Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.[CH3:8][C:9]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])[O:10]1.[OH-].[Na+].[Cl-].[Na+]>C(O)C>[CH3:8][C:9]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13](=[O:14])[CH:12]=[C:11]([CH:15]=[CH:6][C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[O:10]1
Reactant: O=Cc1ccsc1
Reactant: CC1=CC(=O)C(C)(c2ccccc2)O1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(c2ccccc2)OC(C=Cc2ccsc2)=CC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.1 %

Procedure:
To a solution of 3-thiophenecarboxaldehyde (1.07 g, 9.6 mM) and 2,5-dimethyl-2-phenyl-3(2H)-furanone (1.5 g, 8 mM) in ethanol (50 mL), was added 1N aqueous sodium hydroxide (1.6 mL, 1.6 mM). After the reaction solution was stirred at room temperature for one day, saturated aqueous sodium chloride (400 mL) was added. The aqueous layer was extracted with dichloromethane (3×100 mL). The combined dichloromethane extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give a yellow liquid. The liquid was purified by chromatography (silica gel, pet. ether-ethyl acetate) to afford a yellow solid (1.6 g, 71% yield), m.p. 75°-77° C.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:13])([CH3:12])[CH2:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH3:12][C:3]([NH2:2])([CH3:13])[CH2:4][C:5]1[CH:11]=[CH:10][C:8]([NH:9][S:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:22])=[O:21])=[CH:7][CH:6]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(N)Cc1ccc(N)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(N)Cc1ccc(NS(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.6 %

Procedure:
A solution of 4-(2-amino-2-methylpropyl)aniline hydrochloride salt (1.0 g, 4.98 mmol) in anhydrous DMF (30 mL) was treated with benzenesulfonyl chloride (880 mg, 4.98 mmol). The solution was stirred at ambient temperature for 16 h. The solvent was removed under reduced pressure and the residue was washed twice with hexane. The insoluble material was dissolved in water and extracted twice with ethyl ether to remove any remaining neutral impurities. The aqueous layer was separated and basified with excess 1N sodium hydroxide. Upon standing, a crystalline solid soon precipitated. The solid was collected, and dried under vacuum at 60° C. to provide 570 mg (38%) of the desired product as a white crystalline solid. Mp 180–181° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]([O:13]CC)=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:16]([Mg]Br)[CH:17]=[CH2:18]>C1COCC1>[O:4]1[C:5]2([CH2:6][CH2:7][CH:8]([CH:11]([OH:13])[CH2:18][CH:17]=[CH2:16])[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: C=CC[Mg]Br
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Solvent: C1CCOC1
Product: C=CCC(O)C1CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (1.12 g, 5.24 mmol, prepared as described in Pearson, et al. in J. Org. Chem. 1997, 62(16), 5284-5292) in THF (10 mL) cooled to −78° C. under argon was added a allylmagnesium bromide (18 mL, 18 mmol, 1 M in THF) dropwise. After the complete addition, the reaction mixture was allowed to reach room temperature overnight. It was then re-cooled to −78° C. and quenched with saturated NaHCO3 solution and warmed to room temperature. After extraction with ether, the organic layer was concentrated in vacuo and the residue purified by flash chromatography (silica gel, 0-100% ether/hexanes) to afford the product.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[CH:15]=[C:14]([O:16][S:17]([C:20]4[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:5])[CH2:3][CH2:2]1.[CH3:27][NH2:28]>CN1C(=O)CCC1>[CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[CH:15]=[C:14]([O:16][S:17]([C:20]4[CH:25]=[CH:24][C:23]([NH:28][CH3:27])=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: CN
Reactant: O=C(Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1)C1CC1
Solvent: CN1CCCC1=O
Product: CNc1ccc(S(=O)(=O)Oc2ccc3nc(NC(=O)C4CC4)sc3c2)cc1

Procedure:
A solution of 4-fluorobenzenesulfonic 2-(cyclopropanecarbonylamino)benzo-thiazol-6-yl ester (example 7) (25 mg, 63.71 μmol) and methylamine (2N in MeOH, 200 μl) in 300 μl of NMP is heated at 150° C. by microwave for 3 minutes. The crude reaction product is purified by preparative LC/MS (basic medium (pH 9)) to give after freeze-drying 6.7 mg of 4-methylaminobenzene-sulfonic 2-(cyclopropanecarbonylamino)benzothiazol-6-yl ester (beige-colored solid).
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[OH:18])[N:14]=[CH:13][CH:12]=[C:11]2[O:19][C:20]1[C:21]([CH3:30])=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2.Br[CH:32]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:33]([O:35][CH2:36][CH3:37])=[O:34].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:38]([O:40][CH2:41][CH3:42])=[O:39])[N:14]=[CH:13][CH:12]=[C:11]2[O:19][C:20]1[C:21]([CH3:30])=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1O
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Oc1cc2nccc(Oc3cc4ccccc4nc3C)c2cc1OC)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 181.6 %

Procedure:
N,N-Dimethylformamide (3 ml) was added to 6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-ol (compound 352) (50 mg), diethyl 2-bromo-malonate (75 mg), and potassium carbonate (62 mg), and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using hexane-acetone to give the title compound (134 mg, yield 88%).
Reaction SMILES: [C:1]([NH:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].O.[N+:15](C)([O-:17])=[O:16]>>[C:1]([NH:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1CCc2ccccc21
Reactant: C[N+](=O)[O-]
Solvent: O
Product: CC(=O)NC1CCc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cooled suspension of (rac)-N-acetyl-1-aminoindan (Ex. 17, 17.5 g, 0.1 mole) in nitromethane (165 ml), was added dropwise a nitrating mixture (H2SO4HNO3, H2O ) while the temperature was kept between 8° C. and 2° C. stirring was continued for 1.5 hours in the ice-bath and the mixture was then poured on to a mechanically stirred mixture of ice (500 g) and water (1300 ml) stirring being continued for 1 hour. The suspension was filtered, the white solid washed with water and dried (14.05 g, 63.9%). It is sufficiently pure for hydrogenation (Ex. 59).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1.O>CC(C)=O>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:13][S:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[CH2:1][CH2:2][CH2:3]3)(=[O:11])=[O:12])=[O:25])=[CH:19][CH:18]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NS(=O)(=O)c1ccc2c(c1)CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(Nc1ccc(Cl)cc1)NS(=O)(=O)c1ccc2c(c1)CCC2
Yield: 87.4 %

Procedure:
To a mixture of 93.2 g of indane-5-sulfonamide in 300 ml of acetone were added 490 ml of 1 N sodium hydroxide. A solution of 79.36 g of 4-chlorophenylisocyanate in 250 ml of acetone was added to the reaction mixture with stirring. After stirring at room temperature for about 18 hours, the reaction mixture was filtered and 490 ml of 1 N hydrochloric acid were added to the filtrate, thereby providing a fine white precipitate. One liter of water was added, and the solid was recovered by filtration to provide 144.86 g of the desired title product. m.p. 169-172° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C@:4]([N:9]=[C:10]=[O:11])([CH:6]([CH3:8])[CH3:7])N.[OH:13][CH2:14][C:15]1[S:16][CH:17]=[C:18]([CH:20]([CH3:22])[CH3:21])[N:19]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C@H:4]([CH:6]([CH3:8])[CH3:7])[NH:9][C:10]([O:13][CH2:14][C:15]1[S:16][CH:17]=[C:18]([CH:20]([CH3:22])[CH3:21])[N:19]=1)=[O:11]
Reactant: COC(=O)[C@](N)(N=C=O)C(C)C
Reactant: CC(C)c1csc(CO)n1
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@@H](NC(=O)OCc1nc(C(C)C)cs1)C(C)C
Yield: 52.3 %

Procedure:
A solution of 1.4 mmol of α-isocyanato-valine methyl ester and 0.22 g (1.4 mmol) of 2-(hydroxymethyl)-4-isopropylthiazole in 10 ml of chloroform was heated at reflux for 3 h. After being allowed to cool, the solvent was removed in vacuo, and the residue was purified by silica gel chromatography using 2% methanol in chloroform to provide 0.23 g (52%) of the desired compound (Rf 0.54, 5% methanol in dichloromethane). NMR 1H NMR (DMSO-d6) δ 0.87 (d, J=7 Hz, 3 H), 0.88 (d, J=7 Hz, 3 H), 1.23 (d, J=7 Hz, 6 H), 2.04 (octet, J=7 Hz, 1 H), 3.01 (heptet, J=7 Hz, 1 H), 3.73 (s, 3 H), 3.94 (dd, J=8, 6 Hz, 1 H), 5.26 (AA', 2 H), 7.28 (s, 1 H), 7.92 (d, J=8 Hz, 1 H). Mass spectrum: (M+H)+ =31 5.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[F:19][C:20]1[C:21]([O:29][CH3:30])=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([F:19])[C:21]=3[O:29][CH3:30])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: COc1c(F)cccc1B(O)O
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3cccc(F)c3OC)cccc2c1N
Yield: 88 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (116 mg, 0.375 mmol) and (3-fluoro-2-methoxyphenyl)boronic acid (127 mg, 0.75 mmol) were reacted to afford the title compound (117 mg, 88% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.06 (t, J=6.0 Hz, 1H), 8.45 (dd, J=7.5, 2.2 Hz, 1H), 7.74-7.81 (m, 2H), 7.28-7.37 (m, 1H), 7.12-7.21 (m, 2H), 3.54 (s, 3H), 3.31 (apparent q, J=7.0 Hz, 2H), 1.56 (apparent sextet, J=7.0 Hz, 2H), 0.90 (t, J=7.0 Hz, 3H). MS APCI, m/z=355 (M+H) HPLC 1.86 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:16])/[CH:12]=[CH:13]/[CH2:14][CH3:15])=[CH:4][CH:3]=1.[C:17]([CH2:19][C:20]([O:22]CC)=O)#[N:18].CC(C)([O-])C.[K+].O1CCCC1.Cl>C(O)(C)(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N:10]2[C:11](=[O:16])[CH2:12][CH:13]([CH2:14][CH3:15])[CH:19]([C:17]#[N:18])[C:20]2=[O:22])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC#N
Reactant: CC/C=C/C(=O)NCCc1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CCC1CC(=O)N(CCc2ccc(F)cc2)C(=O)C1C#N
Temperature: 80 °C
Reaction time: 18 h
Yield: 76.6 %

Procedure:
A solution of trans 2-pentenoic acid [2-(4-fluorophenyl)ethyl]amide (2.0 g, 9.05 mmol) and ethyl cyanoacetate (1.93 mL, 18.1 mmol) in tert-butanol (30 mL) was treated with a solution of potassium tert-butoxide in tetrahydrofuran (1.0 M, 18.1 mL, 18.1 mmol) and heated at 80° C. After 18 hours, the solution was cooled to room temperature and treated with 1.0 N aqueous hydrochloric acid. The mixture was concentrated under vacuum and the residue was recrystallized from ethanol to provide a pale pink solid (2.0 g, 77%). 1H NMR (300 MHz, CDCl3) δ7.19 (m, 2H), 7.00 (t, J=9 Hz, 2H), 4.01 (m, 2H), 3.50 (d, J=11 Hz, 1H), 2.97 (dd, J=17, 3 Hz, 1H), 2.83 (t, J=8 Hz, 2H), 2.4-2.2 (m, 2H), 1.88 (m, 1H), 1.44 (m, 1H), 1.02 (t, J=7 Hz, 3H). Mass spec (ES−) m/z 287.2 (M+H+, 100%).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([CH2:19][N:20]3[CH:24]=[C:23]([C@@:25]([OH:32])([CH2:30][CH3:31])[C:26]([F:29])([F:28])[F:27])[N:22]=[N:21]3)=[CH:7][CH:8]=2)[N:3]=1.[F:33][C:34]([F:38])([F:37])[CH2:35][O-:36].[Na+]>CN(C=O)C>[F:27][C:26]([F:29])([F:28])[C@:25]([C:23]1[N:22]=[N:21][N:20]([CH2:19][C:6]2[CH:5]=[C:4]3[C:9]([C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[CH:11][C:2]([O:36][CH2:35][C:34]([F:38])([F:37])[F:33])=[N:3]3)=[CH:8][CH:7]=2)[CH:24]=1)([OH:32])[CH2:30][CH3:31]
Reactant: CC[C@](O)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(Cl)nc3c2)nn1)C(F)(F)F
Reactant: [O-]CC(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@](O)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(OCC(F)(F)F)nc3c2)nn1)C(F)(F)F

Procedure:
A solution of (S)-2-(1-{[2-chloro-4-(4-fluorophenyl)quinolin-7-yl]methyl}-1H-1,2,3-triazol-4-yl)-1,1,1-trifluorobutan-2-ol (60 mg, 0.13 mmol) and sodium trifluoroethoxide (79 mg, 0.65 mmol) in DMF (3 mL) was stirred at 120° C. for 1.5 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduce pressure. Purification on silica gel (eluting with ethyl acetate/hexanes, 3:7) gave the title compound. MS (+ESI): 529 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[OH:13][CH2:14][CH2:15][O:16][C:17]1[C:24]([CH3:25])=[CH:23][C:20]([CH:21]=O)=[CH:19][C:18]=1[CH3:26].S([O-])(O)=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[OH:13][CH2:14][CH2:15][O:16][C:17]1[C:24]([CH3:25])=[CH:23][C:20]([C:21]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][CH:9]=[C:8]([O:11][CH3:12])[CH:7]=3)[N:1]=2)=[CH:19][C:18]=1[CH3:26]
Reactant: COc1ccc(N)c(C(N)=O)c1
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1ccc2nc(-c3cc(C)c(OCCO)c(C)c3)[nH]c(=O)c2c1
Temperature: 115 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 2-amino-5-methoxy-benzamide (2.62 g, 15.80 mmol) and 4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde (3.23 g, 16.60 mmol) in N,N-dimethyl acetamide (20 mL), were added sodium hydrogen sulfite (58.5 wt %, 3.44 g, 19.00 mmol) and p-toluenesulfonic acid monohydrate (0.60 g, 3.20 mmol) and the reaction mixture was stirred at 115° C. for 16 hours. Solvent was evaporated in vacuo, water (50 mL) was added, and the separated solid was filtered. The solid was triturated with ether to give 2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-6-methoxy-3H-quinazolin-4-one as a white solid. Yield: 3.56 g (66%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:11])=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].[NH2:12][NH2:13]>CCO>[Cl:11][C:5]1[N:4]=[N:3][C:2]([NH:12][NH2:13])=[C:7]([C:8]([OH:10])=[O:9])[CH:6]=1
Reactant: O=C(O)c1cc(Cl)nnc1Cl
Reactant: NN
Solvent: CCO
Product: NNc1nnc(Cl)cc1C(=O)O
Temperature: 85 °C
Reaction time: 3 h

Procedure:
To a solution of 3,6-dichloropyridazin-4-carboxylic acid (5 g, 26 mmol) in EtOH (200 mL) was added TEA (4 mL, 30 mmol) and hydrazine (5 mL, 80%). The reaction mixture was stirred at 85° C. for 3 hours. After cooled to room temperature, the mixture was concentrated in vacuum to give crude product 6-chloro-3-hydrazinylpyridazine-4-carboxylic acid (4.8 g), which was used for the next step directly without purification. LRMS (M+H+) m/z: calcd 189; found 189.
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH2:12]([NH:15][CH:16]([CH3:21])[CH2:17][CH2:18][CH:19]=[CH2:20])[CH:13]=[CH2:14].C(N(CC)CC)C>C(Cl)Cl>[CH2:4]([O:3][C:1](=[O:2])[N:15]([CH2:12][CH:13]=[CH2:14])[CH:16]([CH3:21])[CH2:17][CH2:18][CH:19]=[CH2:20])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C=CCCC(C)NCC=C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCCC(C)N(CC=C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
Carbobenzyloxy chloride (9.56 g, 8 ml) was added dropwise to a stirred solution of allyl-(1-methyl-pent-4-enyl)-amine (7 g, 50 mmol), triethylamine (5.5 g, 8.0 ml, 57.5 mmol) in CH2Cl2 (100 ml) at 0 C. The reaction mixture was warmed to RT, then was stirred for 2 h. The reaction mixture was diluted with CH2Cl2 (100 ml), then was extracted with water, then brine. The combined organics were dried with MgSO4, filtered, concentrated in vacuo by rotary evaporation, then was chromatographed (silica gel, 4% EtOAc/hexanes) to give the title compound (8.9 g, 65% yield): Liquid Chromatgraphy/Electrospray mass spec: M+H+=274.2
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[NH2:12])[C:5]([O:7][CH3:8])=[O:6].[CH:16](O)=O>>[N+:13]([C:10]1[C:11]2[N:12]=[CH:16][NH:1][C:2]=2[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=1)([O-:15])=[O:14]
Reactant: O=CO
Reactant: COC(=O)c1cc(N)c(N)c([N+](=O)[O-])c1
Product: COC(=O)c1cc([N+](=O)[O-])c2nc[nH]c2c1
Temperature: 25 °C
Yield: 110 %

Procedure:
A solution of methyl 3,4-diamino-5-nitrobenzoate (D245) (1.3 g, 6.16 mmol, 1 equiv) in HCOOH (20 ml) was stirred at 100° C. for 1 h then cooled to room temperature and concentrated in vacuo. The residue was partitioned between AcOEt and a 2N aqueous NaOH solution and the layers were separated. The organic phase was dried over MgSO4 and concentrated in vacuo to give methyl 4-nitro-1H-benzimidazole-6-carboxylate (D250) (1.5 g, 110%) as a light brown solid which was used in the next step without further purification. [M+H]+=222.3, RT=2.29 min.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([CH3:38])([CH3:37])[CH2:34][CH:35]=[O:36])=[CH:29][CH:28]=1>O1CCCC1>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]([CH3:38])([CH3:37])[CH2:34][CH:35]([Sn:17]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:13][CH2:14][CH2:15][CH3:16])[OH:36])=[CH:31][CH:32]=1
Reactant: CC(C)(CC=O)c1ccc(Cl)cc1
Reactant: CCCC[SnH](CCCC)CCCC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)C(O)CC(C)(C)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.1 %

Procedure:
A stirred solution of 5.0 mL (0.036 mole) of diisopropylamine in 100 mL of tetrahydrofuran was cooled to 0° C., and 14.3 mL (0.036 mole) of n-butyllithium (2.5M in hexanes) was added dropwise. Upon completion of addition, 9.6 grams (0.036 mole) of tributyltin hydride was added dropwise during a 15 minute period. The reaction mixture was then stirred at 0° C. for 15 minutes. After this time the reaction mixture was cooled to -78° C., and a solution of 7.0 grams (0.036 mole) of 3-(4-chlorophenyl)-3-methylbutyraldehyde in 10 mL of tetrahydrofuran was added dropwise, while maintaining the reaction mixture temperature below -70° C. The complete addition required about 20 minutes. After this time the reaction mixture was stirred at below -70° C. for ten minutes. The reaction was then quenched by the dropwise addition of about 300 mL of aqueous dilute ammonium chloride solution to the cold reaction mixture. The complete addition required about 10 minutes. The cooling bath was removed, and the reaction mixture was extracted with two 200 mL portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, at a temperature of less than 30° C., yielding 17.4 grams of 3-(4-chlorophenyl)-3-methyl-1-tributylstannylbutanol.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]21[CH2:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([C:27](O)=[O:28])[CH:22]=3)[CH:17]=1)[CH2:12]2.[CH2:30]([NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH2:30]([N:32]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]([C:23]1[CH:22]=[C:21]([NH:20][C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[CH2:12][C:4]2([C:5]4[C:6](=[N:7][CH:8]=[CH:9][CH:10]=4)[NH:11][C:3]2=[O:2])[CH2:19]3)[N:26]=[CH:25][N:24]=1)=[O:28])[CH3:31]
Reactant: CCNc1ccccc1
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CCN(C(=O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1)c1ccccc1

Procedure:
100 mg (0.24 mmol) 6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidine-4-carboxylic acid hydrochloride, 34 μL (0.24 mmol) N-ethylaniline, 0.10 mL (0.72 mmol) TEA and 85 mg (0.27 mmol) TBTU in 1.8 mL DMF were stirred overnight at RT. The purification was carried out by preparative HPLC-MS. The product-containing fractions were combined and lyophilised.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][OH:23])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([CH2:17][C:18]2[CH:25]=[CH:24][C:21]([CH2:22][OH:23])=[CH:20][CH:19]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OCc1ccc(CCl)cc1
Reactant: CC(C)(C)c1cc(-c2ccccc2)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(-c2ccccc2)n(Cc2ccc(CO)cc2)n1
Temperature: 120 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
A mixture of 3-tert-butyl-5-phenyl-1H-pyrazole (2.0 g, 10 mmol), 4-(chloromethyl)benzyl alcohol (1.70 g, 10.8 mmol), potassium carbonate (2.76 g, 20 mmol) and N,N-dimethylformamide (20 mL) was stirred at 120° C. for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (5%-80% ethyl acetate/hexane) to give the title compound (640 mg, yield 20%) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]2)=[CH:12][CH:11]=1)=[O:8].[C:25]1([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([NH2:37])[N:32]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1COCC1.CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:23][CH:20]1[CH2:21][CH2:22][N:17]([CH2:16][C:13]2[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:24]=[C:2]([NH:37][C:33]4[N:32]=[C:31]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH:36]=[CH:35][N:34]=4)[CH:3]=[N:4][CH:5]=3)=[CH:11][CH:12]=2)[CH2:18][CH2:19]1
Reactant: CC1CCN(Cc2ccc(NC(=O)c3cncc(Br)c3)cc2)CC1
Reactant: Nc1nccc(-c2ccccc2)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC1CCN(Cc2ccc(NC(=O)c3cncc(Nc4nccc(-c5ccccc5)n4)c3)cc2)CC1
Temperature: 150 °C
Yield: 41.8 %

Procedure:
A mixture of 5-bromo-N-(4-((4-methylpiperidin-1-yl)methyl)phenyl)nicotinamide (45.6 mg, 0.1 mmol) and 4-phenylpyrimidin-2-amine (25.7 mg, 0.15 mmol), KOBut (22.4 mg, 0.2 mmol), Pd2(dba)3 (4.6 mg, 0.005 mmol) and Xantphos (4.6 mg, 0.008 mmol) in a microwave reaction vessel was suspended in 2 mL of THF. The reaction mixture was heated in a microwave at 150° C. for 90 min. After cooling, the mixture was diluted with DMF, and then filtered with a 0.45 μm microfilter. The obtained filtrate was separated by a semi-preparative HPLC. Collected product fraction was lyophilized to give pure product as a while powder (20 mg, 38%). MS (ESI+) m/z 479.2 [M+H]+.