Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25](=[S:27])[NH2:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:29][C:30](=O)[CH2:31][CH:32]([CH3:34])[CH3:33]>>[CH3:33][CH:32]([CH3:34])[CH2:31][C:30]1[N:26]=[C:25]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[S:27][CH:29]=1
Reactant: CC(C)CC(=O)CBr
Reactant: NC(=S)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: CC(C)Cc1csc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
150 mg (about 0.315 mmol) of the compound from Example 53A and 76 mg (0.426 mmol) of 1-bromo-4-methylpentan-2-one (J. Org. Chem., 19, 2005, 4141-4153) were reacted according to the General Method 3. Yield: 68 mg (40% of theory).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:33])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:34](=[O:37])[CH2:35][CH3:36])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:31][CH2:32]1
Reactant: CCC(=O)Cl
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-methylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f29) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.[CH3:13][C:14]1[CH:15]=[C:16]([CH:25]=[C:26]([CH3:28])[CH:27]=1)[C:17]([N:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[NH2:20])=[O:18]>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH3:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:20][N:19]([C:17](=[O:18])[C:16]1[CH:15]=[C:14]([CH3:13])[CH:27]=[C:26]([CH3:28])[CH:25]=1)[C:21]([CH3:24])([CH3:23])[CH3:22])=[O:8]
Reactant: COc1cccc(C(=O)O)c1C
Reactant: Cc1cc(C)cc(C(=O)N(N)C(C)(C)C)c1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COc1cccc(C(=O)NN(C(=O)c2cc(C)cc(C)c2)C(C)(C)C)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
A solution of 3-methoxy-2-methylbenzoic acid (1.5 g, 0.01 mole) in thionyl chloride (10 mL.) was refluxed for 45 minutes and then stripped under reduced pressure. The residue was dissolved in methylene chloride (50 mL) and added dropwise with cooling at 0° C. to a solution of N-(3,5-dimethylbenzoyl)-N-tert-butylhydrazine (4.4 g. 0.02 mole) in methylene chloride (50 mL). Following the addition, the solution was stirred overnight at room temperature and filtered. The filter-cake was washed extensively with water and ether, and then dried in vacuo to give 2.1 g of N-(3-methoxy-2-methylbenzoyl)-N'-(3,5-dimethylbenzoyl)-N'-tert-butylhydrazine, melting at 204°-204.5° C. 1H-NMR δppm 1.50 (s, 9H, tert-Bu), 1.63 (s, 3H, Ar--CH3), 2.25 (s, 6H, di--CH3) 3.75 (s, 3H, OCH3), 6.26 (d, 1H, Ar), 6.93-7.20 (m, 5H, Ar).
Reaction SMILES: [C:1]1([N:7]([C:14]2[CH:26]=[CH:25][C:24]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([CH2:29][CH3:30])([CH2:27][CH3:28])[C:16]=3[C:15]=2Br)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C(O)C>[S:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1[C:1]1[CH:6]=[CH:5][C:4]([C:20]2[CH:19]=[C:18]3[C:23]([C:24]4[CH:25]=[CH:26][C:14]([N:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[C:8]5[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=5)=[CH:15][C:16]=4[C:17]3([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:22][CH:21]=2)=[CH:3][CH:2]=1
Reactant: CCC1(CC)c2ccccc2-c2ccc(N(c3ccccc3)c3ccccc3)c(Br)c21
Reactant: OB(O)c1nc2ccccc2s1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCC1(CC)c2cc(-c3ccc(-c4nc5ccccc5s4)cc3)ccc2-c2ccc(N(c3ccccc3)c3ccccc3)cc21
Temperature: 87.5 °C

Procedure:
A mixture of diphenylamino-9,9-diethyl-bromofluorene (7.02g, 0.015 mol), benzothiazole boronic acid (7.5 g 0.029 mol.), ethanol (50 ml), in NMP (50 ml) was degassed by bubbling nitrogen through the solution for 20 min. Sodium carbonate (13.0 g, 0.12 mol.) and 5% palladium on charcoal (1.5 g ) were then added, the mixture heated at 85-90° C. for 42 hrs. The resulting solids (18.0 g) that separated upon cooling were collected, washed with ethanol and dried. The solids were then transferred to a chromatograph column containing 300 g of alumina. Elution with 1:1 toluene-heptane gave the product, 4.98 g. (55.5% yield), m.p. 243.6-246.1° C. Recrystallization from toluene did not raise the melting point. Mass Spec: m/z 598, (M+). Analysis calculated for C42H34N2S: C, 84.25; H, 5.72; N, 4.68; S, 5.34. Found: C, 83.87; H, 6.02; N, 5.04; S, 5.29.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:17]4[NH:18][C:19]5[CH2:24][CH2:23][NH:22][CH2:21][C:20]=5[N:25]=4)=[N:13][NH:14]3)=[CH:10][CH:9]=2)[C:5]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:4][C:3]=1[OH:31].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CCN(C(C)C)C(C)C.C(=O)([O-])O.[Na+]>CN(C=O)C>[CH2:17]([NH:18][CH2:19][CH3:20])[CH3:12].[CH2:32]([N:22]1[CH2:23][CH2:24][C:19]2[NH:18][C:17]([C:12]3[C:11]4[C:15](=[CH:16][C:8]([C:6]5[C:5]([CH2:26][C:27]([F:28])([F:29])[F:30])=[CH:4][C:3]([OH:31])=[C:2]([F:1])[CH:7]=5)=[CH:9][CH:10]=4)[NH:14][N:13]=3)=[N:25][C:20]=2[CH2:21]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Oc1cc(CC(F)(F)F)c(-c2ccc3c(-c4nc5c([nH]4)CCNC5)n[nH]c3c2)cc1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNCC
Product: Oc1cc(CC(F)(F)F)c(-c2ccc3c(-c4nc5c([nH]4)CCN(Cc4ccccc4)C5)n[nH]c3c2)cc1F
Temperature: 80 °C
Yield: 21.2 %

Procedure:
To a solution of 2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-5-(2,2,2-trifluoro-ethyl)-phenol (Preparation 39, 100 mg, 168 μmol) in DMF (1 mL), was added benzyl bromide (28.8 mg, 20 μL, 168 μmol), and DIPEA (120 μL, 672 μmol). The reaction mixture was heated at 80° C. for 3 hours. The reaction mixture was then cooled to room temperature and saturated aqueous sodium hydrogen carbonate solution (5 mL) was added. The resulting solid was collected by filtration and washed with further saturated aqueous sodium hydrogen carbonate solution. The crude material was purified by HPLC Method A to afford 10.6 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2C(=O)C=[N+]=[N-])[N:3]=1.CO.[C:19]([O:22][CH2:23]C)(=[O:21])[CH3:20]>C(N(CC)CC)C.C([O-])(=O)C1C=CC=CC=1.[Ag+]>[CH3:23][O:22][C:19](=[O:21])[CH2:20][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([Cl:1])=[N:3]2
Reactant: CCOC(C)=O
Reactant: [N-]=[N+]=CC(=O)c1cccc2nc(Cl)ccc12
Agent: [Ag+]
Agent: O=C([O-])c1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)Cc1cccc2nc(Cl)ccc12
Yield: 55 %

Procedure:
A mixture of 2.17 g (9.37 mmol) 1-(2-chloro-quinolin-5-yl)-2-diazo-ethanone and 20 mL methanol was brought to reflux. A solution of 0.20 g (0.87 mmol) silver benzoate in 1 mL triethylamine was added to the reaction mixture. After 10 min at reflux, TLC analysis (ethyl acetate, silica, Rf prod 0.8) showed starting material consumed. The solvent was removed under reduced pressure and the resulting black residue was purified on 100 g 230-400 mesh silica eluting with 1:1 hexanes/ethyl acetate to give 1.20 g (5.09 mmol, 55%) of (2-chloro-quinolin-5-yl)-acetic acid methyl ester as a white amorphous solid. MS (APCI) m/z 236 (M, 100% abundance), 238 (M+2, 32% abundance). 1H NMR (400 MHz) CDCl3 8.31 (d, J=8.9 Hz, 1H), 7.98 (d, J=8.5 Hz, 1H), 7.74 (m, 1H), 7.49 (d, J=7.2 Hz, 1H), 7.44 (d, J=8.9 Hz, 1H), 4.05 (s, 2H), 3.68 (s, 3H).
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[NH:11][C:12]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:14]=1)C.[OH-].[Na+]>C(O)C.O>[C:21]1([C:12]2[N:11]=[C:10]([S:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:27])=[O:3])[NH:14][C:13]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)CCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Yield: 55 %

Procedure:
Part B. To a solution of 5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentanoic acid ethyl ester (7.6 g, 0.02 mol) in ethanol (200 mL), was added dropwise a solution of sodium hydroxide (7.6 g) in water (200 mL), and the reaction mixture was stirred at reflux under nitrogen for 3 hours. The reaction mixture was concentrated to half the original volume and then extracted with ether. The ether extracts were discarded. The reaction mixture was acidified to pH 1 with 1N hydrochloric acid and extracted with ether, and the combined organic extracts were dried over magnesium sulfate and concentrated under vacuum. The resulting solid was recrystallized from acetonitrile and triturated with hexane to give 5-(4.5-diphenyl-1H-imidazol-2-ylthio) pentanoic acid (3.88 g, 0.011 mol) as a white solid, mp 190°-195°. 1H NMR (DMSO-d6) δ 12.6(s,1H) , 7.6-7.1(m,10H), 3.3-3.1 (m,2H), 2.3-2.1 (m,3H), 1.8-1.6 (m,4H).
Reaction SMILES: [OH:1][CH2:2][N:3]1[C:7](=[O:8])[C:6]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=3)[N:11]([CH3:21])[CH:10]=2)=[C:5]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH3:31])[CH:23]=2)[C:4]1=[O:32].Cl[C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35].N12CCCC1=NCCC2>C1COCC1.CN(C)C1C=CN=CC=1>[CH3:31][N:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]([C:5]2[C:4](=[O:32])[N:3]([CH2:2][O:1][C:34](=[O:35])[O:36][CH2:37][CH:38]=[CH2:39])[C:7](=[O:8])[C:6]=2[C:9]2[C:17]3[C:12](=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=3)[N:11]([CH3:21])[CH:10]=2)=[CH:23]1
Reactant: Cn1cc(C2=C(c3cn(C)c4cc([N+](=O)[O-])ccc34)C(=O)N(CO)C2=O)c2ccccc21
Reactant: C=CCOC(=O)Cl
Agent: C1CN=C2CCCN2C1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: C=CCOC(=O)OCN1C(=O)C(c2cn(C)c3ccccc23)=C(c2cn(C)c3cc([N+](=O)[O-])ccc23)C1=O
Temperature: 20 °C
Reaction time: 14 h

Procedure:
A solution of 200 mg (0.47 mmole) of 1-hydroxymethyl-3-(1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-pyrrole-2,5-dione, prepared as in the example 1a, was dissolved in 90 ml of THF and treated with 300 mg (2.5 mmol) of 4-dimethylaminopyridine (DMAP). To this solution at 5° C. was added 90 mg (0.75 mmole) of allyl chloroformate. While still cool, 300 mg (2.4 mmol) of 1,5-diazabicyclo(4.3.0)non-5-ene (DBN) (Aldrich) was added dropwise. This was stirred for 14 hours at 20° C. The solvent was evaporated and the mixture was purified by chromatography using silica gel and eluting with a mixture of EtOAc/Hexane to afford carbonic acid allyl ester 3-(1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-pyrrol-1-ylmethyl ester as a red solid (m.p. 191-194° C.).
Reaction SMILES: [C:1](O)(=O)[CH3:2].[C:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]3O[C:23]([C:25]([NH2:27])=N)=[CH:22][CH:21]=3)=[CH:16]C=2)=[CH:10][CH:9]=1)(=[NH:7])N.C[N:29](C=O)C>>[C:5]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][C:23]([C:25]#[N:27])=[CH:2][CH:1]=3)=[CH:16][N:29]=2)=[CH:12][CH:13]=1)#[N:7]
Reactant: CC(=O)O
Reactant: N=C(N)c1ccc(-c2ccc(-c3ccc(C(=N)N)o3)cn2)cc1
Reactant: CN(C)C=O
Product: N#Cc1ccc(-c2cnc(-c3ccc(C#N)cc3)nc2)cc1

Procedure:
2-Chloro-5-bromopyrimidine and p-cyanophenylboronic acid were reacted under the above-mentioned Suzuki coupling conditions to give the target dinitrile. Yield 91%, mp 305-306.5° C. (DMF). 1H NMR (DMSO-d6): δ 7.98-8.07 (m, 6H), 8.58 (s, 2H), 9.34 (s, 2H). 13C NMR (DMSO-d6): δ 161.1, 155.5, 140.4, 137.8, 132.6, 132.3, 129.9, 128.0, 127.4, 118.06, 118.00, 113.0, 111.3. MS (ESI) m/e (rel. int.): 282 (M+, 100), 141 (10), 127 (80).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)([O:3][CH3:4])=[O:2].[CH:12]1[CH:17]=CC=CC=1.C1(C)C=CC(S(O)(=O)=[O:25])=CC=1>C(O)CO>[CH2:17]1[O:25][C:8]2([CH2:9][CH2:10][CH:5]([C:1]([O:3][CH3:4])=[O:2])[CH2:6][CH2:7]2)[O:11][CH2:12]1
Reactant: COC(=O)C1CCC(=O)CC1
Reactant: c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: OCCO
Product: COC(=O)C1CCC2(CC1)OCCO2

Procedure:
A mixture of 189.7 g. of 4-carbomethoxy-1-cyclohexanone [3] (obtained as in Example 2B) in 2000 ml. of benzene, 67.5 ml. of ethylene glycol and 2.7 g. of p-toluenesulfonic acid is heated at reflux under a Dean-Stark trap for about 5 hours. After cooling, the solution is washed with saturated aqueous sodium bicarbonate and brine. The oily residue remaining when the organic solvent is evaporated to dryness and is distilled under vacuum to give 231.8 g. of 4-carbomethoxy-1-cyclohexanone ethylene ketal[4] having a boiling point of 95° to 100° C. at 0.30 mm. of Hg.
Reaction SMILES: [NH2:1][C:2]1([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH3:13][C:14]1[CH:23]=[C:22]([CH2:24][N:25]2[C:33]3[C:28](=[CH:29][C:30]([C:34](Cl)=[O:35])=[CH:31][CH:32]=3)[CH:27]=[CH:26]2)[C:21]2[CH2:20][CH:19]=[CH:18][CH2:17][C:16]=2[N:15]=1>C(Cl)Cl.O>[CH3:13][C:14]1[CH:23]=[C:22]([CH2:24][N:25]2[C:33]3[C:28](=[CH:29][C:30]([C:34]([NH:1][C:2]4([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:3][CH2:4][O:5][CH2:6][CH2:7]4)=[O:35])=[CH:31][CH:32]=3)[CH:27]=[CH:26]2)[C:21]2[CH2:20][CH:19]=[CH:18][CH2:17][C:16]=2[N:15]=1
Reactant: Cc1cc(Cn2ccc3cc(C(=O)Cl)ccc32)c2c(n1)CC=CC2
Reactant: COC(=O)CC1(N)CCOCC1
Solvent: ClCCl
Solvent: O
Product: COC(=O)CC1(NC(=O)c2ccc3c(ccn3Cc3cc(C)nc4c3CC=CC4)c2)CCOCC1
Yield: 17.2 %

Procedure:
The methyl (4-aminotetrahydro-2H-pyran-4-yl)acetate (0.13 g, 0.75 mmol) from example (355) was combined with the acid chloride (0.20 g, 0.49 mmol) from step (402b) in methylene chloride (15 ml) and water saturated sodium bicarbonate (15 ml). The reaction was stirred for 3.5 hs, partitioned between methylene chloride and water. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give a solid. This was purified by flash chromatography on silica gel eluting hexane: ethyl acetate (25:75, v:v) to give the methyl {4-[({1-[(2-methyl-5,8-dihydro-4-quinolinyl)methyl]-1H-indol-5-yl}carbonyl)amino]tetrahydro-2H-pyran-4-yl}acetate (0.04 g, 17%) as a solid, MS (M+H)+=472.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[F:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[C:42]=1B(O)O>>[NH2:32][C:4]1[S:3][C:2]([C:42]2[C:43]([CH3:47])=[CH:44][CH:45]=[CH:46][C:41]=2[F:40])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: Cc1cccc(F)c1B(O)O
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cc1cccc(F)c1-c1nc(C(=O)Nc2cnn(C)c2[C@@H]2CC[C@@H](N)[C@H](F)CO2)c(N)s1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6S)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 95), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-fluoro-6-methylphenyl)boronic acid gave 330. 1H NMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H), 7.72 (s, 1H), 7.43-7.32 (m, 3H), 7.21-7.11 (m, 2H), 4.74 (dd, J=11.0, 3.6 Hz, 1H), 4.40-4.17 (m, 2H), 4.16-4.03 (m, 1H), 4.03-3.85 (m, 1H), 3.76 (s, 3H), 3.20-3.09 (m, 1H), 2.46 (s, 3H), 2.06-1.97 (m, 1H), 1.89-1.77 (m, 1H), 1.70-1.58 (m, 3H). LCMS (ES+) m/z 463 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9][N:8]=2)[CH2:3][CH2:2]1.[CH2:16]([Br:24])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CN(C)C=O>[BrH:24].[CH2:16]([N:1]1[CH2:2][CH2:3][CH:4]([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9][N:8]=2)[CH2:5][CH2:6]1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc2c(C3CCNCC3)nsc2c1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Br
Product: c1ccc(CCN2CCC(c3nsc4ccccc34)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A stirred mixture of 5.0 g of 3-(4-piperidinyl)-1,2-benzisothiazole, 4.60 g of phenethyl bromide, 7.95 g of potassium carbonate, 0.25 g of potassium iodide and 90 ml of dimethylformamide was heated at 60° for 20 hrs and stirred for 21/2 days at ambient temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic extracts were dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to yield an oil. The oil was purified by elution column chromatography [silica gel (20:1); using 1% methanol in dichloromethane]. The eluate was evaporated and the residue was dissolved in ether and a saturated hydrogen bromide/ether solution was added dropwise to precipitate the salt. The salt was recrystallized from ether-ethanol 3.0 g (32%) of product, mp 233°-235°.
Reaction SMILES: ClCS([O:6][C:7]1[C:8]([C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[O:24])=[N:9][C:10]([C:14]([NH:17][S:18]([CH2:21]Cl)(=[O:20])=[O:19])([CH3:16])[CH3:15])=[N:11][C:12]=1[OH:13])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O>[F:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][NH:25][C:23]([C:8]2[N:9]=[C:10]3[N:11]([C:12](=[O:13])[C:7]=2[OH:6])[CH2:21][S:18](=[O:19])(=[O:20])[NH:17][C:14]3([CH3:16])[CH3:15])=[O:24])=[CH:32][CH:31]=1
Reactant: CC(C)(NS(=O)(=O)CCl)c1nc(O)c(OS(=O)(=O)CCl)c(C(=O)NCc2ccc(F)cc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC1(C)NS(=O)(=O)Cn2c1nc(C(=O)NCc1ccc(F)cc1)c(O)c2=O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Crude chloride of Step 1 was dissolved in 1,4-dioxane and Cs2CO3 (2 eq.) was added. The reaction mixture was stirred at 100° C. overnight, then cooled down to room temperature, taken up in EtOAc washed with brine, dried over Na2SO4. The solvent was removed under reduced pressure and the resulting brown oil was purified by RP HPLC (C18, 5 μM, H2O/MeCN with 1% of TFA as eluant). Lyophilization of appropriate fractions gave title compound as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[NH:6]([C:8]1[C:9](=[O:21])[N:10]([CH3:20])[C:11]2[C:16]([N:17]=1)=[CH:15][C:14]([O:18][CH3:19])=[CH:13][CH:12]=2)[NH2:7].C(N(CC)CC)C>O1CCOCC1>[CH3:20][N:10]1[C:11]2[C:16](=[CH:15][C:14]([O:18][CH3:19])=[CH:13][CH:12]=2)[N:17]=[C:8]([NH:6][NH:7][C:1](=[O:4])[CH2:2][CH3:3])[C:9]1=[O:21]
Reactant: COc1ccc2c(c1)nc(NN)c(=O)n2C
Reactant: CCC(=O)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCC(=O)NNc1nc2cc(OC)ccc2n(C)c1=O

Procedure:
Propionyl chloride (2.63 g., 28.4 mmol) is added dropwise to a solution of 3-hydrazino-1-methyl-6-methoxy-1H-quinoxalin-2-one (4.5 g., 23.7 mmol) and triethylamine (2.87 g., 28.4 mmol) in 250 ml. of dioxane and stirred at room temperature for four days. The dioxane is then removed under vacuum and the residue washed with water, filtered, and dried at 80° C. under high vacuum. The material is then recrystallized from ethanol, filtered and dried at 80° under high vacuum overnight to yield purified product.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([O:23]CC)=[O:22])[CH:16]=3)=[CH:11][CH:10]=2)[S:3]1.O1CCCC1.CO.[OH-].[Na+]>O>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([OH:23])=[O:22])[CH:16]=3)=[CH:13][CH:14]=2)[S:3]1
Reactant: CCOC(=O)c1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C1NC(=O)C(=Cc2ccc(-c3cccc(C(=O)O)c3)cc2)S1
Yield: 94.7 %

Procedure:
12.6 g (37 mmol) of ethyl 4′-(2,4-dioxo-thiazolidin-5-ylidenemethyl)biphenyl-3-carboxylate, 150 ml of tetrahydrofuran, 15 ml of methanol, a few drops of water and 7.4 g (186 mmol) of sodium hydroxide pellets are introduced into a round-bottomed flask. The mixed is refluxed for 18 hours. The reaction medium is placed in water, acidified to pH 2 and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated. 11.4 g (94%) of the desired product are obtained.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]3[N:14]([C:6]=2[C:5]([CH3:15])=[N:4][N:3]=1)[CH:13]=[CH:12][CH:11]=[CH:10]3.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH3:15][C:5]1[N:4]=[N:3][C:2]([NH:16][CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[C:7]2[C:6]=1[N:14]1[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]1)=[CH:8]2
Reactant: Cc1nnc(Cl)c2cc3ccccn3c12
Reactant: NCCCN1CCCCC1
Product: Cc1nnc(NCCCN2CCCCC2)c2cc3ccccn3c12

Procedure:
Following the procedure of Example 1, reaction of one equivalent of 1-chloro-4-methylpyridazino[4,5-b]indolizine and 10 equivalents of 1-(3-aminopropyl)piperidine at 130° C. gave the title compound as the free base (oil, 83%) after HPLC purification. Trituration with hexane gave a yellow solid (50%), mp 130°-134° C. The free base was then converted to the dihydrochloride salt (MeOH/ethereal HCl/diethyl ether), mp. 302°-303° C.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=[C:7]([CH:8]=O)[C:6]=1[OH:17])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([NH2:21])[CH2:19][NH2:20].[CH3:22][OH:23]>>[C:1]([C:5]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=[C:7]([CH:8]=[N:20][CH2:19][CH2:18][N:21]=[CH:8][C:7]2[C:22](=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=2)[OH:23])[C:6]=1[OH:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCN
Reactant: CC(C)(C)c1cc(C=O)c(O)c(C(C)(C)C)c1
Reactant: CO
Product: CC(C)(C)c1cc(C=NCCN=Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
15 g (0.064 mol) of 3,5-di-tert-butyl salicylaldehyde was dissolved in 500 ml of methanol, and then 1.92 g (0.032 mol) of ethylenediamine was added, and stirred at room temperature for 2 hours. The reaction product thus obtained was filtrated to give 13.3 g (0.0266 mol) of N,N′-bis(3,5-di-tert-butylsalicylidene)ethylenediamine. Next, in a solution obtained by dissolving the above compound in 1000 g of methanol, Co(OAc)2.4H2O was added in an amount of 8.753 g (0.0266 mol), followed by reflux for two hours, and the product thus obtained was subjected to filtration to give a metallosalen complex 1 (N,N′-bis(3,5-di-tert-butylsalicylidene)ethylenediaminato cobalt(II)). The yield was 70%.