Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:9]=1)=[O:7]>O1CCCC1.O>[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:9]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1cn(-c2ccnc3cc(OC)ccc23)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(-n3cc(C(=O)O)c4ccccc43)ccnc2c1
Yield: 72.3 %

Procedure:
0.504 g (12 mmol) of lithium hydroxide monohydrate and 20 cm3 of water are added to 1.3 g (3.91 mmol) of 3-methoxycarbonyl-1-(7-methoxyquinol-4-yl)-1H-indole dissolved in 20 cm3 of tetrahydrofuran. After stirring at reflux for 20 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 30 cm3 of water (pH=10). The resulting aqueous solution is washed with 50 cm3 of ethyl acetate and adjusted to pH 6 with N hydrochloric acid. The resulting precipitate is filtered off and then it is rinsed with three times 20 cm3 of water and twice 20 cm3 of isopropyl ether and dried under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. to give 0.9 g of 3-carboxy-1-(7-methoxyquinol-4-yl)-1H-indole in the form of a white powder. Mass spectrum (EI): m/e 318 (M+•).
Reaction SMILES: [CH3:1][Mg+].[Br-].[CH2:4]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:23]=[C:22]([O:24][CH3:25])[C:21](=[O:26])[C:20]([C:27](N(OC)C)=[O:28])=[N:19]2)=[C:14]([F:33])[CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1COCC1>[C:27]([C:20]1[C:21](=[O:26])[C:22]([O:24][CH3:25])=[CH:23][N:18]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:13][C:14]=2[F:33])[N:19]=1)(=[O:28])[CH3:1]
Reactant: C[Mg+]
Reactant: COc1cn(-c2ccc(OCc3ccccc3)cc2F)nc(C(=O)N(C)OC)c1=O
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cn(-c2ccc(OCc3ccccc3)cc2F)nc(C(C)=O)c1=O
Reaction time: 1 h
Yield: 84.6 %

Procedure:
MeMgBr (1 M solution in THF, 56.4 mL, 56.4 mmol) was added dropwise at −78° C. to a solution of 1-[4-(benzyloxy)-2-fluorophenyl]-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (7.77 g, 18.8 mmol) in THF (120 mL). After stirring for 1 h, the reaction mixture was quenched with 1 M HCl aqueous solution and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with AcOEt and crystallized from hexane/AcOEt to give the title compound (5.86 g, 85% yield) as a pale yellow solid: mp 101-103° C.; 1H NMR (300 MHz, CDCl3): δ ppm 2.67 (3H, s), 3.89 (3H, s), 5.13 (2H, s), 6.84-6.93 (2H, m), 7.34-7.44 (5H, m), 7.48-7.55 (1H, m), 7.69 (1H, d, J=2.3 Hz). Anal. Calcd for C20H17FN2O4: C, 65.21; H, 4.65; N, 7.60. Found: C, 65.37; H, 4.68; N, 7.47.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH:4]=[C:5]([C:9]([OH:11])=[O:10])[C:6]([OH:8])=[O:7]>CCOC(C)=O.CCO.[Pd]>[CH3:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][CH:5]([C:9]([OH:11])=[O:10])[C:6]([OH:8])=[O:7]
Reactant: Cc1ccccc1C=C(C(=O)O)C(=O)O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccccc1CC(C(=O)O)C(=O)O
Reaction time: 2 h

Procedure:
Hydrogenate the acid of Step 1 (24.3 g) in EtOAc (600 ml) and EtOH (100 ml) at 60 psi with 5% Pd/C (1.0 g). After 2 hr., filter and concentrate to obtain the title compound as a beige solid, m.p. 132°-5°.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([CH:26]([OH:33])[C:27]3[CH:32]=[N:31][CH:30]=[CH:29][N:28]=3)[C:10]3[N:14]=[C:13]([O:15][CH2:16][CH3:17])[N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]=3[CH:25]=2)=[C:5]([CH3:34])[O:4][N:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:26]([C:27]3[CH:32]=[N:31][CH:30]=[CH:29][N:28]=3)=[O:33])[C:10]3[N:14]=[C:13]([O:15][CH2:16][CH3:17])[N:12]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[C:11]=3[CH:25]=2)=[C:5]([CH3:34])[O:4][N:3]=1
Reactant: CCOc1nc2c(C(O)c3cnccn3)cc(-c3c(C)noc3C)cc2n1C(=O)OC(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCOc1nc2c(C(=O)c3cnccn3)cc(-c3c(C)noc3C)cc2n1C(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
To 2,2,6,6-tetramethylpiperidine (0.27 mL, 1.56 mmol) in tetrahydrofuran (16 mL) at −78° C. was added n-butyllithium (0.97 mL, 1.56 mmol, 1.6 M in hexanes). After 5 minutes, the reaction was warmed to 0° C. After stirring for 30 minutes, the reaction was cooled to −78° C., and pyrazine (137 mg, 1.69 mmol) in tetrahydrofuran (3.3 mL) and tert-butyl dimethylisoxazol-4-yl)-2-ethoxy-4-formyl-1H-indole-1-carboxylate (498 mg, 1.3 mmol) in tetrahydrofuran (2.6 mL) were added simultaneously in a drop-wise manner. After stirring for 60 minutes, the reaction was quenched with saturated NH4Cl(aq) (10 mL), extracted with ethyl acetate (3×10 mL), dried over Na2SO4, and concentrated in vacuo. Purification by flash chromatography (0-100% ethyl acetate/hexane) afforded tert-butyl 6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-(hydroxy(pyrazin-2-yl)methyl)-1H-benzo[d]imidazole-1-carboxylate. To tert-butyl 6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-(hydroxy(pyrazin-2-yl)methyl)-1H-benzo[d]imidazole-1-carboxylate (50 mg, 0.11 mmol) in dichloromethane (2.5 mL) was added Dess-Martin periodinane (72.4 mg, 0.16 mmol). After 15 minutes, the reaction was quenched with saturated Na2S2O3(aq) (10 mL) and extracted with dichloromethane (3×10 mL), dried over Na2SO4, and concentrated in vacuo. Purification by flash chromatography (0-100% ethyl acetate/hexanes) afforded tert-butyl 6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-(pyrazine-2-carbonyl)-1H-benzo[d]imidazole-1-carboxylate as a yellow oil.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[N:8]=[CH:9][N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14](=[O:21])[N:13]([CH3:22])[CH2:12][C:11]=12)=[O:6])[C:2]#[CH:3].IN1C(=O)CCC1=O.[CH2:31]([NH:34][CH2:35][CH2:36][CH3:37])[CH2:32][CH3:33]>C(O)(=O)C>[CH2:31]([N:34]([CH2:3][C:2]1[O:6][C:5]([C:7]2[N:8]=[CH:9][N:10]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[C:14](=[O:21])[N:13]([CH3:22])[CH2:12][C:11]=23)=[N:4][CH:1]=1)[CH2:35][CH2:36][CH3:37])[CH2:32][CH3:33]
Reactant: C#CCNC(=O)c1ncn2c1CN(C)C(=O)c1ccccc1-2
Reactant: CCCNCCC
Agent: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: CCCN(CCC)Cc1cnc(-c2ncn3c2CN(C)C(=O)c2ccccc2-3)o1
Temperature: 25 °C
Reaction time: 46 h
Yield: 25.4 %

Procedure:
A solution of 2.94 g (0.010 mol) of 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid prop-2-ynylamide in 60 ml of acetic acid was treated with 3.36 g (0.015 mol) of N-iodosuccinimide while gassing with argon. After stirring at room temperature for 46 hrs. the dark suspension obtained was completely freed from the solvents and dried azeotropically several times with toluene. The dark brown solid residue was dissolved in 100 ml of THF, treated with 13.7 ml (0.10 mol) of dipropylamine and stirred at room temperature for 3 hrs. The suspension obtained was completely freed from the solvents, the residue was partitioned between ethyl acetate and 1N aqueous hydrochloric acid and extracted. The aqueous-acidic phase was made basic and extracted with ethyl acetate. The organic phase was concentrated, the orange-brownish product was chromatographed over basic Alox (grade III) with dichloromethane/ethyl acetate 4:1 as the eluent and recrystallized from hot isopropyl ether. There was obtained 1.0 g (25%) of 3-(5-dipropylaminomethyl-oxazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as yellowish crystals; m.p. 133°-135°.
Reaction SMILES: C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[CH:17]1([C:20](Cl)=[O:21])[CH2:19][CH2:18]1.[NH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=1)[C:28]([C:42]([O:44][CH2:45]C)=[O:43])=[C:27]2[C:47]1[CH:52]=[CH:51][C:50]([C:53]([CH3:56])([CH3:55])[CH3:54])=[CH:49][CH:48]=1>ClCCl>[C:53]([C:50]1[CH:49]=[CH:48][C:47]([C:27]2[C:26]3[C:30](=[CH:31][CH:32]=[C:24]([NH:23][C:20]([CH:17]4[CH2:19][CH2:18]4)=[O:21])[CH:25]=3)[N:29]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=3)[C:28]=2[C:42]([O:44][CH3:45])=[O:43])=[CH:52][CH:51]=1)([CH3:56])([CH3:54])[CH3:55]
Reactant: O=C(Cl)C1CC1
Reactant: CCOC(=O)c1c(-c2ccc(C(C)(C)C)cc2)c2cc(N)ccc2n1Cc1cccc(OC)c1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1c(-c2ccc(C(C)(C)C)cc2)c2cc(NC(=O)C3CC3)ccc2n1Cc1cccc(OC)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 36.6 %

Procedure:
Triethylamine (0.12 mL, 91 mg, 0.90 mmol), dimethylaminopyridine (20 mg, 0.16 mmol), and cyclopropanecarbonyl chloride (82 μL, 94 mg, 0.90 mmol) were added successively to a cooled (0° C.) and stirred solution of methyl 5-amino-3-(4-tert-butylphenyl)-1-(3-methoxybenzyl)-1H-indole-2-carboxylate (Example 160, 140 mg, 0.31 mmol) in dichloromethane (10 mL). The reaction was warmed to rt and stirred for 16 h. The solution was diluted with dichloromethane (50 mL), washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. Flash chromatography of the residue over silica gel using 4:1 hexane/ethyl acetate afforded 58 mg (37%) of desired product. The product had: 1H NMR (300 MHz, acetone-D6) δ 9.38 (s, 1 H), 8.02 (d, 1 H), 7.37-7.65 (m, 6 H), 7.19 (dd, 1 H), 6.80 (dd, 1 H), 6.6-6.74 (m, 2 H), 5.81 (s, 2 H), 3.73 (s, 3 H), 3.62 (s, 3 H), 1.70-1.80 (m, 1 H), 1.40 (s, 9 H), 0.82-0.90 (m,2H),0.70-0.78 (m,2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[CH:7][NH:6][C:5]2=O.P(Cl)(Cl)([Cl:21])=O.C(N(C(C)C)C(C)C)C>>[Cl:21][C:5]1[C:4]2[C:9](=[CH:10][C:11]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[C:2]([F:1])[CH:3]=2)[N:8]=[CH:7][N:6]=1
Reactant: O=c1[nH]cnc2cc(N3CCOCC3)c(F)cc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cc2c(Cl)ncnc2cc1N1CCOCC1
Yield: 123.3 %

Procedure:
5.0 g (0.02 mol) of 6-fluoro-7-morpholin-4-yl-3H-quinazolin-4-one were suspended in 37.0 ml (0.04 mol) of phosphoryl chloride at room temperature, 3.4 ml (0.02 mol) of N-ethyldiisopropylamine were subsequently added, and the mixture was heated under reflux for 2 h. Conventional work-up gave 6.6 g of 4-chloro-6-fluoro-7-morpholin-4-ylquinazoline.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:3]=1[CH3:20].[Br:21][C:22]1[CH:23]=[CH:24][C:25]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[C:26]([NH2:28])[CH:27]=1.Cl>O1CCOCC1.CO>[Br:21][C:22]1[CH:23]=[CH:24][C:25]([N:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)=[C:26]([NH:28][C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:3]=2[CH3:20])[CH:27]=1
Reactant: Nc1cc(Br)ccc1N1CCOCC1
Reactant: Cc1c(-c2ccccc2F)nc2cc(F)ccc2c1Cl
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1c(-c2ccccc2F)nc2cc(F)ccc2c1Nc1cc(Br)ccc1N1CCOCC1

Procedure:
Prepared according to Procedure K, Method 1 using 4-chloro-7-fluoro-2-(2-fluorophenyl)-3-methylquinoline (118 mg, 407 μmol), 5-bromo-2-morpholinobenzenamine (105 mg, 407 μmol) and 4.0N hydrochloric acid (0.10 mL, 407 μmol) in 1,4-dioxane in MeOH (1.00 mL) to afford a yellow solid after purification by chromatography on silica gel, eluting with EtOAc-DCM-hexane solvent mixture. Mass Spectrum (ESI) m/e=510.0 & 512.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[S:21]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22]1>>[CH3:20][C:2]1([CH3:1])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:23]3[CH:24]=[CH:25][S:21][CH:22]=3)[CH:9]=2)[C:4](=[O:19])[CH2:3]1
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: OB(O)c1ccsc1
Product: CC1(C)CC(=O)c2ccc(-c3ccsc3)cc21

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and thien-3-yl boronic acid according to the procedure described in example 21. MS m/z 243; HRMS: calcd for C15H14OS+H+, 243.08381; found (ESI, [M+H]+), 243.084.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([NH:10][C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[N:8]([CH3:9])[C:4]=2[C:3]=1[C:21]([NH2:23])=[O:22].[CH2:24]([N:27]=[C:28]=[S:29])[CH:25]=[CH2:26]>CN(C=O)C.[Cl-].[Na+].O>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[NH:10][C:7]1[N:8]([CH3:9])[C:4]2[C:3]([C:21]([NH2:23])=[O:22])=[C:2]([NH:1][C:28]([NH:27][CH2:24][CH:25]=[CH2:26])=[S:29])[CH:20]=[CH:19][C:5]=2[N:6]=1
Reactant: C=CCN=C=S
Reactant: Cn1c(Nc2c(Cl)cccc2Cl)nc2ccc(N)c(C(N)=O)c21
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCNC(=S)Nc1ccc2nc(Nc3c(Cl)cccc3Cl)n(C)c2c1C(N)=O
Temperature: 45 °C
Yield: 51.4 %

Procedure:
A mixture of 100 mg (0.286 mmol) of 5-amino-2-(2,6-dichlorophenylamino)-3-methyl-3H-benzimidazole-4-carboxylic acid amide (Example 7) and 114 mg (1.15 mmol) of allyl isothiocyanate in DMF was warmed at 45° C. for 48 h. The reaction was diluted with 30 mL of brine and extracted with four 15 mL portions of EtOAc. The combined organic layers were washed with five 15 mL portions of brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was adsorbed onto silica gel and chromatographed on silica gel (MeOH-methylene chloride, first 2:98, then 4:96, then 5:95) to afford 66 mg (51%) of 2-(2,6-dichlorophenylamino)-3-methyl-5-(3-allyl-thioureido)-3H-benzimidazole-4-carboxylic acid amide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])[C:8]([CH2:19]Cl)=[CH:7]2.[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C=O)C>[N:21]([CH2:19][C:8]1[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[N:10][C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[CH:3][C:2]=2[Cl:1])=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: Fc1ccccc1-c1nc2c(Cl)cccc2cc1CCl
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cc2cccc(Cl)c2nc1-c1ccccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To stirring solution of 8-chloro-3-(chloromethyl)-2-(2-fluorophenyl)quinoline (0.330 g, 1.08 mmol) in DMF was added sodium azide (0.561 g, 8.62 mmol), and the mixture stirred at room temperature. After 3 hours, the mixture was partitioned between CH2Cl2 and H2O. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure: LC-MS (ESI) m/z 313.0 [M+H]+. The crude product was carried on crude without purification for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[N:11]([CH:15]=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][N:14]=1.F[B-](F)(F)F.[O:24]=[N+:25]=[O:26].O>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[N:11]([C:15]([N+:25]([O-:26])=[O:24])=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][N:14]=1
Reactant: O=[N+]=O
Reactant: Cc1cn2ccnc(-c3ccc(Cl)cc3Cl)c2n1
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CC#N
Product: Cc1nc2c(-c3ccc(Cl)cc3Cl)nccn2c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 1323.8 %

Procedure:
8-(2,4-Dichlorophenyl)-2-methylimidazo[1,2-a]pyrazine (0.10 g, 0.36 mmol) was dissolved in acetonitrile (0.36 mL), then nitronium tetrafluoroborate (72 mg, 0.54 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour under nitrogen atmosphere. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:3) to give 8-(2,4-dichlorphenyl)-2-methyl-3-nitroimidazo[1,2-a]pyrazine (1.54 g) as a yellow oil.
Reaction SMILES: [CH:1]1([CH:7]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([N:28]([CH3:36])[CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[O:27])=[N:24][CH:25]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([N:28]([CH3:36])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[N:24][CH:25]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(F)cc3c2C)C2CCCCC2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)nc2)C2CCCCC2)oc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
To a mixture of ethyl 3-{[(5-{[cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl]amino}pyridin-2-yl)carbonyl](methyl)amino}propanoate (318 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (262 mg, 87%) as a white solid.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[Se:20][C:19]([CH:21]=O)=[CH:18][CH:17]=2)=[C:12]([F:23])[C:11]=1[F:24])[CH3:8].[CH2:25]1[CH2:29]O[CH2:27][CH2:26]1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)CCC.CC(OC)(C)C.O.Cl>[CH2:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[Se:20][C:19]([CH:21]=[CH:29][CH2:25][CH2:26][CH3:27])=[CH:18][CH:17]=2)=[C:12]([F:23])[C:11]=1[F:24])[CH3:8]
Reactant: CCOc1ccc(-c2ccc(C=O)[se]2)c(F)c1F
Reactant: C1CCOC1
Agent: CC(C)(C)[O-]
Agent: CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: COC(C)(C)C
Solvent: O
Product: CCCC=Cc1ccc(-c2ccc(OCC)c(F)c2F)[se]1
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
4.12 g (10.3 mmol) of butyltriphenylphosphonium bromide are initially introduced in 50 ml of THF at 0° C., and 1.04 g (9.27 mmol) of potassium tert-butoxide dissolved in 7 ml of THF are added. After 1.75 h at RT, 2.27 g (7.20 mmol) of 5-(4-ethoxy-2,3-difluorophenyl)selenophene-2-carbaldehyde are added in one portion with ice-cooling, and the batch is stirred at RT for 6 h. The mixture is diluted with MTBE, and water and 2 N hydrochloric acid are added. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with sat. sodium chloride soln. and dried using sodium sulfate. The solution is concentrated to dryness, and the residue is purified by column chromatography (SiO2, n-heptane:EtOAc=5:1-2:1). 2-(4-Ethoxy-2,3-difluorophenyl)-5-pent-1-enylselenophene is obtained as an orange oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1)=[O:4].Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:3]([O:2][CH3:1])=[O:4]
Reactant: Brc1ccccn1
Reactant: COC(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cccc(-c2ccccn2)c1
Temperature: 120 °C
Yield: 74 %

Procedure:
A solution (3-(methoxycarbonyl)phenyl)boronic acid (500 mg, 2.78 mmol), 2-bromopyridine (399 mg, 2.53 mmol), K2CO3 (1.0 g, 7.6 mmol) and Pd(dppf)Cl2 (20 mg) in a mixture of dioxane (10 mL) and water (2.5 mL) was heated under microwave conditions at 120° C. for 0.5 h. The reaction mixture was filtered, concentrated, and the crude product was purified by column chromatography eluting with petroleum ether/ethyl acetate (5:1). (400 mg, yield 74%) MS (ESI+) e/z: 214.1 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]([OH:15])=O)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C(OC([N:23]1[CH2:28][CH2:27][NH:26][C:25]([CH3:30])([CH3:29])[CH2:24]1)=O)(C)(C)C.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].CC1(C)CNCCN1C(C1N=CN(C2C=CC=CC=2)N=1)=O>>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]([N:26]3[CH2:27][CH2:28][NH:23][CH2:24][C:25]3([CH3:30])[CH3:29])=[O:15])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=C(O)c1nnn(-c2cccc(Cl)c2)n1
Agent: CC1(C)CNCCN1C(=O)c1ncn(-c2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CNCCN1C(=O)c1nnn(-c2cccc(Cl)c2)n1

Procedure:
This intermediate was prepared from 2-(3-chloro-phenyl)-2H-tetrazole-5-carboxylic acid and 3,3-dimethyl-piperazine-1-carboxylic acid tert-butyl ester in two steps according to the preparation of (2,2-dimethyl-piperazin-1-yl)-(1-phenyl-1-H-[1,2,4]-triazol-3-yl)-methanone trifluoroacetate.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH3:11])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.[OH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>CC(N(C)C)=O.CCOC(C)=O.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]>[OH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH3:11])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1
Reactant: CNc1c([N+](=O)[O-])ccc(Cl)c1C#N
Reactant: OCc1ccccc1B(O)O
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CNc1c([N+](=O)[O-])ccc(-c2ccccc2CO)c1C#N
Temperature: 68 °C
Reaction time: 16 h
Yield: 80.9 %

Procedure:
6-Chloro-2-methylamino-3-nitro-benzonitrile (500 mg, 2.4 mmol), 2-hydroxymethyl-phenylboronic acid (466 mg, 3.1 mmol), and potassium carbonate (1.30 g, 6.1 mmol) were combined in DMA (10 mL) in a flask purged with nitrogen. Tris(dibenzylideneacetone)dipalladium(0) (108 mg, 0.12 mmol) and 2-dicyclohexylphosphino-2′-(N,N-dimethyl-amino)biphenyl (93 mg, 0.24 mmol) were added, and the reaction stirred at 68° C. under nitrogen for 16 h. The solution was diluted with EtOAc (50 mL), and washed with 1N HCl and brine. Organics were dried (MgSO4) and concentrated in vacuo. Purification by silica gel chromatography (2:1:1 hexanes/CHCl3/EtOAc) gave 550 mg (82%) of the title compound as an orange solid. 1H NMR (400 MHz, CDCl3): δ 8.49 (br s, 1H), 8.35 (d, 1H, J=8.8 Hz), 7.59 (d, 1H, J=7.6 Hz), 7.46 (td, 1H, J=7.6, 1.2 Hz), 7.40 (td, 1H, J=7.6, 1.2 Hz), 7.20 (dd, 1H, J=7.6, 1.2 Hz), 6.60 (d, 1H, J=8.8 Hz), 4.52 (qAB, 2H, J=31.6, 12.8 Hz), 3.46 (s, 3H). MS (ES) [m+H] calc'd for C15H13N3O3, 284; found 284.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]([O:17][C:18]([NH:20][CH2:21][C:22]1([C:25]([OH:27])=O)[CH2:24][CH2:23]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[NH2:28][NH2:29].O>C1COCC1>[C:13]([O:17][C:18](=[O:19])[NH:20][CH2:21][C:22]1([C:25]([NH:28][NH2:29])=[O:27])[CH2:24][CH2:23]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCC1(C(=O)O)CC1
Reactant: NN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCC1(C(=O)NN)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
CDI (12.5 g, 0.077 mol) was added to a 0° C. solution of 1-((tert-butoxycarbonylamino)methyl)cyclopropanecarboxylic acid (15.0 g, 0.07 mol) in THF (250 mL). The mixture was allowed to warm to rt, and stirred at rt. for 2 hrs, and then NH2NH2.H2O (10.5 g, 0.21 mol) was added rapidly. The mixture was stirred for another 1 hr. The reaction mixture was concentrated, and then CH2Cl2 (500 mL) was added. The combined organic layer was washed with H2O (100 mL), dried over Na2SO4, and concentrated to afford tert-butyl(1-(hydrazinecarbonyl)cyclopropyl)methylcarbamate (13.5 g, 84%). ESI-MS (EI+, m/z): 230.2 [M+H]+.