Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[C:7]([CH3:31])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:30])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:29])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:28])[CH2:20][CH2:21][CH:22]=[C:23]([CH3:27])[C:24](O)=[O:25])=[O:5])[CH3:2].[CH3:32][NH:33][CH3:34]>>[CH2:1]([O:3][C:4]([CH:6]=[C:7]([CH3:31])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:30])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:29])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:28])[CH2:20][CH2:21][CH:22]=[C:23]([CH3:27])[C:24]([N:33]([CH3:34])[CH3:32])=[O:25])=[O:5])[CH3:2]
Reactant: CCOC(=O)C=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Reactant: CNC
Product: CCOC(=O)C=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)N(C)C

Procedure:
Starting materials: 19-ethoxycarbonyl-2,6,10,14,18-pentamethyl-2,6,10,14,18-nonadecapentaenoic acid and dimethylamine (50% aqueous dimethylamine solution)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[C:6]1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C=O)C.O.CCOC(C)=O>[N:20]([CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[C:6]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1cc(C(=O)OCC)n(CCCBr)c1
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C(=O)OCC)n(CCCN=[N+]=[N-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a stirred solution of crude diethyl 1-(3-bromopropyl)-1H-pyrrole-2,4-dicarboxylate in DMF (30 mL) was added sodium azide (1 g, 15.4 mmol). The resulting mixture was stirred at rt overnight then diluted with water (30 mL) and EtOAc (150 mL). After separation, the aqueous layer was extracted with EtOAc (2×150 mL). The combined organic layers were washed with brine, dried (MgSO4), and concentrated. Purification via flash chromatography (petroleum ether:EtOAc, 20:1 to 15:1) afforded diethyl 1-(3-azidopropyl)-1H-pyrrole-2,4-dicarboxylate (2 g, 75%). 1H NMR (CDCl3, 300 MHz) δ7.42 (s, 1H), 7.36 (s, 1 H), 4.40 (t, J=6.6 Hz, 2 H), 4.26 (m, 4 H), 3.30 (m, J=6.2 Hz, 2 H), 2.04 (m, 2 H), 1.36 (m, 6 H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][O:13][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][O:14]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(OCCO)cc1
Reactant: C1=COCCC1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(OCCOC2CCCCO2)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of 2-[(4-Nitrophenyl)oxy]ethanol (1 g, 5.4 mmol), in toluene (50 mL) was added 3,4-dihydro-2H-pyran (1.5 mL) and APTS (catalytic amount). The reaction was stirred at 60° C. for 3 hours. The dark solution was then concentrated and purified by flash chromatography using DCM/cyclohexane 30/70 as eluent. The title compound was obtained as an oil (1.33 g, 92%). LC: Rt: 3.12 min.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][CH:6]=1)(=O)[CH3:2].B#B>>[CH2:1]([NH:4][C:5]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][CH:6]=1)[CH3:2]
Reactant: CC(=O)Nc1cccc(C)n1
Agent: B#B
Product: CCNc1cccc(C)n1

Procedure:
The process for producing 6-ethylamino-2-picoline which comprises reacting 6-acetamido-2-picoline with diborane in an inert non-polar solvent at about 0° to 70° C. to produce 6-ethylamino-2-picoline.
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)[C:8]([CH3:26])=[C:7]2[C:27]([OH:29])=[O:28].[CH2:30]([S-:32])[CH3:31].[Na+].I[CH3:35]>CS(C)=O.O>[CH2:30]([S:32][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:25])[F:23])[CH:17]=1)[C:8]([CH3:26])=[C:7]2[C:27]([O:29][CH3:35])=[O:28])[CH3:31]
Reactant: COc1cc2nc(-c3cccc(C(F)(F)F)c3)c(C)c(C(=O)O)c2cc1F
Reactant: CC[S-]
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCSc1cc2c(C(=O)OC)c(C)c(-c3cccc(C(F)(F)F)c3)nc2cc1OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 76.8 %

Procedure:
Sodium hydride (1.27 g, 31.6 mmol) was added portionwise to a suspension of 6-fluoro-3-methyl-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (8.0 g, 21.09 mmol) in dimethyl sulfoxide (50 mL). The mixture was stirred for 20 min. Sodium ethanethiolate (2.168 g, 23.20 mmol) was added and the resulting mixture was stirred at 100° C. for 1 h. The mixture was cooled to room temperature, iodomethane (3.96 mL, 63.3 mmol) was added, and the mixture was stirred for 2 h. The reaction mixture was diluted with water and extracted three times with methylene chloride. The combined organic extracts were washed with brine (two times), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via column chromatography (ISCO, 330 g silica, 0-10% ethyl acetate/methylene chloride) to afford methyl 6-(ethylthio)-3-methyl-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (7.05 g, 77% yield, about 70% pure). MS (m/z) 436.1 (M+H+).
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[CH3:9][NH:10][CH2:11][CH2:12][NH:13][CH3:14].C(=O)(O)[O-].[Na+]>C(O)CC(C)C>[CH3:9][N:10]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH2:11][CH2:12][NH:13][CH3:14]
Reactant: CNCCNC
Reactant: Clc1ccncc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)CCO
Product: CNCCN(C)c1ccncc1
Yield: 50.2 %

Procedure:
A mixture of 4-chloropyridine hydrochloride (15.0 g), N,N'-dimethyl-1,2-ethanediamine (22.0 g) and sodium bicarbonate (25.20 g) in isoamyl alcohol (100 ml) was heated under reflux for 48 hours and then evaporated. The residue was extracted several times with hot dichloromethane and the combined extracts were filtered and evaporated. The residue was distilled to give the product (8.30 g), b.p. 168°-172° @ 15 mm.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[CH:5]=[C:4]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[N:3]=1.[NH3:20]>CO>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:20])[CH:5]=[C:4]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[N:3]=1
Reactant: N
Reactant: O=[N+]([O-])c1c(Cl)cc(-c2c(Cl)cccc2Cl)nc1Cl
Solvent: CO
Product: Nc1cc(-c2c(Cl)cccc2Cl)nc(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2,4-Dichloro-6-(2,6-dichloro-phenyl)-3-nitro-pyridine (94.4 mg, 0.279 mmol, prepared as described in the previous step) was placed in a 8 mL vial equipped with a stir bar and dry MeOH (2 mL) was added via syringe. The resulting solution was gently heated with a heat gun to dissolve the solid and 7M NH3 in MeOH (2.00 mL, 14.0 mmol) was added via syringe. The resulting mixture was stirred at room temperature for 16 h and the solvent was removed under reduced pressure. The resulting residue was purified by preparative thin layer chromatography (TLC) on a 2000μ SiO2 plate developed with 1:4 EtOAc/heptane to yield 2-chloro-6-(2,6-dichlorophenyl)-3-nitropyridin-4-ylamine. 1H-NMR (400 MHz, CDCl3) δ: 7.33-7.45 (m, 2H), 7.27-7.33 (m, 1H), 6.68 (s, 1H), 5.86 (br. s., 2H). LCMS (ESI): Calculated for C11H6ClN3O2: 318.0 (M+H). Measured: 318.0.
Reaction SMILES: [CH2:1]([S:8][C:9]1[S:20][C:12]2=[N:13][CH:14]=[C:15]([O:18][CH3:19])[C:16](=[O:17])[N:11]2[N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[OH:21]OS([O-])=O.[K+].[OH2:27]>CO>[CH2:1]([S:8]([C:9]1[S:20][C:12]2=[N:13][CH:14]=[C:15]([O:18][CH3:19])[C:16](=[O:17])[N:11]2[N:10]=1)(=[O:21])=[O:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: O=S([O-])OO
Reactant: O
Reactant: CCCCCCCSc1nn2c(=O)c(OC)cnc2s1
Agent: [K+]
Solvent: CO
Product: CCCCCCCS(=O)(=O)c1nn2c(=O)c(OC)cnc2s1
Temperature: 65 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
In 55 ml of methanol, 3.3 g of 2-heptylthio-6-methoxy-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was dissolved. A dispersion of 19.4 g of OXONE® suspended in 0 ml of water was added to the methanol solution, and the resulting mixture was warmed to 65° C. and stirred for 1 hour. The residue obtained by the same procedure as in Preparation Example 7 was recrystallized from ethanol and thus 2.7 g of 2-heptanesulfonyl-6-methoxy-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. m.p. 106°~109° C. Yield 51%.
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH3:11][NH2:12].[CH3:13][C:14]1[CH:21]=[C:20]([O:22]C)[CH:19]=[CH:18][C:15]=1[CH:16]=O>>[OH:22][C:20]1[CH:19]=[CH:18][C:15]([C:16]2[N:12]([CH3:11])[C:1](=[O:10])[C:2]3[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:4]=2)=[C:14]([CH3:13])[CH:21]=1
Reactant: CN
Reactant: COc1ccc(C=O)c(C)c1
Reactant: Nc1ccccc1C(=O)O
Product: Cc1cc(O)ccc1-c1nc2ccccc2c(=O)n1C

Procedure:
The entitled compound was obtained according to the method of Example 1-(1), 1-(2) and 1-(3) but using anthranilic acid, methylamine and 2-methyl-4-methoxybenzaldehyde.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@:8]23[CH2:16][N:15]([C:17]4[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=4)[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:9]3)[CH:5]=[CH:6][CH:7]=1.[F:33][C:34]1[C:35]([C:41](O)=[O:42])=[N:36][CH:37]=[C:38]([F:40])[CH:39]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>ClCCl>[C:25]([NH:24][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:14][N:15]([C:17]3[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=3)[CH2:16][C@:8]2([C:4]2[CH:3]=[C:2]([NH:1][C:41]([C:35]3[C:34]([F:33])=[CH:39][C:38]([F:40])=[CH:37][N:36]=3)=[O:42])[CH:7]=[CH:6][CH:5]=2)[N:9]=1)(=[O:32])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Nc1cccc([C@]23CN(c4ncc(F)cn4)C[C@H]2CSC(NC(=O)c2ccccc2)=N3)c1
Reactant: O=C(O)c1ncc(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NC1=N[C@@]2(c3cccc(NC(=O)c4ncc(F)cc4F)c3)CN(c3ncc(F)cn3)C[C@H]2CS1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
N-[(4aR,7aS)-7a-(3-Aminophenyl)-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (0.30 g, 0.67 mmol) is dissolved in dichloromethane (10 mL) and 3,5-difluoropyridine-2-carboxylic acid (138 mg, 0.87 mmol), 1-hydroxybenzotriazole (185 mg, 1.34 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (169 mg, 0.87 mmol) are added. Diisopropylethylamine (0.35 mL, 2 mmol) is added and the reaction is stirred at room temperature overnight. The reaction is purified directly with silica gel chromatography eluting with a 0-100% ethyl acetate/hexanes gradient to give the title compound (330 mg, 84%). ES/MS (m/e): 590 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(O)=[O:2].[C:14](N1C=CN=C1)([N:16]1C=CN=[CH:17]1)=O.CNC>C1COCC1>[NH2:13][S:10]([C:7]1[CH:8]=[CH:9][C:4]([C:1]([N:16]([CH3:17])[CH3:14])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11]
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.4 %

Procedure:
To a solution of 4-carboxybenzenesulfonamide (5 g; 24.8 mmol; 1 eq) in THF (75 mL) at 0° C. is added in one portion 1,1′-carbonyl diimidazole (4.8 g; 29.8 mmol; 1.2 eq) and the reaction mixture is stirred for 3 h at room temperature. A solution of dimethylamine (37.3 mL; 2 M; 74.6 mmol; 3 eq) in THF is added dropwise over 20 min and the reaction mixture is stirred at room temperature for 1 h. The solvent is removed under reduced pressure and the residue is diluted with EtOAc (100 mL) and the organic phase is washed with a 10% solution of NaHCO3 (30 mL). The white precipitate formed in the aqueous phase is filtered off, washed with water and dried under vacuum to afford 4.1 g (72%) of the title compound as a white solid. 1H NMR (DMSO-d6) δ 7.86 (d, J=8.3 Hz, 2H), 7.58 (d, J=8.3 Hz, 2H), 7.45 (s, 2H), 3.00 (s, 3H), 2.88 (s, 3H). HPLC (max plot) 99%; Rt 1.07 min. LC/MS: (ES+): 229.0.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=2[NH2:28])=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=2[NH:28][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)=[CH:19][CH:20]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: COc1ccc(-c2ccc(C)cc2N)cc1
Product: COc1ccc(-c2ccc(C)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 1d (0.088 g, 0.49 mmol) was reacted with the product from Example 214b (107 mg, 0.49 mmol) for 65 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (0.106 g, 45%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.41 (s, 3H) 2.72 (s, 3H) 3.66 (s, 3H) 6.29 (d, J=6.99 Hz, 1H) 6.84 (d, J=8.82 Hz, 2H) 7.27-7.53 (m, 5H) 7.75 (d, J=8.46 Hz, 1H) 8.32 (d, J=6.99 Hz, 1H) 8.90 (d, J=8.46 Hz, 1H) 10.88-11.05 (m, 1H); MS (ESI+) m/z 356.0 (M+H)+; (ESI−) m/z 354.1 (M−H)−.
Reaction SMILES: [I:1]I.[NH2:3][C:4]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]>CCO.S([O-])([O-])(=O)=O.[Ag+2]>[NH2:3][C:4]1[CH:13]=[C:12]([Cl:14])[C:11]([I:1])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: II
Reactant: COC(=O)c1ccc(Cl)cc1N
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: COC(=O)c1cc(I)c(Cl)cc1N
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 101.1 %

Procedure:
To a mixture of iodine (68 g, 0.27 mol) and silver sulfate (84 g, 0.27 mol) in absolute EtOH (2.5 L) was added methyl 2-amino-4-chlorobenzoate (50 g, 0.27 mol). The reaction mixture was allowed to stir at rt for 45 min. The reaction mixture was then filtered through a pad of Celite® and the filtrate was concentrated. The residue was dissolved in EtOAc (2 L) and washed with saturated aqueous NaHCO3 (3×400 mL), water (3×400 mL), and brine. The organic solution was dried over Na2SO4, filtered, and concentrated to give methyl 2-amino-4-chloro-5-iodobenzoate (85 g, 99%).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[NH:21][N:20]=[C:19]([C:22]([OH:24])=O)[CH:18]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:46][CH2:47][C:48]([N:50]1[CH2:55][CH2:54][N:53]([C:56](=[O:65])[C:57]2[CH:62]=[C:61]([Cl:63])[CH:60]=[CH:59][C:58]=2[Cl:64])[CH2:52][CH2:51]1)=[O:49].Cl>CN(C=O)C.O>[Cl:64][C:58]1[CH:59]=[CH:60][C:61]([Cl:63])=[CH:62][C:57]=1[C:56]([N:53]1[CH2:52][CH2:51][N:50]([C:48](=[O:49])[CH2:47][NH:46][C:22]([C:19]2[CH:18]=[C:17]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[OH:10])[NH:21][N:20]=2)=[O:24])[CH2:55][CH2:54]1)=[O:65]
Reactant: O=C(O)c1cc(-c2ccccc2O)[nH]n1
Reactant: NCC(=O)N1CCN(C(=O)c2cc(Cl)ccc2Cl)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(Cl)ccc2Cl)CC1)c1cc(-c2ccccc2O)[nH]n1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 20 %

Procedure:
DIPEA (170.4 mg, 0.23 mL, 1.3 mmol) was added drop wise to 5-(2-Hydroxy-phenyl)-1H-pyrazole-3-carboxylic acid (prepared by the method as described above) (60 mg, 0.29 mmol) in DMF (2 mL). EDCI (140.4 mg, 0.73 mmol) and HOBT (43.6 mg, 0.32 mmol) were then added. After 2 minutes, 2-Amino-1-[4-(2,5-dichloro-benzoyl)-piperazin-1-yl]-ethanone in its HCl salt form (113.9 mg, 0.32 mmol) was added. The resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue purified by column chromatography (using silica gel of 60-120 mesh and 10% MeOH in CHCl3 as eluent) to afford 28 mg (20% yield) of 5-(2-hydroxy-phenyl)-1H-pyrazole-3-carboxylic acid {2-[4-(2,5-dichloro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 97.07%. 1H NMR (DMSO-d6): δ 13.3 (s, 1H), 10.3 (s, 1H), 8.0 (t, 1H), 7.8-7.4 (m, 4H), 7.28-7.1 (t, 1H), 7.1-7.05 (s, 1H), 7.02-6.8 (m, 2H), 4.3-4.1 (d, 2H), 3.8-3.6 (m, 4H), 3.55-3.42 (s, 2H), 3.3-3.1 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH:19]([CH3:21])[CH3:20])[N:16]=[CH:17][N:18]=1)[N:7]=3.[NH2:24][CH2:25][C:26]([OH:28])=[O:27].O[C@H:30]1CN[C@H](C(O)=O)C1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:30][O:27][C:26](=[O:28])[CH2:25][NH:24][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH:19]([CH3:21])[CH3:20])[N:16]=[CH:17][N:18]=1)[N:7]=3
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: NCC(=O)O
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)CNc1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2
Temperature: 25 °C
Yield: 98.5 %

Procedure:
8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (1.0 g, 2.7 mmol), glycine (2.0 g, 27 mmol), copper (I) iodide (0.2 g, 1.08 mmol), trans-4-hydroxy-(L)-proline (0.14 g, 1.08 mmol) and potassium phosphate (1.14 g, 5.4 mmol) in DMSO (10 mL) were heated under nitrogen at 80° C. for 18 h. The reaction mixture was cooled to RT, concentrated in vacuo, loaded onto an SCX-2 cartridge, washed with methanol and eluted with 2M ammonia in methanol. Basic fractions were combined and concentrated in vacuo and the resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% methanol in DCM) to give [2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ylamino]-acetic acid methyl ester (0.407 g, 39% total). 1H NMR 400 MHz (CDCl3) δ: 8.32 (1H, d, J=8.78 Hz), 7.55 (1H, s), 7.26 (1H, s), 6.46 (1H, dd, J=8.79, 2.45 Hz), 6.18 (1H, d, J=2.42 Hz), 6.00 (1H, m), 4.46-4.45 (2H, m), 4.41-4.35 (2H, m), 3.94 (2H, d, J=5.39 Hz), 3.80 (3H, s), 1.59 (6H, t, J=6.88 Hz).
Reaction SMILES: [H-].[Na+:2].[CH3:3][C:4]([CH3:33])([CH3:32])[C:5]#[C:6][C:7]1[S:11][C:10]([C:12]([OH:14])=[O:13])=[C:9]([N:15]([CH:25]2[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]2)[C:16]([CH:18]2[CH2:23][CH2:22][CH:21]([CH3:24])[CH2:20][CH2:19]2)=[O:17])[CH:8]=1.Cl[C:35]1[CH:40]=[C:39]([C:41]([N:43]2[CH2:47][CH2:46][CH2:45][CH2:44]2)=[O:42])[CH:38]=[CH:37][N:36]=1.[OH-].[Na+]>C1COCC1.C(OCC)C>[CH3:33][C:4]([CH3:32])([CH3:3])[C:5]#[C:6][C:7]1[S:11][C:10]([C:12]([O-:14])=[O:13])=[C:9]([N:15]([CH:25]2[CH2:30][CH2:29][CH:28]([O:31][C:37]3[CH:38]=[C:39]([C:41]([N:43]4[CH2:47][CH2:46][CH2:45][CH2:44]4)=[O:42])[CH:40]=[CH:35][N:36]=3)[CH2:27][CH2:26]2)[C:16]([CH:18]2[CH2:23][CH2:22][CH:21]([CH3:24])[CH2:20][CH2:19]2)=[O:17])[CH:8]=1.[Na+:2]
Reactant: O=C(c1ccnc(Cl)c1)N1CCCC1
Reactant: CC1CCC(C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)O)C2CCC(O)CC2)CC1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1CCC(C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)[O-])C2CCC(Oc3cc(C(=O)N4CCCC4)ccn3)CC2)CC1
Temperature: 25 °C
Yield: 16 %

Procedure:
NaH (50 mg of a 60% oil dispersion, 1.14 mmol) was added in portions to a solution of 5-(3,3-dimethyl-but-1-ynyl)-3-[(4-hydroxy-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (128 mg, 0.287 mmol) and (2-chloro-pyridin-4-yl)-pyrrolidin-1-yl-methanone from the previous step (300 mg, 1.42 mmol) in THF (5.0 mL) at 0° C. After 5 min the reaction was warmed to room temperature and then heated at 85° C. overnight. The reaction was cooled, aqueous NaOH (0.5 mL of a 1.0 N solution) was added and the reaction evaporated to dryness to give a solid residue. The solid was suspended in ethyl ether and sonicated for several minutes. The ether layer was removed to give an orange solid that was dried under vacuum and purified by column chromatography on reverse phase C18 silica gel (100% water to 20% acetonitrile/water). Fractions containing product were pooled and lyophilized to give the desired product as a colorless solid (30 mg, 16%). MS (m/z): 618.0 [M−H]−; HPLC retention time: 6.43 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: C(OC(=O)[N:5]([N:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[Cl:17])[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)C>C(O)C.[OH-].[Na+].O>[ClH:17].[Cl:17][C:13]1[N:12]([NH:5][C:6]2[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)N(c1ccncc1)n1cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cl
Product: Clc1cccn1Nc1ccncc1
Yield: 134.7 %

Procedure:
A mixture prepared from a solution of N-(2-chloro-1H-pyrrol-1-yl)-N-(4-pyridinyl)carbamic acid ethyl ester (6 g) in 50 ml of ethanol and 20 ml of 10% aqueous sodium hydroxide solution was warmed for 15 minutes on a steam bath, and thereafter cooled, diluted with 500 ml of water and extracted with dichloromethane. The organic extract was washed with water and saturated sodium chloride and thereafter dried over anhydrous magnesium sulfate, filtered and evaporated to 5 g of an oil. This oil was purified by HPLC (silica, ethyl acetate) to give 3.5 g of a solid, mp 115°-118° C. This material was converted to the hydrochloride salt and recrystallized twice from isopropanol-ether to give 3.4 g of crystals, mp 172°-173° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](=[O:15])[NH:13][N:14]=[C:10]3[CH2:9][CH:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1.[N+](=[CH2:26])=[N-]>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](=[O:15])[N:13]([CH3:26])[N:14]=[C:10]3[CH2:9][CH:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1
Reactant: O=c1[nH]nc2n1-c1ccc(Cl)cc1C(c1ccccc1F)=CC2
Reactant: C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: Cn1nc2n(c1=O)-c1ccc(Cl)cc1C(c1ccccc1F)=CC2
Reaction time: 3 h

Procedure:
A solution of 2.65 g of 8-chloro-6-(2-fluorophenyl)-2,4-dihydro-1H-s-triazolo[4,3-a][1]benzazepin-1-one in a mixture of 16 ml of methanol and 16 ml of methylene chloride is treated at 0° with 100 ml of ethereal diazomethane solution. After 3 hours, a further 33 ml of diazomethane solution are added and the mixture is left to stand for a further 2 hours. After evaporation of the solution, the residue is chromatographed on 80 g of silica gel while eluting with chloroform/ethanol (99:1). The crude product is recrystallized from ether/hexane. There is obtained 8-chloro-6-(2-fluorophenyl)-2,4-dihydro-2-methyl-1H-s-triazolo[4,3-a][1]benzazepin-1-one of melting point 142°-143°.
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[NH:2]1.[CH:12]1([N:15]2[C:23]3[C:18](=[CH:19][C:20]([C:24](OC)=O)=[CH:21][CH:22]=3)[CH:17]=[N:16]2)[CH2:14][CH2:13]1>>[CH:12]1([N:15]2[C:23]3[C:18](=[CH:19][C:20]([CH2:24][N:2]4[C:3](=[O:10])[C:4]5[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=5)[C:1]4=[O:11])=[CH:21][CH:22]=3)[CH:17]=[N:16]2)[CH2:14][CH2:13]1
Reactant: COC(=O)c1ccc2c(cnn2C2CC2)c1
Reactant: O=C1NC(=O)c2ccccc21
Product: O=C1c2ccccc2C(=O)N1Cc1ccc2c(cnn2C2CC2)c1

Procedure:
The titled compound was prepared according to the procedure described in step-3 of Example 13 from isoindoline-1,3-dione and (1-cyclopropyl-1H-indazol-5-yl)methanol (step-2 of Example 28).