Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:10](=O)([O:13]C)[O:11][CH3:12].C[O-].[Na+].Cl>O.C1(C)C=CC=CC=1>[O:7]1[CH2:8][CH2:9][CH:4]([C:1](=[O:3])[CH2:2][C:10]([O:11][CH3:12])=[O:13])[CH2:5][CH2:6]1
Reactant: CC(=O)C1CCOCC1
Reactant: COC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)CC(=O)C1CCOCC1
Temperature: 7.5 °C
Yield: 80.5 %

Procedure:
In a flask made of glass having an inner volume of 500 ml and equipped with a stirring device, a thermometer, a dropping funnel and a distillation device were charged 35.0 g (273 mmol) of 4-acetyltetrahydropyran synthesized in the same manner as in Reference example 2, 280.0 g (3.1 mol) of dimethyl carbonate and 16.3 g (302 mmol) of sodium methoxide, and the mixture was reacted at 80 to 85° C. for 2 hours with distilling by-producing methanol off. After completion of the reaction, the reaction mixture was cooled to 5 to 10° C., and to the reaction mixture were added 175 ml of toluene, 55 ml (330 mmol) of 6 mol/l hydrochloric acid and 35 ml of water in this order. After the organic layer was separated, the aqueous layer was extracted twice with 70 ml of toluene. The organic layer was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (Fluent; hexane/ethyl acetate=1/1 (volume ratio)) to give 40.9 g (Isolation yield: 76%) of methyl 3-(4-tetrahydropyranyl)-3-oxopropanoate with a purity of 93.9% (analytical value by differential diffractometry) as a colorless liquid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:13][C:14]2[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=2)[N:3]=1.[CH3:20][OH:21]>>[CH3:20][O:21][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:13][C:14]2[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=2)[N:3]=1
Reactant: CO
Reactant: Cc1cc(Nc2cc3c(C)cccc3c(Cl)n2)n[nH]1
Product: COc1nc(Nc2cc(C)[nH]n2)cc2c(C)cccc12

Procedure:
Similar procedure as described in example 10 was used, starting from methanol and (1-chloro-5-methyl-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (1-methoxy-5-methyl-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 271(MH+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH2:15][CH3:16])C(C(F)(F)F)=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[CH:26]=1)(C)(C)C.[C:40](O)([C:42]([F:45])([F:44])[F:43])=O>C(Cl)Cl>[CH2:14]([C:12]1[C:40]([C:42]([F:45])([F:44])[F:43])=[CH:10][C:9]2[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1)[CH2:15][CH3:16]
Reactant: O=C(O)C(F)(F)F
Reactant: CCCc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)cc1C(F)(F)F
Solvent: ClCCl
Product: CCCc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cccnc3)c1)=N2

Procedure:
The title compound was prepared from {2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-5-propyl-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M210) (165 mg, 0.31 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (77 mg, 59%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[CH:10][C:9]=1[N+:13]([O-:15])=[O:14].[C:16]([OH:20])(=[O:19])[CH:17]=O>>[N+:13]([C:9]1[CH:10]=[N:11][N:12]2[C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH:17]2[C:16]([OH:20])=[O:19])([O-:15])=[O:14]
Reactant: O=CC(=O)O
Reactant: Nc1ccccc1-c1[nH]ncc1[N+](=O)[O-]
Product: O=C(O)C1Nc2ccccc2-c2c([N+](=O)[O-])cnn21
Yield: 69 %

Procedure:
5-(o-Aminophenyl)-4-nitropyrazole is reacted with glyoxylic acid as described in Example 11 to give 1-nitro-5,6-dihydropyrazolo[1,5-c]quinazoline-5-carboxylic acid with a yield of 69%. M.p.: 203°-205° C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[N:17]([C:24]3[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:31])[N:18]=[CH:19][C:20]=2[CH:21]([CH3:23])[CH3:22])=[CH:10][C:9]=1[CH3:32])[CH3:7])C.[BH4-].[Na+]>C1COCC1.CO>[Cl:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([Cl:30])[C:24]=1[N:17]1[C:16]([CH2:15][O:14][C:11]2[CH:12]=[CH:13][C:8]([CH:6]([CH3:7])[CH2:5][CH2:4][OH:3])=[C:9]([CH3:32])[CH:10]=2)=[C:20]([CH:21]([CH3:23])[CH3:22])[CH:19]=[N:18]1
Reactant: CCOC(=O)CC(C)c1ccc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)cc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1C(C)CCO
Temperature: 25 °C
Reaction time: 72 h

Procedure:
(+/−)-3-{4-[2-(2,6-Dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-butyric acid ethyl ester (0.581 g, 1.19 mmol) is dissolved in THF (15 mL) and methyl alcohol (3 mL). Sodium borohydride is added portionwise until an excess has been added. After stirring at room temperature for 3 days, the reaction is quenched with water followed by 1N HCl. The resulting mixture is extracted two times with ethyl acetate. The organic layers are combined, washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified via flash chromatography eluting with 5-10% ethyl acetate:toluene to give the title compound. 1H NMR (CDCl3) δ 1.134 (d, 3H), 1.262 (d, 6H), 1.456 (s, 2H), 1.764 (m, 2H), 2.223 (s, 3H), 2.939-3.039 (m, 2H), 3.476-3.539 (m, 2H), 4.747 (s, 2H), 6.516 (d, 1H), 6.559 (dd, 1H), 6.99 (d, 1H), 7.263 (t, 1H), 7.372 (d, 2H), 7.663 (s, 1H)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[CH3:9][S:10][C:11](SC)=[CH:12][N+:13]([O-:15])=[O:14]>CN(C=O)C.C(N(CC)CC)C>[NH2:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:1][C:11]([S:10][CH3:9])=[CH:12][N+:13]([O-:15])=[O:14]
Reactant: Nc1ccncc1N
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSC(=C[N+](=O)[O-])Nc1cnccc1N
Yield: 13.1 %

Procedure:
3,4-Diaminopyridine (6.00 g, 55.0 mmol) and 1,1-bis(methylthio)-2-nitroethylene (10.0 g, 60.5 mmol) were dissolved in 60 ml of DMF and 10 ml of triethylamine, followed by reaction at 70° C. for 5 hours. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography [eluent: chloroform:methanol=2:1 (v/v)] to obtain 1.63 g of the intended product (yield: 13.1%)
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH:10]=[C:9]3[CH:12](O)[CH2:13][O:14][C:8]3=[CH:7][C:6]=2[CH2:5][C:4]1=[O:16])[CH3:2].FC(F)(F)C(O)=O>C(#N)C>[CH2:1]([N:3]1[C:11]2[CH:10]=[C:9]3[CH:12]=[CH:13][O:14][C:8]3=[CH:7][C:6]=2[CH2:5][C:4]1=[O:16])[CH3:2]
Reactant: CCN1C(=O)Cc2cc3c(cc21)C(O)CO3
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCN1C(=O)Cc2cc3occc3cc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a slurry of 30.3 g. (0.138 mole) of 5-ethyl-3-hydroxy-6-oxo-2,3,6,7-tetrahydro-furo[2,3-f]indole in 950 ml. of acetonitrile at 25° C. was added 7 ml. of a 10% solution of trifluoroacetic acid in acetonitrile, and the reaction was allowed to stir at room temperature for 12 hours. The clear solution was evaporated to give a quantitative yield of the product. A small sample was recrystallized from hexane, m.p. 112°-113° C.
Reaction SMILES: [CH2:1]([N:8](CC)[C:9]12[CH2:17][CH2:16][CH:13]([CH2:14][CH2:15]1)[CH2:12][N:11]1[C:18](=[O:36])[C:19]([O:27][C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:29])=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:21]=[C:10]21)[C:2]1C=CC=CC=1.Cl.[H][H]>CO.[Pd]>[CH2:1]([NH:8][C:9]12[CH2:17][CH2:16][CH:13]([CH2:14][CH2:15]1)[CH2:12][N:11]1[C:18](=[O:36])[C:19]([O:27][C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:29])=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:21]=[C:10]21)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)c1nc2n(c(=O)c1OC(=O)c1ccccc1)CC1CCC2(N(CC)Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCNC12CCC(CC1)Cn1c2nc(C(=O)OCC)c(OC(=O)c2ccccc2)c1=O

Procedure:
To a mixture of ethyl 10-(benzyl(ethyl)amino)-4-oxo-3-((phenylcarbonyl)oxy)-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylate (120 mg, 0.233 mmol) in methanol (5 mL) was added 1N HCl (0.256 mL, 0.256 mmol) followed by Pd/C (24.77 mg, 0.023 mmol) and the mixture stirred under 1 atm hydrogen for 18 h. The mixture was filtered and the solids thoroughly washed with dichloromethane. The filtrate was concentrated under reduced pressure and dried under high vacuum overnight to afford the title compound.
Reaction SMILES: C1(C)C=CC(S(O[CH:11]([CH3:28])[CH2:12][NH:13][S:14]([C:17]2[C:18]3[CH:19]=[CH:20][CH:21]=[N:22][C:23]=3[C:24]([Cl:27])=[CH:25][CH:26]=2)(=[O:16])=[O:15])(=O)=O)=CC=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[CH2:35][CH2:36][NH2:37]>O1CCCC1>[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[CH2:35][CH2:36][NH:37][CH:11]([CH3:28])[CH2:12][NH:13][S:14]([C:17]1[C:18]2[CH:19]=[CH:20][CH:21]=[N:22][C:23]=2[C:24]([Cl:27])=[CH:25][CH:26]=1)(=[O:15])=[O:16]
Reactant: COc1ccc(CCN)cc1OC
Reactant: Cc1ccc(S(=O)(=O)OC(C)CNS(=O)(=O)c2ccc(Cl)c3ncccc23)cc1
Solvent: C1CCOC1
Product: COc1ccc(CCNC(C)CNS(=O)(=O)c2ccc(Cl)c3ncccc23)cc1OC
Temperature: 70 °C
Yield: 50.7 %

Procedure:
50 ml of a tetrahydrofuran solution containing 4.58 g of N-(2-paratoluenesulfonyloxypropyl)-8-chloro-5-quinolinesulfonamide and 4.95 g of 3,4-dimethoxyphenethylamine was heated at 70° C. for 8 hours in a sealed vessel. Then, the solvent was removed by distillation under reduced pressure to obtain a residue. The thus obtained residue was subjected to purification by silica gel column chromatography [Wacogel C-200, 200 g; solvent: a mixture of methanol and chloroform (5% methanol)] to obtain 2.37 g of N-[2-(3,4-dimethoxyphenethylamino)-2-methylethyl]-8-chloro-5-quinolinesulfonamide (60) (yield: 51%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[N:5][N:6]=1.CCN(C(C)C)C(C)C.[CH:16]1([CH2:21][CH:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23](Cl)=[O:24])[CH2:20][CH2:19][CH2:18][CH2:17]1>C(Cl)Cl>[CH:16]1([CH2:21][CH:22]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:23]([NH:1][C:2]2[S:3][CH:4]=[N:5][N:6]=2)=[O:24])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Nc1nncs1
Reactant: O=C(Cl)C(CC1CCCC1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1nncs1)C(CC1CCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To 2-amino-1,3,4-thiadiazole (220 mg, 21 mmol), 0.4 mL DIEA and 7 mL of DCM is added a solution of the title C compound, 3-cyclopentyl-2-phenylpropionyl chloride (500 mg, 21 mmol) in 2 mL of DCM. The mixture is stirred at ambient temperature for 2-3 h, the mixture is evaporated, and the residue is treated with 10 mL 1 N HCl and extracted twice with ethyl acetate. The combined extracts are washed with brine, saturated sodium bicarbonate solution, and brine and dried over anhydrous magnesium sulfate. Filtration and evaporation afford 3-cyclopentyl-2-phenyl-N-[1,3,4]thiadiazol-2-yl-propionamide as an orange foam: 1H NMR (400 MHz, DMSO-d6) δ 11 (m, 2H), 1.4 (m, 2H), 1.5 (m, 3H), 1.7(m, 3H), 2.1 (ddd, J=13.3, 7.8, 7.7 Hz, 1H), 4.0 (dd, J=8.1, 7.1 Hz, 1H), 7.2 (s, 1H), 7.3 (m, 4H), 9.1 (s, 1H), 12.8 (s, 1H); LC/MS 302 (M+1), 300 (M−1).
Reaction SMILES: [F:1][C:2]1[C:17]([Br:18])=[CH:16][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[O:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]1[C:17]([Br:18])=[CH:16][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH:22]4[CH2:23][CH2:24][O:19][CH2:20][CH2:21]4)[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2cc(F)c(Br)cc2n1C1CCNCC1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1[nH]c2cc(F)c(Br)cc2n1C1CCN(C2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of fluoro-6-bromo-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one (D46) (50 mg, 0.16 mmol), tetrahydro-4H-pyran-4-one (112 mg, 1.12 mmol) and triethylamine (49 mg, 0.48 mmol) in dichloromethane (5 ml) under argon was added portionwise sodium triacetoxyborohydride (240 mg, 1.12 mmol). The mixture was stirred at room temperature for 24 hrs, diluted with dichloromethane (5 ml) washed with 0.5N sodium hydroxide solution, dried (MgSO4) and concentrated in approx half volume before adding to a silica gel column which was subsequently eluted with 2-20% methanol in dichloromethane to afford 5-fluoro-6-bromo-1-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one. The isolated product was converted to the hydrochloride salt which was obtained as a colourless solid, 34 mg, 49%. MH+=398, and 400, 1H NMR (HCl salt) (DMSO-d6) δ: 1.24 (2H, m), 1.73 (3H, m), 1.89 (2H, m), 2.03 (2H, m), 2.83 (2H, m), 3.17 (2H, m), 3.58 (2H, m), 3.76 (1H, m), 4.59 (2H, m) 7.04 (1H, d, J=8 Hz), 7.94 (1H, d, J=5 Hz), 10.89 (1H, bs) and 11.32 (1H, s).
Reaction SMILES: Cl.[CH3:2][C:3]12[CH:20]([O:21][CH2:22][CH2:23][O:24]C3CCCCO3)[CH2:19][CH:6]([CH2:7][CH:8]1[O:9][CH2:10][CH2:11][O:12]C1CCCCO1)[C:5]([CH3:32])([CH3:31])[O:4]2>CO>[CH3:2][C:3]12[CH:20]([O:21][CH2:22][CH2:23][OH:24])[CH2:19][CH:6]([CH2:7][CH:8]1[O:9][CH2:10][CH2:11][OH:12])[C:5]([CH3:32])([CH3:31])[O:4]2
Reactant: CC1(C)OC2(C)C(OCCOC3CCCCO3)CC1CC2OCCOC1CCCCO1
Agent: Cl
Solvent: CO
Product: CC1(C)OC2(C)C(OCCO)CC1CC2OCCO
Temperature: 25 °C

Procedure:
Concentrated aqueous HCl) 0.5 ml) was added to a solution of 1,3,3-trimethyl-6,7-bis(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)-2-oxabicyclo[2.2.2]octane 0.8 g, 10 mmol) in methanol (30 ml). The solution was stirred over night at ambient temperature after which time no traces of starting material were present by TLC (SiO2/CHCl3/MeOH, 100:1, (v/v)). The solution was filtered, concentrated and the residue was dissolved in CHCl3 and dried (K2CO3) to yield (2.46 g. 9 mmol, 90%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:13]([O-:15])=[O:14])=[C:7]([S:9](O)(=[O:11])=[O:10])[CH:8]=1.O=S(Cl)[Cl:18]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:13]([O-:15])=[O:14])=[C:7]([S:9]([Cl:18])(=[O:11])=[O:10])[CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc([N+](=O)[O-])c(S(=O)(=O)O)c1
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(S(=O)(=O)Cl)c1

Procedure:
In a similar fashion using route 39 general procedure 96, 5-methoxy-2-nitro-benzenesulfonic acid 447 (2.0 g, 8.58 mmol), SOCl2 (9.4 ml) and (0.2 ml) DMF gave the title compound (2.5 g) which was used in the next step without further purification. The structure was confirmed by 1H NMR.
Reaction SMILES: [C:1]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:2]([C:7]([N:9]2[CH2:14][C:13](=O)[CH2:12][CH2:11][CH:10]2[CH2:16][NH:17][C:18]([C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:29]=2[N:28]=[CH:27][CH:26]=[CH:25]3)=[O:19])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH2:36]([NH2:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH2:36]([NH:43][CH:13]1[CH2:14][N:9]([C:7]([C:2]2[C:1]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])[CH:10]([CH2:16][NH:17][C:18]([C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:29]=2[N:28]=[CH:27][CH:26]=[CH:25]3)=[O:19])[CH2:11][CH2:12]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: NCc1ccccc1
Reactant: O=C1CCC(CNC(=O)c2cccc3cccnc23)N(C(=O)c2ccccc2-c2ccccc2)C1
Product: O=C(NCC1CCC(NCc2ccccc2)CN1C(=O)c1ccccc1-c1ccccc1)c1cccc2cccnc12

Procedure:
N-((5-(Benzylamino)-1-(biphenylcarbonyl)piperidin-2-yl)methyl)quinoline-8-carboxamide was prepared according general procedure N using N-((1-(biphenylcarbonyl)-5-oxopiperidin-2-yl)methyl)quinoline-8-carboxamide and benzyl amine. (ESI) 555 (M+H).
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([CH:13]([CH3:15])[CH3:14])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:18][CH2:19][C@H:20]([OH:22])[CH3:21]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH:13]([C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:18]([CH2:19][C@H:20]([OH:22])[CH3:21])[C:5]=32)=[CH:10][CH:9]=1)([CH3:15])[CH3:14]
Reactant: C[C@@H](O)CN
Reactant: CC(C)c1ccc2c(c1)C(=O)C(CC=O)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1ccc2c(c1)-c1c(ccn1C[C@@H](C)O)C2
Reaction time: 0.75 h
Yield: 69.8 %

Procedure:
A solution of 2.16 g of (RS)-2-(2-oxoethyl)-6-isopropyl-1-indanone and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (R)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which time the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 1.78 g (70%) of (R)-1-(7-isopropyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.[N+:18]([O:21][CH:22]1[O:29][CH:28]2[CH:24]([O:25][CH2:26][C@@H:27]2O)[CH2:23]1)([O-:20])=[O:19].Cl.CN(C)CCCN=C=NCC>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([O:16][C@@H:27]1[CH2:26][O:25][CH:24]3[CH:28]1[O:29][CH:22]([O:21][N+:18]([O-:20])=[O:19])[CH2:23]3)=[O:15])[CH:7]=[CH:6]2
Reactant: O=[N+]([O-])OC1CC2OC[C@H](O)C2O1
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1ccc2cc([C@H](C)C(=O)O[C@@H]3COC4CC(O[N+](=O)[O-])OC43)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
To a solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 1 g, 4.43 mmol) and (2S)-7-(nitrooxy)-4,8-dioxabicyclo(3.3.0) octan-2-ol (isosorbide 5-mononitrate, 1 g, 5.21 mmol) in anhydrous dichloromethane (25 mL) were added 1-(3(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (EDAC, 1.17 g, 1.4 eq) and a catalytic amount of N,N-dimethylaminopyridine (DMAP) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with CH2Cl2 and washed H2O, brine, dried over sodium sulfate, filtered, and the organic extracts were evaporated. The product was purified by column chromatography on silica gel eluting with EtOAc:hexane (3:7 to 1:1) to give the title compound (1.71 g, 97.6% yield) as a white crystalline solid. Mp 112–113° C. 1H NMR (300 MHz, CDCl3) δ 7.67 (m, 3H), 7.37 (m, 1H), 7.14 (m, 2H), 5.26 (m, 2H), 4.78 (t, J=5.2 Hz, 1H), 4.21 (d, J=4.9 Hz, 1H), 4.02–3.77 (m, 5H), 3.92 (s, 3H), 1.56 (d, 3H, J=7.1 Hz); LRMS (APIMS) m/z 404 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[NH:13][CH2:14][CH:15]([OH:21])[CH2:16][C:17]([O:19][CH3:20])=[O:18])([O-])=O>[Pd].O1CCCC1>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH:13][CH2:14][CH:15]([OH:21])[CH2:16][C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)CC(O)CNc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)CC(O)CNc1c(N)cccc1N
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.9 %

Procedure:
Under hydrogen gas atmosphere, a mixture of methyl 4-[(2,6-dinitrophenyl)amino]-3-hydroxybutanoate (Reference Example 79; 2.53 g, 8.45 mmol), 10% palladium on carbon (50% wet, 500 mg) and tetrahydrofuran (85 mL) was stirred at room temperature for 6 hr. The reaction mixture was filtered and concentrated in vacuo to give the title compound as a solid (2.00 g, 8.36 mmol, 99%).
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[C:13]3[CH2:24][CH2:23][NH:22][CH2:21][C:14]3=[N:15][C:16]=2[NH:17][CH:18]([CH3:20])[CH3:19])[CH2:7][CH2:6]1.C(N(CC)CC)C.[C:37](Cl)(=[O:40])[O:38][CH3:39]>C(Cl)Cl>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][CH:5]1[CH2:6][CH2:7][N:8]([C:11]2[N:12]=[C:13]3[CH2:24][CH2:23][N:22]([C:37]([O:38][CH3:39])=[O:40])[CH2:21][C:14]3=[N:15][C:16]=2[NH:17][CH:18]([CH3:20])[CH3:19])[CH2:9][CH2:10]1
Reactant: COC(=O)Cl
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CCc2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(NC(C)C)nc2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
To a solution of 2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine (45.6 mg, 0.113 mmol) and triethylamine (0.039 mL, 0.283 mmol) in DCM (0.75 mL) was added methyl carbonochloridate (0.013 mL, 0.170 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 hr, warmed to 23° C., and concentrated via rotary evaporation. The resulting crude material was partitioned between EtOAc and H2O. The organic phase was washed with brine, dried over Na2SO4, filtered, rinsed with EtOAc, and concentrated via rotary evaporation. The crude material was dissolved in toluene (0.5 mL) and purified via medium pressure chromatography using a 2% to 80% gradient eluant of EtOAc in heptane on a 12 g silica gel column (Single Step™) to give the title compound (48.7 mg, 93%) as a white foam. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.17-1.19 (m, 6H), 1.80-1.94 (m, 2H), 2.06 (ddd, J=9.5, 5.9, 3.2 Hz, 2H), 2.64 (t, J=5.9 Hz, 2H), 2.82-2.94 (m, 2H), 3.19-3.31 (m, 2H), 3.64 (s, 3H), 3.64-3.69 (m, 2H), 4.07-4.17 (m, 1H), 4.35 (br s, 2H), 4.51 (tt, J=8.1, 3.9 Hz, 1H), 5.53 (d, J=8.3 Hz, 1H), 7.01 (dddd, J=9.3, 8.1, 3.2, 1.5 Hz, 1H), 7.26-7.35 (m, 2H); ESI-MS m/z [M+H]+ 461.9.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:35])=[C:7]2[C:12](=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:8]2)=[O:4].[NH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:21]([N:11]1[C:12]2[C:7](=[C:6]([OH:35])[C:5]([C:3]([NH:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:4])=[N:14][C:13]=2[C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)[CH:8]=[C:9]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:10]1=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1nc(-c2ccncc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2ccncc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 34.5 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-pyridin-4-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (36 mg, 0.078 mmol), β-alanine (693 mg, 7.8 mmol) and NaOMe solution (11.7 mL, 5.8 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (20-100% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration to give 14 mg of the title compound as a light yellow solid. MS: (+) m/z 521.34 (M+1).
Reaction SMILES: CO[C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH:5]=1.Cl.C[O:24][C:25]([C:27]1([NH2:36])[CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28]1)=[O:26]>>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([NH:36][C:27]2([C:25]([OH:26])=[O:24])[CH2:28][C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:35]2)=[O:21])=[CH:5][C:6]=1[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19]
Reactant: COC(=O)c1ccc(OC)c(C(=O)c2ccccc2C)c1
Reactant: COC(=O)C1(N)Cc2ccccc2C1
Agent: Cl
Product: COc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1C(=O)c1ccccc1C

Procedure:
The compound of step 1 was hydrolyzed in analogy to example 2 and the obtained acid reacted with 2-amino-indane-2-carboxylic acid methyl ester hydrochloride in analogy to step 2 of example 13. The obtained ester was hydrolyzed in analogy to example 2.