Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-:1][S:2]([O-:4])=[O:3].[Na+].[Na+].Cl[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]>O.CCO>[CH2:12]([O:11][C:9]([CH2:8][S:2]([OH:4])(=[O:1])=[O:3])=[O:10])[CH3:13]
Reactant: CCOC(=O)CCl
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CS(=O)(=O)O
Yield: 100.1 %

Procedure:
To a solution of Na2SO3 (10 g, 79 mmol.) in 50 mL of H2O was added a solution of ethyl 2-chloroacetate (12.7 mL, 119 mmol.) in 55 mL of EtOH. The mixture was heated at reflux for 6 h, after which time all the volatiles were removed by evaporation under reduced pressure. The concentrated materials were dried to afford crude (ethoxycarbonyl)methanesulfonic acid (13.3 g, 100%) used directly without purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH2:56]([O:58][C:59]([C:61]1[CH:66]=[N:65][C:64]([NH2:67])=[CH:63][N:62]=1)=[O:60])[CH3:57]>ClCCl>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:67][C:64]2[N:65]=[CH:66][C:61]([C:59]([O:58][CH2:56][CH3:57])=[O:60])=[N:62][CH:63]=2)=[O:30])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnc(N)cn1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cn1
Reaction time: 8 h
Yield: 26.2 %

Procedure:
A solution of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (79.9 mg, 0.171 mmol) in dichloromethane (3 ml) was treated with DIPEA (89.0 mg, 0.685 mmol) and DIPHENYLPHOSPHINIC CHLORIDE (103 mg, 0.428 μmol, Aldrich) and stirred for 30 mins under argon before 5-AMINO-PYRAZINE-2-CARBOXYLIC ACID ETHYL ESTER (30.4 mg, 0.173 mmol, Ark Pharm) was added and the reaction was stirred overnight. The reaction mixture was diluted with dichloromethane and extracted with H2O. The organic layer was washed with sat NaHCO3, H2O, and sat NaCl and purified by flash chromatography using ethyl acetate and n-hexanes to give ethyl 5-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)pyrazine-2-carboxylate (27.6 mg, 26%) which was used in the next step.
Reaction SMILES: Br[C:2]1[C:3](=[O:36])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[CH3:63][O:64][C:65]1[N:70]=[CH:69][C:68](B(O)O)=[CH:67][CH:66]=1>>[F:17][C:15]1[CH:16]=[C:11]([C:10]2[C:9]3[C:4](=[CH:5][C:6]([O:19][CH2:20][CH2:21][CH2:22][N:23]4[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:30])[CH2:27][CH2:28]4)=[CH:7][CH:8]=3)[C:3](=[O:36])[C:2]=2[C:68]2[CH:69]=[N:70][C:65]([O:64][CH3:63])=[CH:66][CH:67]=2)[CH:12]=[C:13]([F:18])[CH:14]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc3c(c2)C(=O)C(Br)=C3c2cc(F)cc(F)c2)CC1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: COc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCCN4CCN(C(=O)OC(C)(C)C)CC4)cc3C2=O)cn1

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using t-butyl 4-(3-(2-bromo-3-(3,5-difluorophenyl)-1-oxo-1H-inden-6-yloxy)propyl)piperazine-1-carboxylate obtained in Step 1 of Example 104 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, 6-methoxy-3-pyridinylboronic acid instead of 3-pyridinylboronic acid, and being purified by silica gel column chromatography (EtOAc/hexanes=1:1) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18](O)=[O:19])=[C:15]3[C:10]([CH:11]=[C:12]([F:28])[C:13]([F:27])=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH:33]1([NH2:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]3)[C:18]([NH:39][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:19])=[C:15]3[C:10]([CH:11]=[C:12]([F:28])[C:13]([F:27])=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)C(c1c2cc(F)c(F)cc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Reactant: NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Product: O=C(NC1CCCCC1)C(c1c2cc(F)c(F)cc2nn1-c1ccc(Cl)cc1)C1CCCCC1

Procedure:
In analogy to the procedure described in example 6, [rac]-[2-(4-chloro-phenyl)-5,6-difluoro-2H-indazol-3-yl]-cyclohexyl-acetic acid was converted into the corresponding acid chloride with thionyl chloride which subsequently reacted with cyclohexylamine (CAS Reg. No. 108-91-8) in the presence of DMAP to give the title compound as off-white solid. MS: m/e=486.4 [M+H+].
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[C:7]([Br:14])=[C:6]([OH:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4][C:3]1=2.[CH3:20][O:21][CH2:22]Cl.C(N(C(C)C)CC)(C)C.[Br-]>C(Cl)Cl>[Br:14][C:7]1[C:8]2[C:9]([CH3:12])([CH3:13])[CH2:10][CH2:11][C:2]([CH3:19])([CH3:1])[C:3]=2[CH:4]=[C:5]([C:16]([OH:18])=[O:17])[C:6]=1[O:15][CH2:20][O:21][CH3:22]
Reactant: COCCl
Reactant: CC1(C)CCC(C)(C)c2c1cc(C(=O)O)c(O)c2Br
Agent: [Br-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1c(C(=O)O)cc2c(c1Br)C(C)(C)CCC2(C)C
Temperature: 45 °C

Procedure:
To a solution of 4-bromo-3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl acid (Compound M), 233 mg, 0.71 mmol) in 6 ml of CH2Cl2 was added chloromethyl methyl ether (0.162 ml, 2.1 mmol), diisopropylethyl amine (0.764 ml, 4.2 mmol) and a catalytic amount of tetrabutylammouimn bromide. The reaction mixture was heated to 45° C. for 2 h. The reaction mixture was concentrated and the residue was purified by column chromatography (ethyl acetate/hexane 1/9) to yield the methoxymethyl ester of the title compound as a white solid (200 mg). This white solid was further dissolved in 20 ml of EtOH. An aqueous solution of NaOH (0.5 ml, 1M) was added. The reaction mixture was stirred at room temperature for over night. The EtOH was removed and the residue was added 2 ml of ethyl acetate and 3 ml of water. This mixture was very slowly acidified with 10% HCl to PH=7. The ethyl acetate layer was separated and washed with brine, dried over Na2SO4. After filtration of the drying agent and removal of solvent, the reaction yielded the title compound as a white solid (155 mg). 1H NMR d 7.99 (s, 1H), 5.20 (s, 2H), 3.66 (s, 3H), 1.74 (m, 2H), 1.67 (m, 2H), 1.60 (s, 6H), 1.32 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[C:5]([NH2:16])[CH:4]=1.[CH:17]1(/[CH:23]=[CH:24]/[C:25]([Cl:27])=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.Cl>CO>[ClH:27].[CH:17]1(/[CH:23]=[CH:24]/[C:25]2[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[C:6]3[CH:14]=[CH:15][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[N:16]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C(Cl)/C=C/C1CCCCC1
Reactant: COc1ccc(Nc2ccccn2)c(N)c1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: COc1ccc2c(c1)nc(/C=C/C1CCCCC1)n2-c1ccccn1

Procedure:
Free base of the titled compound was prepared from 4-methoxy-2-amino-N-(2-pyridyl)aniline and (E)-3-cyclohexylacryloyl chloride according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base was dissolved with a 10% methanol solution of hydrogen chloride (5 ml). Concentration and recrystallization from ethyl acetate/n-hexane yielded the titled compound.
Reaction SMILES: [Cl:1][C:2]1[C:12](Cl)=[C:11]([C:14](=[N:22][OH:23])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].[H-].[Na+].Cl>C1C=CC=CC=1.CN(C)C=O>[Cl:1][C:2]1[C:12]2[O:23][N:22]=[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[C:11]=2[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: O=C(O)COc1ccc(C(=NO)c2ccccc2F)c(Cl)c1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=C(O)COc1ccc2c(-c3ccccc3F)noc2c1Cl

Procedure:
A mixture of 0.3 g of 2,3-dichloro-4-(2-fluorobenzohydroximoyl)phenoxyacetic acid and 0.05 g of sodium hydride in 5 ml of benzene and 5 ml of dimethylformamide is refluxed for 3 hours. To the mixture, after it has been permitted to cool there is added 5% hydrochloric acid causing the benzene to separate. The benzene is evaporated in vacuo and the resulting precipitate is collected by filtration and recrystallized from aqueous ethyl alcohol to yield the product {[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid having a melting point of 188° to 189° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]=1[O:12][CH3:13])[C:6](O)=[O:7].C(Cl)(=O)C([Cl:20])=O>ClCCl.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]=1[O:12][CH3:13])[C:6]([Cl:20])=[O:7]
Reactant: COc1cc(C(=O)O)cc([N+](=O)[O-])c1OC
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(C(=O)Cl)cc([N+](=O)[O-])c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound (F) was prepared as described in the procedure of compound (C). The 3,4-dimethoxy-5-nitrobenzoyl chloride was prepared by the reaction of 3,4-dimethoxy-5-nitrobenzoic acid (585 mg, 2.57 mmol) with oxalyl chloride (0.36 mL, 4.1 mmol) in dichloromethane using N,N-dimethylformamide as a catalyst. The resulting mixture was stirred at room temperature for 1 h, the volatile liquids were removed and the resulting acid chloride was used without further purification.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]2[C:10]([C:11](=[O:30])[C:12]([N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:15]3)=[O:13])=[CH:9][NH:8][C:7]=12.[Cl-:33].OCC1N=C[NH2+]N=1>N1C=CC=CC=1.[Cu]>[Cl:33][C:2]1[N:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]2[C:10]([C:11](=[O:30])[C:12]([N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:15]3)=[O:13])=[CH:9][NH:8][C:7]=12
Reactant: [Cl-]
Reactant: COc1cnc(Br)c2[nH]cc(C(=O)C(=O)N3CCc4c(cccc4-c4ccccn4)C3)c12
Agent: [Cu]
Agent: OCC1=N[NH2+]C=N1
Solvent: c1ccncc1
Product: COc1cnc(Cl)c2[nH]cc(C(=O)C(=O)N3CCc4c(cccc4-c4ccccn4)C3)c12
Temperature: 145 °C
Yield: 19.8 %

Procedure:
A mixture of 1-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(5-(pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethane-1,2-dione (30 mg, 0.061 mmol), 3-(hydroxymethyl)-1H-1,2,4-triazol-1-ium chloride (18.15 mg, 0.183 mmol) and copper (11.64 mg, 0.183 mmol) in pyridine (1 mL) was heated at 145° C. for 2 hours, LCMS indicated no starting material remained. The reaction mixture was filtered and the clear solution purified by prep. HPLC to give 1-(7-chloro-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(5-(pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethane-1,2-dione as a colorless oil (5.4 mg, 19%). LCMS: m/e 447.02 (M+H)+, 1.52 min (method 9). 1H NMR (500 MHz, MeOD) δ ppm 2.80-3.06 (m, 2H) 3.67-3.99 (m, 5H) 4.75-5.08 (m, 2H) 7.32-7.67 (m, 3H) 7.72-7.83 (m, 1H) 7.94-8.18 (m, 2H) 8.32-8.42 (m, 1H) 8.51-8.67 (m, 1H) 8.84-8.95 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:14][C:5]2=[CH:6][C:7]3[NH:11][C:10]([SH:12])=[N:9][C:8]=3[CH:13]=[C:4]2[O:3]1.[OH-].[Na+].Cl.Cl[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>O>[CH3:1][C:2]1([CH3:15])[O:3][C:4]2=[CH:13][C:8]3[NH:9][C:10]([S:12][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)=[N:11][C:7]=3[CH:6]=[C:5]2[O:14]1
Reactant: ClCc1ccccn1
Reactant: CC1(C)Oc2cc3nc(S)[nH]c3cc2O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(C)Oc2cc3nc(SCc4ccccn4)[nH]c3cc2O1
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
To 4.45 g of 2,2-dimethyl-5H-1,3-dioxolo-(4,5-f)benzimidazole-6-thiol, suspended in 100 ml of alcohol, were added dropwise while stirring 1.63 g of sodium hydroxide in 50 ml of water and, after 30 minutes, there were added 3.4 g of 2-chloromethyl-pyridine hydrochloride. The mixture was left to boil at reflux overnight, then evaporated and the residue was taken up in 500 ml of ethyl acetate. This was washed with 100 ml of 3 N sodium hydroxide, three times with 100 ml of water, dried over sodium sulfate and evaporated in vacuo. The crude product was recrystallized from acetontrile. There were obtained 4.6 g (73.4% of theory) of 2,2-dimethyl-6-[(2-pyridyl-methyl)thio]-5H-1,3-dioxolo(4,5-f)benzimidazole of melting point 210°-211° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17].N1CCCCC1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:15][C:16]([OH:18])=[O:17])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)CC(=O)O
Reactant: COc1ccc(C=O)cc1[N+](=O)[O-]
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COc1ccc(C=CC(=O)O)cc1[N+](=O)[O-]
Temperature: 120 °C

Procedure:
4-methoxy-3-nitro-benzaldehyde (compound of Example 5; 1.05 g, 5.79 mmol) and malonic acid (1.32 g, 1.27 mmol) were dissolved in pyridine (20 mL) under stirring and piperidine (1 mL) was added to the pyridine solution. The reaction mixture was heated at 75° C. to 80° C. for 3 h, after which the temperature was further increased to 120° C. and maintained at this temperature for 6 h. At the end of the reaction, pyridine was evaporated, followed by addition of aqueous HCl (1:1) to obtain pH ˜4. The solid obtained was filtered, washed with cold water and dried.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][NH:27]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.C(N(CC)CC)C.Cl.[N:39]1([CH2:44]/[CH:45]=[CH:46]/[C:47](O)=[O:48])[CH2:43][CH2:42][CH2:41][CH2:40]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:47](=[O:48])/[CH:46]=[CH:45]/[CH2:44][N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c([C@@H]3CCCN3)nc(-c3ccc(C(=O)Nc4ccccn4)cc3)c12
Reactant: O=C(O)/C=C/CN1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1nccn2c([C@@H]3CCCN3C(=O)/C=C/CN3CCCC3)nc(-c3ccc(C(=O)Nc4ccccn4)cc3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
To a solution of (S)-4-(8-Amino-3-(pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide (intermediate 2b, 19.7 mg, 0.049 mmol), triethylamine (20 mg, 0.197 mmol, 0.027 mL) and (E)-4-(pyrrolidin-1-yl)but-2-enoic acid hydrochloride (9.45 mg, 0.049 mmol) in dichloromethane (2 mL) was added HATU (18.75 mg, 0.049 mmol). The mixture was stirred for 30 min at room temperature. The mixture was washed with water dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC. Fractions containing product were collected and reduced to dryness to afford 7.1 mg of (S,E)-4-(8-amino-3-(1-(4-(pyrrolidin-1-yl)but-2-enoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide (26.8% yield). Data: UPLC (C) Rt: 1.25 min; m/z 537.4 (M+H)+.
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].[F:9][C:10]([F:27])([F:26])[O:11][C:12]1[CH:25]=[CH:24][C:15]([CH2:16][NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:14][CH:13]=1.CCOCC>C[N+]([O-])=O>[N+:7]([C:13]1[CH:14]=[C:15]([CH:24]=[CH:25][C:12]=1[O:11][C:10]([F:9])([F:26])[F:27])[CH2:16][NH:17][C:18](=[O:23])[C:19]([CH3:21])([CH3:22])[CH3:20])([O-:8])=[O:6]
Reactant: O=[N+]=O
Reactant: CC(C)(C)C(=O)NCc1ccc(OC(F)(F)F)cc1
Agent: F[B-](F)(F)F
Solvent: C[N+](=O)[O-]
Solvent: CCOCC
Product: CC(C)(C)C(=O)NCc1ccc(OC(F)(F)F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Nitronium tetrafluoroborate (3.97 g, 29.9 mmol) was added in portions over 5 min to N-(4-trifluoromethoxy-benzyl)-2,2-dimethyl-propionamide (4.1 g, 15 mmol) in MeNO2 (35 mL) and the mixture was stirred at rt for 1 h. The mixture was treated with ice and Et2O was added. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was treated with PE and the sub-title compound was filtered off.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[O-:18][C:19]#[N:20].[Na+].C(O)(=O)/C=C\C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:19]([NH2:20])=[O:18])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1
Reactant: N#C[O-]
Reactant: COC1=Cc2ccccc2Nc2ccccc21
Agent: O=C(O)/C=C\C(=O)O
Agent: [Na+]
Solvent: ClCCl
Product: COC1=Cc2ccccc2N(C(N)=O)c2ccccc21
Temperature: 25 °C

Procedure:
To a 1 L 4-necked round bottom flask was added 10.0 g (0.045 mol) of 10-methoxyiminostilbene, 150.0 ml of dichloromethane, 37.0 g (0.57 mol) of sodium cyanate and 15.0 g (0.13 moles) of maleic acid and stirred at room temperature. The contents were heated to reflux (40-45° C.) under vigorous stirring for about 6 to about 8 hours. After completion of the reaction (detected by TLC) the reaction mass was filtered and washed with 50.0 ml dichloromethane. The dichloromethane layer was washed with water (50.0 ml×2) and the layers were separated.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[C:11]([S:16][CH3:17])=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8].[SH:18][C:19]1[O:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>O.CN(C=O)C>[O:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[S:18][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[C:11]([S:16][CH3:17])=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8]
Reactant: CSc1ncccc1NC(=O)CCCCCBr
Reactant: Sc1nc2ccccc2o1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ncccc1NC(=O)CCCCCSc1nc2ccccc2o1
Temperature: 80 °C
Reaction time: 3 h
Yield: 80512.2 %

Procedure:
To a DMF (2 ml) solution of this amide (159 mg, 0.5 mmol) and 2-mercaptobenzoxazole (83 mg, 0.55 mmol) were added 18-crown-6 (13 mg, 0.05 mmol) and potassium carbonate (83 mg, 0.6 mmol), and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (silica gel 20 g, eluent—hexane:ethyl acetate=5:2→2:1) to obtain 156 g (yield 81%) of a desired compound as a colorless needle crystal.
Reaction SMILES: O[C:2]1([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)=[C:3]1[C:20]([O:22]CC)=[O:21].C1OC2C=CC(C3C4C(=CC=CC=4)C(=O)C=3C(OCC)=O)=CC=2O1.COC1C=C([Mg]Br)C=CC=1>C1COCC1>[CH3:32][O:31][C:27]1[CH:26]=[C:25]([CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]([C:11]3[CH:16]=[CH:15][C:14]4[O:17][CH2:18][O:19][C:13]=4[CH:12]=3)[CH:3]2[C:20]([OH:22])=[O:21])[CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1cccc(OC)c1
Agent: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1=O
Agent: COc1cccc([Mg]Br)c1
Solvent: C1CCOC1
Product: COc1cccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C(=O)O)c1
Reaction time: 0.25 h
Yield: 100 %

Procedure:
Ethyl (1RS)-1-Hydroxy-1-(3-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate. To a solution of ethyl 3-(3,4-methylenedioxyphenyl)-1-oxoindene-2-carboxylate (100 mg, 0.31 mmol) in THF (2 ml) under an argon atmosphere at 0° C. was added a solution of freshly prepared 3-methoxyphenyl magnesium bromide (0.31 mmol). After stirring for 15 min, additional 3-methoxyphenyl magnesium bromide (0.06 mmol) was added. Stirring was continued for 45 min, at which time thin layer chromatographic analysis indicated that the reaction was incomplete. Additional 3-methoxyphenyl magnesium bromide (0.12 mmol) was added. After stirring for 2 h more, the mixture was partitioned between 3M HCl and EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3, H2O and saturated aqueous NaCl. The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 15% EtOAc/hexanes to afford the title compound (150 mg, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:13][CH3:14])[C:11]=1[OH:12])[C:6]([OH:8])=[O:7].[C:15](OC(=O)C)(=[O:17])[CH3:16].N1C=CC=CC=1>O>[C:15]([O:12][C:11]1[C:10]([O:13][CH3:14])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:2][CH3:1])(=[O:17])[CH3:16]
Reactant: COc1cc(C(=O)O)cc(OC)c1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: COc1cc(C(=O)O)cc(OC)c1OC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 3,5-dimethoxy-4-hydroxybenzoic acid (3.00 g) and acetic anhydride (30 ml) was dropwise added pyridine (15 ml) with ice-cooling over a 5 minutes period. After stirring at room temperature for 30 minutes, the reaction mixture was poured into water and stirred at room temperature for 30 minutes followed by extracting thrice with ethyl acetate. The combined extract was washed with 10% hydrochloric acid, dried and concentrated. The residue was recrystallized from a mixture of methylene chloride and hexane to afford the title compound (3.13 g), melting at 192°-194° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[C@@H:11]([NH2:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[C:28]2[CH2:34][C:35](O)=[O:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[OH:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[C:28]2[CH2:34][C:35]([NH:19][C@H:11]([C:7]1[N:6]([CH2:5][C:4]2[CH:20]=[CH:21][CH:22]=[CH:23][C:3]=2[O:2][CH3:1])[CH:10]=[CH:9][N:8]=1)[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:36]
Reactant: COc1ccccc1Cn1ccnc1[C@@H](N)Cc1ccccc1
Reactant: O=C(O)Cc1c[nH]c2ccc(O)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccccc1Cn1ccnc1[C@H](Cc1ccccc1)NC(=O)Cc1c[nH]c2ccc(O)cc12
Reaction time: 0.5 h

Procedure:
(S)-1-(1-(2-methoxybenzyl)-1H-imidazol-2-yl)-2-phenylethanamine (75 mg, 0.2 mmol), 2-(5-hydroxy-1H-indol-3-yl)acetic acid (47 mg, 0.25 mmol) and HATU (97 mg, 0.26 mmol) were combined in DMF (2 mL) and treated with diisopropylethylamine (70 μL). The reaction was stirred for 30 min and the purified by RP HPLC to provide the title compound: 1H NMR (400 MHz, DMSO-d6) δ 10.53 (d, 1H), 8.67 (d, 1H), 7.58 (s, 1H), 7.38-7.28 (m, 2H), 7.20-7.12 (m, 3H), 7.12-6.98 (m, 4H), 6.91-6.79 (m, 3H), 6.72 (d, 1H), 6.57 (dd, 1H), 5.38-5.31 (m, 1H), 5.17 (d, 2H), 3.71 (s, 3H), 3.40-3.22 (m, 3H), 3.16 (dd, 1H). MS (m/z) 481.2 [M+H]+.