, 1.524 g (9.9 mmol) of recrystallized N-bromosuccinimide, 170 mg benzoyl peroxide, and 20 mL CCl4 was refluxed under argon for 3 hours. The hot solution was filtered through a glass sintered filter and rinsed with 20 mL of hot CCl4 until the crystals became colorless. The crystals were washed with 6 mL of cold CCl4 and the solution was concentrated under reduced vacuum. The crude product was recrystallized from hexane and dried under vacuum. The resultant yield was 43%. Rf=0.25 (ethyl Acetate/hexane; 15:85). 1H-NMR: δ 7.85 (dd, aromatic, 2H), 7.75 (d, aromatic, 2H), 7.51 (d, aromatic, 2H), 7.17 (dd, aromatic, 2H), 4.52 (s, methyl, 3H). 13C-NMR: δ 195.0 (carbonyl); 166.5, 164.5, 142.5, 138.5, 133.4, 130.4, 129.2, 115.8, 115.5 (aromatic); 31.1 (alkyl).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][NH:14][C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>C(O)C.O>[CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][NH:14][C:15]2[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:24][CH:25]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(NCc2ccc(OCc3ccccc3)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(NCc2ccc(OCc3ccccc3)cc2)cc1

Procedure:
A mixture of 10 g. of ethyl p-[p-(benzyloxy)benzylamino]benzoate (prepared as described in Example 11) 10 g. of potassium hydroxide and 200 ml. of ethanol-water (9:1) are refluxed for 4.5 hours. While hot, the mixture is acidified with concentrated hydrochloric acid. Dilution with water and filtration gives tan crystals which are recrystallized from glacial acetic acid to give off-white crystals, m.p. 206°-208° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[Cl:17][C:18]1[CH:26]=[CH:25][C:24]([S:27](=[O:31])(=[O:30])[NH:28][CH3:29])=[CH:23][C:19]=1[C:20](O)=[O:21]>>[C:14]([C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH2:13][CH2:12][N:11]([C:20]([C:19]3[CH:23]=[C:24]([S:27]([NH:28][CH3:29])(=[O:31])=[O:30])[CH:25]=[CH:26][C:18]=3[Cl:17])=[O:21])[CH2:10][CH2:9]2)=[C:2]([F:1])[CH:3]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)c1ccc(N2CCNCC2)c(F)c1
Reactant: CNS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Product: CNS(=O)(=O)c1ccc(Cl)c(C(=O)N2CCN(c3ccc(C(C)=O)cc3F)CC2)c1

Procedure:
The title compound was prepared according to the procedure D described for example 2 from 1-(3-Fluoro-4-piperazin-1-yl-phenyl)-ethanone and 2-Chloro-5-methylsulfamoyl-benzoic acid (CAS: 68901-09-7; BE 620741) (69%, light yellow foam, M−H: 452.1)
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:20]=[C:21]([CH2:25][NH2:26])[CH:22]=[CH:23][CH:24]=1>>[F:17][C:18]([F:27])([F:28])[C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=1)[CH2:25][NH:26][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Product: O=c1[nH]c2ncccc2c2cc(NCc3cccc(C(F)(F)F)c3)ccc12
Yield: 20.6 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 448 using 6 (230 mg, 1.0 mmol) and (3-(trifluoro-methyl)phenyl)methanamine (350 mg, 1.00 mmol) to provide 451 (76 mg, 20% yield) as a white powder. LC-MS (M+H=370, obsd.=370). 1H NMR (400 MHz, DMSO-D6) δ 11.51 (s, 1H), 8.59 (d, J=8.1, 1H), 8.42 (dd, J=1.6, 4.7, 1H), 8.00 (d, J=8.8, 1H), 7.70 (m, 2H), 7.60 (d, J=6.9, 2H), 7.41 (d, J=2.1, 1H), 7.25 (dd, J=4.7, 8.0, 1H), 6.97 (dd, J=2.2, 8.8, 1H), 4.63 (s, 2H).
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[NH2:40][C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][C:48]=1[NH2:49])[C:44]#[N:45]>C(Cl)(Cl)Cl>[NH2:49][C:48]1[CH:47]=[CH:46][C:43]([C:44]#[N:45])=[CH:42][C:41]=1[NH:40][C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([CH2:8][N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH3:7])=[CH:17][CH:16]=1
Reactant: CCCN(CCC)Cc1ccc(C(=O)O)cc1
Reactant: N#Cc1ccc(N)c(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: CCCN(CCC)Cc1ccc(C(=O)Nc2cc(C#N)ccc2N)cc1
Reaction time: 2 h
Yield: 52.3 %

Procedure:
The compound (1.01 g) obtained in Example 29-3, WSCI hydrochloride (973 mg), and HOBt (894 mg) were dissolved in chloroform (30 ml), and the whole was stirred for 2 hours. Then, the compound (445 mg) obtained in Example 29-1 was added thereto and the whole was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. Then, the residue was dissolved in chloroform and washed with a saturated ammonium chloride aqueous solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated saline solution. After that, the resultant was dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (613 mg) as an orange solid.
Reaction SMILES: C(O[C:4]1[C:5](=[O:17])[C:6](=[O:16])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])C.[Cl:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21]>CS(C)=O>[Cl:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH:21][C:4]1[C:5](=[O:17])[C:6](=[O:16])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15]
Reactant: CCOc1c(Nc2ccccc2O)c(=O)c1=O
Reactant: Nc1ccccc1Cl
Solvent: CS(C)=O
Product: O=c1c(Nc2ccccc2O)c(Nc2ccccc2Cl)c1=O
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a solution of 3-ethoxy-4-(2-hydroxyanilino)-cyclobut-3-ene-1,2-dione (50 mg, 0.21 mmol) in DMSO (1.5 mL) was added 2-chloroaniline (0.023 mL, 0.21 mmol) and reaction was stirred at 110° C. overnight. Reaction was purified on HPLC (acetonitrile:water) and product was concentrated down. Solid was dried in vacuo. LC-MS (m/z) 315 (M+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([OH:13])=[O:12])=[N:2]1.[CH3:14]O>S(=O)(=O)(O)O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[N:2]1
Reactant: O=C(O)Cc1n[nH]c2ccccc12
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1n[nH]c2ccccc12

Procedure:
A solution of 2-(1H-indazol-3-yl)acetic acid (300 mg, 1.70 mmol) in methanol (15 mL) containing 5 drops of concentrated sulfuric acid was refluxed for 14 hours. The reaction mixture was concentrated under reduced pressure to a low volume, and then diluted with ethyl acetate (8 mL). The organic layer was treated with water (2×5 mL) and 10% sodium bicarbonate solution (5 mL). The ethyl acetate phase was collected, dried over sodium sulfate and concentrated to quantitatively obtain the title compound as crystalline solid upon drying at high vacuum. C10H10N2O2, Mr=190.20; 1H NMR (400 MHz, DMSO-d6) d: 3.62 (s, 3H), 4.01 (s, 2H), 7.09 (td, J=0.8/7.4 Hz, 1H), 7.33 (td, J=1.0/7.7 Hz, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) d: 33.04 (s, —CH2—), 52.17 (s, —OCH3), 110.49 (s, C7′), 120.29 (s), 120.43 (s), 122.20 (s, C4a′), 126.40 (s, C6′), 138.83 (s, C7a′), 141.20 (s, C3′), 171.03 (s, >C═O); LCMS (ESI) tR: 1.65 min (>99%, UV254), m/z: 191.2 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].O.Cl.[NH:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1>>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:18]3[CH2:19][CH2:20][NH:15][CH2:16][CH:17]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Product: O=[N+]([O-])c1ccc2c(C3=CCNCC3)c[nH]c2c1
Yield: 97.8 %

Procedure:
Beginning with 6.0 gm (37.0 mMol) 6-nitro-1H-indole and 11.4 gm (74.0 mMol) 4-piperidone hydrochloride monohydrate, 8.8 gm (97%) of the title compound were recovered as an orange solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1.[OH:29][C:30]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[F:15][C:14]([F:17])([F:16])[C:13]([C:6]1[C:7]([CH3:12])=[N:8][C:9]2[C:4]([C:5]=1[C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:21][CH:20]=1)=[CH:3][C:2]([N:33]1[CH2:34][CH2:35][C:30]([OH:29])([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:31][CH2:32]1)=[CH:11][CH:10]=2)=[O:18]
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C(F)(F)F
Product: Cc1nc2ccc(N3CCC(O)(c4ccccc4)CC3)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 17 %

Procedure:
The title compound was prepared from 1-[6-Bromo-4-(4-methanesulfonyl-phenyl)-2-methyl-quinolin-3-yl]-2,2,2-trifluoro-ethanone [example 24] and 4-hydroxy-4-phenylpiperidine according to the procedure of example 25, except that the reaction time was of 16 h. Yield: 17%; MS: m/z=569 (M+H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:18]=[CH:17][C:6]2[N:7]([OH:16])[C:8]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)=[N:9][C:5]=2[CH:4]=1.[CH2:19]1COCC1.CI>>[CH3:19][O:16][N:7]1[C:6]2[CH:17]=[CH:18][C:3]([S:2][CH3:1])=[CH:4][C:5]=2[N:9]=[C:8]1[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: CSc1ccc2c(c1)nc(-c1cccnc1)n2O
Reactant: C1CCOC1
Solvent: CI
Product: COn1c(-c2cccnc2)nc2cc(SC)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 5-(methyl-thio)-2-(pyridin-3-yl)-1H-benzo[d]imidazol-1-ol (0.36 g, 0.001 mol) in THF (20 ml) NaH (60% suspension in mineral oil), (0.14 g, 0.003 mol) was added. After stirring for the next 20 min at room temperature methyl iodide (0.39 g, 0.002 mol) was added drop wise. The resulting solution was continued to stir at room temperature for the next 3 h. The reaction was quenched with ice cold water and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with brine dried over Na2SO4 and concentrated under vacuum to afford to afford the crude compound which was purified by chromatography to obtain title compound 1-methoxy-5-(methyl-thio)-2-(pyridin-3-yl)-1H-benzo[ ]imidazole as a stick brown solid. 1H NMR (400 MHz, DMSO-d6), δ 9.47 (s, 1H), 8.74-8.73 (m, 1H), 8.53-8.50 (m, 1H), 7.71 (s, 1H), 7.49-7.33 (m, 3H), 4.05 (s, 3H) 2.58 (s, 3H). MS (M+1): 272.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[CH:12][N:13]([CH2:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:14]=2)=[CH:6][CH:5]=1)([O-])=O.C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[CH:12][N:13]([CH2:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:14]=2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)CCn1cnc(-c2ccc([N+](=O)[O-])cc2)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)OC(=O)CCn1cnc(-c2ccc(N)cc2)c1
Temperature: 40 °C
Yield: 76 %

Procedure:
Palladium (10% w/w on carbon, 50% wet, 260 mg, 2.443 mmol) was added to a solution of 1,1-dimethylethyl 3-[4-(4-nitrophenyl)-1H-imidazol-1-yl]propanoate (for a preparation see Intermediate 97) (2.6 g, 8.19 mmol) and ammonium formate (1.29 g, 20.48 mmol) in ethanol (50 mL). The reaction mixture was refluxed for 4 h then was cooled to approximately 40° C. and filtered through celite whilst still warm. Most of the solvent was removed in vacuo from the filtrate to give 1,1-dimethylethyl 3-[4-(4-aminophenyl)-1H-imidazol-1-yl]propanoate (1.8 g, 6.26 mmol, 76%) as a yellow solid.
Reaction SMILES: [O:1]=[CH:2][CH:3]([C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([O:16][CH3:17])[CH:10]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[BH4-].[Na+].O>CO>[OH:1][CH2:2][CH:3]([C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([O:16][CH3:17])[CH:10]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(C=O)c1cc(C)cc(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)C(CO)c1cc(C)cc(OC)c1
Temperature: -10 °C
Reaction time: 3 h
Yield: 103.6 %

Procedure:
A stirred solution of ethyl 3-oxo-2-(3-methoxy-5-methylphenyl)propionate (1.9 g; 8.1 mmol; from step (v) above) in MeOH (50 mL) was cooled to −15° C. NaBH4 (0.61 g; 16 mmol) was then added in portions. The mixture was stirred for 3 hours at −15 to −5° C. Water was then added, and resultant mixture concentrated. The aqueous phase was extracted with EtOAc, the organic phase was washed with water, dried (Na2SO4) and evaporated to yield 2.0 g (59%) of sub-title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][C@@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1)=[O:9])=[O:5].[CH3:24][O:25][C:26]1[N:31]=[C:30]([O:32][CH3:33])[C:29]([CH:34]=O)=[CH:28][N:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C1COCC1>[NH2:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][C@@H:11]1[CH2:15][CH2:14][N:13]([CH2:34][C:29]2[C:30]([O:32][CH3:33])=[N:31][C:26]([O:25][CH3:24])=[N:27][CH:28]=2)[CH2:12]1)=[O:9])=[O:5]
Reactant: COc1ncc(C=O)c(OC)n1
Reactant: Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ncc(CN2CC[C@@H](NC(=O)CNC(=O)c3cc(C(F)(F)F)ccc3N)C2)c(OC)n1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
(R)-3-[[N-(2-Amino-5-trifluoromethylbenzoyl)glycyl]amino]pyrrolidine (17.2 mg, 0.04 mmol) was dissolved in THF (1 mL), and 2,4-dimethoxy-5-pyrimidinecarboxaldehyde (6.7 mg, 0.04 mmol) was added to the resulting solution. Sodium triacetoxyborohydride (12.7 mg, 0.06 mmol) and glacial acetic acid (2.4 mg, 0.04 mmol) were subsequently added to the mixture. The resulting mixture was stirred at 50° C. for 24 hours and then concentrated. The residue was dissolved in dichloromethane (1 mL) and washed with a 1 M aqueous solution (1 mL) of NaOH. The organic layer was collected and concentrated, and a dichloromethane solution of 25% trifluoroacetic acid (1 mL) was added. The resulting mixture was stirred at room temperature for 1 hour and then concentrated. The obtained residue was purified by HPLC to thereby provide (R)-3-[[N-(2-amino-5-trifluoromethylbenzoyl)glycyl]amino]-1-(2,4-dimethoxypyrimidin-5-ylmethyl)pyrrolidine (Compd. No. 2175) (18.6 mg, 78%). The purity was determined by RPLC/MS (98%). ESI/MS m/e 483 (M++H, C21H25F3N6O4).