Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:9][C@H:8]([C:10]([OH:12])=O)[C@H:7]([CH2:13][CH3:14])[CH2:6]1)(=[O:3])[CH3:2].[NH:15]([C:17]1[N:18]=[C:19]2[CH:25]=[CH:24][N:23]([S:26]([C:29]3[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:20]2=[N:21][CH:22]=1)[NH2:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O>[CH2:13]([C@H:7]1[C@@H:8]([C:10]([NH:16][NH:15][C:17]2[N:18]=[C:19]3[CH:25]=[CH:24][N:23]([S:26]([C:29]4[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=4)(=[O:28])=[O:27])[C:20]3=[N:21][CH:22]=2)=[O:12])[CH2:9][C@@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:6]1)[CH3:14]
Reactant: CC[C@@H]1C[C@H](NC(C)=O)C[C@@H]1C(=O)O
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CC[C@@H]1C[C@H](NC(C)=O)C[C@@H]1C(=O)NNc1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.7 %

Procedure:
To a mixture of (1S,2R,4S)-4-acetamido-2-ethylcyclopentanecarboxylic acid (3.03 g, 15.2 mmol) in DCM (90 mL) was added 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (4.20 g, 13.8 mmol, Example #4, Step D), HATU (5.53 g, 14.5 mmol) and TEA (7.72 mL, 55.4 mmol). After stirring at ambient temperature for about 2 h, the reaction was diluted with water (60 mL). The layers were separated and the aqueous layer was extracted with DCM (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 0-5% MeOH in DCM to give N-((1S,3R,4S)-3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentyl)acetamide (7.0 g, 90%, 87% purity) as a tan foam: LC/MS (Table 1, Method a) Rt=1.96 min; MS m/z: 485 (M+H)+. To a solution of impure N-((1S,3R,4S)-3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)-cyclo-pentyl)acetamide (9.40 g, 19.4 mmol) in 1,4-dioxane (100 mL) was added TEA (8 mL, 58 mmol) and thionyl chloride (1.9 mL, 27.1 mmol). The reaction mixture was heated at about 80° C. for about 2 h, and then cooled to about 0° C. and saturated aqueous NaHCO3 and EtOAc (100 mL each) were added. The layers were separated and the aqueous layer was extracted with additional EtOAc (2×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 50-100% EtOAc/MeOH/Et2NH (90:9:1) in EtOAc to give N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)acetamide (6.00 g, 66%): LC/MS (Table 1, Method a) Rt=2.03 min; MS m/z: 467 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:21]([O-])=O)=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[C:6]#[N:7].O>C(O)(=O)C.[Fe]>[NH2:21][C:4]1[C:3]([O:2][CH3:1])=[C:10]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: COc1c(OCCCN2CCOCC2)ccc(C#N)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: COc1c(OCCCN2CCOCC2)ccc(C#N)c1N
Temperature: 0 °C
Reaction time: 4 h
Yield: 92.6 %

Procedure:
3-Methoxy-4-(3-morpholin-4-ylpropoxy)-2-nitrobenzonitrile (Step 2, 7.7 g, 24.1 mmol) was suspended in acetic acid (170 mL) and cooled to 0° C. Water (0.4 mL) was added, followed by iron powder (6.7 g, 120 mmol) and the resulting mixture was stirred at room temperature for 4 h at which time the reaction mixture was filtered through a pad of Celite and washed with acetic acid (400 mL). The filtrate was concentrated under reduced pressure to 100 mL and diluted with EtOAc (200 mL) at which time potassium carbonate was added slowly. The resulting slurry was filtered through a pad of Celite washing with EtOAc and water. The layers were separated and the organic layer was washed with saturated sodium bicarbonate solution. The organic layer was separated and passed through a pad of silica gel. The resultant solution was concentrated under reduced pressure to provide the title compound (6.5 g, 92%): 1H NMR (DMSO-d6) δ: 7.13 (1H, d), 6.38 (1H, d), 5.63 (2H, br s), 4.04 (2H, t), 3.65 (3H, s), 3.55 (4H, m), 2.41 (2H, t), 2.38 (4H, m), 1.88 (2H, m).
Reaction SMILES: [C:1]1([CH2:11][N:12]2[C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([OH:25])[C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][C:17]=3[C:26](=[O:28])[NH2:27])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[CH2:30][C:31]([O:33][CH3:34])=[O:32]>CN(C=O)C.C(OCC)(=O)C>[C:1]1([CH2:11][N:12]2[C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([O:25][CH2:30][C:31]([O:33][CH3:34])=[O:32])[C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][C:17]=3[C:26](=[O:28])[NH2:27])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc2ccccc12
Reactant: COC(=O)CBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc2ccccc12
Reaction time: 0.25 h
Yield: 84.6 %

Procedure:
40% Methanolic Triton B (0.2 mL, 0.26 mM) was added to a solution of the 9-[(1-naphthyl)methyl]-4-hydroxy-5-carbamoyl carbazole (80 mg, 0.22 mM) in 7 mL DMF at room temperature. After 15 minutes, methyl bromoacetate (40 mg, 0.3 mM) was added and the resultant mixture stirred at room temperature for 3 hours. The mixture was diluted with ethyl acetate, washed twice with H2O, and once with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 81 mg (85%) of the {9-[(1-naphthyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (CDCl3) δ 8.2 (d, 1H, J=8 Hz), 8.05 (d, 1H, J=8 Hz), 7.85-7.0 (m, 11H), 6.65 (d, 1H, J=8 Hz), 6.3 (d, 1H, J=8 Hz), 6.2 (s, 2H), 4.95 (s, 2H), and 3.8 (s, 3H). IR (KBr, cm−1) 3364, 1739, 1630, 1582, 1500, 1455, 1285, 1232, 1153, and 774. MS (FD) m/e 438.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:24])=[C:8]2[CH:14]=[CH:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[C:9]2=[CH:10][N:11]=1)=[O:5])C.[NH2:25][CH2:26][C:27]([OH:29])=[O:28].C[O-].[Na+].CO>>[OH:24][C:7]1[C:6]([C:4]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:5])=[N:11][CH:10]=[C:9]2[N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH:13]=[CH:14][C:8]=12
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1ncc2c(ccn2Cc2ccccc2OC)c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1Cn1ccc2c(O)c(C(=O)NCC(=O)O)ncc21

Procedure:
Prepared in analogy to that of Example 1(e) from 1-(2-methoxy-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 356 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[CH3:10][O:11]/[N:12]=[C:13](/[C:21]1[O:26][CH2:25][CH2:24][O:23][N:22]=1)\[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>C1(C)C=CC=CC=1>[CH3:10][O:11]/[N:12]=[C:13](/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1)\[C:21]1[O:26][CH2:25][CH2:24][O:23][N:22]=1
Reactant: CO/N=C(/C1=NOCCO1)c1ccccc1O
Reactant: Fc1c(Cl)ncnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CO/N=C(\C1=NOCCO1)c1ccccc1Oc1ncnc(Cl)c1F
Temperature: 82.5 °C
Reaction time: 1.5 h
Yield: 88 %

Procedure:
To a solution of 4,6-dichloro-5-fluoropyrimidine (DCFP) (100 g, 0.564 mol) in toluene (500 mL) was added (E)-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O-methyl oxime (13) (77.8 g, 0.466 mol), K2CO3 (76 g, 0.55 mol), followed by the addition of DMF (50 mL) at ambient temperature. The reaction mixture was stirred at 80-85° C. for 1-2 h. The progress of the reaction was monitored by the HPLC analysis. Upon completion of the reaction, the reaction mixture was washed with water (500 mL) and 10% brine solution (250 mL) to obtain the product in toluene layer meeting the desired specifications. Yield—88-98%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:38]1(=[O:48])[NH:42][C:41](=[O:43])[C:40]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:39]12.C(OC(N=NC(OCC)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:42]2[C:38](=[O:48])[C:39]3[C:40](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:41]2=[O:43])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(CCCCO)CC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCCCN2C(=O)c3ccccc3C2=O)CC1
Temperature: 15 °C
Reaction time: 8 h

Procedure:
136 g (<528 mmol) 4-[1-tert-butoxycarbonylpiperidin-4-yl)-butan-1-ol (crude product), 135.3 g (516 mmol) Triphenylphosphine and 75.9 g (516 mmol) phthalimide are suspended in 1800 ml THF and 89.9 g (516 mmol) azodicarboxylic acid diethyl ester are added dropwise within three hours under protective atmosphere and light cooling (to ca. 15° C.). The mixture is left to stand at RT overnight without further cooling. Subsequently, the solvent is removed under vacuum and the oily residue is dissolved in 500 ml acetic acid ethyl ester and held at 0° C. overnight. The sedimented precipitate is filtered and discarded. The solution is concentrated under vacuum and the oily residue is chromatographically purified over silica gel with CHCl3 and crystallized from 200 ml isopropanol after drawing off the solvent. Colorless crystals remain with a MP of 100–102° C.; yield: 108.5 g (57%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][C:8]([O:10]C)=[O:9])=[CH:5][C:4]2[CH:12]([CH3:22])[CH2:13][C:14]3[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=3[C:16](=[O:17])[C:3]1=2.[OH-].[Na+]>C(O)C.O>[CH3:1][N:2]1[C:6]([CH2:7][C:8]([OH:10])=[O:9])=[CH:5][C:4]2[CH:12]([CH3:22])[CH2:13][C:14]3[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=3[C:16](=[O:17])[C:3]1=2
Reactant: COC(=O)Cc1cc2c(n1C)C(=O)c1ccccc1CC2C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1Cc2ccccc2C(=O)c2c1cc(CC(=O)O)n2C

Procedure:
To a suspension of methyl 5,10-dihydro-1,4-dimethyl-10-oxo-4H-benzo-[5,6]-cyclohepta[1,2-b]pyrrol-2-acetate (26 mg, 0.087 mmoles) in a mixture of 4 cc ethanol and 0.5 cc water, slight ice-bath cooling, is added 0.06 cc of 2.5 N sodium hydroxide solution. After stirring overnight (nitrogen atmosphere) at ambient temperatures, water (4 cc) is added, the ethanol removed in vacuo, the mixture filtered, and the filtrate acidified with 2 N hydrochloric acid. After aging, the supernatent aqueous solution is decanted from the yellow oil that forms, and the oil washed well with water. The oil is then dissolved in ether, the ether solution dried and concentrated to 20.3 mg (83%) of 5,10-dihydro-1,4-dimethyl-10-oxo-4H-benzo[5,6]cyclohepta[1,2-b]pyrrol-2-yl-acetic acid as a yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][NH:5][C:6](=[O:21])[N:7]([CH:18]([CH3:20])[CH3:19])[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(N(CC)CC)C>[C:23]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][N:7]([CH:18]([CH3:19])[CH3:20])[C:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:22])=[O:21])=[CH:16][CH:15]=1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)N(CCOc1ccc(N)cc1)C(=O)NCCN(C)C
Solvent: CCN(CC)CC
Product: CC(C)N(CCOc1ccc(NC(=O)c2ccccc2)cc1)C(=O)NCCN(C)C

Procedure:
The title compound is prepared by reacting the compound of Example 64: N'-[2-(dimethylamino)ethyl]-N-(1-methylethyl)-N-[2-(4-aminophenoxy)ethyl]urea with benzoyl chloride in triethylamine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[C:6]([CH2:13][C:14]1C=C[C:17](Cl)=[CH:16][CH:15]=1)=[C:5]2[Cl:21].[S:22]1C=CC=C1CC(C(O)=O)C(O)=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[C:6]([CH2:13][C:14]1[S:22][CH:17]=[CH:16][CH:15]=1)=[C:5]2[Cl:21]
Reactant: O=C(O)C(Cc1cccs1)C(=O)O
Reactant: Clc1ccc(Cc2c(Cl)nc3ccc(Br)cc3c2Cl)cc1
Product: Clc1nc2ccc(Br)cc2c(Cl)c1Cc1cccs1

Procedure:
The title compound was prepared by substituting 2-(4-chlorobenzyl)malonic acid (Intermediate 3: step b) with 2-(thiophen-2-ylmethyl)malonic acid (Intermediate 9: step b) then following the procedure described for the preparation of 6-bromo-2,4-dichloro-3-(4-chlorobenzyl)quinoline (Intermediate 3: step c).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15](=[O:18])[CH2:16]Br)=[CH:11][CH:12]=2)[C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH3:19])[CH2:6][C:5]1([CH3:27])[CH3:26])(=[O:3])[CH3:2].[F:28][C:29]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:30]=1[CH2:31][NH2:32].C(N(CC)C(C)C)(C)C>O1CCOCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]([CH2:16][NH:32][CH2:31][C:30]3[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:29]=3[F:28])=[O:18])=[CH:11][CH:12]=2)[C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH3:19])[CH2:6][C:5]1([CH3:27])[CH3:26])(=[O:3])[CH3:2]
Reactant: NCc1ccc(F)cc1F
Reactant: CC(=O)N1c2ccc(NC(=O)CBr)cc2C(C)(c2ccccc2)CC1(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(NC(=O)CNCc3ccc(F)cc3F)cc2C(C)(c2ccccc2)CC1(C)C
Temperature: 40 °C
Reaction time: 18 h

Procedure:
A mixture of 1-acetyl-6-(bromoacetyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg), 2,4-difluorobenzylamine (6.0 mg) and N,N-diisopropylethylamine (10 μl) in dioxane (2 ml) was stirred at 40° C. for 18 h. The reaction mixture was concentrated in vacuo. The residue was chromatographed on silicagel in dichloromethane/methanol=1/095/5 (v/v) as eluent.
Reaction SMILES: [CH2:1]([O:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=1)[C:23]([OH:25])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].S(Cl)(Cl)=O.[NH:41]([CH2:47][C:48]([O:50][CH3:51])=[O:49])[CH2:42][C:43]([O:45][CH3:46])=[O:44]>>[CH3:51][O:50][C:48](=[O:49])[CH2:47][N:41]([CH2:42][C:43]([O:45][CH3:46])=[O:44])[C:23](=[O:25])[C:22]1[CH:26]=[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=[C:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:21]=1
Reactant: COC(=O)CNCC(=O)OC
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCc2ccccc2)cc(C(=O)O)c1
Solvent: O=S(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCc2ccccc2)cc(C(=O)N(CC(=O)OC)CC(=O)OC)c1

Procedure:
Conversion of 3-(octadecyloxy)-5-(phenylmethoxy)benzoic acid to the acid chloride with thionyl chloride followed by treatment with dimethyl iminodiacetate gave N-(2-methoxy-2-oxoethyl)-N-[3-(octadecyloxy)-5-(phenylmethoxy)benzoyl]glycine methyl ester as an oil after chromatography on 50 g of silica gel using 25% ethyl acetate-hexane. The structure was confirmed by the nmr spectrum.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([C:43]#[N:44])[CH:38]=2)[CH:32]=1)=[O:30])(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([C:43]#[N:44])[CH:38]=2)[CH:32]=1)=[O:30])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(C#N)c2)c1
Product: CCc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C#N)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J33) (228 mg, 0.75 mmol) and 3-[3-(2-cyano-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K24) (242 mg, 0.75 mmol) according to the general procedure M. Obtained as a light brown solid (308 mg, 74%).
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[CH2:16][CH2:15][N:14]([CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(C)(C)C.[I-].[Na+].C(N(CC)CC)C.Cl[CH2:47][CH:48]([OH:50])[CH3:49]>CN(C)C=O>[OH:50][CH:48]([CH3:49])[CH2:47][N:11]1[CH2:10][CH2:9][N:8]([CH2:7][C:6]([OH:36])=[O:5])[CH2:19][CH2:18][N:17]([CH2:20][C:21]([OH:23])=[O:22])[CH2:16][CH2:15][N:14]([CH2:28][C:29]([OH:31])=[O:30])[CH2:13][CH2:12]1
Reactant: CC(O)CCl
Reactant: CC(C)(C)OC(=O)CN1CCNCCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(O)CN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1,4,7,10-Tetraazacyclododecane-4,7,10-triacetic acid tri-t-butyl ester (129 mg, 0.25 mmol) (Example 22(a)) was dissolved in dimethylformamide. Sodium iodide (7.5 mg, 0.5 mmol), triethylamine (76 mg, 0.75 mmol) and 3-chloro-2-propanol (48 mg, 0.5 mmol) were added to the stirred mixture at ambient temperature. The mixture was stirred for 4 hours at ambient temperature, the temperature was then raised to 100° C. and kept there for 2 hours. The solvent was evaporated, and the residue was dissolved in dichloromethane (2 ml) and washed with water (1 ml). Trifluoroacetic acid (2 ml) was added to the organic phase and the mixture was stirred at ambient temperature for 1 hour. The solvents were evaporated and the residue dissolved in water (4 ml). The aqueous solution was washed with ether (5×2 ml). The aqueous solution was acidified, the water was evaporated, and the title compound was isolated as a hygroscopic white powder. Yield 75 mg (74%) The structure was confirmed by 1HNMR and 13CNMR.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[S:6][C:7]2[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[C:11]([O:18][CH3:19])=[CH:10][C:8]=2[N:9]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:19][O:18][C:11]1[C:12]([O:16][CH3:17])=[C:13]([O:14][CH3:15])[C:7]2[S:6][C:5]([CH2:4][CH2:3][CH2:2][N:20]3[CH2:25][CH2:24][N:23]([CH2:2][CH2:3][CH2:4][C:5]4[S:6][C:7]5[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[C:11]([O:18][CH3:19])=[CH:10][C:8]=5[N:9]=4)[CH2:22][CH2:21]3)=[N:9][C:8]=2[CH:10]=1
Reactant: COc1cc2nc(CCCBr)sc2c(OC)c1OC
Reactant: C1CNCCN1
Product: COc1cc2nc(CCCN3CCN(CCCc4nc5cc(OC)c(OC)c(OC)c5s4)CC3)sc2c(OC)c1OC

Procedure:
2-(3-Bromopropyl)-5,6,7-trimethoxybenzothiazole (328 mg) and piperazine (39 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]([CH:23]1[CH2:27][CH2:26][N:25]([CH2:28][C:29](O)=[O:30])[CH2:24]1)=[O:22].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH3:19][O:20][C:21]([CH:23]1[CH2:27][CH2:26][N:25]([CH2:28][C:29](=[O:30])[N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:12]=[CH:11][C:10]([C:13]4[N:14]=[CH:15][CH:16]=[CH:17][N:18]=4)=[CH:9][CH:8]=3)[CH2:2][CH2:3]2)[CH2:24]1)=[O:22]
Reactant: c1cnc(-c2ccc(N3CCNCC3)cc2)nc1
Reactant: COC(=O)C1CCN(CC(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C1CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cc3)CC2)C1
Reaction time: 24 h
Yield: 83.1 %

Procedure:
2-(4-piperazin-1-yl-phenyl)-pyrimidine (compound 10 from Step 7, 14.7 mmol) and 1-Carboxymethyl-pyrrolidine-3-carboxylic acid methyl ester (compound 5 from Step 3, 17.6 mmol) were dissolved in 72 ml of DMF. Triethylamine (8 ml, 57 mmol), 1-hydroxybenztriazole (2.29 gm) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) (3.43 gm, 18 mmol) were added and the reaction mixture stirred for 24 hrs. After washing with brine, extracting with dichloromethane, and drying over magnesium sulfate, the mixture was evaporated and chromatographed on silica gel to obtain 5.0 gm of title product.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].S(Cl)([Cl:16])=O>CN(C=O)C.C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([Cl:16])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(F)c(C(=O)O)cc1Br
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cc(F)c(C(=O)Cl)cc1Br
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere, 5-bromo-2-fluoro-4-methoxybenzoic acid (10.0 g) was suspended in DMF/toluene solution (50 mL) (DMF concentration: 300 ppm). To the suspension was added dropwise thionyl chloride (5.73 g) at 70° C. After stirring at 70° C. for 2 hr, the completion of the reaction was confirmed by HPLC. Toluene and excess thionyl chloride were evaporated under reduced pressure. To the concentrated residue was added toluene (30 mL), and the mixture was concentrated again under reduced pressure. To the obtained acid chloride (5-bromo-2-fluoro-4-methoxybenzoic acid chloride) was added toluene (30 mL), and the mixture was directly used in the next step.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][C:5]1([CH2:26][CH3:27])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH2:8][CH2:7][O:6]1)=[CH:16][C:15]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:14][CH:13]=3.CO.[OH-].[K+]>O>[CH2:26]([C:5]1([CH2:4][C:3]([OH:28])=[O:2])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH2:8][CH2:7][O:6]1)=[CH:16][C:15]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[CH:14][CH:13]=3)[CH3:27]
Reactant: CCC1(CC(=O)OC)OCCc2c1[nH]c1ccc(OCc3ccccc3)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC1(CC(=O)O)OCCc2c1[nH]c1ccc(OCc3ccccc3)cc21
Temperature: 25 °C
Yield: 93 %

Procedure:
A mixture consisting of the ester (29.0 g, 0.0765 mol) of Step A, methanol (800 mL), water (50 mL) and potassium hydroxide (16.0 g, 0.29 mol) is refluxed for 4 hours. The reaction mixture is cooled to room temperature, concentrated and diluted with water (500 mL). The aqueous layer is washed with ether (2×200 mL) and made acidic with a 1:1 mixture of concentrated HCl and water to pH 2.71 is extracted with chloroform (4×300 mL) and the combined chloroform layers are washed once with water (2×300 mL), once with brine (300 mL), dried (MgSO4), filtered and concentrated to give 26.0 g of title compound, m.p. 163°-165° C.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[N:12]=[C:11]([S:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8]>C(O)CC>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[S:13][C:11]1[N:12]=[C:5]2[NH:2][N:3]=[C:7]([NH2:8])[C:6]2=[CH:9][CH:10]=1
Reactant: NN
Reactant: N#Cc1ccc(Sc2ccc(F)cc2F)nc1Cl
Solvent: O
Solvent: CCCO
Product: Nc1n[nH]c2nc(Sc3ccc(F)cc3F)ccc12
Temperature: 80 °C
Yield: 39.1 %

Procedure:
0.561 mL (11.57 mmol) of hydrazine monohydrate is added under nitrogen to a stirring solution of 1.09 g (3.86 mmol) of 2-chloro-6-(2,4-difluorophenylthio)nicotinonitrile in 15 mL of propanol. The reaction medium is heated at 80° C. for 4 hours. A precipitate is obtained when the reaction medium is returned to room temperature. This precipitate is filtered and rinsed with ethanol. The solid is dissolved in an ethyl acetate fraction and washed with a 1N HCl solution. The organic phase is dried on magnesium sulfate and dry evaporated to yield 420 mg (39%) of 6-(2,4-difluorophenylthio)-1H-pyrazolo[3,4-b]pyridin-3-amine in the form of a yellow solid.