Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=2[CH3:18])[CH:3]=1.OB(O)[C:21]1[CH:22]=[N:23][CH:24]=[N:25][CH:26]=1>C(O)C>[CH3:18][C:10]1[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:9]=1[NH:8][C:4]1[CH:3]=[C:2]([C:21]2[CH:22]=[N:23][CH:24]=[N:25][CH:26]=2)[N:7]=[CH:6][N:5]=1
Reactant: OB(O)c1cncnc1
Reactant: Cc1ccc([N+](=O)[O-])cc1Nc1cc(Cl)ncn1
Solvent: CCO
Product: Cc1ccc([N+](=O)[O-])cc1Nc1cc(-c2cncnc2)ncn1
Yield: 21.1 %

Procedure:
3.28 g of 2-[(6-chloro)pyrimidin-4-ylamino]-1-methyl-4-nitrobenzene (Reference Example 20 (step 1)) were dissolved with heating in 130 ml of anhydrous ethanol. 1.69 g of dihydroxy(5-pyrimidinyl)borane was added, and then deaeration was performed, followed by purging with argon. 5.82 g of potassium carbonate and 2.15 g of tetrakis(triphenylphosphine)palladium (0) were added in turn, and then the mixture was heated at reflux for 7.5 hours. The reaction solution was mixed with water, followed by extraction with ethyl acetate twice, and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was crystallized by adding chloroform-methanol to obtain 808 mg of the objective compound as ocherous crystals.
Reaction SMILES: C(O)(=O)C(O)=O.[CH3:7][N:8]([CH2:10][C:11]1[O:15][C:14]([CH2:16][SH:17])=[CH:13][CH:12]=1)[CH3:9].Cl[CH2:19][CH2:20][NH:21][C:22]([NH:27][CH3:28])=[CH:23][N+:24]([O-:26])=[O:25].[OH-].[K+]>O>[CH3:9][N:8]([CH2:10][C:11]1[O:15][C:14]([CH2:16][S:17][CH2:19][CH2:20][NH:21][C:22]([NH:27][CH3:28])=[CH:23][N+:24]([O-:26])=[O:25])=[CH:13][CH:12]=1)[CH3:7]
Reactant: CNC(=C[N+](=O)[O-])NCCCl
Reactant: CN(C)Cc1ccc(CS)o1
Agent: O=C(O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CNC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Reaction time: 2.5 h
Yield: 45.7 %

Procedure:
To a stirred mixture of 5-[(dimethylamino)methyl]-2-furanmethane-thiol oxalate (1:1) (1.31 g) and N-(2-chloroethyl)-N'-methyl-2-nitro-1,1-ethenediamine (1.08 g) in water (20 ml) at 45° under an atmosphere of nitrogen was added a solution of potassium hydroxide (1.04 g) in water (3 ml). The solution was stirred at 45° for 2.5 hr. and at room temperature for 15 hr. The solution was then evaporated in vacuo, the residue dissolved in water and a stream of air passed into the mixture for 15 mins. The mixture was extracted with ether (2×15 ml) and the aqueous fraction evaporated in vacuo. To the residue was added tetrahydrofuran (70 ml), an excess of anhydrous sodium carbonate, and decolourising charcoal. After 1 hr the mixture was filtered, the filtrate evaporated in vacuo and the oily residue dissolved in 4-methyl-pentan-2-one (8 ml). The solid which separated was filtered and washed with 4-methylpentan-2-one to give the title compound (0.72 g), m.p. 63°-66°, which was not depressed on admixture with a sample prepared according to the method of Example 15 in British Patent Specification No. 1565966.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9](Cl)=[O:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[NH2:12][C@H:13]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:14]1>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][N:15]2[CH2:16][CH2:17][C@H:13]([NH:12][C:9]([C:4]34[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]3)[CH2:2][CH2:3]4)=[O:10])[CH2:14]2)=[CH:21][CH:22]=1
Reactant: O=C(Cl)C12CCN(CC1)CC2
Reactant: N[C@H]1CCN(CCc2ccc(F)cc2)C1
Product: O=C(N[C@H]1CCN(CCc2ccc(F)cc2)C1)C12CCN(CC1)CC2

Procedure:
1-Azabicyclo[2.2.2]octane-4-carbonyl chloride and (S)-3-amino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine were reacted under the same conditions as in Example 53 to give (S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)-1-azabicyclo[2.2.2]octane-4-carboxamide.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12]([C:14]1[O:18][C:17]([CH:19]=O)=[CH:16][CH:15]=1)[CH3:13]>C(O)(=O)C.CCO>[CH2:12]([C:14]1[O:18][C:17]([CH:19]=[N:9][NH:8][C:6](=[O:7])[C:5]2[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=2)=[CH:16][CH:15]=1)[CH3:13]
Reactant: NNC(=O)c1ccc(O)cc1
Reactant: CCc1ccc(C=O)o1
Solvent: CC(=O)O
Solvent: CCO
Product: CCc1ccc(C=NNC(=O)c2ccc(O)cc2)o1
Temperature: 25 °C
Yield: 85.2 %

Procedure:
To a solution of 4-hydroxy-benzoic acid hydrazide (0.3 g, 0.002 mol) and 5-ethyl-2-furaldehyde (0.25 g, 0.002 mol) in abs. EtOH (10 mL), was added 1 drop of acetic acid. The reaction mixture was refluxed for 5 hours. The reaction mixture was cooling to room temperature and concentrated to remove solvent. The resulting residue was solidified by pet ether to give red solid 0.44 g, in 85% yield, mp: 60.5° C. 1H NMR (DMSO-d6) δ 11.53 (s, 1H), 10.16 (s, 1H), 8.24 (s, 1H), 7.79 (d, 2H), 6.87 (d, 2H), 6.81 (s, 1H), 2.71 (q, 2H), 1.24 (t, 3H). 13C NMR (DMSO-d6) δ 164.5, 162.1, 161.2, 149.8, 138.5, 131.5, 125.7, 116.9, 116.7, 108.9, 22.8, 13.8. Anal. Calcd for C14H14N2O3: C, 65.11; H, 5.46; N, 10.85. Found: C, 65.00; H, 5.36; N, 10.55.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[SH:20][C:21]1[S:22][C:23]([C:26]([OH:30])([CH2:28][CH3:29])[CH3:27])=[CH:24][N:25]=1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([S:20][C:21]4[S:22][C:23]([C:26]([OH:30])([CH3:27])[CH2:28][CH3:29])=[CH:24][N:25]=4)=[CH:3][CH:4]=3)[O:9][C:8](=[O:12])[CH:7]=2)=[CH:14][CH:15]=1
Reactant: CCC(C)(O)c1cnc(S)s1
Reactant: O=c1cc(-c2ccc(F)cc2)c2ccc(Br)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCC(C)(O)c1cnc(Sc2ccc3c(-c4ccc(F)cc4)cc(=O)oc3c2)s1

Procedure:
Employing the procedure described in Example 1, Step 3, using 7-bromo-4-(4-fluorophenyl)-2H-chromen-2-one, 2-(2-mercapto-1,3-thiazole-5-yl)butan-2-ol and K2CO3 in NMP, the title compound was obtained. 1H NMR (400 MHz, acetone-d6): δ 7.72 (s, 1H), 7.63-7.68 (m, 2H), 7.51 (d, 1H), 7.43 (d, 1H), 7.33-7.41 (m, 3H), 6.38 (s, 1H), 1.93-1.80 (m, 2H), 1.61 (s, 3H), 0.90 (t, 3H).
Reaction SMILES: Br[C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[NH:8][C:9]([C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[C:31]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32]>>[C:31]([C:35]1[CH:40]=[CH:39][C:38]([C:2]2[CH:3]=[CH:4][C:5]([CH2:6][C:7]3[NH:8][C:9]([C:20]4[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=4)=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=4[Cl:19])[N:11]=3)=[CH:29][CH:30]=2)=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: O=[N+]([O-])c1ccc(-c2[nH]c(Cc3ccc(Br)cc3)nc2-c2ccc(Cl)cc2Cl)cc1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: CC(C)(C)c1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)c(-c4ccc([N+](=O)[O-])cc4)[nH]3)cc2)cc1

Procedure:
2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-5-(4-nitro-phenyl)-1H-imidazole (prepared according to general procedure A) (1.0 g, 2 mmol) was treated as described in general procedure G using 4-tert-butylphenylboronic acid (712 mg, 4 mmol) to give 2-(4′-tert-butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-5-(4-nitro-phenyl)-1H-imidazole, which was treated as described in general procedure L using 2-(trimethylsilyl)ethoxymethyl chloride (0.7 mL, 4 mmol) to give 2-(4′-tert-butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-5-(4-nitro-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H -imidazole.
Reaction SMILES: [O:1]=[C:2]1[N:8]([O:9][CH2:10][CH:11]=[CH2:12])[CH:7]2[CH2:13][N:3]1[N:4]([CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=12>C(Cl)Cl.FC(F)(F)C(O)=O>[O:1]=[C:2]1[N:8]([O:9][CH2:10][CH:11]=[CH2:12])[CH:7]2[CH2:13][N:3]1[N:4]([CH2:18][C:19]([OH:21])=[O:20])[C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=12
Reactant: C=CCON1C(=O)N2CC1c1ccccc1N2CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCON1C(=O)N2CC1c1ccccc1N2CC(=O)O
Reaction time: 0.25 h
Yield: 41 %

Procedure:
The ester obtained in Example 24 is dissolved in 2.5 cm3 of CH2Cl2 and 7.5 cm3 of trifluoroacetic acid. After 15 min, the solvent is evaporated by entraining it with toluene, and then the compound is crystallized from ether. 519 mg of the expected acid (41%) are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Br:12])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2.[NH:13]1[CH2:17][CH2:16][N:15]=[C:14]1S(O)(=O)=O>C(O)C(C)C>[Br:12][C:3]1[C:2]([NH:1][C:14]2[NH:15][CH2:16][CH2:17][N:13]=2)=[CH:11][CH:10]=[C:9]2[C:4]=1[N:5]=[CH:6][CH:7]=[N:8]2
Reactant: O=S(=O)(O)C1=NCCN1
Reactant: Nc1ccc2nccnc2c1Br
Solvent: CC(C)CO
Product: Brc1c(NC2=NCCN2)ccc2nccnc12
Temperature: 25 °C
Yield: 61 %

Procedure:
A mixture of 6-amino-5-bromo quinoxaline (prepared using the method reported by Danielewicz U.S. Pat. No. 3,890,319) (0.224 g, 2 mmol), imidazoline-2-sulfonic acid (0.30 g, 2 mmol) and isobutanol (3 ml) was heated to 125° C. and maintained at this temperature for 16 hours. The mixture was then cooled to room temperature and concentrated in vacuo to give a brown residue which was chromatographed (silica gel, 9:1 CHCl3 /CH3OH saturated with NH3 (g)) to yield 0.177 g (a yield of 61%) of the title compound as a yellow solid, which was characterized spectroscopically.
Reaction SMILES: C([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:24]3[C:19](=[N:20][CH:21]=[N:22][C:23]=3[NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[NH:18][N:17]=2)=[CH:11][CH:10]=1)(OC(C)(C)C)=O.Cl.C(OCC)C>CO>[ClH:32].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:24]3[C:19](=[N:20][CH:21]=[N:22][C:23]=3[NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[NH:18][N:17]=2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Nc1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 0.25 g (0.553 mmol) of 3-[4-(N-BOC-amino)-phenylamino]-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Example 65) and 10 ml of a 3N solution of hydrochloric acid in methanol is stirred at RT for 20 hours. Then 10 ml of diethyl ether are added, the reaction mixture is filtered and the filter residue is digested in hot methanol. After cooling, filtering and washing the filter residue with diethyl ether, the crystals are dried for 15 hours under a high vacuum at 100° C. and then left to stand under ambient conditions for 24 hours, yielding the title compound containing 10.97% hydrogen chloride and 4.34% water; m.p. 211-213° C.; EI-MS: (M)+ =351.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]1[N:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][CH:8]=1.C(N(CC)C(C)C)(C)C.Cl[CH2:27][O:28][CH3:29]>C(Cl)(Cl)Cl>[CH3:27][O:28][CH2:29][N:3]1[CH:4]=[CH:5][S:1][C:2]1=[N:6][C:7]1[N:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)c1cccc(Nc2nccs2)n1
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COCn1ccsc1=Nc1cccc(C(=O)OC)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a mixture of 4.85 g (20.6 mmol) of methyl 6-(thiazol-2-ylamino)-pyridine-2-carboxylate, 7.20 ml (41.2 mmol) of N,N-diisopropylethylamine and 100 ml of chloroform was added 2.35 ml (30.9 mmol) of chloromethylmethyl ether followed by stirring at room temperature for 1 hour. The reaction mixture was washed with 100 ml of water for three times and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to about 20 ml in total and the resulting solid was filtered. The resulting solid was washed with ether and dried in vacuo to give 6.38 g (20.6 mmol) of the title compound as a white solid.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[C:12]([C:17]#N)[CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5]C=[CH:3][CH:2]=1.C(OC([C:31]1C2C(=CC=CC=2)C=C[N:32]=1)(C)C)(=O)C1C=CC=CC=1>>[CH2:6]([CH:1]([C:7]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:17][C:31]#[N:32])[C:11]=2[CH:10]=[CH:9][N:8]=1)[CH2:2][CH3:3])[CH3:5]
Reactant: N#Cc1cccc2c(-c3ccccc3)nccc12
Reactant: CC(C)(OC(=O)c1ccccc1)c1nccc2ccccc12
Product: CCC(CC)c1nccc2c(CC#N)cccc12

Procedure:
1-(1-Ethylpropyl)isoquinoline and N-hydroxymethyl dichloroacetamide were reacted in the same way as in step (b) of Example 18 to afford 1-(1-ethylpropyl)-5-dichloroacetylaminomethylisoquinoline. The product was successively reacted in the same way as in steps (c), (d), (e) and (f) of Example 18 to afford 1-(1-ethylpropyl)-isoquinoline-5-acetonitrile. The product was treated in the same way as in Example 3 to afford 1-(1-ethylpropyl)-isoquinoline-5-acetic acid as an oil. The hydrochloride of the product was in the form of colorless prisms having a melting point of 107° to 109° C.
Reaction SMILES: C=O.[Cl:3][C:4]1[CH:29]=[CH:28][C:7]2[N:8]3[C:12]([CH2:13][NH:14][CH2:15][C:6]=2[CH:5]=1)=[N:11][N:10]=[C:9]3[CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:18][CH2:17]1.[C:30](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:3][C:4]1[CH:29]=[CH:28][C:7]2[N:8]3[C:12]([CH2:13][N:14]([CH3:30])[CH2:15][C:6]=2[CH:5]=1)=[N:11][N:10]=[C:9]3[CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[N:23]=[CH:24][CH:25]=[CH:26][N:27]=2)[CH2:18][CH2:17]1
Reactant: Clc1ccc2c(c1)CNCc1nnc(C3CCN(c4ncccn4)CC3)n1-2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1Cc2cc(Cl)ccc2-n2c(nnc2C2CCN(c3ncccn3)CC2)C1
Reaction time: 18 h
Yield: 64.1 %

Procedure:
Formaldehyde (37% w/v aqueous, 0.1 ml, 1.2 mmol) was added to a solution of the amine of example 12 (100 mg, 0.26 mmol) in dichloromethane (5 ml). The mixture was stirred at room temperature for 0.25 hours before sodium triacetoxyborohydride (111 mg, 0.53 mmol) was added, and the reaction mixture was stirred for a further 18 hours. The mixture was partitioned between 2N aqueous sodium hydroxide solution (10 ml) and dichloromethane (10 ml). The organic layer was evaporated under reduced pressure and purified by chromatography on silica gel using methanol in dichloromethane (5:95) as eluant to afford the title compound as a brown foam (66 mg).
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[C:5]([OH:25])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1.Br[CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31].C(=O)([O-])[O-].[K+].[K+].FC(F)OC1C(OCC(C)(C)C)=C(/C=C/C2N=C3N(C=2C(O)=O)C=CS3)C=CC=1>CN(C)C=O>[F:26][CH:2]([F:1])[O:3][C:4]1[C:5]([O:25][CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1c(/C=C/c2cccc(OC(F)F)c2O)nc2sccn12
Reactant: CC(C)CCBr
Agent: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)O)cccc1OC(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(/C=C/c2cccc(OC(F)F)c2OCCC(C)C)nc2sccn12
Yield: 100.2 %

Procedure:
Alkylation of Intermediate 6 (400 mg, 1.052 mmol) with 1-bromo-3-methylbutane (159 mg, 1.262 mmol) in presence of potassium carbonate (159 mg, 1.157 mmol) in anhydrous N,N-dimethylformamide (4 mL) as described in Intermediate 7A gave 475 mg of the compound as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.93 (t, J=6.6 Hz, 6H), 1.40 (t, J=7.2 Hz, 3H), 1.66 (q, J=6.3 Hz, 2H), 1.82-1.90 (m, 1H), 3.96 (t, J=6.3 Hz, 2H), 4.40 (q, J=6.9 Hz, 2H), 7.19 (t, J=71.4 Hz, 1H), 7.20-7.28 (m, 2H), 7.42-7.50 (m, 1H), 7.53-7.60 (m, 1H), 7.80 (s, 2H), 8.13 (d, J=4.2 Hz, 1H); APCI-MS (m/z) 451.23 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[C:22]([N:23]4[CH2:28][CH2:27][CH:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH2:25][CH2:24]4)=[N:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([C:35]([O:37]CC)=[O:36])[CH:19]=4)[N:14]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.O>[C:1]1([CH:7]2[CH2:8][CH2:9][N:10]([C:13]3[C:22]([N:23]4[CH2:24][CH2:25][CH:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH2:27][CH2:28]4)=[N:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([C:35]([OH:37])=[O:36])[CH:19]=4)[N:14]=3)[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1ccc2nc(N3CCC(c4ccccc4)CC3)c(N3CCC(c4ccccc4)CC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(N3CCC(c4ccccc4)CC3)c(N3CCC(c4ccccc4)CC3)nc2c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of ethyl 2,3-bis(4-phenylpiperidin-1-yl)quinoxaline-6-carboxylate (150 mg, 0.29 mmol, 1.00 equiv) in methanol (25 mL) and a solution of sodium hydroxide (58 mg, 1.45 mmol, 5.00 equiv) in water (2 mL). The resulting solution was stirred for 3 h at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 30 mL of water. The pH value of the aqueous solution was adjusted to 3 with 1N hydrochloric acid. The resulting solids were collected by filtration. The solid was dried in an oven under reduced pressure and purified by re-crystallization from methanol. This resulted in 80 mg (56%) of 2,3-bis(4-phenylpiperidin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[OH:26][CH2:27][C:28]([NH:32][S:33]([C:36]1[CH:37]=[N:38][CH:39]=[C:40](Br)[CH:41]=1)(=[O:35])=[O:34])([CH2:30][OH:31])[CH3:29]>>[OH:26][CH2:27][C:28]([NH:32][S:33]([C:36]1[CH:37]=[N:38][CH:39]=[C:40]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:41]=1)(=[O:35])=[O:34])([CH2:30][OH:31])[CH3:29]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(CO)(CO)NS(=O)(=O)c1cncc(Br)c1
Product: CC(CO)(CO)NS(=O)(=O)c1cncc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (200 mg, 0.56 mmol) and 5-bromo-pyridine-3-sulfonic acid (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide (example B.4) (165 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (120 mg, 35%). MS (ISP) 600.2 [(M+H)+]; mp 228-231° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.COC1C=CC=CC=1N[C:19](=[O:24])[CH2:20][C:21]([OH:23])=[O:22]>>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:19](=[O:24])[CH2:20][C:21]([OH:23])=[O:22])=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cc1
Reactant: COc1ccccc1NC(=O)CC(=O)O
Product: COc1ccc(NC(=O)CC(=O)O)cc1
Yield: 56 %

Procedure:
Starting from 4-methoxyaniline and following the procedure described above for the synthesis of compound 27 (example 8, scheme 8), title compound 157 was obtained in 56% yield. MS (m/z): 210.0 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[CH3:9][O:10][C:11]1[CH:16]=[C:15]([CH3:17])[NH:14][C:13](=[O:18])[C:12]=1[CH2:19][NH:20][C:21]([C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]([CH:32]([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH3:33])[C:24]=1[CH3:40])=[O:22].CCN(CC)CC>CCO>[CH3:9][O:10][C:11]1[CH:16]=[C:15]([CH3:17])[NH:14][C:13](=[O:18])[C:12]=1[CH2:19][NH:20][C:21]([C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]([CH:32]([CH:34]2[CH2:35][CH2:36][N:37]([C:2]3[N:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH2:38][CH2:39]2)[CH3:33])[C:24]=1[CH3:40])=[O:22]
Reactant: COc1cc(C)[nH]c(=O)c1CNC(=O)c1c(C)n(C(C)C2CCNCC2)c2ccccc12
Reactant: Clc1ncccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cc(C)[nH]c(=O)c1CNC(=O)c1c(C)n(C(C)C2CCN(c3ncccn3)CC2)c2ccccc12
Temperature: 100 °C
Yield: 64.6 %

Procedure:
To a re-sealable vial was added 2-chloropyrimidine (185 mg, 1.611 mmol), (R or S)-N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(piperidin-4-yl)ethyl)-1H-indole-3-carboxamide hydrochloride (508 mg, 1.074 mmol) (Compound 326), and EtOH (8 mL). To this solution was added Et3N (449 μl, 3.22 mmol). The vial was sealed and heated to 100° C. overnight. The solution was allowed to cool to room temperature and concentrated in vacuo. The crude residue was purified via silica gel chromatography (hexanes: (3:2 DCM:IPA)) to afford the title compound as a solid (357 mg, 0.694 mmol, 64.6% yield). LCMS 515 (M+1)+; 1H NMR (DMSO-d6, 400 MHz) δ 11.60 (s, 1 H), 8.30 (d, J=4.7 Hz, 2 H), 7.76 (d, J=7.6 Hz, 1 H), 7.73-7.64 (m, 2 H), 7.14-7.01 (m, 2 H), 6.55 (t, J=4.7 Hz, 1 H), 6.15 (s, 1 H), 4.84-4.75 (m, 1 H), 4.57-4.47 (m, 1 H), 4.33 (d, J=4.2 Hz, 2 H), 4.22-4.11 (m, 1 H), 3.84 (s, 3 H), 2.92-2.81 (m, 1 H), 2.63-2.52 (m, 4 H), 2.20 (s, 3H), 2.05-1.94 (m, 1 H), 1.61-1.49 (m, 4 H), 1.34-1.21 (m, 1 H), 1.04-0.91 (m, 1 H), 0.83-0.75 (m, 1 H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([C:15]([N:17]([CH:31]([CH3:33])[CH3:32])[C@@H:18]3[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]3)=[O:16])[C:12]([CH3:14])=[CH:13][C:8]=2[O:7][C:6]([CH3:35])([CH3:34])[C:5]1=[O:36].C(N(CC)CC)C.[C:44](Cl)(=[O:46])[CH3:45]>O1CCCC1>[C:44]([NH:1][CH2:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([C:15]([N:17]([CH:31]([CH3:32])[CH3:33])[C@@H:18]3[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:19]3)=[O:16])[C:12]([CH3:14])=[CH:13][C:8]=2[O:7][C:6]([CH3:34])([CH3:35])[C:5]1=[O:36])(=[O:46])[CH3:45]
Reactant: CC(=O)Cl
Reactant: Cc1cc2c(cc1C(=O)N(C(C)C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1)N(CCN)C(=O)C(C)(C)O2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NCCN1C(=O)C(C)(C)Oc2cc(C)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To tert-butyl (3R)-3-[{[4-(2-aminoethyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (200 mg) were added triethyl-amine (0.040 ml), tetrahydrofuran (3 ml), acetyl chloride (0.04 ml) under ice-cooling, and the mixture was stirred at room temperature for one hour. After the reaction was complete, the mixture was concentrated, and the obtained residue was purified by silica gel column chromatography (chloroform/methanol=9/1) to give the title compound (80 mg) as colorless amorphous.
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=[C:6]([CH2:11][C:12]([OH:14])=O)[N:5]=1.[CH3:15][C:16]1([CH3:25])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH2:17]1.CN(C)CCCN=C=NCC>CN(C)C=O.N1C=CC=CC=1>[Cl:10][C:8]1[CH:9]=[C:4]([O:3][CH3:2])[N:5]=[C:6]([CH2:11][C:12]([N:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16]([CH3:25])([CH3:15])[CH2:17]2)=[O:14])[N:7]=1
Reactant: COc1cc(Cl)nc(CC(=O)O)n1
Reactant: CC1(C)CNc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: [Na]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COc1cc(Cl)nc(CC(=O)N2CC(C)(C)c3ccccc32)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 41 %

Procedure:
0.5 g of the sodium salt of (4-methoxy-6-chloropyrimidin-2-yl)acetic acid (example 8b, step 3b), 0.33 g of 3,3-dimethyl-2,3-dihydro-1H-indole (CAS 1914-02-9), 0.4 ml of pyridine and 5 ml of dimethylformamide are placed in a three-necked flask so as to obtain a homogeneous brown solution. 512 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide are added at ambient temperature and the mixture is stirred at ambient temperature for 20 hours. The resulting product is concentrated in a rotary evaporator under vacuum, 40 ml of water are added, extraction is carried out with 3 times approximately 25 ml of dichloromethane, washing is carried out with 50 ml of saturated NaCl solution, drying is carried out over MgSO4, and the resulting product is filtered through a VF filter. The compound obtained is purified by chromatography on silica gel (40-63 μm), elution being carried out with a 98/2 dichloromethane/methanol mixture. The fractions containing the expected compound are combined and evaporated under reduced pressure. 2-(4-Chloro-6-methoxypyrimidin-2-yl)-1-(3,3-dimethyl-2,3-dihydroindol-1-yl)ethanone is isolated: 0.3 g of a yellow oil; yield 41%, which is used as it is in the next step.