Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[C:11]([O:15][C:16](=[O:38])[CH2:17][N:18]1[C:22]2[CH:23]=[CH:24][C:25]([NH:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:26][C:21]=2[N:20]=[C:19]1[CH2:35][CH2:36][CH3:37])([CH3:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.Cl>[C:11]([O:15][C:16](=[O:38])[CH2:17][N:18]1[C:22]2[CH:23]=[CH:24][C:25]([N:27]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:5](=[O:6])[C:4]3[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)=[CH:26][C:21]=2[N:20]=[C:19]1[CH2:35][CH2:36][CH3:37])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: CCCc1nc2cc(NCc3ccccc3)ccc2n1CC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)c3cccc(F)c3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Fluoro-benzoyl chloride (42 μL, 0.36 mmol) was added to a solution of (5-benzylamino-2-propyl-benzoimidazol-1-yl)-acetic acid tert-butyl ester (45 mg, 0.12 mmol), DIEA (41 μL, 0.24 mmol) and DMAP (15 mg, 0.12 mmol) in CH2Cl2 (1 mL), and stirred overnight at room temperature. The reaction solution was diluted with aqueous HCl (1.0 M) and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the subtitle compound that was used without further purification. MS calculated for C30H32FN3O3+H: 502, observed: 502.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[Li]CCCC.CCCCCC.CON(C)[C:23]([C@@H:25]1[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]1)=[O:24]>C1COCC1>[Cl:1][C:2]1[C:3]([F:8])=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:23]([C@@H:25]1[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]1)=[O:24]
Reactant: Fc1ccccc1Cl
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cccc(Cl)c2F)C1
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
To a stirred solution of 1-chloro-2-fluoro-benzene (13.0 g, 0.1 mol) in THF (250 mL) at −75° C. was added dropwise 2.5 M BuLi in hexane (40 mL, 0.1 mol) over 45 min. After additional stirring for 30 min at −75° C., a solution of (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)-piperidine-1-carboxylate (21.76 g, 0.08 mol) in THF (100 mL) was added dropwise over 30 min. The mixture was allowed to warm from −70° C. to 0° C. The mixture was quenched with satd aq NH4Cl, extracted with EtOAc (3×) and the combined organic layers were dried over Na2SO4. Solvent removal and flash column chromatography, eluting with 5% EtOAc/PE afforded (R)-tert-butyl 3-(3-chloro-2-fluorobenzoyl)piperidine-1-carboxylate (19.2 g, 70%). 1H NMR (400 MHz, CDCl3): 1.45 (s, 9H), 1.63 (m, 2H), 1.76 (m, 1H), 2.06 (m, 1H), 2.87 (m, 1H), 3.15 (m, 1H), 3.25 (m, 1H), 3.9 (m, 1H), 4.2 (m, 1H), 7.18 (m, 1H), 7.60 (m, 2H). MS (E/Z): 342 (M+H+).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[C:36]([C:40]3[O:44][CH:43]=[N:42][CH:41]=3)[CH:37]=[N:38][CH:39]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[O:44]1[C:40]([C:36]2[CH:35]=[C:34]([C:2]3[N:11]=[C:10]([NH:12][CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=4)[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][C:8]=4[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:3]=3)[CH:39]=[N:38][CH:37]=2)=[CH:41][N:42]=[CH:43]1
Reactant: CC1(C)OB(c2cncc(-c3cnco3)c2)OC1(C)C
Reactant: Clc1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: c1ccc(-c2cccc3nc(-c4cncc(-c5cnco5)c4)nc(NCc4ccccn4)c23)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 10 %

Procedure:
To a solution of 2-chloro-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (0.115 g, 0.330 mmol) in 1,4-dioxane (6 mL) and H2O (1.5 mL) under nitrogen was added, 5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)oxazole (0.10 g, 0.36 mmol) and potassium carbonate (0.136 g, 0.990 mmol). The reaction mixture was degassed with nitrogen for 15 min. (1,1′-Bis(diphenylphosphino)-ferrocene)palladium (II) chloride dichloromethane complex (0.026 g, 0.033 mmol) was added and the reaction mixture was again degassed for 10 min with nitrogen. The reaction mixture was stirred at 100° C. for 16 h, then allowed to cool to room temperature and quenched with water. The reaction mixture was transferred to a separation funnel and the aqueous layer extracted with ethyl acetate. The combined organic portions were washed with water and saturated NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in dichloromethane to provide 2-(5-(oxazol-5-yl)pyridin-3-yl)-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (0.015 g) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.70 (s, 1H); 9.03 (s, 1H); 8.27 (d, 2H, J=3.6 Hz); 8.03 (s, 1H0; 7.77 (t, 1H, J=7.6 Hz); 7.70-7.58 (m, 2H); 7.54-7.47 (m, 5H0; 7.33-7.28 (m, 1H); 7.20-7.10 (m, 5H0; 6.82 (br, 1 h); 4.80 (d, 2H, J=4.4 Hz). LCMS Method Y: retention time 1.98 min; [M+1]=457.2; HPLC Method A1: purity 98.7%, retention time=7.09 min.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:18]([O-:20])=[O:19])[C:15]=2[CH3:17])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:17][C:15]1[C:14]([N+:18]([O-:20])=[O:19])=[CH:13][CH:12]=[C:11]2[C:16]=1[NH:8][CH2:9][CH2:10]2
Reactant: Cc1c([N+](=O)[O-])ccc2c1N(C(=O)OC(C)(C)C)CC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c([N+](=O)[O-])ccc2c1NCC2
Reaction time: 1.5 h
Yield: 97.2 %

Procedure:
To a solution of 1-t-butoxycarbonyl-2,3-dihydro-7-methyl-6-nitroindole (5.00 g, 17.9 mmol), as prepared above (Example 1C), in methylene chloride (75 mL) is slowly added trifluoroacetic acid (15 mL). The reaction is stirred for 1.5 hours then partitioned between 200 mL of methylene chloride and 200 mL of 1 M aqueous sodium hydroxide solution. The methylene chloride layer is collected, dried over magnesium sulfate, filtered and evaporated to dryness on a rotary evaporator to afford 3.1 g of 2,3-dihydro-7-methyl-6-nitroindole as an orange solid (97% yield).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[N:5]=[C:4]([S:23][CH3:24])[N:3]=1.C(N(C(C)C)C(C)C)C.[CH2:34]([CH2:36][NH2:37])[OH:35]>O1CCOCC1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH:13]2[CH2:14][CH2:15][N:10]([C:6]3[C:7]([C:8]#[N:9])=[C:2]([NH:37][CH2:36][CH2:34][OH:35])[N:3]=[C:4]([S:23][CH3:24])[N:5]=3)[CH2:11][CH2:12]2)=[CH:17][CH:18]=1
Reactant: CSc1nc(Cl)c(C#N)c(N2CCC(c3ccc(F)cc3)CC2)n1
Reactant: NCCO
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nc(NCCO)c(C#N)c(N2CCC(c3ccc(F)cc3)CC2)n1
Yield: 83.6 %

Procedure:
A dispersion of 200 mg (0.55 mmol) of 4-chloro-6-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-methylsulfanyl-pyrimidine-5-carbonitrile and 84 mg (0.6 mmol) of N-ethyl-diisopropylamine in 4 ml of dioxane was treated at 65° C. with 37 mg (0.6 mmol) of ethanolamine during 18 h. For the working-up, the reaction mixture was evaporated, and, thereafter, the residue obtained was directly chromatographed on silica gel using a 5:1 mixture of toluene and ethyl acetate as the eluent yielding 177 mg (0.46 mmol, 83% of theory) of the 4-[4-(4-fluoro-phenyl)-piperidin-1-yl]-6-(2-hydroxy-ethylamino)-2-methylsulfanyl-pyrimidine-5-carbonitrile as a yellowish oil which crystallized on standing. MS: [M+H]+=388.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][CH:9]=[C:8]1[C:18]([N:20]([CH2:42][CH:43]([CH3:45])[CH3:44])[C@H:21]1[CH2:26][C@@H:25]([C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:28])[CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]1)=[O:19].C(OCC)(=O)C.[ClH:52]>C(OCC)(=O)C>[ClH:52].[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][CH:9]=[C:8]1[C:18]([N:20]([CH2:42][CH:43]([CH3:45])[CH3:44])[C@H:21]1[CH2:26][C@@H:25]([C:27]([N:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)=[O:28])[CH2:24][NH:23][CH2:22]1)=[O:19]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)ccc1-c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](C(=O)N3CCOCC3)C2)ccc1-c1ccccc1
Reaction time: 1 h

Procedure:
tert-Butyl (3S,5R)-3-[{[1-(4-methoxybutyl)-5-phenyl-1H-pyrrol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (150 mg) was dissolved in ethyl acetate (5 ml), 4N hydrogen chloride-ethyl acetate (5 ml) was added and the mixture was stirred for 1 hr. The solvent was evaporated under reduced pressure to give the object product (110 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:9]1[C:14]([C:15]2[O:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:22][CH:21]=3)=[N:17][N:16]=2)=[CH:13][C:12](B2OC(C)(C)C(C)(C)O2)=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:53]1[CH:58]=[CH:57][C:56]([S:59]([CH:62]([CH3:64])[CH3:63])(=[O:61])=[O:60])=[CH:55][N:54]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]([C:45]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:46])[C:9]1[C:14]([C:15]2[O:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[CH:22][CH:21]=3)=[N:17][N:16]=2)=[CH:13][C:12]([C:53]2[CH:58]=[CH:57][C:56]([S:59]([CH:62]([CH3:64])[CH3:63])(=[O:60])=[O:61])=[CH:55][N:54]=2)=[CH:11][N:10]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(Cc1ccc(-c2nnc(-c3cc(B4OC(C)(C)C(C)(C)O4)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)o2)cc1)C(=O)OC(C)(C)C
Reactant: CC(C)S(=O)(=O)c1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3nnc(-c4ccc(CN(C)C(=O)OC(C)(C)C)cc4)o3)c2)nc1
Temperature: 95 °C
Reaction time: 2 h

Procedure:
The reaction mixture from Method F Step 1 was diluted with DMF (2 mL) an 2-bromo-5-isopropylsulfonyl-pyridine [Compound I-7a; prepared according to Method F-1] (48 mg, 0.1817 mmol), Pd(PPh3)2Cl2 (6.263 mg, 0.01514 mmol) and 2M aqueous Na2CO3 (227.1 μL, 0.4542 mmol) were added. The reaction was degassed with nitrogen and stirred at 95° C. for 2 hours in a sealed tube. The reaction mixture was partitioned between EtOAc and brine and the aqueous layer extracted with EtOAc (×2). The combined organic extracts were washed with brine (×3), dried (MgSO4), filtered and concentrated in vacuo. The crude residue was used in the deprotection step without further purification.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[CH3:7][C:8]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:9]=1[O:10][CH2:11][C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=1[C:14]([C:17]#[N:18])=[N:15]O.S(OC)(OC)(=O)=O>CC(C)=O>[CH3:7][C:8]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:9]=1[O:10][CH2:11][C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=1[C:14]([C:17]#[N:18])=[N:15][O:4][CH3:1]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(C)c(OCc2ccccc2C(C#N)=NO)c1
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: CON=C(C#N)c1ccccc1COc1cc(C)ccc1C
Reaction time: 0.08 h
Yield: 92.4 %

Procedure:
Potassium carbonate (3.32 g, 0.024 mol) and acetone (200 ml) were added to 2-(2,5-dimethylphenoxymethyl)-α-hydroxyiminobenzyl cyanide (E/Z=15/85) (5.61 g, 0.02 mol). The mixture was stirred for 5 minutes. Then dimethyl sulfate (3.03 g, 0.024 mol) was added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the resulting insoluble materials were removed. To the residue obtained after evaporation under reduced pressure, toluene (50 ml) and 1N aqueous sodium hydroxide solution (50 ml) were added. The mixture was stirred for 1 hour. After stirring, water (150 ml) was added. The mixture was extracted with ether (150 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(2,5-dimethylphenoxymethyl)-α-methoxyiminobenzyl cyanide (5.44 g, Yield: 92.4%, E/Z=15/85).
Reaction SMILES: [C:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH:2]=1.[F:7][C:8]1[CH:9]=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[C:12](O)[CH:13]=1.CCOC(/N=N/C(OCC)=O)=O>>[CH:1]1([O:6][C:10]2[CH:9]=[C:8]([F:7])[CH:13]=[CH:12][C:11]=2[N+:15]([O-:17])=[O:16])[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: OC1=CCCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Product: O=[N+]([O-])c1ccc(F)cc1OC1CC=CC1

Procedure:
Prepared analogously to XVI.1 from 1 g cyclopentenol, 1.57 g 5-fluoro-2-nitro-phenol and 1.89 ml DEAD.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:9]1(=O)[O:14][C:12](=[O:13])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[C:11]3[C:10](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9]2=[O:14])=[N:6][CH:7]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1ccc(N)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(N2C(=O)c3ccccc3C2=O)nc1

Procedure:
A mixture containing 5-methylpyridin-2-amine (5.4 g, 50 mmol), phthalic anhydride (8.88 g, 60 mmol) and DIEA (19 ml, 110 mmol) in toluene (30 ml) is refluxed for 18 hours, and cooled. The solvent is removed by rotary evaporation. The crude product is purified by silica gel flash chromatography to afford 2-(5-methylpyridin-2-yl)isoindoline-1,3-dione as a dark brown oil. LC-MS m/z: 239.1 (M+1).
Reaction SMILES: C(OC([NH:8][C:9]1([C:12]2[NH:13][C:14]([C:22]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:23]=3[N:24]=[C:25]([NH:33][CH2:34][C:35]([F:38])([F:37])[F:36])[C:26]([CH3:32])=[N:27]4)=[CH:15][C:16]=2[C:17]([O:19]CC)=[O:18])[CH2:11][CH2:10]1)=O)(C)(C)C.[ClH:39]>O1CCOCC1.O>[ClH:39].[NH2:8][C:9]1([C:12]2[NH:13][C:14]([C:22]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:23]=3[N:24]=[C:25]([NH:33][CH2:34][C:35]([F:36])([F:38])[F:37])[C:26]([CH3:32])=[N:27]4)=[CH:15][C:16]=2[C:17]([OH:19])=[O:18])[CH2:10][CH2:11]1
Reactant: CCOC(=O)c1cc(-c2cccc3nc(C)c(NCC(F)(F)F)nc23)[nH]c1C1(NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc2cccc(-c3cc(C(=O)O)c(C4(N)CC4)[nH]3)c2nc1NCC(F)(F)F
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
A mixture of ethyl 2-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-5-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)-1H-pyrrole-3-carboxylate (381a, 970 mg, 1.81 mmol) and LiOH monohydrate (381 mg, 9.09 mmol) in dioxane (8.0 mL) and water (4.00 mL) was heated at 110° C. for 5 h. It was concentrated to dryness and the remaining solid was treated with 4.0 M HCl solution in 1,4-dioxane (11.36 mL, 45.5 mmol) at RT and stirred for 30 min. The reaction mixture was concentrated to give 2-(1-aminocyclopropyl)-5-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (381b) as a red-orange solid. It was used in the subsequent step without further purification assuming quantitative yield. m/z (ESI, +ve ion) 406.1 (M−35)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[OH:19])=[N:10][C:9]=2[CH:20]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH:32](I)([CH3:34])[CH3:33]>O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[O:19][CH:32]([CH3:34])[CH3:33])=[N:10][C:9]=2[CH:20]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)I
Reactant: CC(C)(C)c1ccc2oc(-c3ccncc3O)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1cnccc1-c1nc2cc(C(C)(C)C)ccc2o1
Temperature: 60 °C
Yield: 60.5 %

Procedure:
To a mixture of 0.30 g of 4-(5-tert-butylbenzoxazole-2-yl)pyridin-3-ol, 0.17 g of potassium carbonate and 3 ml of DMF, 0.21 g of isopropyl iodide was added at room temperature. The reaction mixture was stirred while heating at 60° C. for two hours. The mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.21 g of 5-tert-butyl-2-(3-isopropoxypyridin-4-yl)benzoxazole (hereinafter, referred to as “active compound 104”).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[CH2:23][S:24](Cl)(=[O:26])=[O:25].N1C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][S:24]([CH2:23][C:14]2[CH:15]=[C:16]([C:19]([F:20])([F:21])[F:22])[CH:17]=[CH:18][C:13]=2[Cl:12])(=[O:26])=[O:25])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: O=S(=O)(Cl)Cc1cc(C(F)(F)F)ccc1Cl
Reactant: COC(=O)c1nccnc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1nccnc1NS(=O)(=O)Cc1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a solution of 3-amino-pyrazine-2-carboxylic acid methyl ester (commercially available) (2.0 g) and (2-chloro-5-trifluoromethyl-phenyl)-methanesulfonyl chloride (Example 1.2) (4.2 g) in dichloromethane (32 ml) was added dropwise pyridine (5.3 ml) over a period of 5 minutes at ambient temperature. The reaction mixture was stirred at ambient temperature for 23 hours. Dichloromethane (50 ml) was added to the reaction mixture and the mixture was washed with aqueous sulfuric acid (2M) (3×30 ml). The phases were separated and the organic layer was concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/dichloromethane from 0:10 to 1:9) to give 3-(2-chloro-5-trifluoromethyl-phenylmethanesulfonylamino)-pyrazine-2-carboxylic acid methyl ester as a white solid (4.728 g). 1H-NMR (400 MHz, CDCl3): 10.30 (s, 1H), 8.59 (s, 1H), 8.47 (s, 1H), 7.77 (bs, 1H), 7.54-7.60 (m, 2H), 5.15 (s, 2H), 4.04 (s, 3H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:12]1[N:17]=[C:16]([Cl:18])[CH:15]=[CH:14][N:13]=1.[OH-].[Na+]>O.CC(C)=O>[Cl:18][C:16]1[CH:15]=[C:14]([O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[N:13]=[CH:12][N:17]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Clc1ccnc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2cc(Cl)ncn2)cc1
Temperature: 62.5 °C
Reaction time: 1 h

Procedure:
4-Nitrophenol (2.8 g, 20.1 mmol), 2,4-dichloro-pyrimidine (3 g, 20.1 mmol), NaOH (0.8 g, 20.1 mmol) dissolved in H2O/acetone (80 ml; 1:1) are stirred at 60-65° C. for 1 h. The reaction solution is concentrated under reduced pressure and flash chromatographed (silica gel, 4.5×22 cm, AcOEt/hexane=1:4) to give the title compound of Stage 21.2 as a colorless solid: M+H=252/254; 1H-NMR (400 MHz, DMSO-d6): 8.67 (s, 1H, pyrimidinyl), 8.34 (d, 9 Hz, 2H, phenyl), 7.58 (d, 9 Hz, 2H, phenyl), 7.53 (s, 1H, pyrimidinyl); Rf (AcOEt/hexane=1:1): 0.16; m.p.=125.4-126.6° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[N:8][C:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:10]([N+:17]([O-])=O)[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:5])[CH3:2].C(O)(=O)C>C(O)C>[NH2:17][C:10]1[C:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:8][C:7]([S:26]([C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=2)(=[O:28])=[O:27])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1c(S(=O)(=O)c2ccc(C)cc2)nc(-c2ccccc2)c([N+](=O)[O-])c1C(=O)OCC
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1c(S(=O)(=O)c2ccc(C)cc2)nc(-c2ccccc2)c(N)c1C(=O)OCC
Temperature: 80 °C
Reaction time: 4.5 h
Yield: 43.8 %

Procedure:
In 10 ml of ethanol was suspended 0.35 g of 3,4-diethoxycarbonyl-5-nitro-6-phenyl-2-(p-tolylsulfonyl)pyridine, whereto 2 ml of acetic acid and 0.15 g of reduced iron were added. The mixture was stirred at 80° C. for 4.5 hours. After ethanol was distilled off, the residue was neutralized with an aqueous solution of sodium hydrogencarbonate, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over sodium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel flash column chromatography with chloroform/ethyl acetate (4:1) as the eluent, to give 0.144 g of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:13][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][N:8]=1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc2[nH]nc(Br)c2c1
Yield: 130.5 %

Procedure:
To a solution of 12.4 g of 5-nitro-1H-indazole in 100 ml carbon tetrachloride were added 16.2 g of N-bromosuccinimide and 0.62 g of 2,2′-azobisisobutyronitrile, and the mixture was heated under reflux for 1 hour. The reaction mixture was cooled, and the resulting crystals were filtrated and washed with diethyl ether, to give 24.0 g of the title compound as a pale yellow powder.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13]([C:15]1[C:16]2[CH:17]=[CH:18][NH:19][C:20]=2[CH:21]=[CH:22][CH:23]=1)=[O:14].[CH:24]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([NH:29][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:12][C:13]([C:15]2[C:16]3[CH:17]=[CH:18][NH:19][C:20]=3[CH:21]=[CH:22][CH:23]=2)=[O:14])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NC1CCCC1
Reactant: O=C(Nc1ccccc1OCCCBr)c1cccc2[nH]ccc12
Product: O=C(Nc1ccccc1OCCCNC1CCCC1)c1cccc2[nH]ccc12

Procedure:
Using the procedure of Example 41, Step B, 4 g of the product of Step A of Example 41 and 2.11 ml of cyclopentylamine were reacted to obtain 3.3 g of N-[2-[3-(cyclopentylamino)propoxy]phenyl]-1H-indol-4-carboxamide and then 2.8 g of its hydrochloride melting at 244° C.
Reaction SMILES: C(N(CC)CC)C.[Br:8][CH:9]([CH:12](Br)[C:13]([F:16])([F:15])[F:14])[C:10]#[N:11]>O1CCCC1>[Br:8]/[C:9](=[CH:12]\[C:13]([F:16])([F:15])[F:14])/[C:10]#[N:11]
Reactant: N#CC(Br)C(Br)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#C/C(Br)=C/C(F)(F)F
Reaction time: 1 h
Yield: 67.4 %

Procedure:
Triethylamine (317 g, 0.037 mol) is added dropwise to a solution of 2,3-dibromo-4,4,4-trifluorobutyronitrile (5.32 g, 0.023 mol) and tetrahydrofuran (100 mL). A voluminous white precipitate forms during the addition. Stirring is continued for 1 hour, then the solid is filtered off and washed with tetrahydrofuran. The tetrahydrofuran is distilled off to give a dark brown oil. Bulb to bulb distillation (15 mm, 24° C.) of the oil yields the title product as a clear colorless liquid (3.1 g, 82%). NMR spectral analyses identifies a 6:1 mixture of E:Z.