Azzindani/Open_Reaction_Data huggingface dataset:
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.[NH2:17][CH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[OH-].[K+]>C(O)(C)(C)C.CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:14]=[C:6]1[C:5]2[CH:15]=[CH:16][C:2]([NH:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:26][CH:27]=3)=[CH:3][C:4]=2[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)(C)O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(CNc2ccc3c(=O)[nH]c4ncccc4c3c2)cc1
Temperature: 125 °C
Reaction time: 0.17 h
Yield: 7.4 %

Procedure:
6 (100 mg, 0.43 mmol), 4-(aminomethyl)benzoic acid (0.19 mL, 1.30 mmol), Pd2(dba)3 (16 mg, 0.02 mmol), X-Phos (24 mg, 0.05 mmol), and KOH (73 mg, 1.30 mmol) were suspended in tert-butanol (3 mL), and stirred for 10 minutes at 125° C. via microwave. The reaction mixture was diluted with DMF and filtered. The crude product was purified directly via prep-LC-MS to provide 453 (11 mg, 7% yield) as a white powder. LC-MS (M+H=346, obsd.=346). 1H NMR (400 MHz, DMSO-D6) δ 11.49 (s, 0H), 8.55 (s, 2H), 8.41 (s, 1H), 7.95 (d, J=29.0, 3H), 7.56 (s, 2H), 7.38 (s, 2H), 7.25 (s, 1H), 6.97 (s, 1H), 4.60 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:11]([S:12]([N:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.CCOCC>[Br:18][CH2:1][C:2]1[C:11]([S:12]([N:15]([CH3:17])[CH3:16])(=[O:13])=[O:14])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc(S(=O)(=O)N(C)C)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: COC(=O)c1cccc(S(=O)(=O)N(C)C)c1CBr

Procedure:
A mixture of 25.7 g of the product from Example 10, 17.8 g of N-bromosuccinimide, and 1.0 g benzoyl peroxide in 350 ml carbon tetrachloride was stirred at reflux temperature for 3.5 hours and then at room temperature overnight. The by-product succinimide was removed by filtration and the filtrate concentrated in vacuo to afford an oil which was dissolved in ether and washed with two portions of water. Drying and evaporation of the ether layer afforded a viscous yellow oil which was shown by 1H NMR analysis to consist of the title compound and unreacted starting material in a ratio of approximately 2:1. This mixture was carried directly on to the next step.
Reaction SMILES: [CH:1]1[C:9]([NH2:10])=[CH:8][C:7]2[CH2:11][CH2:12][N:5]3[C:6]=2[C:2]=1[C:3]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:4]=13.[C:19]([CH2:23][C:24](Cl)=[O:25])([CH3:22])([CH3:21])[CH3:20]>ClCCl>[CH3:20][C:19]([CH3:22])([CH3:21])[CH2:23][C:24]([NH:10][C:9]1[CH:1]=[C:2]2[C:6]3=[C:7]([CH2:11][CH2:12][N:5]3[C:4]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:3]2=3)[CH:8]=1)=[O:25]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Nc1cc2c3c(c1)c1c(n3CC2)CCCCCC1
Solvent: ClCCl
Product: CC(C)(C)CC(=O)Nc1cc2c3c(c1)c1c(n3CC2)CCCCCC1
Yield: 36.7 %

Procedure:
Following the procedure of Example 1, Step 4, 4,5,7,8,9,10,11,12-octahydrocycloocta[b]pyrrolo[3,2,1-hi]indol-2-amine (0.15 g, 0.54 mmol), t-butylacetyl chloride (0.063 mL, 0.54 mmol) and poly-(4-vinylpyridine) (500 mg) in dichloromethane (12 mL) provided 3,3-dimethyl-N-4,5,7,8,9,10,11,12-octahydrocycloocta[b]pyrrolo[3,2,1-hi]indol-2-ylbutanamide (67 mg). MS (ES) m/z 339.2; HPLC purity 100% at 210-370 nm, 11.1 min.; 100% at 250 nm, 11.1 min.; Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN and MeOH) for 10 min, hold 4 min); HRMS: calcd for C22H30N2O+H+, 339.24309; found (ESI, [M+H]+), 339.2441.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.[H-].[Na+].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15](Cl)[N:14]=1>CN(C=O)C>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:14]=1
Reactant: Clc1cccc(Cl)n1
Reactant: COc1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Sc2cccc(Cl)n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
4-Methoxythiophenol (Aldrich, St. Louis, Mo., Cat. No. 109525; 0.91 mL, 7.4 mmol) was dissolved in DMF (10 mL) and chilled to 0° C. in an ice bath. NaH (0.227 g, 9.5 mmol) was added slowly and the mixture was allowed to stir under an inert atmosphere. After 1 hour, 2,6-dichloropyridine (1.000 g, 6.8 mmol) was added to the mixture and the ice bath was removed. The resulting mixture was allowed to stir under inert atmosphere overnight. The mixture was quenched with 1N NaOH and diluted with DCM. The aqueous layer was extracted with 4:1 DCM/MeOH three times, and the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (1-30% DCM/hexanes) to give 2-chloro-6-(4-methoxyphenylthio) pyridine (0.950 g, 56% yield) as a yellow oil. MS (ESI pos. ion) m/z: 252 (MH+). Calculated exact mass for Cl2H10ClNOS: 251.
Reaction SMILES: C([Mg]Cl)(C)C.[O:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:11][C:12]([CH3:24])([CH3:23])[C:13]([NH:15][C:16]1[CH:21]=CC=C(Br)[N:17]=1)=[O:14].C1(C)C=CC=CC=1.CN(C)C=O>C(O)(=O)C>[CH3:11][C:12]([CH3:24])([CH3:23])[C:13]([NH:15][C:16]1[CH:21]=[CH:7][CH:8]=[C:9]([CH:10]=[O:6])[N:17]=1)=[O:14]
Reactant: CC(C)(C)C(=O)Nc1cccc(Br)n1
Reactant: C1CCOC1
Agent: CC(C)[Mg]Cl
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)Nc1cccc(C=O)n1
Temperature: 13 °C
Reaction time: 24 h

Procedure:
A solution of 2.1 M isopropylmagnesium chloride in tetrahydrofuran (555.3 g, 1.20 mol) was added over 1.5 hours to the crude solution of 2-(trimethylacetylamino)-6-bromopyridine in toluene (501.2 g of crude solution from previous step, 0.500 mol) maintaining the temperature below 3° C. The resulting mixture was aged at 5° C. for 24 hours. Dimethylformamide (112.3 g, 1.54 mol) was added over 20 min maintaining the temperature at 11-15° C. After 15 min, the solution was transferred into 1 L of 10% aqueous acetic acid and the biphasic mixture stirred for 30 min. The organic phase was separated and combined with 500 mL of 20 wt % aqueous sodium hydrogen sulfite. The biphasic mixture was stirred vigorously for 45 min. The aqueous layer was separated and treated with 500 mL of 20 wt % aqueous Na2CO3, then extracted with ethyl acetate (2×500 mL). The combined organic layers were concentrated to approximately 400 mL at 50° C., 600 mmHg. The concentrate was dried over 8 g of MgSO4 and filtered to give 363.7 g of yellow solution (25.65 wt % title aldehyde, 93.28 assay g).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH:8]([C:9]([O:11][CH3:12])=[O:10])[CH2:7][NH:6][C:5]1=[O:13].Br.Br[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>CN1CCCC1=O>[CH3:3][N:4]1[CH:8]([C:9]([O:11][CH3:12])=[O:10])[CH2:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[C:5]1=[O:13]
Reactant: COC(=O)C1CNC(=O)N1C
Reactant: BrCc1ccccn1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COC(=O)C1CN(Cc2ccccn2)C(=O)N1C
Temperature: 0 °C
Reaction time: 20 h
Yield: 25.4 %

Procedure:
A suspension of sodium hydride (240 mg, 6 mmol, 60% dispersion in oil) in N-methyl-2-pyrrolidinone (6 ml) was stirred at 0° C. under argon. A solution of methyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (474 mg, 3 mmol) (prepared as described in step (ii) of Example 8) in N-methyl-2-pyrrolidinone (3 ml) was added dropwise over 10 minutes. The reaction was stirred at 0° C. for 15 minutes and 2-(bromomethyl)pyridine hydrobromide (835 mg, 3.3 mmol) was added portionwise over 5 minutes. The mixture was stirred at 0° C. for 30 minutes and then at room temperature for 20 hours. The reaction was treated with ice water and extracted with dichloromethane. The mixture was applied to a SCX ion exchange cartridge and washed with methanol and then 2M ammonia in methanol. The basic fractions were combined and evaporated. The residue was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give methyl 3-methyl-2-oxo-1-(2-pyridinylmethyl)-4-imidazolidinecarboxylate (190 mg), LC/MS [M+H]+=250. (ii) A stirred solution of methyl 3-methyl-2-oxo-1-(2-pyridinylmethyl)-4-imidazolidinecarboxylate (190 mg, 0.76 mmol) in tetrahydrofuran (1.5 ml)/water (1 ml) at 0° C. was treated with lithium hydroxide (55 mg, 2.28 mmol) and the reaction mixture was stirred at 0-5° C. for 3 hours. The reaction was acidified to pH 2 with 2N hydrochloric acid and the solvent was evaporated. The residue was dried to give 3-methyl-2-oxo-1-(2-pyridinylmethyl)-4-imidazolidinecarboxylic acid which was used crude in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[C:11]([NH2:13])=[O:12].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.O>N1C=CC=CC=1>[C:11]([C:3]1[CH:4]=[C:5]([C:6](=[O:7])[NH2:8])[CH:9]=[CH:10][C:2]=1[NH:1][S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)(=[O:22])=[O:21])(=[O:12])[NH2:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NC(=O)c1ccc(N)c(C(N)=O)c1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(C(N)=O)cc2C(N)=O)cc1
Temperature: 25 °C
Yield: 51 %

Procedure:
To a solution of 4-aminoisophthalamide (1.00 g (5.58 mmol) in pyridine (10.0 ml), p-toluenesulfonyl chloride (1.06 g (5.58 mmol) was added with stirring at room temperature. After 3 hours' stirring at room temperature, water was added to the reaction mixture to separate crystals. The crystals were filtered and washed with water and ethyl acetate to give 0.94 g (51%) of 2′,4′-dicarbamoyl-p-toluenesulfonanilide as white crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:44])[NH:7][CH2:8][CH:9]([NH:19][C:20](=[O:43])[C@@H:21]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:22][CH2:23][NH:24]C(OCC1C=CC=CC=1)=O)[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:44])[NH:7][CH2:8][CH:9]([NH:19][C:20](=[O:43])[C@@H:21]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:22][CH2:23][NH2:24])[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC(CNC(=O)OC(C)(C)C)NC(=O)[C@H](CCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC(CNC(=O)OC(C)(C)C)NC(=O)[C@H](CCN)NC(=O)OC(C)(C)C
Reaction time: 15 h

Procedure:
116 mg (0.186 mmol) of di-tert-butyl[2-({(2S)-4-{[(benzyloxy)carbonyl]amino}-2-[(tert-butoxycarbonyl)amino]butanoyl}amino)propane-1,3-diyl]biscarbamate (Example 156A) are dissolved in 20 ml of ethanol. 30 mg of palladium on activated carbon (10%) are added thereto, and the mixture is then hydrogenated under atmospheric pressure for 15 h. The reaction mixture is filtered through prewashed kieselguhr and the filtrate is concentrated on a rotary evaporator in vacuo. The crude product is reacted without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([O:10][CH:11]([CH3:13])[CH3:12])[CH:7]=[C:6]([OH:14])[CH:5]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][C:29](F)=[CH:28][CH:27]=1)(=[O:25])=[O:24]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:5]=[C:6]([O:14][C:29]2[CH:30]=[CH:31][C:26]([S:23]([CH3:22])(=[O:25])=[O:24])=[CH:27][CH:28]=2)[CH:7]=[C:8]([O:10][CH:11]([CH3:12])[CH3:13])[CH:9]=1
Reactant: COC(=O)c1cc(O)cc(OC(C)C)c1
Reactant: CS(=O)(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(OC(C)C)c1
Temperature: 115 °C
Yield: 101.1 %

Procedure:
To a solution of 3-hydroxy-5-isopropoxy-benzoic acid methyl ester (3.20 g, 15.2 mmol) in DMF (80 mL) was added Cs2CO3 (5.45 g, 16.7 mmol) and 4-fluorophenyl methyl sulfone (2.65 g, 15.2 mmol) at rt. The resulting mixture was heated at 115° C. for 12 hr. Then the mixture was concentrated. The resulting residue was partitioned between EtOAc and water. The aqueous layer was separated and extracted with EtOAc (2×). Combined organic layers were washed with water (1×), dried and concentrated to a residue, which was purified by silica gel flash chromatography (7.5×30 cm, hexane/EtOAc, v/v 5:1, 2:1, 1:1). Fractions containing the mono-alkylation product were pooled and concentrated to give 3-isopropoxy-5-(4-methanesulfonyl-phenoxy)-benzoic acid methyl ester (5.60 g, 100%) as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 8.90 (d, J=9 Hz, 2H), 7.41 (m, 1H). 7.26 (m, 1H), 7.10 (d, J=9 Hz, 2H), 6.79 (m, 1H), 4.56-4.63 (m, 1H), 3.90 (s, 3H), 3.06 (s, 3H), 1.35 (d, J=6 Hz, 6H).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[CH:6]=[C:7]([CH:29]=[CH:30][CH:31]=1)[O:8][CH:9]1[N:17](CC2C=CC(C(O)(C)C)=CC=2)[CH:16]=[CH:15][CH:14]=[C:10]1[C:11]([OH:13])=O)=[O:4].[NH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([OH:44])([CH3:43])[CH3:42])=[CH:37][CH:36]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=N)C>CN(C)C=O.O>[CH3:32][N:2]([CH3:1])[C:3]([C:5]1[CH:6]=[C:7]([CH:29]=[CH:30][CH:31]=1)[O:8][C:9]1[N:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([OH:44])([CH3:42])[CH3:43])=[CH:37][CH:36]=1)=[O:13])=[O:4]
Reactant: CC(C)(O)c1ccc(CN)cc1
Reactant: CN(C)C(=O)c1cccc(OC2C(C(=O)O)=CC=CN2Cc2ccc(C(C)(C)O)cc2)c1
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cccc(Oc2ncccc2C(=O)NCc2ccc(C(C)(C)O)cc2)c1

Procedure:
To a stirred solution of 2-(3-Dimethylcarbamoyl-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl]-nicotinic acid (0.300 grams, 1.05 mmole), 2-(4-Aminomethyl-phenyl)-propan-2-ol (0.190 grams, 1.15 mmole), and 1-hydroxybenzotriazole hydrate (0.155 grams, 1.15 mmole) in dry dimethylformamide (5 ml) was added 1-(3-dimethylamino)-propyl)-3-ethylcarbodiimide hydrochloride (0.242 grams, 1.26 mmole) and stirred over night. The mixture poured into 100 ml water and extracted with ethyl acetate. The combined extracts were washed with 1 N NaOH, water and brine, dried over MgSO4, filtered and concentrated to give an oil that was purified by chromatography on silica gel eluting with 2.5% methanollmethylene chloride (0.360 g). 1H NMR (CDCl3) d 1.54 (6H, s), 3.00 (3H, s), 3.08 (3H, s), 4.66 (2H, d), 7.20 (3H, m), 7.29 (4H, m), 7.43 (2H, m) 8.08 (1H, m), 8.18 (1H, dd), 8.63 (1H, dd); MS: m/e 433 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26](O)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([O:15][C:12]2[CH:13]=[CH:14][C:8]3[CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[S:10][C:9]=3[CH:11]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CCOC(=O)c1cc2ccc(O)cc2s1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cc2s1
Yield: 94.4 %

Procedure:
The above prepared 6-hydroxy-benzo[b]thiophene-2-carboxylic acid ethyl ester (0.206 g, 0.927 mmol, see example 7, step 1 and 2) was dissolved in 5 mL of THF and treated successively at −10° C. with 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.261 g, 1.4 eq.), triphenylphosphine (0.340 g, 1.4 eq.) and DIAD (0.255 mL, 2 eq.), and the mixture then kept at ambient temperature over night. Pouring onto crashed ice, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane AcOEt=85/15), yielded 0.355 g of the title compound as colorless gum.
Reaction SMILES: C(OC([NH:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[CH:17]=[CH:18][N:19]3[C:24]([C:25]=2[CH3:26])=[C:23]([CH:27]2[CH2:29][CH2:28]2)[CH:22]=[C:21]([C:30]([O:32]CC)=[O:31])[C:20]3=[O:35])=[CH:11][C:10]=1[CH3:36])=O)(C)(C)C.Cl.[OH-].[Na+]>C1COCC1>[NH2:8][C:9]1[C:10]([CH3:36])=[CH:11][C:12]([C:16]2[CH:17]=[CH:18][N:19]3[C:24]([C:25]=2[CH3:26])=[C:23]([CH:27]2[CH2:28][CH2:29]2)[CH:22]=[C:21]([C:30]([OH:32])=[O:31])[C:20]3=[O:35])=[CH:13][C:14]=1[CH3:15]
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3cc(C)c(NC(=O)OC(C)(C)C)c(C)c3)ccn2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(-c2ccn3c(=O)c(C(=O)O)cc(C4CC4)c3c2C)cc(C)c1N
Temperature: 50 °C
Reaction time: 3 h
Yield: 38.7 %

Procedure:
14 mg of ethyl 8-(4-tert-butoxycarbonylamino-3,5-dimethylphenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (Example 12) was dissolved in 1 ml of THF. 1 ml of 3 N hydrochloric acid was added to the obtained solution, and they were stirred at 50° C. for 3 hours. 2 ml of 3 N sodium hydroxide was added to the reaction mixture, and they were stirred at 50° C. for 14 hours and then neutralized with 1 N hydrochloric acid. The crystals thus precipitated were taken by the filtration to obtain 4 mg of 8-(4-amino-3,5-dimethylphenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:12])=[N:7][CH2:6][CH2:5]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH3:12])[NH:7][CH2:6][CH2:5]2
Reactant: CC1=NCCc2cc(F)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC1NCCc2cc(F)ccc21

Procedure:
In close analogy to the procedure described above, 6-fluoro-1-methyl-3,4-dihydro-isoquinoline is reacted with sodium triacetoxyborohydride to provide the title compound.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2.[OH-].[Na+].CN(C)[CH:21]=[O:22]>O>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH:21]=[O:22]
Reactant: COc1ccc2[nH]ccc2c1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1ccc2[nH]cc(C=O)c2c1
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
To stirred dimethylformamide is added dropwise phosphorus oxychloride. The mixture is stirred for 10 min and a solution of 5-methoxyindole in dimethylformamide is added dropwise. The mixture is heated to 40° C. for 45 min, cooled to room temperature and then treated with a solution of sodium hydroxide in water. The mixture is heated to 50° C. for 10 min, cooled to room temperature, poured onto crushed ice and filtered. The filter cake is recrystallised (methanol) to give the product as a white solid.
Reaction SMILES: Cl[C:2]1[C:3]([OH:16])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18].CCN(C(C)C)C(C)C>CS(C)=O.O>[CH2:17]([N:19]([CH2:20][CH3:21])[C:2]1[C:3]([OH:16])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2)[CH3:18]
Reactant: CCNCC
Reactant: COC(=O)c1ccc2nc(O)c(Cl)nc2c1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCN(CC)c1nc2cc(C(=O)OC)ccc2nc1O
Temperature: 70 °C
Reaction time: 2 h
Yield: 30.8 %

Procedure:
To a solution of methyl 3-chloro-2-hydroxyquinoxaline-6-carboxylate (450 mg, crude) in DMSO (5 mL) was added diethylamine (550 mg, 7.52 mmol), DIEA (492 mg, 3.81 mmol). After stirring for 2 h at 70° C., the resulting solution was diluted with water (50 mL), extracted with ethyl acetate (4×20 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 5% ethyl acetate in petroleum ether to afford methyl 3-(diethylamino)-2-hydroxyquinoxaline-6-carboxylate as a yellow solid (160 mg).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26](O)=[O:27])#[N:2].C(Cl)(=O)C(Cl)=O.[CH:35]([C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1)([CH3:37])[CH3:36].N1C=CC=CC=1>C1COCC1.O.CN(C=O)C>[C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([NH:42][C:41]1[CH:43]=[CH:44][C:38]([CH:35]([CH3:37])[CH3:36])=[CH:39][CH:40]=1)=[O:27])#[N:2]
Reactant: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)O)n([C@H]3CCCc4ccccc43)c2n1
Reactant: CC(C)c1ccc(N)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)Nc3ccc(C(C)C)cc3)n([C@H]3CCCc4ccccc43)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (300 mg, 0.808 mmol) in THF (3 ml) were added DMF (0.03 ml) and oxalylchloride (0.0846 ml, 0.970 mmol), the mixture was stirred at room temperature for 1 hour and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of 4-isopropylaniline (130 mg, 0.968 mmol), pyridine (0.262 ml, 3.24 mmol) and THF (3 ml), and the mixture was stirred under ice-cooling for 2 hours and at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give the objective product as a solid material.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Br)#[N:2].[OH:11][C:12]1([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20]>>[OH:11][C:12]1([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:5][C:4]3[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=3[C:1]#[N:2])=[CH:27][CH:26]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20]
Reactant: N#Cc1ccccc1CBr
Reactant: CC(C)S(=O)(=O)NC1CCCCC1(O)c1ccc(O)cc1
Product: CC(C)S(=O)(=O)NC1CCCCC1(O)c1ccc(OCc2ccccc2C#N)cc1
Yield: 71 %

Procedure:
The title compound is prepared in a manner analogous to the procedure set forth in Example 48 from 2-cyanobenzyl bromide and [2-hydroxy-2-(4-hydroxyphenyl)cyclohexyl][(methylethyl)sulfonyl]amine to provide 501 mg as a brown oil. This material was purified via silica gel chromatography employing the Chromatotron® using a 4000 micron rotor while eluting with a solvent of methylene chloride/ethyl acetate 9:1 to yield the title compound (291 mg, 71%) as a white solid. Ion spray M.S. 427.4 (M*−1). Calculated for C23H28N2O4S-½H2O: Theory: C 63.12, H 6.70, N 6.40. Found: C 63.20, H 6.64, N 6.28.