Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[C:5]([Cl:17])=[CH:4][N:3]=1.[CH3:18][C:19]1[CH:23]=[C:22]([NH2:24])[N:21]([CH:25]([CH3:27])[CH3:26])[N:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].N#N.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[Cl:17][C:5]1[C:6]([NH:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])=[CH:7][C:2]([NH:24][C:22]2[N:21]([CH:25]([CH3:27])[CH3:26])[N:20]=[C:19]([CH3:18])[CH:23]=2)=[N:3][CH:4]=1
Reactant: N#Cc1ccccc1Nc1cc(Cl)ncc1Cl
Reactant: Cc1cc(N)n(C(C)C)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: N#N
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2cc(Nc3ccccc3C#N)c(Cl)cn2)n(C(C)C)n1
Yield: 52.3 %

Procedure:
The solution of 2-[(2,5-dichloro-4-pyridinyl)amino]benzonitrile (110 g, 396 mmol), 3-methyl-1-(1-methylethyl)-1H-pyrazol-5-amine (55.1 g, 396 mmol), and cesium carbonate (387 g, 1187 mmol) in 1,4-dioxane (2.5 L) was degassed by N2 stream, and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (19.71 g, 31.7 mmol) followed by palladium acetate (3.55 g, 15.83 mmol) were added. The reaction mixture was heated to reflux for overnight under N2. The reaction mixture was filtered and the liquid was concentrated. Ethyl acetate (1500 mL), followed by 1 M HCl (1000 mL) were added. Layers were separated. Ethyl acetate was washed with 1 M HCl until no product was observed by HPLC (1000 mL total, 1×). HCl phases were combined, and backwashed with ethyl acetate (3×1000 mL), until the product peak was relativity pure in the HCL layer. The HCl layer was then basified with NaOH (50 w/w followed by 1 M) to ph˜4 resulting in a cloudy solution. Ethyl acetate (2000 mL) was added and layers were separated. The ethyl acetate was washed with brine and evaporated. After neutralization—after addition of ethyl acetate—the reaction mixture was filtered to get some product. Also isolation of product during evaporation can be done by filtration of white solid, which comes from the mother liquor. All solids and evaporated products were combined. 2-[(5-Chloro-2-{[3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]amino}-4-pyridinyl)amino]benzonitrile (80 g, 207 mmol, 52.4% yield) was isolated as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.24 (d, J=6.57 Hz, 6H) 2.08 (s, 3H) 4.34 (quin, J=6.57 Hz, 1H) 5.87 (s, 1H) 5.97 (s, 1H) 7.41 (td, J=7.58, 1.01 Hz, 1H) 7.47 (d, J=8.08 Hz, 1H) 7.75 (td, J=7.83, 1.52 Hz, 1H) 7.90 (dd, J=7.83, 1.52 Hz, 1H) 7.94 (s, 1H) 8.42 (d, J=17.43 Hz, 2H); HPLC Rt=2.36 min, MS (ESI): [M+H]+=367.1, 368.1.
Reaction SMILES: CCCCCC.[H-].[Na+].[Br:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([OH:17])=[CH:12][C:11]=1[CH3:18].[CH3:19][O:20][CH2:21]Cl>O1CCCC1.[OH-].[Na+]>[Br:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([O:17][CH2:19][O:20][CH3:21])=[CH:12][C:11]=1[CH3:18]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCOc1cc(C)c(Br)c(C)c1
Temperature: 0 °C
Reaction time: 0.01 h
Yield: 73.6 %

Procedure:
Under nitrogen atmosphere, hexane (50 mL) was added to sodium hydride (50% in oil, 12.6 g, 264 mmol). The mixture was stirred for 30 sec, and stood still, and the supernatant was removed. Tetrahydrofuran (460 mL) was added thereto, and the mixture was cooled to 0° C. A solution of 4-bromo-3,5-dimethylphenol (53.0 g, 264 mmol) in tetrahydrofuran (50 mL) was added slowly dropwise. After completion of the dropwise addition, and the mixture was stirred at 0° C. for 10 min, allowed to warm to room temperature, and was stirred for 20 min. Then, chloromethyl methyl ether (22.3 g, 277 mmol) was added slowly at room temperature, and the mixture was stirred for 24 hr. The reaction mixture was diluted with 1 M aqueous sodium hydroxide solution (80 mL). Tetrahydrofuran was evaporated under reduced pressure, and the residue was extracted with diethyl ether. The extract was washed successively with 2 M aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=0:100-10:90) to give the title compound (47.6 g, yield 74%) as a colorless oil.
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:15](=[O:16])[N:5]2[C:6]([C:12]([OH:14])=[O:13])=[C:7]([CH:10]=[O:11])[CH2:8][S:9][C@H:4]12.N1C=CC=CC=1>CO>[NH2:2][C@@H:3]1[C:15](=[O:16])[N:5]2[C@@H:4]1[S:9][CH2:8][C:7]([CH:10]=[O:11])=[C:6]2[C:12]([OH:14])=[O:13]
Reactant: NC1C(=O)N2C(C(=O)O)=C(C=O)CS[C@H]12
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: N[C@@H]1C(=O)N2C(C(=O)O)=C(C=O)CS[C@H]12

Procedure:
2.64 g of the hydrochloride of 6-amino-1,4,5a,6-tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-aceto[2,1-b]furo[3,4-d][1,3]thiazine (hydroxylactone of the hydrochloride of 7-amino-3-formyl-3-cephem-4-carboxylic acid) are dissolved in 50 ml of methanol. A solution of 0.78 g of pyridine in 10 ml of methanol is added dropwise to this solution whilst stirring and cooling with ice. The precipitated product is filtered off under nitrogen whilst excluding moisture, washed with a little methanol and dried over a drying agent in vacuo at room temperature. (6R-trans)-7-amino-3formyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid is thus obtained in the form of a light brown powder.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1([C:23]([O:25]CC)=[O:24])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.Cl>[Li+].[OH-]>[CH2:1]([O:8][CH2:9][C:10]1([C:23]([OH:25])=[O:24])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(COCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COCc2ccccc2)(C(=O)O)CC1
Yield: 66 %

Procedure:
1-tert-Butyl 4-ethyl 4-(benzyloxymethyl)piperidine-1,4-dicarboxylate from step A (0.500 g, 1.3 mmol) was dissolved in 1 N aq. LiOH (15 mL) and THF (10 mL) and was heated at 50° C. for 24 hours. The reaction mixture was acidified with 1 N HCl and extracted with Et2O. The organic extract was washed with brine, dried over MgSO4, and concentrated under vacuum to afford the title compound (0.3 g, 65%). MS (ES+) [M+H]+=349.
Reaction SMILES: [C:1]([C:3]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:20])([F:19])[F:18])=[C:4](OC)[CH3:5])#[N:2].C(=O)(O)O.[NH2:25][C:26]([NH2:28])=[NH:27].O>CN(C)C(=O)C>[NH2:27][C:26]1[N:28]=[C:1]([NH2:2])[C:3]([CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:18])([F:20])[F:19])=[C:4]([CH3:5])[N:25]=1
Reactant: N=C(N)N
Reactant: COC(C)=C(C#N)CCCc1ccccc1C(F)(F)F
Agent: O=C(O)O
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1nc(N)nc(N)c1CCCc1ccccc1C(F)(F)F
Yield: 40.6 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 7.6 grams (0.027 mole) of 3-cyano-2-methoxy-6-(2-trifluoromethylphenyl)-2-hexene and 12.2 grams (0.068 mole) of guanidine carbonate in 35 mL of N,N-dimethylacetamide was heated at about 150° C. for 40 hours. After this time, the reaction mixture was poured into 300 mL of water. The resultant solid was collected by filtration, and was then slurried in 100 mL of diethyl ether. The solid was again collected by filtration and was subjected to column chromatography on silica gel. Elution was accomplished using 10% methanol in methylene chloride. The product-containing fractions were combined and concentrated under reduced pressure, yielding 3.4 grams of 2,4-diamino-5-[3-(2-trifluoromethylphenyl)propyl]-6-methyl-pyrimidine, mp 151°-158° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][C:18]([C:22]([OH:24])=[O:23])=[CH:17][CH:16]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl.[CH2:26](O)[CH3:27]>>[CH2:1]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][C:18]([C:22]([O:24][CH2:26][CH3:27])=[O:23])=[CH:17][CH:16]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1cc2cc(C(=O)O)ccc2[nH]1
Reactant: CCO
Agent: Cl
Product: CCCCCCCCCCCCc1cc2cc(C(=O)OCC)ccc2[nH]1

Procedure:
A solution of 2-(n-dodecyl)indole-5-carboxylic acid (13.8 g) in ethanol (80 ml) containing a solution of hydrogen chloride gas in ethanol (100 ml of strength 39% w/v) was refluxed for 6 hours. The solid which separated on cooling was collected and was recrystallised from ethanol to give ethyl 2-(n-dodecyl)indole-5-carboxylate (11.2 g), in the form of a buff powder, m.p. 77°-79° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:22][N:5]2[C:6](=[O:21])[CH2:7][CH2:8][N:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=3)[CH2:10][C@@H:4]2[CH2:3]1.Br[C:24]1[CH:29]=[N:28][C:27]([CH:30]2[CH2:32][CH2:31]2)=[CH:26][N:25]=1.CC(C)([O-])C.[K+]>O1CCCC1>[CH:30]1([C:27]2[N:28]=[CH:29][C:24]([O:1][C@@H:2]3[CH2:22][N:5]4[C:6](=[O:21])[CH2:7][CH2:8][N:9]([C:11]5[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][N:12]=5)[CH2:10][C@@H:4]4[CH2:3]3)=[N:25][CH:26]=2)[CH2:32][CH2:31]1
Reactant: O=C1CCN(c2ccc(C(F)(F)F)cn2)C[C@@H]2C[C@H](O)CN12
Reactant: Brc1cnc(C2CC2)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1CCN(c2ccc(C(F)(F)F)cn2)C[C@@H]2C[C@H](Oc3cnc(C4CC4)cn3)CN12
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.1 %

Procedure:
To (8S,9aS)-8-hydroxy-2-[5-(trifluoromethyl)pyridin-2-yl]octahydro-5H-pyrrolo[1,2-a][1,4]diazepin-5-one (74 mg, 0.235 mmol, Part D), 2-bromo-5-cyclopropylpyrazine (79 mg, 0.4 mmol) in tetrahydrofuran (1.2 mL) was added potassium tert-butoxide (0.47 ml, 0.47 mmol, 1 M in tetrahydrofuran). The mixture was stirred at room temperature overnight. The mixture was purified by chromatography on silica gel (ethyl acetate) to give 48 mg (47%) of the titled compound as a solid. 1H NMR (400 MHz, CDCl3) δ ppm 0.88-1.04 (m, 4H), 2.00 (m, 1 H), 2.15 (br d, J=14 Hz, 1 H), 2.66 (m, 1 H), 2.72 (m, 2 H), 3.36 (dd, J=14, 10 Hz, 1 H), 3.48 (m, 1 H), 3.83 (dd, J=12, 8 Hz, 1 H), 3.90 (br d, J=12 Hz, 1 H), 4.03 (m, 1H), 4.34 (br d, J=15 Hz, 1 H), 4.63 (d, J=14 Hz, 1 H), 5.44 (m, 1H), 6.65 (d, J=9 Hz, 1 H), 7.66 (dd, J=9, 2 Hz, 1 H), 7.95 (s, 1 H), 8.06 (s, 1 H), 8.41 (s, 1H); MS (ESI) m/z 434.0 (M+H)+.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21][Cl:22])=[N:19][C:18]([C:23](O)=[O:24])=[N:17]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[CH2:39]([CH2:41][NH2:42])[OH:40]>O1CCCC1>[C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21][Cl:22])=[N:19][C:18]([C:23]([NH:42][CH2:41][CH2:39][OH:40])=[O:24])=[N:17]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1nc(CCl)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1
Reactant: NCCO
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCCO)c1nc(CCl)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1
Reaction time: 0.08 h

Procedure:
To a stirred solution of 3.76 parts of 1-(2-benzoyl-4-chlorophenyl)-5-chloromethyl-1H-1,2,4-triazole-3-carboxylic acid and 1.4 volume part of triethylamine in 60 volume parts of dry tetrahydrofuran, 1.0 volume part of ethyl chlorocarbonate is added dropwise under cooling with ice-salt. After 5 minutes, a solution of 1.2 volume part of ethanolamine in 10 volume parts of dry tetrahydrofuran is added dropwise to the mixture. After evaporation of the solvent below 40°C under reduced pressure, the residue is diluted with water. This procedure yields 1-(2-benzoyl-4-chlorophenyl)-5-chloromethyl-N-(2-hydroxyethyl)-1H-1,2,4-triazole-3-carboxamide as crystals. Recrystallization from ethanol gives colorless prisms melting at 170°-171°C.
Reaction SMILES: [C:1]1([CH2:7][C@H:8]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:9](=[O:15])[CH2:10][CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:25]([O:32][C:33](=[O:39])[C@@H:34]1[CH2:38][CH2:37][CH2:36][NH:35]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:25]([O:32][C:33](=[O:39])[C@@H:34]1[CH2:38][CH2:37][CH2:36][N:35]1[C:12](=[O:14])[CH2:11][CH2:10][C:9](=[O:15])[C@@H:8]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
A solution of the free acid compound 9 (200 mg, 0.6224 mmol, 1.0 eq.) and L-proline benzyl ester hydrochloride (150 mg, 0.6224 mmol, 1.0 eq.) in dry CH2Cl2 (15 mL) was cooled at 0° C. 1-Hydroxybenzotriazole hydrate (HOBt) (84 mg, 0.6224 mmol, 1.0 eq.), N-ethyl-N′-(dimethylaminopropyl)-carbodiimide hydrochloride (EDC.HCl) (120 mg, 0.6224 mmol, 1.0 eq.) and iPr2NEt (0.22 mL, 1.245 mmol, 2.0 eq.) were added and the resulting mixture stirred at 0° C. for 2 h. The cooling bath was removed and the reaction mixture then stirred for a further 72 h at room temperature. The reaction mixture was diluted with H2O (30 mL) and the extracted with EtOAc (3×30 mL). The combined organic extract were washed sequentially with saturated aqueous NaHCO3 (30 mL), brine (30 mL), and dried over anhydrous MgSO4. Evaporation of the solvent gave a crude residue, which was subjected to column chromatography on silica gel elution with 33% EtOAc-hexane to afforded the (5S)-6-phenyl-5-[(tert-butyloxycarbonyl)-amino]-4-oxo-hexanoyl-L-proline benzyl ester 10 as a yellow viscous oil (0.255 g, 81%); Rf 0.30 (33% EtOAc-hexane); IR (liquid film) ν 1750 (CO), 3150 (CONH) cm−1; 1H NMR (300 MHz, CDCl3) δH 1.39 (9H, s, (CH3)3), 2.00-2.18 (4H, m, —CH2CH2—), 2.48-2.80 (3H, m, —CH2CO and —CHαPh), 2.94 (2H, m, —CH2CO), 3.18 (1H, m, —CHβPh), 3.60 (2H, m, —CH2N—), 4.53 (2H, m, 2×—CH—), 5.09 (1H, m, —NH—), 5.15 (2H, dd, J=2.0 and 10.5 Hz, —OCH2Ph) and 7.13-7.38 (10H, m, Ar—H); 13C NMR (75 MHz, CDCl3) δC 21.0, 22.6, 24.7, 28.3, 29.2, 31.4, 31.7, 34.7, 46.5, 59.5, 60.3, 66.7, 126.8 (2C), 127.0, 127.6, 128.1, 128.4 (2C), 128.5, 128.7, 129.3, 135.7, 136.6, 155.2, 170.3, 171.1, 172.1 and 208.0; HRMS m/z calcd for C29H36N2O6 (M+) 508.25912, found 508.25734.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][N:10]3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19]1[N:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22].C(N(C(C)C)CC)(C)C.CCCP(=O)=O>O1CCCC1.C(OCC)(=O)C>[CH3:17][O:18][C:19]1[N:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:15][C:13]1[CH:12]=[CH:11][N:10]2[CH:16]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[C:9]2[N:14]=1)=[O:22]
Reactant: Nc1ccn2cc(-c3ccccc3)nc2n1
Reactant: COc1ncccc1C(=O)O
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ncccc1C(=O)Nc1ccn2cc(-c3ccccc3)nc2n1
Temperature: 60 °C
Reaction time: 18 h
Yield: 11 %

Procedure:
A mixture of 2-phenylimidazo[1,2-a]pyrimidin-7-amine (200 mg, 951 μmol, Eq: 1.00), 2-methoxynicotinic acid (146 mg, 951 μmol, Eq: 1.00), diisopropylethylamine (369 mg, 498 μl, 2.85 mmol, Eq: 3) and propylphosphonic anhydride in ethyl acetate 50% (1.21 g, 1.12 ml, 1.9 mmol, Eq: 2) in tetrahydrofuran (10 ml) is stirred for 18 hours at 60° C. The mixture is diluted with ethyl acetate and washed 2 times with water and once with brine, the organic layer was separated, dried over magnesium sulfate, filtrated and evaporated. The crude material was applied on silicagel and purified by flash chromatography over a 20 g silicagel column using ethyl acetate/methanol 0-10% as eluent affording 2-methoxy-N-(2-phenylimidazo[1,2-a]pyrimidin-7-yl)nicotinamide (36 mg, 11%) as a light yellow solid. MS: m/e=346.1 (M+H+), mp: 225-226° C.
Reaction SMILES: C([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[CH:20][CH:21]=[N:22]3)=[C:17]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:16]=2)=[CH:11][C:10]=1[Cl:31])C1C=CC=CC=1.C1CC=CCC=1>CCO.[OH-].[OH-].[Pd+2]>[Cl:31][C:10]1[CH:11]=[C:12]([C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[CH:20][CH:21]=[N:22]3)=[C:17]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:16]=2)[CH:13]=[CH:14][C:9]=1[NH2:8]
Reactant: Clc1cc(-c2cc3ncccc3c(N3CCOCC3)n2)ccc1NCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCC=CC1
Solvent: CCO
Product: Nc1ccc(-c2cc3ncccc3c(N3CCOCC3)n2)cc1Cl
Temperature: 80 °C
Yield: 25.7 %

Procedure:
To the mixture of 4 and benzyl-[2-chloro-4-(5-morpholin-4-yl-[1,6]naphthyridin-7-yl)-phenyl]-amine (60 mg, 1:1.4, 0.128 mmol, 1 eq) in dry EtOH (3 mL) was added Pd(OH)2 (30 mg, 50% w/w) and 1,4-cyclohexanediene (240 μL, 2.56 mmol, 20 eq) under Ar(g). The mixture was heated at 80° C. overnight. Additional quantities of Pd(OH)2 (30 mg, 50% w/w) and 1,4-cyclohexanediene (240 μL, 2.56 mmol, 20 eq) were then added, and the mixture was again heated at 80° C. overnight. Once cooled down, the reaction mixture was filtered through a short celite pad, and eluted with MeOH (10 mL). The solvent was then removed in vacuo and the residue was further purified by silica gel column chromatography using hexane/EtOAc (1:9-0:1) as eluant to furnish E as a pale yellow solid (11.2 mg, 26%).
Reaction SMILES: [SH:1][C:2]1[S:3][CH2:4][CH2:5][N:6]=1.[CH3:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[C:18](=[O:40])[NH:19][C:20](=[O:39])[C:21]=2[C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH2:31][CH2:32][CH2:33]OS(C)(=O)=O)[CH:23]=2)=[CH:9]1>>[CH3:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[C:18](=[O:40])[NH:19][C:20](=[O:39])[C:21]=2[C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH2:31][CH2:32][CH2:33][S:1][C:2]3[S:3][CH2:4][CH2:5][N:6]=3)[CH:23]=2)=[CH:9]1
Reactant: SC1=NCCS1
Reactant: Cn1cc(C2=C(c3cn(CCCOS(C)(=O)=O)c4ccccc34)C(=O)NC2=O)c2ccccc21
Product: Cn1cc(C2=C(c3cn(CCCSC4=NCCS4)c4ccccc34)C(=O)NC2=O)c2ccccc21
Yield: 17.2 %

Procedure:
In an analogous manner to that described in Example 59, from 27 mg of 2-mercaptothiazoline and 100 mg of the product of Example 58, there were obtained 18 mg of 3-(1-methyl-3-indolyl)-4-[1-[3-(2-thiazolin-2-ylthio)propyl]-3-indolyl]-1H-pyrrole-2,5-dione m.p. 170°-173° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]([C:25]3[C:30]([Cl:31])=[CH:29][C:28]([C:32]([F:35])([F:34])[F:33])=[CH:27][N:26]=3)[S:12]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=3)(=[O:14])=[O:13])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[OH-].[Na+].Cl>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]([C:25]3[C:30]([Cl:31])=[CH:29][C:28]([C:32]([F:33])([F:35])[F:34])=[CH:27][N:26]=3)[S:12]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)(=[O:14])=[O:13])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3occc3c2)c2ncc(C(F)(F)F)cc2Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(S(=O)(=O)N(Cc2ccc3occc3c2)c2ncc(C(F)(F)F)cc2Cl)cc1
Temperature: 60 °C
Yield: 72.8 %

Procedure:
To a solution of methyl 4-(N-(benzofuran-5-ylmethyl)-N-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)sulfamoyl)benzoate (step-2 of Example 1, 2.3 g, 4.3 mmol) in THF (15 mL) was added 2 M aqueous NaOH (9.0 mL) at room temperature, and the mixture was heated at 60° C. for 2 hrs. The mixture was cooled with ice bath, and acidified by the addition of 2 M aqueous HCl (10 mL). The mixture was extracted with DCM (30 mL×2), dried over Na2SO4, filtered and the filtrate was concentrated to give a white solid. The residual solid was triturated with IPE (50 mL), the precipitates were collected by filtration, washed with IPE, and dried in vacuo at 50° C. to give 1.6 g (74% yield) of the titled compound as a white powder.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:7]2[N:8]=[C:9]([C:14]([O:16]C)=O)[C:10]([CH3:13])=[C:11]([CH3:12])[C:6]2=[N:5][N:4]=1.[CH2:18]([NH2:20])[CH3:19]>CO>[CH2:18]([NH:20][C:14]([C:9]1[C:10]([CH3:13])=[C:11]([CH3:12])[C:6]2[N:7]([C:3]([NH2:2])=[N:4][N:5]=2)[N:8]=1)=[O:16])[CH3:19]
Reactant: CCN
Reactant: COC(=O)c1nn2c(N)nnc2c(C)c1C
Agent: Cl
Solvent: CO
Product: CCNC(=O)c1nn2c(N)nnc2c(C)c1C
Temperature: 0 °C
Reaction time: 6 h

Procedure:
Methyl 3-amino-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine-6-carboxylate hydrochloride (W1.145; 200 mg) was dissolved in methanol, cooled to 0° C., slowly admixed dropwise with ethylamine (1.81 ml; 2 M in THF) and stirred at 0° C. for 6 h. Then a further equivalent of ethylamine was added and the mixture was left to stand at RT over the weekend. Subsequently, the mixture was concentrated and purified using silica gel (24 g cartridge, dichloromethane/methanol gradient of 0-20% in 60 min). 149 mg of the title compound were obtained.
Reaction SMILES: [CH2:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH:2]1[O:11]/[N:12]=[C:13](/[C:19](=[O:21])[CH3:20])\[C:14]([O:16][CH2:17][CH3:18])=[O:15].[Br:22]Br>C(Cl)(Cl)(Cl)Cl>[Br:22][CH2:20][C:19](=[O:21])/[C:13](=[N:12]/[O:11][CH:2]1[CH2:3][CH2:4][CH:5]2[CH:10]([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:1]1)/[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: BrBr
Reactant: CCOC(=O)/C(=N\OC1CCC2CCCCC2C1)C(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C(=N\OC1CCC2CCCCC2C1)C(=O)CBr
Temperature: 25 °C

Procedure:
Ethyl (Z)-2-(decahydronaphth-2-yloxyimino)-3-oxobutyrate (1.7 g) in carbon tetrachloride (10 ml) was treated with bromine (0.29 ml). The mixture was stirred at room temperature for lh, then the solvent was evaporated under reduced pressure. The residue was dissolved in ether, washed with water, dried (MgSO4) and evaporated under reduced pressure. The title compound (0.7 g) was isolated by flash chromatography on silica eluting with chloroform:carbon tetrachloride. δH (CDCl3) 1.33 (3H, t), 1.10-2.00 (16H, m), 6.35 (2H, s), 4.40 (2H, q), and 4.40 (1H, m).
Reaction SMILES: C([Li])CCC.[C:6]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:7][C:8]([OH:10])=O.N1C=CC=CC=1C1C=CC=CN=1.[F:27][C:28]1[C:36]([O:37][CH3:38])=[C:35]([F:39])[CH:34]=[CH:33][C:29]=1C(Cl)=O>O1CCCC1.C(OCC)(=O)C>[OH:10]/[C:8](/[C:34]1[CH:33]=[CH:29][C:28]([F:27])=[C:36]([O:37][CH3:38])[C:35]=1[F:39])=[CH:7]\[C:6]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: COc1c(F)ccc(C(=O)Cl)c1F
Reactant: CCOC(=O)CC(=O)O
Agent: [Li]CCCC
Agent: c1ccc(-c2ccccn2)nc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\O)c1ccc(F)c(OC)c1F
Temperature: 25 °C

Procedure:
Compound I is prepared using the general method of Wierenga and Skulnick (Wierenga, W.; Skulnick, H. I. J. Org. Chem. 1979, 44, 310-311). n-Butyllithium (1.6 M in hexanes) is added to a cooled (−78° C.) solution of tetrahydrofuran (50 mL) containing ethyl hydrogen malonate (2.6 mL, 22 mmol) and 2,2′-bipyridyl (˜1 mg as indicator). The temperature of the reaction mixture is allowed to rise to ca. −5° C. during the addition of n-butyllithium. Sufficient n-butyllithium (30 mL, 48 mmol) is added until a pink color persists at −5° C. for 5-10 min. A solution of 2,4-difluoro-3-methoxybenzoyl chloride (H) (11.1 mmol, vide supra) in tetrahydrofuran (10 mL) is added in one portion to the reaction mixture that has been recooled to −78° C. The resulting mixture is allowed to warm to room temperature, diluted with ethyl acetate (100 mL), and quenched with a 1 M aqueous solution of hydrochloric acid. The organic layer is washed with a 5% aqueous solution of sodium bicarbonate (2×80 mL), followed by brine (2×80 mL), dried over sodium sulfate, and evaporated under reduced pressure to give the crude product. This material is purified by flash column chromatography (eluting with 20% v/v ethyl acetate in hexanes) to give pure I as a white solid. NMR (300 MHz, CDCl3): (keto, predominant tautomer, ˜80%) δ1.20 (t, JH-H=7.0 Hz, 3H, CO2CH2CH3), 3.88 (d, JH-F=4.0 Hz, 2H, CH2CO2CH2CH3), 3.98 (apparent t, JH-F=1.0 Hz, 3H, OCH3), 4.15 (q, JH-H=7.0 Hz, 2H, CO2CH2CH3), 6.92 (ddd, JH-F=11.0 Hz, JH-H=9.0 Hz, JH-F=2.0 Hz, 1H, aromatic H-5), 7.57 (ddd, JH-H=9.0 Hz, JH-F=7.5 Hz, JH-F=6.0 Hz, 1H, aromatic H-6). LCMS m/z calcd for C12H12F2O4 258 ([M+]); found 259 ([M+H]+).