Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[O:12][CH2:11][CH2:10][CH:9]2[C:14]([OH:16])=O)([O-:3])=[O:2].[CH:17]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)([CH3:19])[CH3:18].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH:17]([C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:14]([CH:9]2[C:8]3[C:13](=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][CH:7]=3)[O:12][CH2:11][CH2:10]2)=[O:16])=[CH:22][CH:21]=1)([CH3:19])[CH3:18]
Reactant: O=C(O)C1CCOc2c1cccc2[N+](=O)[O-]
Reactant: CC(C)c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1ccc(NC(=O)C2CCOc3c2cccc3[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 89.6 %

Procedure:
To a solution of 8-nitrochroman-4-carboxylic acid (3.0 g) and 4-isopropylaniline (2.0 g) in dimethylformamide (30 mL) were added N-hydroxybenzotriazole hydrate (2.0 g) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (2.8 g), and the mixture was stirred at room temperature. After the completion of the reaction, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography to give N-(4-isopropylphenyl)-8-nitrochroman-4-carboxamide (4.1 g).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)=O.O.[NH2:18]N>C(O)C>[N+:13]([C:9]1[CH:8]=[C:7]([C:5]2[CH:4]=[CH:3][NH:2][N:18]=2)[CH:12]=[CH:11][CH:10]=1)([O-:15])=[O:14]
Reactant: NN
Reactant: CN(C)/C=C/C(=O)c1cccc([N+](=O)[O-])c1
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cccc(-c2cc[nH]n2)c1
Reaction time: 5 h
Yield: 100.9 %

Procedure:
2.5 g (11 mmol) of (2E)-3-(dimethylamino)-1-(3-nitrophenyl)prop-2-en-1-one were dissolved in 25 ml of ethanol and 2.3 ml of hydrazine hydrate 98% (46 mmol) were added. The resulting solution was refluxed under stirring for 5 hours. The solvent was then evaporated and the crude was dissolved with dichloromethane and washed with water. The organic layer was dried over sodium sulphate and the solvent removed in vacuo. The residue was then triturated with diisopropylether and collected by filtration, giving 2.1 g of the title compound (98%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].CN(C)CCN(C)C.[C:17]1([S:23]([N:26]2[C:34]3[CH:33]=[CH:32][N:31]=[C:30]([Cl:35])[C:29]=3[CH:28]=[CH:27]2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl[C:37]([O:39][CH2:40][CH3:41])=[O:38]>C1COCC1>[CH2:40]([O:39][C:37]([C:27]1[N:26]([S:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)(=[O:25])=[O:24])[C:34]2[CH:33]=[CH:32][N:31]=[C:30]([Cl:35])[C:29]=2[CH:28]=1)=[O:38])[CH3:41]
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Cl)nccc21
Reactant: CCOC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: CN(C)CCN(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(Cl)nccc2n1S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 117 %

Procedure:
Lithium diisopropylamide (3.2 mL of a 1.5 M solution in THF, 4.80 mmol) is added to a solution of tetramethylethylenediamine (0.71 mL, 4.75 mmol) and 1-benzenesulfonyl-4-chloro-1H -pyrrolo[3,2-c]pyridine (1 g, 3.42 mmol) in THF (13 mL). The resulting yellow solution is stirred at −78° C. for 1 hour, and then ethyl chloroformate (0.78 mL, 8.16 mmol) is added dropwise. The mixture is slowly brought to room temperature over a 3.5 hour period. The reaction is quenched with saturated NH4Cl solution and then diluted with ethyl acetate. The organic layer is washed with brine, dried over MgSO4, filtered and concentrated to give a light brown solid (1.46 g) as the product which is used in the subsequent step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8](S(C3C=CC=CC=3)(=O)=O)[C:9]([CH3:11])=[CH:10][C:3]=12.C(=O)([O-])[O-].[K+].[K+].CO>O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([CH3:11])=[CH:10][C:3]=12
Reactant: Cc1cc2c(Cl)ccnc2n1S(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1cc2c(Cl)ccnc2[nH]1
Temperature: 90 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
A mixture of 4-chloro-2-methyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (4.73 g), potassium carbonate (6.4 g), methanol (45 ml), and water (15 ml) was stirred at 90° C. for 2 hours. After the mixture was cooled, the obtained needle crystals were filtered and washed with water to obtain 4-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridine (1.85 g).
Reaction SMILES: [H-].[Na+].ClC1C=CC([C:8](=O)[CH2:9][NH:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:21])=[CH:17][C:18]=3[Cl:20])[N:13]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:12]=2[C:29]([O:31][CH2:32][CH3:33])=[O:30])=CC=1.CI.[O:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1.CN(C)C=O>>[Cl:20][C:18]1[CH:17]=[CH:16][C:42]([C:43](=[O:39])[CH2:8][CH2:9][NH:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:21])=[CH:17][C:18]=3[Cl:20])[N:13]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[C:12]=2[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:41][CH:40]=1
Reactant: CCOC(=O)c1c(NCC(=O)c2ccc(Cl)cc2)c2c(Cl)cc(Cl)cc2n1C(=O)OC(C)(C)C
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1c(NCCC(=O)c2ccc(Cl)cc2)c2c(Cl)cc(Cl)cc2n1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Suspend sodium hydride (160 mg of a 60% dispersion, 4 mmol) in anhydrous tetrahydrofuran/dimethylformamide (3 mL/2:1) and cool to 0° C. under a nitrogen atmosphere. Add 3-[(p-chlorophenacyl)amino]-2-carbethoxy-4,6-dichloro-1-(tert-butyloxycarbonyl)-indole (2 g, 3.9 mmol) in tetrahydrofuran/dimethylformamide (10 mL/2:1) dropwise to the suspension. Stir at 0° C. for 30 minutes. Add methyl iodide (0.137 mL, 2.2 mmol) and stir for 30 minutes at 0° C. Warm the reaction to room temperature and after 4 hours quench with water (20 mL). Extract with ethyl acetate (20 mL), wash with saturated sodium chloride, dry over magnesium sulfate, filter and concentrate in vacuo to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[N:47]1([C:52]([C:54]2[N:55]=[C:56]([C:63]([F:66])([F:65])[F:64])[N:57]3[CH2:62][CH2:61][NH:60][CH2:59][C:58]=23)=[O:53])[CH2:51][CH2:50][CH2:49][CH2:48]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:60]1[CH2:61][CH2:62][N:57]2[C:56]([C:63]([F:66])([F:64])[F:65])=[N:55][C:54]([C:52]([N:47]3[CH2:51][CH2:50][CH2:49][CH2:48]3)=[O:53])=[C:58]2[CH2:59]1)=[O:5]
Reactant: O=C(c1nc(C(F)(F)F)n2c1CNCC2)N1CCCC1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCCC3)c2C1
Reaction time: 12 h
Yield: 18.8 %

Procedure:
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (417 mg, 1.40 mmol) was dissolved in 5 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1 g, 2.80 mmol), crude pyrrolidin-1-yl-[3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl]methanone 18a (400 mg, 1.40 mmol) and N,N-diisopropylethylamine (0.7 mL, 4.20 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure, added with 20 mL of H2O, extracted with ethyl acetate (10 mL×3). The organic phase was combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[4-fluoro-3-[1-(pyrrolidine-1-carbonyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one 18 (150 mg, yield 18.0%) as a light yellow solid.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[Cl:11][C:12]1[C:17]([CH3:18])=[C:16]([N+:19]([O-:21])=[O:20])[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)=[C:14]([CH:29]([NH2:31])[CH3:30])[CH:13]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:11][C:12]1[C:17]([CH3:18])=[C:16]([N+:19]([O-:21])=[O:20])[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)=[C:14]([CH:29]([NH:31][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:30])[CH:13]=1
Reactant: Brc1ncnc2[nH]cnc12
Reactant: Cc1c(Cl)cc(C(C)N)c(-c2cccc(F)c2)c1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1c(Cl)cc(C(C)Nc2ncnc3[nH]cnc23)c(-c2cccc(F)c2)c1[N+](=O)[O-]
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-9H-purine (41 mg, 0.21 mmol), 1-(4-chloro-3′-fluoro-5-methyl-6-nitrobiphenyl-2-yl)ethanamine (54 mg, 0.17 mmol), and N,N-diisopropylethylamine (0.06 mL, 0.35 mmol) in isopropyl alcohol (0.7 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C20H17ClFN6O2 (M+H)+: m/z=427.1. found: 427.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C@:12]12[CH2:17][C@H:16]1[CH2:15][NH:14][CH2:13]2.Br[CH2:19][CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].C(N(CC)CC)C.N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1>C1COCC1>[CH3:28][C:26]([Si:23]([CH3:25])([CH3:24])[O:22][CH2:21][CH2:20][CH2:19][N:14]1[CH2:15][C@H:16]2[C@:12]([C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=3[F:1])([CH2:17]2)[CH2:13]1)([CH3:27])[CH3:29]
Reactant: Fc1cc(C(F)(F)F)ccc1[C@@]12CNC[C@@H]1C2
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCN1C[C@@H]2C[C@]2(c2ccc(C(F)(F)F)cc2F)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.8 %

Procedure:
A mixture of (1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (150 mg, 0.6 mmol), [(3-bromopropyl)oxy](1,1-dimethylethyl)dimethylsilane (233 mg, 0.92 mmol), triethylamine (185 mg, 1.83 mmol) and Nal (20 mg) in THF (2 mL) was stirred at r.t. for 20 h. The reaction mixture was concentrated under vacuum, water was added and the aqueous phase was extracted with EtOAc. The organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated under vacuum and the crude was purified by column chromatography (eluting with EtOAc/cyclohexane 3/7) to give 245 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[CH2:12]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[C:2]=1[CH3:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1c(NCc2ccccc2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.4 %

Procedure:
2-Methyl-3-nitroaniline (3.40 g, 22.3 mmoles) and benzaldehyde (3.9 mL, 38 mmoles) in dichloroethane (78 mL) were treated with glacial acetic acid (5.1 mL, 89 mmoles). The yellow reaction mixture was stirred for 4 hours at room temperature, treated with sodium triacetoxyborohydride (9.5 g, 44.6 mmoles) and allowed to stir overnight at room temperature. The mixture was poured into saturated aqueous NaHCO3 (400 mL), extracted with diethyl ether (400 mL) and the phases separated. The organic phase was washed with brine (200 mL), dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 10:1→4:1 hexanes:ethyl acetate) to provide the title compound as a yellow solid (4.72 g, 87%).
Reaction SMILES: C1(C)C=CC=CC=1.Br[C:9]1[S:10][CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15].[Cl:17][C:18]1[CH:23]=[CH:22][C:21](OB(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[N+:14]([C:13]1[CH:12]=[CH:11][S:10][C:9]=1[C:21]1[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccsc1Br
Reactant: OB(O)Oc1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccsc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 105.5 %

Procedure:
To 50 ml of toluene, 1 g of 2-bromo-3-nitrothiophene, 0.75 g of 4-chlorophenylboric acid, 5 ml of a 2M-aqueous potassium carbonate solution and 2 ml of ethanol were added and stirred at room temperature for 30 minutes in a nitrogen atmosphere. Successively 0.28 g of Pd(PPh3)4 was added and heat-refluxed for 2 hours. The aqueous layer was separated from the reaction mixture and the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue thus obtained was purified by silica gel column chromatography to obtain 1.1 g of the product as a yellow crystal. The yield was 98%. 1H-NMR(CDCl3, δ value):7.29(1H, d, J=5.9), 7.43(4H, s), 7.66(1H, d, J=5.9)
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1.[Cl:21][CH2:22][CH2:23][CH2:24]Br>O1CCCC1>[Cl:21][CH2:22][CH2:23][CH2:24][N:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:11]=[CH:10][C:9]([CH3:8])=[CH:14][CH:13]=2)[CH2:16][CH2:17]1
Reactant: ClCCCBr
Reactant: Cc1ccc(N2CCNCC2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(N2CCN(CCCCl)CC2)cc1
Reaction time: 6 h

Procedure:
55.4 ml (0.4 mol) triethylamine were added to a solution of 35.2 g (0.2 mol) 1-(4-methylphenyl)-piperazine and 31.5 g (0.2 mol) 1-chloro-3-bromopropane in 41 ml anhydrous tetrahydrofuran and the reaction mixture then stirred for six hours at 60°-65°C. Thereafter, the crystals which had precipitated out were filtered off with suction and the filtrate was evaporated in a vacuum. There was obtained a quantitative yield of crude 1-(3-chloropropyl)-4-(4-methylphenyl)-piperazine which was purified by rapid distillation at an efficient oil pump vacuum. The yield was 41.23 g (80% of theory); b.p. 147°-150°C/0.05 mm HG; m.p. 34°-36°C.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)[C:15]([C:16](=O)[CH:17]=[CH:18]N(C)C)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH:30]1([NH:35][C:36]([NH2:38])=[NH:37])CCCC1.CC(C)([O-])C.[K+].O>O1CCCC1>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)[C:15]([C:16]4[CH:17]=[CH:18][N:38]=[C:36]([NH:35][CH3:30])[N:37]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C=CC(=O)c1c(-c2ccncc2)nn2c(NC3CCCC3)cccc12
Reactant: N=C(N)NC1CCCC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CNc1nccc(-c2c(-c3ccncc3)nn3c(NC4CCCC4)cccc23)n1
Temperature: 25 °C
Yield: 74.1 %

Procedure:
To a solution of 1-[7-(cyclopentylamino)-2-(4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one (From example 1, 0.13 g, 0.35 mmol) in tetrahydrofuran (10 mL) was added cyclopentyl guanidine hydrochloride (0.06 g, 0.38 mmol) followed by potassium tert-butoxide (0.085 g, 0.76 mmol). The resulting mixture was heated at reflux for 12 hours. Upon cooling to room temperature, water was added. The mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with brine, dried (magnesium sulfate), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (1:20 methanol-ethyl acetate) to give the title compound (100 mg, 75%) as a yellow solid. 1H NMR (CDCl3): δ 8.72 (d, 2H), 8.13 (d, 1H), 7.65 (m, 3H), 7.35 (t, 1H), 6.43 (d, 1H), 6.10 (d, 1H), 6.05 (d, 1H), 5.10 (m, 1H), 4.05 (m, 1H), 3.05 (d, 3H), 1.2–2.2 (m, 8H); MS m/z 386 (M+1).
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[NH2:2].C([O:14][C:15](=O)[CH2:16][C:17]([CH3:19])=O)C>>[O:14]=[C:15]1[N:1]([C:3]2[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=2)[N:2]=[C:17]([CH3:19])[CH2:16]1
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)CC(C)=O
Product: CC1=NN(c2ccc(C(=O)O)cc2)C(=O)C1

Procedure:
From the reaction of 4-hydrazinobenzoic acid and ethylacetoacetate, 4-(4,5-dihydro-5-oxo-3-methyl-1H-pyrazol-1-yl)-benzoic acid is obtained. Subsequent reaction with 2-ethylaniline yeilds 4-(4-(2-ethylanilinomethylene)-4,5-dihydro-5-oxo-3-methyl-1H-pyrazol-1-yl)-benzoic acid, Mp 291° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[CH:4][N:3]=1.C1C(=O)N([I:17])C(=O)C1>C(O)(=O)C>[CH2:8]([C:6]1[N:5]=[CH:4][NH:3][C:2](=[O:1])[C:7]=1[I:17])[CH3:9]
Reactant: O=C1CCC(=O)N1I
Reactant: CCc1cc(O)ncn1
Solvent: CC(=O)O
Product: CCc1nc[nH]c(=O)c1I
Reaction time: 30 h

Procedure:
To a stiffed solution of 70 g (0.56 mol) 4-hydroxy-6-ethyl pyrimidine in acetic acid is added 127 g (0.56 mol) NIS portion wise at RT within 15 min The reaction is stiffed for 30 h at RT until all starting material is consumed. The reaction mixture is diluted with water and the solid product is filtered off and washed with sodium thiosulfate solution to remove excess iodine. After drying, the desired product is obtained as a solid (90 g; 64%) which is used without further purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[F:15][C:16]1[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=1)[CH2:19][C:20]1[N:25]=[C:24]([C:26](O)=[O:27])[CH:23]=[CH:22][CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:26](=[O:27])[C:24]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:19][C:18]2[CH:29]=[CH:30][CH:31]=[C:16]([F:15])[CH:17]=2)[N:25]=1
Reactant: O=C(O)c1cccc(Cc2cccc(F)c2)n1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(Cc2cccc(F)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
A mixture of 2-(5-Chloro-1H-indol-3-yl)ethanamine hydrochloride (0.044 g; 0.187 mmol), 6-(3-fluorobenzyl)picolinic acid (0.045 g; 0.196 mmol), HATU (0.073 g; 0.192 mmol) and N,N-diisopropylethylamine (0.082 mL; 0.466 mmol) in DMF (3 mL) was stirred overnight at room temperature and was concentrated in vacuo. The residue was dissolved in dichloromethane and the organic layer was washed three times with water and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent 2 to 20% of ethyl acetate in dichloromethane) to give 0.053 g (70%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-6-(3-fluorobenzyl)picolinamide as a white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:20]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[CH:18]=[CH:17][C:4]=1[CH:5]=[C:6]1[CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1>O1CCOCC1.O1CCOCC1.C(Cl)Cl>[NH:8]1[CH2:9][C:6](=[CH:5][C:4]2[CH:17]=[CH:18][C:19]([C:21]([O:23][CH3:24])=[O:22])=[CH:20][C:3]=2[Cl:2])[CH2:7]1
Reactant: COC(=O)c1ccc(C=C2CN(C(=O)OC(C)(C)C)C2)c(Cl)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1ccc(C=C2CNC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.5 %

Procedure:
A 4 M solution of HCl in dioxane (5 mL) was added to a solution of tert-butyl 3-(2-chloro-4-(methoxycarbonyl)benzylidene)azetidine-1-carboxylate (0.27 g, 0.66 mmol) in dioxane:DCM (1:1 v/v, 10 mL) and the mixture was stirred at room temperature for 3 h. Salt precipitation was observed. The reaction mixture was diluted with diethyl ether (20 mL). The precipitate was filtered, washed with ether and dried overnight to get the HCl salt of methyl 4-(azetidin-3-ylidenemethyl)-3-chlorobenzoate (0.12 g) as an off-white solid. ES+(M+H)+238
Reaction SMILES: C([N:8]([CH2:39][CH3:40])[CH2:9][C:10]([NH:12][C@H:13]([C:25]([NH:27][C@H:28]([C:36]([NH2:38])=[O:37])[CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:26])[CH2:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:11])(OC(C)(C)C)=O.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]>ClCCl>[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42].[NH:8]([CH2:39][CH3:40])[CH2:9][C:10]([NH:12][C@H:13]([C:25]([NH:27][C@H:28]([C:36]([NH2:38])=[O:37])[CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:26])[CH2:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:11]
Reactant: CCN(CC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N[C@@H](CC1CCCCC1)C(N)=O)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNCC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N[C@@H](CC1CCCCC1)C(N)=O
Temperature: 5 °C

Procedure:
BOC-N(Et)Gly-(L)-Asp(OBzl)-(L)-Cha-NH2 is dissolved in dichloromethane (~1:12 wt/wt), and to that solution is added TFA at ambient temperature. This is then stirred until HPLC indicates complete reaction (3-5 hours). The solution is concentrated to about 1/2 volume at 40°-45° C. To this warm solution is added MTBE (~1:10 wt/wt vs. BOC-N(Et)Gly-(L)-Asp(OBzl)-(L)-Cha-NH2) while maintaining the temperature >40° C. The mixture is slowly cooled to about 5° C. and stirred for 1 hour to ensure complete crystallization. The resulting solids are filtered, and washed with chilled MTBE. The solids are dried under reduced pressure and analyzed for content of TFA·N(Et)Gly-(L)-Asp(OBzl)-(L)-Cha-NH2 (HPLC wt/wt assay). Yield is generally nearly quantitative, purity >95 A %.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)=[O:4].ClC(OCC)=O.Cl.[NH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[I:34])[C:29]#[N:30].Cl>CN(C)C=O.C(N(CC)CC)C>[I:34][C:33]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=1[O:25][CH2:24][CH2:23][NH:22][C:9](=[O:11])[C:8]1[CH:7]=[CH:6][C:5]([C:3](=[O:4])[N:2]([CH3:1])[CH3:14])=[CH:13][CH:12]=1
Reactant: CN(C)C(=O)c1ccc(C(=O)O)cc1
Reactant: N#Cc1ccc(I)c(OCCN)c1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(C(=O)NCCOc2cc(C#N)ccc2I)cc1
Reaction time: 0.08 h

Procedure:
600 mg (3.1 mmol) of 4-dimethylcarbamoylbenzoic acid and 1.25 g of triethylamine were stirred in dimethylformamide. 336 mg (3.1 mmol) of ethyl chloroformate was added to the resultant mixture, and they were stirred for 5 minutes. 3-(2-aminoethoxy)-4-iodobenzonitrile monohydrochloride was added to the mixture. The temperature was elevated to room temperature. After stirring for 2 hours, 1 N hydrochloric acid was added to the mixture. After extracting with ethyl acetate, the organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous NaCl a solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was washed with ethyl acetate to obtain the title compound. Further, the residue obtained after the evaporation of the solvent from the wash solution was purified by the silica gel chromatography (ethyl acetate/methanol) to obtain the title compound.