Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:22])=[C:4]([C:17]([CH3:21])=[CH:18][C:19]=1[CH3:20])[NH:5][CH2:6][C:7]([N:9]([CH3:16])[CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:8].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl>[NH2:1][C:2]1[C:3]([CH3:22])=[C:4]([C:17]([CH3:21])=[CH:18][C:19]=1[CH3:20])[NH:5][CH2:6][C:7]([N:9]([CH:10]1[CH2:15][CH2:14][N:13]([C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:12][CH2:11]1)[CH3:16])=[O:8]
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc(C)c(NCC(=O)N(C)C2CCNCC2)c(C)c1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(NCC(=O)N(C)C2CCN(C(=O)c3ccccc3)CC2)c(C)c1N
Temperature: 0 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
A mixture solution of 300 mg of the compound (23) obtained in the Example 23, 114 μl of benzoyl chloride and 206 μl of triethylamine in 5 ml of methylene chloride were stirred for 2 hours at 0° C. After the reaction, the solvent was removed and the obtained residue was purified by amine-coated silica gel (Fuji Silysia Chemical Ltd.; NH-DM1020) column chromatography (methylene chloride:ether=1:1) to give the above-mentioned compound (128) in 66% yield.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[C:14]45O[C:13]4([C:22](=[O:23])[C:21]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[NH:15]5)[CH2:12][N:11]3[CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:9][C:4]=2O[CH2:2]1.[CH2:32](Cl)Cl>Cl.CN(C=O)C>[CH2:25]([N:11]1[CH:12]=[C:13]2[C:14]([NH:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[C:22]2=[O:23])=[C:10]1[C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:32][C:4]=2[CH:9]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: ClCCl
Reactant: O=C1c2ccccc2NC23OC12CN(Cc1ccccc1)C3c1ccc2c(c1)OCO2
Agent: Cl
Solvent: CN(C)C=O
Product: O=c1c2ccccc2[nH]c2c(-c3ccc4c(c3)CCO4)n(Cc3ccccc3)cc12

Procedure:
The title compound was prepared by stirring 3-(1,3-benzodioxol-5-yl)-2,3-dihydro-2-(phenylmethyl)-3a,9a-epoxy-1H-pyrrolo[3,4-b]quinolin-9-(4H)-one, prepared as in Example 1, with HCl (2 drops of 1N aqueous solution) in a mixture of CH2Cl2 and DMF (4:1) for 72 hours at room temperature.
Reaction SMILES: [N:1]([CH:4]1[CH2:13][CH2:12][C:11]2[CH:10]=[C:9]([C:14]#[N:15])[CH:8]=[CH:7][C:6]=2[CH:5]1[OH:16])=[N+:2]=[N-:3].Cl.[NH2:18][OH:19].C(=O)(O)[O-].[Na+].CCOC(C)=O>CC(O)C>[N:1]([CH:4]1[CH2:13][CH2:12][C:11]2[CH:10]=[C:9]([C:14](=[N:18][OH:19])[NH2:15])[CH:8]=[CH:7][C:6]=2[CH:5]1[OH:16])=[N+:2]=[N-:3]
Reactant: N#Cc1ccc2c(c1)CCC(N=[N+]=[N-])C2O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NC1CCc2cc(C(N)=NO)ccc2C1O
Temperature: 25 °C
Yield: 94.7 %

Procedure:
Racemic (5S*,6R*)-6-azido-5-hydroxy-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (400 mg, 1.9 mmol) and hydroxylamine hydrochloride (260 mg, 3.7 mmol) were mixed in 2-propanol (7.5 mL). To this suspended solution was added sodium bicarbonate (627 mg, 7.5 mmol) and the solution was heated at reflux for 2 hr. Then the reaction mixture was cooled to room temperature and diluted by EtOAc (50 mL) and washed with water and brine. The combined aqueous layers were extracted again by EtOAc. The combined organic layers were dried (MgSO4) and concentrated to afford pure racemic (5S*,6R*,E/Z)-6-azido-N′,5-dihydroxy-5,6,7,8-tetrahydronaphthalene-2-carboximidamide (445 mg, 1.8 mmol, 96% yield).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([C:19]([CH2:21][C:22](OCC)=[O:23])=O)([F:18])([F:17])[F:16].CS(O)(=O)=O>>[CH2:1]([C:8]1[CH:13]=[C:12]2[C:11](=[CH:10][CH:9]=1)[O:14][C:22](=[O:23])[CH:21]=[C:19]2[C:15]([F:18])([F:17])[F:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(Cc2ccccc2)cc1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: CS(=O)(=O)O
Product: O=c1cc(C(F)(F)F)c2cc(Cc3ccccc3)ccc2o1
Temperature: 65 °C
Yield: 44.3 %

Procedure:
A stirred suspension of 4-benzylphenol (4.67 g, 25.4 mmol), CF3COCH2CO2Et (7.00 g, 38.0 mmol), & MeSO3H (8.5 mL, 130.9 mmol) was heated at 65° C. for 9 h. On cooling, the mixture was partitioned between Et2O (200 mL) and H2O (50 mL), then the aqueous phase was basicified with 2 M NaOH. The organic layer was separated and washed with H2O and brine, before being dried (MgSO4). Filtration, solvent evaporation, and column chromatography (4:1 PE-Et2O) furnished 6-benzyl-4-trifluoromethylchromen-2-one (3.42 g, 44%): δH (CDCl3)=4.10 (s, 2H), 6.85 (s, 1H), 7.20–7.40 (m, 5H), 7.45 (dd, 1H), 7.60 (d, 1H). This compound (2.00 g, 6.6 mmol) was dissolved in H2SO4 (20 mL), then the whole was stirred for 15 minutes. The mixture was carefully treated with crushed ice (80 g), then the resulting white precipitate was collected by filtration. The precipitate was air-dried, before being treated with hot THF (100 mL). After filtration, the filtrate was concentrated to yield 4-(2-oxo-4-trifluoromethyl-2H-chromen-6-ylmethyl)benzenesulfonic acid (2.20 g, 87%): δH ((CD3)2SO)=4.05 (s, 2H), 7.00 (s, 1H), 7.20 (d, 2H), 7.45 (d, 1H), 7.50–7.60 (m, 4H). This compound was reacted with (COCl)2, as described above in Preparation 2, to give a solid which was dissolved in EtOAc, before being filtered and concentrated to produce the title compound (2.30 g, 87%): Rf (2:1 PE-EtOAc)=0.60.
Reaction SMILES: [ClH:1].[N:2]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([NH2:13])=[NH:12])[CH2:6][CH2:5][CH2:4][CH2:3]1.CC[O-].[Na+].[CH2:21]([O:28][C:29]1[CH:30]=[C:31]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[C:32]([NH:34]N)=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl.CCOCC>C(O)C>[ClH:1].[CH2:21]([O:28][C:29]1[CH:30]=[C:31]([C:32]2[NH:34][N:13]=[C:11]([C:10]3[CH:14]=[CH:15][CH:16]=[C:8]([CH2:7][N:2]4[CH2:6][CH2:5][CH2:4][CH2:3]4)[CH:9]=3)[N:12]=2)[CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: N=C(N)c1cccc(CN2CCCC2)c1
Reactant: COc1ccc(C(=O)NN)cc1OCc1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: COc1ccc(-c2nc(-c3cccc(CN4CCCC4)c3)n[nH]2)cc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
To a stirred ethanolic suspension of 3-pyrrolidin-1-ylmethyl-benzamidine hydrochloride salt (1:2) (414 mg, 1.5 mmol, 1.5 eq.) in ethanol (15 ml) was added 1.2N NaOEt in ethanol (3.4 ml, 4 eq.) over 3 min. and stirring was then continued for 30 min. at r.t. 3-Benzyloxy-4-methoxy-benzoic acid hydrazide (272 mg, 1 mmol) in ethanol was added at 20° C. and the resulting mixture was heated to reflux for 50 hrs. Upon cooling, the product mixture was filtered, the solvent was evaporated and the residue chromatographed over 20 g SiO2 (Merck 230-400 mesh) with CH2Cl2-MeOH (2M NH3) 96:4 affording a solid. This material was dissolved in ethanol at r.t. and an excess 2N HCl/ether solution (1.0 ml, 2 mmol) was added. After 30 min. the solvent was evaporated and the residue dried under high vacuum at 30° C. overnight affording the title compound (326 mg, 89% yield) as a yellow solid. MS: m/e=441.6 (M+H+)
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15](Cl)=[O:16])[S:14][C:5]=3[C:4]=2[CH:3]=1.[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[NH:21][CH3:22].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[N:21]([CH3:22])[C:15]([C:13]1[S:14][C:5]2[C:4]3[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:9]=3[O:8][CH2:7][C:6]=2[CH:12]=1)=[O:16]
Reactant: CNc1ccccc1Cl
Reactant: O=C(Cl)c1cc2c(s1)-c1cc(F)ccc1OC2
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C(=O)c1cc2c(s1)-c1cc(F)ccc1OC2)c1ccccc1Cl
Temperature: 25 °C
Yield: 28 %

Procedure:
To a reaction vial charged with 8-fluoro-4H-thieno[3,2-c]chromene-2-carbonyl chloride (0.05 g, 0.2 mmol) and 2-chloro-N-methylaniline (0.034 g, 0.24 mmol) was added a catalytic amount of DMAP. Pyridine in methylene chloride (1.2 M, 0.66 mL) was added and the reaction was stirred at room temperature with LC/MS monitor. The reaction was complete in a couple hours. After aqueous work up, the reaction was concentrated in vacuo, taken into DMF at 100 mg/ml and purified by preparative RP-HPLC to give 165bp. Yield=28% of theoretical. MS: (ESI+)=374.8
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[NH:20]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:21]1>>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:20]4[CH2:24][CH2:23][CH:22]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=5)[CH2:21]4)[N:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: c1ccc(C2CCNC2)nc1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Product: O=C(O)c1cn(C2CC2)c2nc(N3CCC(c4ccccn4)C3)c(F)cc2c1=O
Yield: 88 %

Procedure:
Starting from 7-chloro-1-cyclopropyl-6-fluoro -1, 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (1.33 g, 4.7 mmol) and 2-(3-pyrrolidinyl) pyridine, a procedure analogous to that given in Example 1 provided the title compound (1.64 g, 88%) as an off-white solid, mp 203°-204° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-])=O)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]>C(O)C.[Pd]>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(F)cc1C(=O)O
Yield: 97.9 %

Procedure:
A solution of Compound 33 (10 g, 54 mmol) in ethanol (100 mL) was stirred under hydrogen in the presence of 10% Pd/C (0.5 g) at room temperature for 4 h. The solution was filtered through celite. The solvent was evaporated under reduced pressure to yield 8.2 g (98%) of white solids. M.P. 142° C. 1H NMR (DMSO-d6): 6.71 (dd, J=4.9, 8.9 Hz, 1H), 7.15 (dt, J=2.9, 8.4 Hz, 1H), 7.37 (dd, J=2.9, 9.8 Hz, 1H), 8.60 (s, 1H). EIMS m/z 156 (M+1).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:9][CH2:8][CH2:7][CH:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:5]1.[CH3:18]S(C)=O>>[O:3]1[C:4]2([CH2:9][CH2:8][CH2:7][C@@H:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[CH2:5]2)[CH2:18]1
Reactant: CS(C)=O
Reactant: CC(C)(C)OC(=O)NC1CCCC(=O)C1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC2(CO2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Me3SOI (56.2 mmol) in DMSO (80 ml) was added NaH (51.5 mmol) and stirred at room temperature for 2 h until the solution become clear. The resulting solution was added tert-butyl 3-oxocyclohexylcarbamate (23.4 mmol) and stirred at rt overnight. The reaction was quenched with water and extracted with hexane. The extracts were combined and dried using anhydrous sodium sulfate. The product was purified using Biotage. The final products, isomer 1 and isomer 2, were well separated on silicon column with 15%-20% ethyl acetate in hexane. Each single diastereomer was used for the next step.
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]([CH:7]1[CH2:9][CH2:8]1)[CH2:5][OH:6].Cl[CH2:11][C:12](OCC)=[O:13]>C1(C)C=CC=CC=1>[CH:7]1([C@@H:4]2[NH:3][C:12](=[O:13])[CH2:11][O:6][CH2:5]2)[CH2:9][CH2:8]1
Reactant: CCOC(=O)CCl
Reactant: N[C@H](CO)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1COC[C@H](C2CC2)N1
Temperature: 25 °C
Yield: 21.9 %

Procedure:
To a cold, stirred suspension of sodium hydride (600 mg, 14.99 mmol) in toluene (20 mL) was added dropwise a solution of (S)-2-amino-2-cyclopropylethanol (680 mg, 6.72 mmol)) in toluene (12 mL). The reaction mixture was then allowed to warm to room temperature and a solution of ethyl chloroacetate (824 mg, 6.72 mmol) in toluene (4 mL) was added dropwise. The resulting mixture was stirred for 3 h at room temperature. The mixture was then quenched with the addition of 10 mL of 1N aq. hydrochloric acid and concentrated under vacuum. The residue was diluted with THF, dried with magnesium sulfate, concentrated under vacuum and filtered through a pad of silica gel, flushing with additional THF. The resulting filtrate was concentrated under vacuum, and the residue was further purified by flash chromatography (ISCO, 12 g silica gel column, using a 0-100% ethyl acetate in n-heptane gradient as the eluent to afford 208 mg of (S)-5-cyclopropylmorpholin-3-one as a white solid (MS: (M+H)+=142.2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]2[CH:7]=[CH:8][CH2:9][CH2:10][NH:11][C:5]=2[CH:4]=1.FC(F)(F)C(O)=O>C(O)C.[OH-].[Pd+2].[OH-]>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][NH:11][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)NCCC=C2
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: COc1ccc2c(c1)NC=CC=C2
Reaction time: 16 h
Yield: 169.6 %

Procedure:
To a solution of the 8-methoxydihydrobenzazepine (0.45 g, 1.6 mmol) from step F above in ethanol (60 mL) were added trifluoroacetic acid (0.8 mL) and palladium(II) hydroxide (0.15 g, 0.21 mmol). The reaction solution was shaken under hydrogen (35 psi) for 16 hours. The resultant reaction mixture was filtered through a pad of Celite and the filtrate obtained was concentrated in vacuo to give the desired 8-methoxybenzazepine (0.47 g, quantitative), which was used in the next step without purification: ESI MS m/z 282 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:8]3[C:12]([CH2:13][CH2:14][C:15]=2[CH:16]=1)=[N:11][N:10]([C:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:9]=3)=[O:4].[H-].[Na+].[CH3:38]I>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:38])[C:7]2[C:8]3[C:12]([CH2:13][CH2:14][C:15]=2[CH:16]=1)=[N:11][N:10]([C:17]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH:9]=3)=[O:4]
Reactant: COC(=O)c1cc2c([nH]1)-c1cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)nc1CC2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(n1C)-c1cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)nc1CC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76 %

Procedure:
To a solution of 7-trityl-1,4,5,7-tetrahydro-1,6,7-triaza-as-indacene-2-carboxylic acid methyl ester XVII (1.1 mmol) in dry DMF (5 mL), NaH (2 eq) was added, the mixture was stirred at rt for 15 min then methyl iodide (2 eq) was added and the mixture was stirred at rt for 2 h. The mixture was poured into aq saturated NaH2PO4, extracted with AcOEt and the organic layer washed with water, dried (Na2SO4) and concentrated. The crude material was triturated with ethanol and filtered. Obtained the title compound (76% yield). ESI (+) MS: m/z 474 (MH+). 1H NMR (300 MHz): 2.48-2.59 (m, 1H), 2.62-2.92 (m, 3H), 3.79 (s, 3H), 3.89 (s, 3H), 6.44 (s, 1H), 7.11-7.31 (m, 15H), 7.61 (s, 1H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:30]=[CH:29][C:13]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([O:27]C)=[O:26])=[CH:21][CH:20]=3)[C:15]([CH3:17])=[N:16][C:12]=2[CH:11]=1.[OH-].[Na+].CO>C(Cl)(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:30]=[CH:29][C:13]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([OH:27])=[O:26])=[CH:21][CH:20]=3)[C:15]([CH3:17])=[N:16][C:12]=2[CH:11]=1
Reactant: COC(=O)c1ccc(Cn2c(C)nc3cc(-c4nc5ccccc5o4)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1Cc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.8 %

Procedure:
To a solution of 5-(benzoxazol-2-yl)-1-(4-methoxycarbonylphenylmethyl)-2-methylbenzimidazole (see Working Example 113-3) (55 mg, 0.138 mmol) in chloroform (3 mL) was added aqueous sodium hydroxide solution (1 M, 0.6 mL, 0.6 mmol). This two-layer solution was homogenized by the addition of methanol, and this was stirred at room temperature for 20 hours. After the reaction was complete, the solution was concentrated, aqueous acetic acid solution was added, and this was stirred at room temperature. The precipitated crystals were filtered, and after washing with water were dried to yield the title compound (45.9 mg, 87% yield) as yellow crystals.
Reaction SMILES: [CH2:1]1[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH2:4][C@H:3]([C:14]([OH:16])=[O:15])[NH:2]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>O>[C:24]([N:2]1[C@@H:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:1]1)([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]
Reactant: O=C(O)[C@H]1Cc2c([nH]c3ccccc23)CN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)[C@H]1Cc2c([nH]c3ccccc23)CN1C(=O)OCc1ccccc1
Reaction time: 0.08 h

Procedure:
5.00 g (3R)-1,2,3,4-Tetrahydro-9H-pyrido[3,4-b]-indole-3-carboxylic acid is suspended in 50 ml water/50 ml tetrahydrofuran and 5.15 g sodium carbonate is added. The mixture is stirred for 5 minutes and 3.94 g benzyl chloroformate is added and the mixture stirred overnight. The mixture is evaporated in vacuo to remove the THF, the aqueous residue acidified with 1N hydrochloric acid and the resulting solid extracted into ethyl acetate. The organic solution is washed with 1N HCl, water, brine, and dried over sodium sulfate. The solution is filtered, evaporated and the residue crystallized from toluene to give (3R)-2-carbobenzoxy-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylic acid, m.p. 181°-184° C.
Reaction SMILES: [CH:1]1([N:4]([CH3:29])[C:5]2[C:6]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][C:23]([CH3:28])=[CH:22]4)=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=3)[CH2:3][CH2:2]1.[OH-].[Na+].O>CO>[CH:1]1([N:4]([CH3:29])[C:5]2[C:6]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][C:23]([CH3:28])=[CH:22]4)=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=3)[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccc2nc(-c3ccc4[nH]c(C)cc4c3)c(N(C)C3CC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc2cc(-c3nc4ccc(C(=O)O)cc4nc3N(C)C3CC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.2 %

Procedure:
To a solution of methyl 3-[cyclopropyl(methyl)amino]-2-(2-methyl-1H-indol-5-yl)quinoxaline-6-carboxylate (74.7 mg, 0.19 mmol) in methanol (30 ml) was added NaOH (32 mg, 0.80 mmol), water (1 ml) with stirring overnight at room temperature. The resulting solution was extracted ethyl acetate (2×50 ml), and adjusted pH to 5 with AcOH. The resulting solution was extracted with ethyl acetate (3×30 ml), dried over anhydrous sodium sulfate, concentrated under vacuum to give a residue, which was purified via silica gel chromatography (20% methanol in ethyl acetate) to afford 3-[cyclopropyl(methyl)amino]-2-(2-methyl-1H-indol-5-yl)quinoxaline-6-carboxylic acid as a yellow solid (13.6 mg, 19%).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[N:22]([CH2:23][CH2:24][CH3:25])[N:21]=[C:20]([CH2:26][CH3:27])[C:19]=2[C:28]([O:30][CH3:31])=[O:29])=[CH:13][CH:12]=1)(=[O:4])=[O:3].[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.OP([O-])(O)=O.[K+]>N1C=CC=CC=1>[CH2:26]([C:20]1[C:19]([C:28]([O:30][CH3:31])=[O:29])=[C:18]([CH2:17][C:14]2[CH:13]=[CH:12][C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[S:2]([NH:1][C:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:39])(=[O:3])=[O:4])=[CH:16][CH:15]=2)[N:22]([CH2:23][CH2:24][CH3:25])[N:21]=1)[CH3:27]
Reactant: CCCn1nc(CC)c(C(=O)OC)c1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: c1ccncc1
Product: CCCn1nc(CC)c(C(=O)OC)c1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
To a solution of the compound obtained in example 44 (0.5 g, 1.13 mmol) in pyridine (10.8 mL) was added benzoyl chloride (0.13 mL) and the reaction mixture was stirred at room temperature under an argon atmosphere for 12 h. Then, saturated aqueous KH2PO4 (33 mL) was added and it was extracted with EtOAc. The organic phase was unwashed with 1N HCl, dried and concentrated to a crude product. This was chromatographed on silica gel (hexane-EtOAc, 1:1) to afford the title compound as a foam (0.64 g, 100%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][C:48]([CH3:53])([CH3:52])[C@H:49]([NH2:51])[CH3:50]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:51][C@H:49]([CH3:50])[C:48]([CH3:53])([CH3:52])[CH3:47])=[O:43])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: C[C@@H](N)C(C)(C)C
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N[C@H](C)C(C)(C)C)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with (R)-(-)-3,3-dimethyl-2-butylamine (Aldrich) to give the title product. LC-MS (ES+) 748 [(M+H)+].
Reaction SMILES: C1COCC1.[Cl:6][C:7]1[C:8]2[N:9]([C:13]([C@H:16]3[CH2:21][CH2:20][C@H:19]([C:22](OC)=[O:23])[CH2:18][CH2:17]3)=[N:14][CH:15]=2)[CH:10]=[CH:11][N:12]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)(=O)C>[Cl:6][C:7]1[C:8]2[N:9]([C:13]([C@H:16]3[CH2:17][CH2:18][C@H:19]([CH2:22][OH:23])[CH2:20][CH2:21]3)=[N:14][CH:15]=2)[CH:10]=[CH:11][N:12]=1
Reactant: COC(=O)[C@H]1CC[C@H](c2ncc3c(Cl)nccn32)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC[C@H]1CC[C@H](c2ncc3c(Cl)nccn32)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A THF solution (1.00 L) of trans-methyl 4-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexanecarboxylate (29.70 g, 101.1 mmol) was cooled to −78° C. and was charged with LAH (1M in THF, 25.3 mmol, 25.3 mL) dropwise. After 30 min., the reaction mixture was charged with additional LAH (25.3 mmol) at −78° C. and then, allowed to stir at −78° C. for 1.5 h. The reaction was slowly warmed up to r.t. and stirred for additional 30 min. Ethyl acetate, Na2SO4.10H2O, and silica gel were added to the reaction mixture and concentrated in vacuo to give an orange solid. The crude mixture was purified by a silica gel glass column chromatography (eluted with 2:3 EtOAc/DCM to 100% EtOAc) to obtain the title compound as a slightly yellow-tinted white solid; 1H NMR (CDCl3, 400 MHz) δ 1.14-1.30 (m, 2H), 1.61-1.75 (mc, 1H), 1.84 (ddd, J=13.2, 13.2, 13.2, 3.2 Hz, 2H), 1.98-2.13 (m, 4H), 2.19 (s, br, —OH), 2.94 (tt, J=11.6, 3.2 Hz, 1H), 3.56 (d, J=6.0 Hz, 2H), 7.31 (d, J=5.2 Hz, 1H), 7.64 (dd, J=5.2, 1.2 Hz, 1H), 7.79 (d, J=0.8 Hz, 1H); MS (ES+): m/z 266.21/268.17 (100/89) [MH+]. HPLC: tR=2.38 min (OpenLynx, polar—5 min). MS (ES+): m/z 266.21 (100) [MH+], 268.17 (80) [MH+2}, 289.18 (20) [MH+3]; tR(polar-5 min/openlynx) 2.36 min.