Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][C:16]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].Br[CH2:29][CH2:30][O:31][CH3:32]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:29][CH2:30][O:31][CH3:32])[C:8]2[C:13]([C:14]=1[CH2:15][C:16]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1Cc1cccc2ccccc12
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Cc2cccc3ccccc23)c2ccccc2n1CCOC
Temperature: 22 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester (170 mg, from Exp. 64.2.) in dimethylformamide (1.0 ml) was added NaH (1.3 eq.), the mixture was stirred at 22° C. for 30 min. 1-Bromo-2-methoxy-ethane (99 mg) was added, the mixture was stirred for 17 h and partitioned between aqueous NH4Cl and AcOEt. The organic layer was dried, evaporated and the residue was chromatographed on silica (n-heptane/AcOEt, 20:1) to give 1-(2-methoxy-ethyl)-3-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give the title compound as a white semisolid. MS: 358.1 ([M−H]−).
Reaction SMILES: [Cl-].[C:2]([O:7][C@H:8]1[C@H:16]([CH3:17])[O:15][C:14](=[O:18])[C@@H:13]([NH3+:19])[CH2:12][O:11][CH2:10][C@@H:9]1[CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1)(=[O:6])[CH:3]([CH3:5])[CH3:4].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[OH:64][C:65]1[C:66]([C:73](O)=[O:74])=[N:67][CH:68]=[CH:69][C:70]=1[O:71][CH3:72].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[C:2]([O:7][C@@H:8]1[C@@H:9]([CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)[CH2:10][O:11][CH2:12][C@H:13]([NH:19][C:73](=[O:74])[C:66]2[C:65]([OH:64])=[C:70]([O:71][CH3:72])[CH:69]=[CH:68][N:67]=2)[C:14](=[O:18])[O:15][C@H:16]1[CH3:17])(=[O:6])[CH:3]([CH3:5])[CH3:4]
Reactant: COc1ccnc(C(=O)O)c1O
Reactant: CC(C)C(=O)O[C@@H]1[C@@H](Cc2cccc3ccccc23)COC[C@H]([NH3+])C(=O)O[C@H]1C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccnc(C(=O)N[C@H]2COC[C@H](Cc3cccc4ccccc34)[C@@H](OC(=O)C(C)C)[C@H](C)OC2=O)c1O
Reaction time: 0.17 h
Yield: 88 %

Procedure:
To a suspension of (3S,7S,8R,9S)-8-(isobutyryloxy)-9-methyl-7-(naphthalen-1-ylmethyl)-2-oxo-1,5-dioxonan-3-aminium chloride in CH2Cl2 (2 mL) were added PyBOP (248 mg, 0.477 mmol) and 3-hydroxy-4-methoxypicolinic acid (81 mg, 0.477 mmol) followed by the dropwise addition of N-ethyl-N-isopropylpropan-2-amine (249 μl, 1.43 mmol). After 10 min everything solubilized and stirring was continued for 2 h. The reaction was treated with Celite®, the solvent removed under reduced pressure, and the resulting adsorbed crude material was purified by flash chromatography (SiO2, 0→100% EtOAc/hexanes) to provide (3S,6S,7R,8S)-3-(3-hydroxy-4-methoxypicolin-amido)-6-methyl-8-(naphthalen-1-ylmethyl)-4-oxo-1,5-dioxonan-7-yl isobutyrate as a white powder (210 mg, 88%): mp 139-142° C.; 1H NMR (400 MHz, CDCl3) δ 11.91 (s, 1H), 8.50 (d, J=8.3 Hz, 1H), 8.01-7.92 (m, 2H), 7.89-7.82 (m, 1H), 7.74 (d, J=8.2 Hz, 1H), 7.49 (dddd, J=14.7, 8.1, 6.9, 1.5 Hz, 2H), 7.40 (dd, J=8.2, 7.0 Hz, 1H), 7.30 (dd, J=6.9, 1.2 Hz, 1H), 6.84 (d, J=5.2 Hz, 1H), 5.20-5.02 (m, 3H), 4.04 (dd, J=11.7, 7.3 Hz, 1H), 3.92 (s, 3H), 3.60 (d, J=4.1 Hz, 2H), 3.43 (dd, J=11.7, 7.1 Hz, 1H), 3.23 (dd, J=14.2, 3.2 Hz, 1H), 2.79-2.64 (m, 2H), 2.36-2.23 (m, 1H), 1.43-1.37 (m, 3H), 1.29 (dd, J=7.0, 3.6 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 176.37, 171.12, 168.88, 155.32, 148.71, 140.60, 134.68, 133.97, 131.94, 130.09, 128.97, 127.76, 127.35, 126.02, 125.57, 125.37, 123.45, 109.55, 76.95, 74.38, 72.09, 56.07, 51.42, 44.93, 34.37, 32.19, 19.14, 19.07, 18.26; HRMS-ESI (m/z) [M+H]+ calcd for C30H35N2O8 expected, 551.2388. found 551.2388.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][CH:17]=1)[O:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([O-:4])=[O:3].C(N(CC)CC)C.Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([OH:42])([C:38]([F:41])([F:40])[F:39])[C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=1>ClCCl>[F:35][C:34]([F:36])([F:37])[C:33]([C:30]1[CH:31]=[CH:32][C:27]([CH2:26][N:12]2[CH2:11][CH2:10][CH:9]([O:8][C:7]3[CH:15]=[CH:16][CH:17]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=3)[CH2:14][CH2:13]2)=[CH:28][CH:29]=1)([OH:42])[C:38]([F:39])([F:41])[F:40]
Reactant: O=[N+]([O-])c1cccc(OC2CCNCC2)c1
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(OC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Reaction time: 20 h
Yield: 70.4 %

Procedure:
To a stirred mixture of 4-(3-nitrophenoxy)piperidine hydrochloride (11.87 mmol, 3.07 g) and triethylamine (35.6 mmol, 4.96 mL, 3.60 g) in dichloromethane was added 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (11.87 mmol, 4.00 g). The reaction was stirred for 20 hours then was filtered. The filtrate was chromatographed on silica (eluting with a gradient of dichloromethane to ethyl acetate) to give the title compound (4 g). MS (ESI) m/z 479.0 [M+H]+
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]#[CH:10])(=O)=O.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(N(C(C)C)CC)(C)C>C1COCC1>[CH2:6]([N:20]1[CH2:21][CH2:22][N:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=2)[CH2:18][CH2:19]1)[CH2:7][CH2:8][C:9]#[CH:10]
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: C#CCCCOS(C)(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C#CCCCN1CCN(c2ccccn2)CC1
Yield: 71.2 %

Procedure:
A solution of pent-4-ynyl methanesulfonate (1.05 g), 1-(pyridin-2-yl)piperazine (1.02 g) and diisoproylethylamine (1.2 mL) in THF (5 mL) was heated to reflux overnight. The mixture was concentrated, diluted with aq. NaOH 2M (10 mL) and extracted with DCM (2×50 mL). Drying (Na2SO4) and silica gel flash chromatography (EtOAc/hexane 2:1→2:0) afforded 1-(pent-4-ynyl)-4-(pyridin-2-yl)piperazine (1.02 g).
Reaction SMILES: [CH:1]([OH:3])=O.CC(OC(C)=O)=O.[Br:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15]>C1(C)C=CC=CC=1>[Br:11][C:12]1[CH:13]=[C:14]([NH:15][CH:1]=[O:3])[CH:16]=[CH:17][CH:18]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=CO
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=CNc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.6 %

Procedure:
A solution of formic acid (24.3 g, 98%, 528 mmol) in Ac2O (43.94 g, 430 mmol) was heated to 55° C. for 2 hours, cooled to room temperature. The mixture was diluted with toluene (25 mL) followed by the addition of of 3-bromoaniline (28 g, 163 mmol) in toluene (40 mL). The solution was stirred cold for 30 minutes after which the solvents were removed under vacuo and the residue crystallized from hexane to give N-(3-bromophenyl)formamide (32.79 g). The material was added in portions to 1M. BH3 in THF (450 mL) at 0° C., heated to refluxing for 3 hours and cooled to ambient temperature. The solvents were removed under reduced pressure, the residue was treated with aqueous hydrochloric acid (1M, 200 mL) for for ½ hour, the pH was adjusted to 12 with the addition of sodium hydroxide (1M). The solution was extracted with diethyl ether (3×75 mL), the combined ether layers dried (MgSO4, filtered and concentrated under reduced pressure to give the titled compound (29.48).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]3[CH2:14]N(C(OC(C)(C)C)=O)C[CH2:17][C:12]=3[NH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[O:25]1CCCC(=O)[CH2:26]1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]3[CH2:14][CH2:26][O:25][CH2:17][C:12]=3[NH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(F)c(F)c3)c2C1
Reactant: O=C1CCCOC1
Product: Fc1ccc(-c2n[nH]c3c2CCOC3)cc1F

Procedure:
Intermediate 16B was prepared according to the procedure for the synthesis of intermediate 15 by replacing 1-Boc-4-piperidone with dihydro-2H-pyran-3(4H)-one LCMS (+ESI) m/z=236 [M+H]+. 1H NMR (CDCl3) δ 7.37-7.41 (m, 1H), 7.29-7.32 (m, 1H) 7.17-7.24 (m, 1H), 4.76 (s, 2H), 3.95 (t, J=5.5 Hz, 2H), 2.84 (t, J=5.5 Hz, 2H).
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])[CH3:7].[CH3:18]O>ClCCl>[CH2:6]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([O:13][CH3:18])=[O:12])[CH3:7]
Reactant: CCOc1ccccc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCOc1ccccc1C(=O)OC

Procedure:
Concentrated sulphuric acid (0.5 ml) was added to a solution of 2-ethoxybenzoic acid (50 g, 0.301 mol) in methanol (500 ml) and the resulting mixture heated under reflux for 70 hours, then evaporated under reduced pressure to give an oil which was dissolved in dichloromethane (300 ml). This solution was washed successively with water (150 ml), aqueous sodium bicarbonate solution (150 ml) and water (150 ml), then evaporated under reduced pressure to give the title compound (49.7 g) as an oil. δ (CDCl3): 1.44 (3H,t), 3.90 (3H,s), 4.12 (2H,q), 6.95 (2H,m), 7.44 (1H,t), 7.78 (1H,d).
Reaction SMILES: C(OC([NH:8]C1C=CN=CC=1B(O)O)=O)(C)(C)C.[CH2:18]([N:22]1[C:34]([CH2:35][CH:36]([CH3:38])[CH3:37])=[C:33]2[C:24]([C:25]([NH2:39])=[N:26][C:27]3[CH:28]=[CH:29]C=[CH:31][C:32]=32)=[N:23]1)[CH2:19][CH2:20][CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:18]([N:22]1[C:34]([CH2:35][CH:36]([CH3:38])[CH3:37])=[C:33]2[C:24]([C:25]([NH2:39])=[N:26][C:27]3[CH:28]=[CH:29][N:8]=[CH:31][C:32]=32)=[N:23]1)[CH2:19][CH2:20][CH3:21]
Reactant: CC(C)(C)OC(=O)Nc1ccncc1B(O)O
Reactant: CCCCn1nc2c(N)nc3ccccc3c2c1CC(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCCCn1nc2c(N)nc3ccncc3c2c1CC(C)C
Temperature: 100 °C
Yield: 1.5 %

Procedure:
2-Butyl-1-(2-methylpropyl)-2H-pyrazolo[3,4-c]-1,6-naphthyridin-4-amine was synthesized from 4-[(tert-butoxycarbonyl)amino]pyridin-3-ylboronic acid (2.48 g, 10.4 mmol) and 4-bromo-1-butyl-5-(2-methylpropyl)-1H-pyrazole-3-carbonitrile (prepared as described in Parts A-F of Example 4, 1.56 g, 5.49 mmol) according to the reaction conditions described in Examples 52-54. Additional palladium (II) acetate (50 mg) and triphenylphosphine (170 mg) were added after the reaction had been heated for 23 hours. After the addition, the flask was placed under vacuum and back-filled with nitrogen twice. The solution was heated at 100° C. for an additional 29 hours. The reaction was worked-up and purified as described in Example 54, but was not recrystallized from acetonitrile, to provide 25 mg of 2-butyl-1-(2-methylpropyl)-2H-pyrazolo[3,4-c]-1,6-naphthyridin-4-amine as an off-white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:9]=2/[CH:10]=[C:11]2/[C:12](=[O:17])[NH:13][C:14](=[O:16])[S:15]/2)[CH2:4]1>CO.Cl.O.[Fe]>[NH2:22][C:19]1[CH:20]=[CH:21][C:8]([N:5]2[CH2:6][CH2:7][CH:3]([N:2]([CH3:1])[CH3:25])[CH2:4]2)=[C:9]([CH:18]=1)/[CH:10]=[C:11]1/[C:12](=[O:17])[NH:13][C:14](=[O:16])[S:15]/1
Reactant: CN(C)C1CCN(c2ccc([N+](=O)[O-])cc2/C=C2\SC(=O)NC2=O)C1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CO
Product: CN(C)C1CCN(c2ccc(N)cc2/C=C2\SC(=O)NC2=O)C1
Temperature: 80 °C
Reaction time: 1 h
Yield: 54.8 %

Procedure:
To a mixture of (Z)-5-(2-(3-(dimethylamino)pyrrolidin-1-yl)-5-nitrobenzylidene)thiazolidine-2,4-dione (100 mg, 0.28 mmol) (Method 149) and iron (154 mg, 2.76 mmol) chip in MeOH (10 mL) was added 5 drops of conc. HCl and 5 drops of water. The mixture was stirred at 80° C. for 1 hr. The mixture was loaded into silica gel, purified with ISCO (100% ethyl acetate to methanol/ethyl acetate=50%) to yield a red solid which was repurified with Gilson (acetonitrile:water:0.1% TFA=0% to 50% fro 7 min) to yield a yellow solid as (Z)-5-(5-amino-2-(3-(dimethylamino)pyrrolidin-1-yl)benzylidene)thiazolidine-2,4-dione (51.0 mg, 38.6%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.55 (brs, 1 H), 11.32 (brs, 1 H), 10.30 (brs, 2 H), 7.80 (s, 1 H), 7.42 (m, 2 H), 7.19 (m, 1 H), 3.95 (m, 1 H), 3.39-3.27 (m, 4 H), 2.78 (s, 6 H), 2.30-2.10 (m, 2 H); m/z 333.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:6]=1[CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[NH2:1][CH2:4][C:5]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:6]=1[CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 2-(azidomethyl)-4-chlorobenzylcarbamate (10.9 g, 36.73 mmol) in THF (60 ml) and water (6 ml) was added triphenylphospine (10.59 g, 40.40 mmol). The reaction was heated to 65 C. and stirred overnight at room temperature. The reaction was concentrated in vacuo and flashed with 4% (10% NH4OH/MeOH)/dichlor-omethane. A second purification using silica gel column chromatography with a careful gradient of 3 to 5% (10% NH4OH/MeOH)/dichloro methane gave the title compound.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C1(C)C=CC=CC=1.O>[C:16]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-Benzyl-4-piperidone (122.2 g, 0.645 mole) in 500 ml toluene was warmed to 45° C. Benzyl chloroformate (130 ml, 155 g, 0.915 mole) was added in a thin, steady stream, and the reaction mixture heated to reflux for 2 hours, cooled to ambient temperature, diluted with 250 ml H2O and stirred vigorously 0.5 hour. The organic layer was separated, washed 1×400 ml 6N HCl and then 1×100 ml saturated NaCl, dired (MgSO4), treated with activated carbon, and concentrated to an oil. The oil was distributed between 400 ml ethyl acetate and 400 ml of H2O containing 67.0 g NaHSO3, stirred 0.5 hour, and the aqueous layer separated, washed with 3 portions of ether, made basic with aqueous NaOH and extracted with fresh ether. The ether layer was dried and reevaporated to yield purified title product as an oil, 136.1 g.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH3:16])=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:7]=2[CH:23]=1.FC(F)(F)C(O[C:29](=O)[C:30](F)(F)F)=O>CN(C)C=O>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16][CH2:11][N:12]([CH2:13][CH2:29][CH3:30])[CH2:6][CH2:5][CH3:4])=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:7]=2[CH:23]=1
Reactant: CSc1ccc2c(c1)C(c1ccccn1)=NCc1nnc(C)n1-2
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCN(CCC)CCc1nnc2n1-c1ccc(SC)cc1C(c1ccccn1)=NC2

Procedure:
In the manner given in Example 1, a solution of 8-methylthio-1-methyl-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in dimethylformamide, N,N,N',N'-tetrapropyldiaminomethane and trifluoroacetic anhydride (in 0.2 molar excess compared to the N,N,N',N'-tetrapropyldiaminomethane) are reacted together to give 8-methylthio-1-[2-(dipropylamino)ethyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=1)[C:10]([N:12]1[CH2:17][CH2:16][C:15]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1)=[O:11])=O)(C)(C)C.ClCCl.FC(F)(F)C(O)=O.[OH-].[Na+]>>[NH2:8][C@H:9]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=1)[C:10]([N:12]1[CH2:13][CH2:14][C:15]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:17]1)=[O:11]
Reactant: CCOC(=O)C1(C2CCCCC2)CCN(C(=O)[C@@H](Cc2ccc(Cl)c(Cl)c2)NC(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1(C2CCCCC2)CCN(C(=O)[C@H](N)Cc2ccc(Cl)c(Cl)c2)CC1
Reaction time: 2 h
Yield: 85.4 %

Procedure:
300 mg (0.54 mmol) of ethyl 1-[(R)-2-tert-butoxycarbonylamino-3-(3,4-dichloro-phenyl)propionyl]-4-cyclohexylpiperidine-4-carboxylate are diluted in 5 ml of a 4/1 dichloromethane/trifluoroacetic acid solution. After stirring for 2 hours, the mixture is poured into aqueous 1N sodium hydroxide solution and then extracted with dichloromethane. The organic phase is dried over sodium sulfate, filtered and concentrated. 210 mg of ethyl 1-[(R)-2-amino-3-(3,4-dichlorophenyl)propionyl]-4-cyclohexylpiperidine-4-carboxylate in the form of a white powder are obtained in a yield of 86%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:24])[C:6]=1[N:7]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][CH3:16])[CH:10]([NH:17]C(=O)C(F)(F)F)[CH2:9][CH2:8]1.C(OC([NH:32][C:33]1[S:37][C:36]([C:38]2[C:43]([F:44])=[CH:42][CH:41]=[CH:40][C:39]=2[F:45])=[N:35][C:34]=1[C:46](O)=[O:47])=O)(C)(C)C>>[NH2:32][C:33]1[S:37][C:36]([C:38]2[C:43]([F:44])=[CH:42][CH:41]=[CH:40][C:39]=2[F:45])=[N:35][C:34]=1[C:46]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:24])[C:6]=1[N:7]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][CH3:16])[CH:10]([NH2:17])[CH2:9][CH2:8]1)=[O:47]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: CCOC1CCN(c2c(N)cnn2C)CCC1NC(=O)C(F)(F)F
Product: CCOC1CCN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3N)cnn2C)CCC1N
Yield: 60 %

Procedure:
Following the procedure for Example 107, starting from N-(1-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-ethoxyazepan-4-yl)-2,2,2-trifluoroacetamide and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)-thiazole-4-carboxylic acid gave 385 as a brown solid (127 mg, 60% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 7.85 (s, 1H), 7.42-7.28 (m, 1H), 7.04 (t, J=8.9 Hz, 2H), 6.19 (s, 2H), 3.78-3.58 (m, 4H), 3.47-3.35 (m, 1H), 3.38-3.25 (m, 2H), 3.25-3.16 (m, 3H), 3.09-3.01 (m, 1H), 2.13 (d, J=14.7 Hz, 1H), 2.00 (d, J=14.7 Hz, 1H), 1.92-1.82 (m, 1H), 1.84-1.58 (m, 3H), 1.22 (t, J=7.0 Hz, 3H). LCMS (ES+) m/z 492 (M+1)
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][C:14](OC(C)=O)=[O:15]>C1COCC1>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:14](=[O:15])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (750 mg, 3.26 mmol; Example 1, Step H), TEA (1363 μL, 9.78 mmol), and Ac2O (646 μL, 6.85 mmol) were placed in THF (15 mL) at room temperature and stirred for 30 minutes. The reaction was then filtered, and the solid product was dried to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)acetamide (595 mg, 2.19 mmol, 67% yield).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[CH2:13][S:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1.[N:25]1([CH2:30][C@@H:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)O)[CH:29]=[CH:28][N:27]=[CH:26]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[N:25]1([CH2:30][C@@H:31]([O:1][C:2]2[CH:11]=[CH:10][C:9]3[C:8](=[O:12])[CH2:7][CH2:6][CH2:5][C:4]=3[C:3]=2[CH2:13][S:14][C:15]2[CH:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: COC(=O)c1ccc(SCc2c(O)ccc3c2CCCC3=O)cc1
Reactant: O[C@@H](Cn1ccnc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 99 %

Procedure:
Using method in Example 154, this compound was prepared from methyl 4-(2-hydroxy-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methylsulfanylbenzoate (1.81 g, 5.3 mmol), (R)-2-imidazol-1-yl-1-phenylethanol (1.00 g, 5.3 mmol), Ph3P (2.10 g, 8.0 mmol), and diethyl azodicarboxylate (1.39 g, 8.0 mmol) and purified by a silica-column (eluting with dichloromethane-MeOH 20:1) as a solid-foam, 2.70 g, 99% yield; mp 75° C. NMR spectrum was consistent with structure. Calcd. For C30H28N2O4S.H2O:
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:18](=[O:20])[CH3:19])[C:10]([O:14][CH2:15][C:16]#[CH:17])=[CH:11][CH:12]=2)[O:7][C:6](=[O:21])[CH:5]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH:27]=O>C(O)C.O>[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:18](=[O:20])[CH:19]=[CH:27][C:26]3[CH:29]=[C:30]([O:34][CH3:35])[C:31]([O:32][CH3:33])=[C:24]([O:23][CH3:22])[CH:25]=3)[C:10]([O:14][CH2:15][C:16]#[CH:17])=[CH:11][CH:12]=2)[O:7][C:6](=[O:21])[CH:5]=1
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: C#CCOc1ccc2c(C)cc(=O)oc2c1C(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C#CCOc1ccc2c(C)cc(=O)oc2c1C(=O)C=Cc1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 4-methyl-7-prop-2-ynyloxy-8-acetylcoumarin (1.92 g, 0.0075 mol) and 3,4,5-trimethoxy-benzaldehyde (1.47 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified. The precipitate is separated by filtration and dried under vacuum. The compound is crystallized by ethanol to give 1.1 of product m.p. 191-93° C., 1H-NMR (CDCl3) δ: 2.45 (s, 3H); 2.53-2.56 (m, 1H); 3.83-3.85 (m, 9H); 4.82 (d, 2H, J=2.2 Hz); 6.20 (s, 1H); 6.72 (s, 2H); 6.92 (d, 1H, J=16 Hz); 7.12 (d, 1H, J=8.9 Hz); 7.15 (d, 1H, J=16 Hz); 7.67 (d, 1H, J=8.9 Hz).
Reaction SMILES: [OH-].[K+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]=[O:10])[CH:4]=1.[N+:11]([CH2:13][C:14]([N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:15])#[C-:12]>CO>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C@@H:9]2[O:10][CH:12]=[N:11][C@H:13]2[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])[CH:4]=1
Reactant: O=Cc1cccnc1
Reactant: [C-]#[N+]CC(=O)N1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([C@@H]1N=CO[C@H]1c1cccnc1)N1CCCC1
Yield: 35.7 %

Procedure:
To a stirred and cooled (0° C.) solution of potassium hydroxide (0.55 g, 9.80 mmol) in methanol (10 mL) were added a mixture of 3-pyridine carboxaldehyde (1.03 mL, 10.84 mmol) and 2-isocyano-1-(pyrrolidin-1-yl)ethanone BLE 04098 (1.50 g, 10.86 mmol). The solution was stirred 3 h at 0° C. and then concentrated. The residue was partitioned between ethyl acetate (100 mL) and water. The organic layer was combined with two additional ethyl acetate extracts (2×100 mL), washed with aqueous sodium chloride and dried over MgSO4, filtered and evaporated. Concentration afforded a crude product which was purified by column chromatography on silica (CH2Cl2:MeOH=98:2) to yield to trans-(4,5-dihydro-5-(pyridin-3-yl)oxazol-4-yl)(pyrrolidin-1-yl)methanone BLE 04110B (0.95 g, 39% yield) as a pale yellow pale solid.