Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:21]([C:28](O)=[O:29])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:32][N:33]([CH3:42])[CH2:34][CH2:35][CH2:36][N:37]=C=NCC.C1(N)CCCCC1.CO>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:21]([C:28](=[O:29])[NH:37][CH2:36][CH2:35][CH2:34][N:33]([CH3:42])[CH3:32])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(C(=O)O)c3c2CCCC3)CC1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: NC1CCCCC1
Product: CN(C)CCCNC(=O)c1ccc(S(=O)(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c2c1CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(4-Carboxy-5,6,7,8-tetrahydro-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid tert-butyl ester (76 mg, 0.17 mmol) was dissolved in dichloromethane (2 mL). 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (32 mg, 0.17 mmol) was added followed by cyclohexylamine (21 mg, 24 ml, 0.21 mmol). The reaction was stirred overnight at room temperature. The reaction was diluted with dichloromethane (15 m10 and charged to a separatory funnel. The organic layer was washed twice with water, brine and dried over MgSO4. Filtration and concentration in vacuo afforded a clear oil that was subjected to flash column chromatography (96:4 dichloromethane:methanol). Concentration of the more polar fractions afforded 4-[4-(3-dimethylamino-propylcarbamoyl)-5,6,7,8-tetrahydro-naphthalene-1-sulfonylamino]-piperidine-1-carboxylic acid tert-butyl ester (F-30) as a yellow solid. Wt.: 40 mg, (45%). 1H NMR (300 MHz, CDCl3) δ 9.05 (s, 1H), 7.98 (d, 1H), 7.31 (d, 1H), 5.02 (d, 1H), 3.96 (m, 3H), 3.37 (m, 2H), 3.20 (m, 2H), 2.83 (m, 4H), 2.70 (s, 6H), 2.13 (m, 2H), 1.97 (m, 2H), 1.83 (m, 4H), 1.42 (s, 9H), 1.32 (m, 4H); LC/MS m/z 523 (M+H)+. Concentration of the less polar fractions afforded 4-(4-cyclohexylcarbamoyl-5,6,7,8-tetrahydro-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid tert-butyl ester (F-31) as a clear oil. Wt.: 28 mg (32%) 1H NMR (300 MHz, CDCl3) δ 7.87 (d, 1H), 7.20 (d, 1H), 5.73 (d, 1H), 4.38 (d, 1H), 3.91 (m, 3H), 3.22 (m, 1H), 3.12 (m, 2H), 2.89 (m, 2H), 2.73 (m, 2H), 2.03 (m, 2H), 1.78 (m, 8H), 1.74 (m, 2H), 1.43 (s, 9H), 1.27 (m, 6H); LC/MS m/z 518 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:10]([C:15](=[O:25])[N:16]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[N:17]=3)=[CH:11][NH:12][C:13]=2[CH3:14])[CH:5]=[CH:6][CH:7]=1.CN(C)/[CH:28]=[N:29]/[N:30]=[CH:31]/N(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.CS(C)=O>C1(C)C=CC=CC=1>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([N:16]2[C:15](=[O:25])[C:10]3=[CH:11][NH:12][C:13]([CH3:14])=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([N:1]5[CH:31]=[N:30][N:29]=[CH:28]5)[CH:3]=4)[C:9]3=[N:17]2)=[CH:19][CH:20]=1
Reactant: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1-c1cccc(N)c1
Reactant: CN(C)/C=N/N=C/N(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1-c1cccc(-n2cnnc2)c1
Yield: 38 %

Procedure:
A mixture of 7-(3-aminophenyl)-2-(4-chlorophenyl)-2,5-dihydro-6-methylpyrazolo[4,3-c]pyridin-3-one (0.100 g, 0.285 mmol), N,N-dimethylformamide azine (Bartlett, R. K.; Humphrey, I. R. J. Chemn. Soc. C 1967, 1664) (41.3 mg, 0.290 mmol), and p-toluenesulfonic acid (10 mg, 0.053 mmol) in toluene (4 ml) was heated at reflux under nitrogen for 7 days, adding more p-toluenesulfonic acid (10 mg, 0.053 mmol) and some DMSO after 1 day. The solvents were removed in vacuo and the residue was purified by flash chromatography (silica gel, 5-15% MeOH/CH2Cl2), then trituration in hot MeOH-CH2Cl2, to leave 0.0436 g (38%) of the title compound as a yellow solid; mp >350° C.; 1H NMR (360 MHz, DMSO-d6) δ2.29 (3H, s), 7.41 (2H, d, J 9.1 Hz), 7.59 (1H, d, J 7.7 Hz), 7.70 (1H, t, J 7.7 Hz), 7.79 (1H, dd), 7.87 (1H, fine t), 8.11 (2H, d, J 8.9 Hz), 8.62 (1H, s), 9.18 (2H, s), 12.52 (1H, br s); MS (ES+) m/z 403/405 1MH]+. Anal. found: C, 61.14; H, 3.79; N, 20.29. C21H15ClN6O.0.5H2O requires: C, 61.24; H, 3.92; N, 20.41%.
Reaction SMILES: CC1C=NC=C(C=1)C(NC1CCNCC1)=O.ClC1C=CC(C=O)=CC=1OCC.[Cl:29][C:30]1[CH:54]=[CH:53][C:33]([CH2:34][N:35]2[CH2:40][CH2:39][CH:38]([NH:41][C:42]([C:44]3[CH:45]=CC=[C:48]4[C:52]=3[NH:51][CH:50]=[CH:49]4)=[O:43])[CH2:37][CH2:36]2)=[CH:32][C:31]=1[O:55][CH2:56][CH3:57].B.N1C=CC=CC=1>ClCCCl.C(O)(=O)C>[Cl:29][C:30]1[CH:54]=[CH:53][C:33]([CH2:34][N:35]2[CH2:40][CH2:39][CH:38]([NH:41][C:42](=[O:43])[C:44]3[CH:45]=[C:49]([CH3:48])[CH:50]=[N:51][CH:52]=3)[CH2:37][CH2:36]2)=[CH:32][C:31]=1[O:55][CH2:56][CH3:57]
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cccc4cc[nH]c34)CC2)ccc1Cl
Agent: B
Agent: CCOc1cc(C=O)ccc1Cl
Agent: Cc1cncc(C(=O)NC2CCNCC2)c1
Solvent: ClCCCl
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: CCOc1cc(CN2CCC(NC(=O)c3cncc(C)c3)CC2)ccc1Cl
Reaction time: 16 h
Yield: 57 %

Procedure:
To a solution of 5-methyl-N-(piperidin-4-yl)-nicotinamide (22 mg, 0.10 mmol), 4-chloro-3-ethoxy-benzaldehyde (22 mg, 0.12 mmol) in DCE:EtOH (1:11 mL) was added acetic acid (25 μL) and pyridine-borane complex (25 μL, 8M in pyridine, 0.2 mmol). The reaction was shaken for 16 h, after which time it was concentrated and purified by reversed phase HPLC (MeCN:H2O) affording the title compound (22 mg, 57%). MS: 388.4 (MH+)
Reaction SMILES: [CH3:1][CH:2]([CH2:23][NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:3]([N:5]([CH2:10][C:11]1[CH:21]=[C:20]([Cl:22])[C:14]2[O:15][CH2:16][CH2:17][CH2:18][O:19][C:13]=2[CH:12]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])=[O:4].C=O.[C:34](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[CH3:1][CH:2]([CH2:23][N:24]([CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH3:34])[C:3]([N:5]([CH2:10][C:11]1[CH:21]=[C:20]([Cl:22])[C:14]2[O:15][CH2:16][CH2:17][CH2:18][O:19][C:13]=2[CH:12]=1)[CH2:6][CH:7]([CH3:8])[CH3:9])=[O:4]
Reactant: CC(=O)O
Reactant: CC(C)CN(Cc1cc(Cl)c2c(c1)OCCCO2)C(=O)C(C)CNCc1ccccc1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)CN(Cc1cc(Cl)c2c(c1)OCCCO2)C(=O)C(C)CN(C)Cc1ccccc1
Reaction time: 8 h

Procedure:
A mixture of (±)-2-Methyl-3-(benzylamino)-N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutylpropanamide (26 mg), paraformaldehye (16 mg), glacial acetic acid (90 μl) and sodium triacetoxyborohydride (26 mg) was dissolved in tetrahydrofuran (5 ml), and stirred overnight. The mixture was partitioned between aq. potassium carbonate (1N, 10 mL) and ethyl acetate (15 ml). The organic layer was concentrated and the residue was purified by flash chromatography on silica (40% ethyl acetate in hexane) to yield a resin: MS (m+1)=459.2; H NMR (500 MHz, CDCl3) 0.95 (m, 6H), 2.00 (m, 1H), 2.05 (m, 1H), 2.25 (m, 2H), 2.30 (m, 3H), 2.55 (t, 1H), 2.65 (t, 1H), 2.90 (m, 1H), 3.05 (d, 1H), 3.25 (d, 1H), 3.60 (m, 2H), 4.15 (m, 2H), 4.35 (m, 2H), 4.50 (m, 2H), 6.6-7.0 (m, 2H), 7.0-7.5 (m, 5H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH2:12]([N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C.O>[CH2:12]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=2)[CH2:21][CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(NC2CCN(Cc3ccccc3)CC2)nc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 48.9 %

Procedure:
A mixture of methyl 6-chloronicotinate (5.14 g), 1-benzyl-4-aminopiperidine (6.84 g) and K2CO3 (5.38 g) in DMF (30 ml) was stirred at 100° C. for 12 hours under atmospheric pressure of nitrogen. The reaction mixture was poured into a mixture of AcOEt and water and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (98:2). The eluted fractions containing the desired product were collected and evaporated in vacuo to give methyl 6-[(1-benzyl-4-piperidyl)amino]nicotinate (4.77 g)
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH3:16].C(OCC)(=O)C>C(O)(C)C>[Br:1][C:2]1[C:3]([NH:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:4][C:5]([NH2:16])=[N:6][CH:7]=1
Reactant: N
Reactant: Clc1ncc(Br)c(NC2CCOCC2)n1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: Nc1ncc(Br)c(NC2CCOCC2)n1
Temperature: 130 °C
Yield: 77 %

Procedure:
To a suspension of compound 32 (6.60 g, 23 mmol) in isopropyl alcohol (40 ml) was added ammonia (aq. 28%, 80 ml). This reaction mixture was heated to 130° C. for 14 hours in a pressure vessel. The reaction mixture was cooled down to room temperature and to this mixture was added ethyl acetate. The reaction mixture was washed with water and brine. The ethyl acetate layer was dried with sodium sulfate and concentrated to give compound 33 (4.75 g, 77%). 1H NMR (500 MHz, CD3OD) δ ppm 7.79 (1 H, s), 4.24 (1 H, m), 3.99-4.02 (2 H, dd, J=11.0, 2.2 Hz), 3.52 (2 H, td, J=11.9, 2.0 Hz), 1.92-1.96 (2 H, m), 1.69 (2 H, m); LCMS-ESI (POS), M/Z, M+1: Found 273, Calculated 273.0
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)=[N:6][N:5]=[CH:4][NH:3]1.NN>C(Cl)Cl.CCO>[NH2:9][CH2:8][C:7]1[C:2](=[O:1])[NH:3][CH:4]=[N:5][N:6]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1nnc[nH]c1=O
Agent: NN
Solvent: CCO
Solvent: ClCCl
Product: NCc1nnc[nH]c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A slurry of 2-(5-oxo-4,5-dihydro-[1,2,4]triazin-6-ylmethyl)isoindole-1,3-dione (4 g, 15.6 mmol) in DCM/EtOH (1:1) (150 mL) was charged with anhydrous hydrazine (1.23 mL, 39.0 mmol) and stirred at rt for 18 h. The reaction mixture was concentrated in vacuo and the off-white solid was triturated with warm CHCl3 and filtered through a fritted funnel. The solid was then triturated with hot boiling MeOH and filtered through a fritted funnel resulting in an off-white solid. The material was triturated a second time as before and dried overnight resulting in the title compound as a white solid, which was taken on to the next step without further purification; 1H NMR (DMSO-d6, 400 MHz) δ 3.88 (s, 2H), 8.31 (s, 1H); MS (ES+): m/z 127.07 (100) [MH+], HPLC: tR=0.34 min (MicromassZQ, polar—5 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][NH2:11])=[CH:5][CH:4]=1.[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24].Cl>C(OCC)(=O)C.[Cl-].[Na+].O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[N:12]([CH2:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[C:23](=[O:24])[NH:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(CCN[C@@H](CN)c2ccc(OC)cc2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(CCN2C(=O)NC[C@H]2c2ccc(OC)cc2)cc1
Yield: 96.9 %

Procedure:
A solution of 1-(R)-(4-methoxyphenyl)-N1-[2-(4-methoxyphenyl)ethyl]ethane-1,2-diamine (446 g, 1.48 mol) in ethyl acetate (2.25 L) is placed in a water bath and 1,1′-carbonyldiimidazole (264 g, 1.62 mol) is added in portions. The reaction is then heated to reflux for 1.5 hours after which the solution is cooled, treated with 1N HCl (2×1.5 L), brine (2×1.5 L), dried over Na2SO4 and set aside in the cold. After standing the precipitate which forms is removed by filtration and the solvent removed under reduced pressure to afford 468 g (96% yield) of the desired product. Chiral HPLC of the product thus obtained to have 99.5% of the desired (R) enantiomer present.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:28][CH2:27][CH2:26][N:25]([CH3:29])[CH2:24][CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:29][N:25]1[CH2:26][CH2:27][CH2:28][N:22]([C:3]2[C:2]([C:32]3[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23][CH2:24]1
Reactant: OB(O)c1cccnc1
Reactant: CN1CCCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: CN1CCCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cccnc2)CC1

Procedure:
A mixture of 5-bromo-6-(4-methyl-1,4-diazepan-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 146.1, 74 mg, 0.150 mmol), pyridin-3-ylboronic acid (18.5 mg, 0.150 mmol) and Na2CO3 (48 mg, 0.450 mmol) in a mixture of DME (3.2 mL), EtOH (0.43 mL), and water (0.64 mL) was flushed with argon. Pd(PPh3)2Cl2 (5.3 mg, 0.0075 mmol) was added and the mixture was subjected to MW irradiation at 125° C. for 30 min. The RM was evaporated to dryness under reduced pressure and the residue was triturated with THF and filtered. The filtrate was evaporated to dryness under reduced pressure and the crude product was purified by preparative LC-MS. TFA was removed using a SPE PL-HCO3 (StratoSpheres™ VariPure IPE) cartridge to afford the title compound. UPLC-MS (Condition 8) tR=1.71 min, m/z=472.1 [M+H]+, m/z=470.2 [M−H]−.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([C:7]1[N:8]([CH3:21])[C:9]2[C:14]([C:15]=1[C:16](O)=[O:17])=[CH:13][CH:12]=[C:11]([O:19][CH3:20])[CH:10]=2)[CH3:6].[CH3:22][NH2:23]>>[CH3:22][NH:23][C:16]([C:15]1[C:14]2[C:9](=[CH:10][C:11]([O:19][CH3:20])=[CH:12][CH:13]=2)[N:8]([CH3:21])[C:7]=1[CH2:5][CH3:6])=[O:17]
Reactant: CCc1c(C(=O)O)c2ccc(OC)cc2n1C
Reactant: CN
Solvent: O=S(Cl)Cl
Product: CCc1c(C(=O)NC)c2ccc(OC)cc2n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
Thionyl chloride (0.383 ml, 4.45 mmole) was added to a solution of 2-ethyl-6-methoxy-1-methyl-1H-indole-3-carboxylic acid 73e (0.347 g, 1.48 mmole). The reaction mixture was heated to reflux for 30 min and concentrated. The residue was dissolved in 5 ml CH2Cl2 and added methylamine (2.0 M in THF, 2.22 ml, 4.44 mmole). The reaction mixture was stirred at room temperature for 1 hr, then concentrated. The residue was purified by flash column chromatography (2-5% CH3OH in CH2Cl2) to give yellow color solid (0.267 g, 73%). 1H NMR (CDCl3) δ7.47 (1H, d, J=8.7 Hz), 6.80 (1H, s), 6.69 (1H, d, J=8.7 Hz), 3.47 (3H, s), 3.58 (3H, s), 3.00 (2H, q, J=7.4 Hz), 2.83 (3H, s), 1.14 (3H, t, J=7.4 Hz). ESIMS (MH+): 247.10.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11]C)=[O:10])=[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:5]=[C:4]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[N:3]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=[O:10])=[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:5]=[C:4]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(N2CCCCC2)nc1-c1ccccc1
Temperature: 100 °C
Yield: 79.9 %

Procedure:
To a solution of methyl 2-(4-methyl-6-phenyl-2-(piperidin-1-yl)pyrimidin-5-yl)pentanoate (48 mg; 0.131 mmol) in methanol (1.306 mL) was added a 10 N sodium hydroxide solution (131 μL; 1.306 mmol) and the mixture was heated at 100° C. for 18 h. The volatiles were removed under reduced pressure and the residue was dissolved in water, the mixture was then acidified by adding 6N hydrochloric acid until a precipitate formed. The solid was isolated by filtration and dried under reduced pressure over phosphorus pentoxide to give 37 mg (80%) of the title compound as a white solid. ESI/APCI(+): 354 (M+H). 1H NMR (DMSO-d6) δ 12.58 (1H, br s); 7.44 (5H, m); 3.71 (4H, m); 3.63 (1H, m); 2.28 (3H, s); 1.88 (1H, m); 1.60 (2H, m); 1.50 (4H, m); 1.43 (1H, m); 0.90 (2H, m); 0.57 (3H, t).
Reaction SMILES: [OH:1][C@H:2]1[CH2:54][C@@:53]2([CH3:55])[C@@H:13]([CH2:14][CH2:15][C@:16]2([O:56][C:57](=[O:60])[CH2:58][CH3:59])[C:17](=[O:52])[CH:18]([O:20][C:21](=[O:51])[C@H:22]([CH:48]([CH3:50])[CH3:49])[NH:23][C:24](=[O:47])[C@@H:25]2[CH2:29][CH2:28][CH2:27][N:26]2[C:30](=[O:46])[C@H:31]([CH3:45])[NH:32][C:33](=[O:44])[C@H:34]([CH3:43])[NH:35]C(OC(C)(C)C)=O)[OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:63])[C:9]([C@@H:10]([CH3:61])[CH2:11]2)=[CH:8][C:7](=[O:62])[CH:6]=[CH:5]1.C(N(C(C)C)CC)(C)C.[Cl:73][C:74]1[CH:79]=[CH:78][C:77]([S:80](Cl)(=[O:82])=[O:81])=[CH:76][CH:75]=1>O1CCCC1>[OH:1][C@H:2]1[CH2:54][C@@:53]2([CH3:55])[C@@H:13]([CH2:14][CH2:15][C@:16]2([O:56][C:57](=[O:60])[CH2:58][CH3:59])[C:17](=[O:52])[CH:18]([O:20][C:21](=[O:51])[C@H:22]([CH:48]([CH3:49])[CH3:50])[NH:23][C:24](=[O:47])[C@@H:25]2[CH2:29][CH2:28][CH2:27][N:26]2[C:30](=[O:46])[C@H:31]([CH3:45])[NH:32][C:33](=[O:44])[C@H:34]([CH3:43])[NH:35][S:80]([C:77]2[CH:78]=[CH:79][C:74]([Cl:73])=[CH:75][CH:76]=2)(=[O:82])=[O:81])[OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:63])[C:9]([C@@H:10]([CH3:61])[CH2:11]2)=[CH:8][C:7](=[O:62])[CH:6]=[CH:5]1
Reactant: CCC(=O)O[C@]1(C(=O)C(O)OC(=O)[C@@H](NC(=O)[C@@H]2CCCN2C(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(C)C)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)O[C@]1(C(=O)C(O)OC(=O)[C@@H](NC(=O)[C@@H]2CCCN2C(=O)[C@H](C)NC(=O)[C@H](C)NS(=O)(=O)c2ccc(Cl)cc2)C(C)C)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Temperature: 25 °C
Reaction time: 23 h
Yield: 70 %

Procedure:
100 mg (0.11 mmol) of H-Ala-Ala-Pro-Val-O-MPP x TFA (Example 3) and 300 μl (1.71 mmol) of diisopropylethylamine are dissolved in 5 ml of tetrahydrofuran, mixed with 238 mg (1.13 mmol) of 4-chlorobenzenesulfonic acid chloride and stirred for 23 hours at room temperature. The residue that remains after removal of the solvent i.vac. is chromatographed. Gradient chromatography on 25 g of silica gel 60 (hexane/acetone 2:1→1:2) yields 75 mg (70%) of N-(N-(N-(N-(4-chlorobenzenesulfonyl)-L-alanyl)-L-alanyl)-L -prolyl)-L-valine [11β,21-dihydroxy-3,20-dioxo-6α-methyl-17-propionyloxy-pregna-1,4-dien-21-yl] ester, and, after recrystallization from dichloromethane/diisopropyl ether, 47 mg (44%) of crystalline product.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH:8]=[CH:9][N:10]([C:15]3[CH:16]=[N:17][CH:18]=[C:19]([C@@H:21]4[CH2:25][CH2:24][CH2:23][N:22]4[C:26](=[O:45])[C@@H:27]([NH:31][C:32](=[O:44])[C@@H:33]([N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH3:36])[CH3:34])[CH:28]([CH3:30])[CH3:29])[CH:20]=3)[C:11]=2[CH:12]=[CH:13][CH:14]=1)=[O:5])C.[Li+].[OH-]>C1COCC1.CO.O>[C:40]([O:39][C:37]([N:35]([CH3:36])[C@@H:33]([CH3:34])[C:32]([NH:31][C@@H:27]([CH:28]([CH3:29])[CH3:30])[C:26]([N:22]1[CH2:23][CH2:24][CH2:25][C@H:21]1[C:19]1[CH:20]=[C:15]([N:10]2[C:11]3[CH:12]=[CH:13][CH:14]=[C:6]([C:4]([OH:5])=[O:3])[C:7]=3[CH:8]=[CH:9]2)[CH:16]=[N:17][CH:18]=1)=[O:45])=[O:44])=[O:38])([CH3:43])([CH3:42])[CH3:41]
Reactant: CCOC(=O)c1cccc2c1ccn2-c1cncc([C@@H]2CCCN2C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1c1cncc(-n2ccc3c(C(=O)O)cccc32)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89 %

Procedure:
To a solution of 1-[5-((S)-1-{(S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-3-methyl-butyryl}-pyrrolidin-2-yl)-pyridin-3-yl]-1H-indole-4-carboxylic acid ethyl ester (I-1A-1d: 1.2 g, 1.9 mmol) in THF (5 mL) and MeOH (1.7 mL) was added a solution of LiOH (0.080 g, 3.5 mmol) in water (1.7 mL). The mixture was stirred at room temperature for 5 hours. More LiOH (0.023 g, 0.97 mmol) was added and stirring continued for overnight. The reaction mixture was quenched with water and concentrated under reduced pressure to remove THF. The remaining mixture was diluted with water and neutralized with 1 M HCl dropwise until pH=4. The white precipitate formed was filtered and dried in vacuo to give the titled compound as a white powder (1.0 g, 87%).
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([O:12]C)=[O:11])=[N:8][CH:9]=1.[OH-].[Na+].Cl>O1CCOCC1>[F:14][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:12])=[O:11])=[N:8][CH:9]=1
Reactant: COC(=O)c1ccc(OC(F)F)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(OC(F)F)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To a solution of methyl 5-(difluoromethoxy)picolinate (0.750 g, 3.69 mmol) in 1,4-dioxane (18.46 ml) was added sodium hydroxide, 1N aqueous solution (7.4 ml, 7.4 mmol) and the reaction mixture was stirred at RT for overnight. Then hydrogen chloride, 4.0M solution in 1,4-dioxane (1.8 ml, 7.38 mmol) was added and stirred for 1 h. The reaction mixture was concentrated and was diluted with water and extracted with EtOAc. The organic extract was dried over MgSO4, filtered and concentrated to give 5-(difluoromethoxy)picolinic acid (0.6013 g, 3.18 mmol, 86% yield). MS m/z: 190.2 [M+H].
Reaction SMILES: [CH2:1]([Li])CCC.[C:6]1([N:12]2[CH:16]=[CH:15][CH:14]=[CH:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CN(CCN(C)C)C.IC>CCCCCC.C1COCC1.O>[C:6]1([N:12]2[CH:16]=[CH:15][CH:14]=[C:13]2[CH3:1])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc(-n2cccc2)cc1
Reactant: [Li]CCCC
Agent: CN(C)CCN(C)C
Solvent: CI
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cccn1-c1ccccc1
Reaction time: 3 h
Yield: 97.9 %

Procedure:
Butyllithium (0.700 mol, 280 mL of 2.5 M solution in hexane) was added slowly at room temperature to a mixture of 1-phenylpyrrole (0.695 mol, 100 g) and TMEDA (0.700 mol, 106 mL) in hexane (80 mL) and stirred for 3 h. The slurry was diluted with 300 mL of THF and iodomethane (0.771 mol, 48 mL) was added slowly maintaining the temperature between 35-40 C. After stirring at room temperature for 16 h, 250 mL of water were added and the organic layer was separated. The aqueous layer was extracted with ether (2×100 mL) and the combined organic fractions were dried over MgSO4. After filtration, evaporation of solvents and TMEDA yielded 107 g of light brown oil (98% yield, +95% purity by GC). 1H-NMR δ (CDCL3): 7.29-7.44 (m, 5H), 6.80 (m, 1H), 6.23 (m, 1H), 6.08 (m, 1H), 2.24 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([NH:9][CH3:10])[C:3]=1[N+:11]([O-:13])=[O:12].[NH3:14]>O.C(O)C>[Cl:8][C:6]1[CH:5]=[C:4]([NH:9][CH3:10])[C:3]([N+:11]([O-:13])=[O:12])=[C:2]([NH2:14])[CH:7]=1
Reactant: CNc1cc(Cl)cc(Cl)c1[N+](=O)[O-]
Reactant: N
Solvent: CCO
Solvent: O
Product: CNc1cc(Cl)cc(N)c1[N+](=O)[O-]

Procedure:
0.034 mole (7.5 g) of 2,4-dichloro-6-methylaminonitrobenzene is added in an autoclave to 100 ml of a 28% strength solution of ammonia in water and 50 ml of ethanol. The reaction mixture is heated to 145°-150° C. for 12 hours, the pressure being 12 kg/cm2After cooling, the expected product precipitates from the reaction mixture. After being filtered off and reslurried in water, it is dried hot under vacuum in the presence of phosphorus pentoxide. Recrystallized from isopropanol, it melts at 129° C.