Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC(C[N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][O:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[C:12](=[O:27])[N:11]([CH3:28])[C:10]=3[N:9]=[C:8]2[O:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH:30]1([O:29][C:8]2[NH:7][C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][O:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[C:12](=[O:27])[N:11]([CH3:28])[C:10]=3[N:9]=2)[CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(OC1CCCC1)n2Cc1ccc(Cl)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2[nH]c(OC3CCCC3)nc21
Yield: 87.4 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-8-(cyclopentyloxy)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (180 mg, 0.35 mmol) in methanol (10 mL) was added ammonium formate (220 mg, 3.5 mmol) and 5% Pd/C (20 mg). The reaction was refluxed under nitrogen atmosphere overnight. The mixture was cooled and filtered. The filtrate was concentrated to give 8-(cyclopentyloxy)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (120 mg, 87.6% yield) as white solid. LCMS retention time 1.345 min; LCMS MH+-THP 309.
Reaction SMILES: [F:1][C:2]([F:25])([CH:22]([F:24])[F:23])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[CH:14][N:13]([C@H:16]([CH3:20])[C:17](Cl)=[O:18])[C:12]2=[O:21])=[CH:7][CH:6]=1.[Cl-].[Al+3].[Cl-].[Cl-].[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1>ClCCl>[F:30][C:31]1[CH:32]=[C:33]([F:37])[CH:34]=[CH:35][C:36]=1[C:17](=[O:18])[C@H:16]([N:13]1[CH:14]=[CH:15][N:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][C:2]([F:25])([F:1])[CH:22]([F:24])[F:23])=[CH:6][CH:7]=2)[C:12]1=[O:21])[CH3:20]
Reactant: C[C@H](C(=O)Cl)n1ccn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O
Reactant: Fc1cccc(F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C[C@H](C(=O)c1ccc(F)cc1F)n1ccn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O
Temperature: 0 °C

Procedure:
(2R)-2-[3-[4-(2,2,3,3-Tetrafluoropropoxy)phenyl]-2,3-dihydro-2-oxo-1H-imidazol-1-yl]propanoyl chloride (1.5 g) was dissolved in 30 ml of dichloromethane, to which 3.8 ml of 1,3-difluorobenzene and 2.3 g of anhydrous aluminum chloride (powder) were added. The mixture was refluxed with heating for 5 hours. The reaction solution was cooled, poured into 100 ml of ice water and extracted with 100 ml of ethyl acetate. The extract was washed with 50 ml of 1N-hydrochloric acid and 50 ml of a saturated aqueous solution of sodium chloride successively, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (silica gel: 50 g, eluent; hexane:ethyl acetate:acetic acid=2:1:0.03) and crystallized from 10 ml of diisopropyl ether to give 0.25 g of 1-[(1R)-2-(2,4-difluorophenyl)-2-oxo-1-methylethyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H,3H)-imidazolone as colorless powdery crystals.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:23]=[CH:22][C:8]([O:9][C:10]([NH:12][C@@H:13]([CH2:17][S:18]([OH:21])(=[O:20])=[O:19])[C:14]([OH:16])=[O:15])=[O:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(=O)([O-])O.[Na+:28].C(=O)(OC1C=CC([N+]([O-])=O)=CC=1)OC1C=CC(NC(=O)C)=CC=1>O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]([NH:12][C@@H:13]([CH2:17][S:18]([O-:21])(=[O:20])=[O:19])[C:14]([O-:16])=[O:15])=[O:11])=[CH:22][CH:23]=1)(=[O:3])[CH3:2].[Na+:28].[Na+:28]
Reactant: CC(=O)Nc1ccc(OC(=O)N[C@@H](CS(=O)(=O)O)C(=O)O)cc1
Agent: CC(=O)Nc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1ccc(OC(=O)N[C@@H](CS(=O)(=O)[O-])C(=O)[O-])cc1
Yield: 94 %

Procedure:
Disodium (2R)-2-((4-acetamidophenoxy)carbonylamino)-3-sulfonatopropanoate (13) was prepared following the General Procedure for the Preparation of Alkali Metal Salts (Procedure B). (2R)-2-[(4-Acetamidophenoxy)carbonylamino]-3-sulfo-propanoic acid (13a) (83 mg, 0.24 mmol), dissolved in 2.0 mL of water, was reacted with 40.3 mg (0.48 mmol; 2.0 eq.) of sodium hydrogencarbonate (NaHCO3) dissolved in 0.5 mL of water. The mixture was sonicated with agitation for three (3) minutes, frozen, and the solvents lyophilized off to afford 88 mg (95% yield) of the title compound (13) as a colorless solid. 1H NMR (300 MHz, D2O): δ=7.21 (d, J=8.7, 2H), 6.97 (d, J=9.0, 2H), 4.36-4.32 (m, 1H), 3.28-3.22 (m, 1H), 3.12-3.04 (m, 1H), 1.96 (s, 3H) ppm. LC/MS: LC/MS (ESI): m/z=347.0 [M+H]+, 714.7 [2M+Na]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:24])=[CH:4][C:5]([O:20]COC)=[C:6]([CH:19]=1)[C:7]([C:9]1[C:14]([O:15]COC)=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8].Cl>CO>[Br:1][C:2]1[C:3]([Cl:24])=[CH:4][C:5]([OH:20])=[C:6]([CH:19]=1)[C:7]([C:9]1[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8]
Reactant: COCOc1cc(Cl)c(Br)cc1C(=O)c1ncccc1OCOC
Agent: Cl
Solvent: CO
Product: O=C(c1cc(Br)c(Cl)cc1O)c1ncccc1O
Temperature: 50 °C
Reaction time: 5 h
Yield: 97.6 %

Procedure:
To a solution of 2-(5-bromo-4-chloro-2-methoxymethoxybenzoyl)-3-methoxymethoxypyridine (7.73 g) in methanol (250 ml) was added hydrochloric acid (12.5 ml), which was stirred for 5 hours at 50° C. Methanol was distilled off under reduced pressure. To the residue was added ethyl acetate (5 ml), which was poured into water. Crystalline precipitate then formed was collected by filtration, washed with ethyl acetate 10 and dried to give 2-(5-bromo-4-chloro-2-hydroxybenzoyl)-3-hydroxypyridine (5.95 g) (Compound A-8).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[N:11]=[C:12](O)[C:13]2[CH:19]=[CH:18][CH:17]=[N:16][C:14]=2[N:15]=1.S(Cl)([Cl:23])=O.CN(C=O)C>C(Cl)(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[N:11]=[C:12]([Cl:23])[C:13]2[CH:19]=[CH:18][CH:17]=[N:16][C:14]=2[N:15]=1
Reactant: O=S(Cl)Cl
Reactant: Oc1nc(-c2cc3ccccc3s2)nc2ncccc12
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Clc1nc(-c2cc3ccccc3s2)nc2ncccc12
Temperature: 25 °C

Procedure:
To a suspension of 2-(1-benzothien-2-yl)pyrido[2,3-d]pyrimidin-4-ol (150 mg, 0.54 mmol) in chloroform (10 mL) was added thionyl chloride (0.47 mL, 6.4 mmol) and a catalytic amount of DMF. The reaction was heated to reflux for 4 h and allowed to cool to rt. The solvent was removed under reduced pressure and the resultant product was (18.2 mg, 12%) used directly in the next step without further purification. HPLC/MS: (M+H)+ 298.2 m/z; Retention time (LC-MS)=3.76 min; 1H NMR (DMSO)-D6): 9.24(1H, m); 8.73(1H, d); 8.55(1H, s); 8.10(2H, t); 7.86(1H, m); 7.50(2H, m).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.Br[CH2:14][CH:15]1[CH2:17][CH2:16]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.CCOC(C)=O>[CH:15]1([CH2:14][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]3)[CH2:17][CH2:16]1
Reactant: BrCC1CC1
Reactant: O=C1CCCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C1CCCc2cc(OCC3CC3)ccc21
Temperature: 80 °C
Yield: 86.5 %

Procedure:
To a solution of 6-hydroxy-1-tetralone (2.0 g, 12.3 mmol) in ACN (30 mL) was added (bromomethyl)cyclopropane (2.0 g, 14.7 mmol) and K2CO3 (3.4 g, 24.6 mmol) at rt. The mixture was heated at 80° C. overnight. After the reaction was cooled to rt, it was diluted with EtOAc, filtered, and concentrated. The residue was purified by column chromatography (20:1 PE/EtOAc) to give 2.3 g (87%) of the title compound as a yellow solid. 1H NMR (300 MHz, CDCl3): δ 0.35-0.40 (2H, m), 0.65-0.71 (2H, m), 1.25-1.32 (1H, m), 2.08-2.16 (2H, m), 2.62 (2H, t, J=6.3 Hz), 2.93 (2H, t, J=6.0 Hz), 3.87 (2H, d, J=7.2 Hz), 6.71 (1H, s), 6.83 (1H, dd, J=2.1, 8.4 Hz), 8.01 (1H, d, J=8.4 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([NH:16][NH2:17])=[O:15])=[C:12]([C:18]2[CH:19]=[N:20][N:21]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])[C:22]=2[C:23]([F:26])([F:25])[F:24])[O:11][N:10]=1.[CH:34](OC)(OC)OC>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]2[O:15][CH:34]=[N:17][N:16]=2)=[C:12]([C:18]2[CH:19]=[N:20][N:21]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])[C:22]=2[C:23]([F:25])([F:26])[F:24])[O:11][N:10]=1
Reactant: COC(OC)OC
Reactant: NNC(=O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2ccccc2F)c1C(F)(F)F
Product: Fc1ccccc1-n1ncc(-c2onc(-c3c(F)cccc3Cl)c2-c2nnco2)c1C(F)(F)F
Yield: 46.4 %

Procedure:
A solution of 3-(2-chloro-6-fluorophenyl)-5-(1-(2-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carbohydrazide (0.076 g, 0.157 mmol) in 4 g trimethyl orthoformate was kept in a sealed tube at 125° C. for 3 days. The solution was evaporated to dryness and the residue was crystallized from heptane to give 36 mg (46%) of a yellowish solid of example 15. Result of LC/MS MH+: 493.75; 1H NMR (methanol-d4; 400 MHz) δ ppm: 7.30-7.35 (1H, m, CH-arom.), 7.42-7.48 (3H, m, CH-arom.), 7.60-7.70 (3H, m, CH-arom.), 8.51 (1H, s, CH-oxadiazole), 8.93 (1H, s, CH-pyraz.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C@@H:12]([CH2:16][OH:17])[C:13]([OH:15])=O)(=[O:10])=[O:9].[F:18][C:19]([F:33])([F:32])[C:20]1[C:21]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:22][CH:23]=[CH:24][CH:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C@@H:12]([CH2:16][OH:17])[C:13](=[O:15])[N:29]1[CH2:30][CH2:31][N:26]([C:21]2[C:20]([C:19]([F:33])([F:18])[F:32])=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:27][CH2:28]1)(=[O:9])=[O:10]
Reactant: O=C(O)[C@H](CO)NS(=O)(=O)c1ccccc1Cl
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Product: O=C([C@H](CO)NS(=O)(=O)c1ccccc1Cl)N1CCN(c2ncccc2C(F)(F)F)CC1

Procedure:
In analogy to example 2, (S)-2-(2-chloro-benzenesulfonylamino)-3-hydroxy-propionic acid was reacted with 1-[3-(trifluoromethyl)pyrid-2-yl]-piperazine to give 2-chloro-N-{(S)-1-hydroxymethyl-2-oxo-2-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-ethyl}-benzenesulfonamide as a colorless foam. MS: 493.0 ([M+H]+)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14].C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C1(C)C=CC=CC=1>[CH2:26]([O:25][C:23]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])=[O:24])[CH3:27]
Reactant: Cc1ccccc1-c1ccccc1N
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1ccccc1-c1ccccc1C
Yield: 45.7 %

Procedure:
The above compound, 2-amino-2′-methyl-biphenyl (11.0 g, 60 mmol) was added to dry toluene (250 mL) containing triethyl amine (24 g, 24 mmol) and stirred under a nitrogen pad. Ethyl chloroformate (26 g, 240 mmol) was slowly added to the stirred solution via a syringe. The reaction mixture was washed with brine and the organics separated, dried over magnesium sulfate and concentrated to give N-ethoxycarbonyl-2-amino-2′methyl biphenyl as a colorless oil (7.0 g, 46% yield) whose structure was confirmed by GCMS and NMR.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[N:4]([CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]#[N:39])[CH:29]=1)[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:7]=1[C:16]1[CH:21]=[C:20]([CH:22]([CH3:24])[CH3:23])[CH:19]=[CH:18][C:17]=1[O:25][CH3:26].C([O-])([O-])=[O:42].[K+].[K+].OO.O>CS(C)=O.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:40])[N:4]([CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([NH2:39])=[O:42])[CH:29]=1)[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:14])([F:15])[F:13])[CH:9]=[CH:8][C:7]=1[C:16]1[CH:21]=[C:20]([CH:22]([CH3:24])[CH3:23])[CH:19]=[CH:18][C:17]=1[O:25][CH3:26]
Reactant: COC(=O)N(Cc1cc(C#N)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)ccc1OC
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)N(Cc1cc(C(N)=O)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of methyl[3-cyano-5-(trifluoromethyl)benzyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate (35.0 mg, 0.06 mmol) (Example 36) in DMSO (248 μL) was cooled to 0° C. Next, K2CO3 (17.4 mg, 0.05 mmol) was added followed by 30% H2O2 (42.2 μL), and the reaction was slowly warmed to room temperature. After stirring at room temperature for 15 minutes, the mixture was diluted with EtOAc (50 mL) and poured into H2O (15 mL). The organic extract was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography with 5% to 80% EtOAc/hexanes afforded methyl[3-(aminocarbonyl)-5-(trifluoromethyl)benzyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate. Rf=0.45 (20% EtOAc/hexanes). LCMS=583.3 (M+1)+. 1H NMR (C6D6, 500 MHz, 70° C.) δ 7.75 (s, 1H), 7.68 (s, 2H), 7.35 (s, 1H), 7.34 (s, 1H), 7.08-7.04 (m, 2H), 6.87 (d, J=2.5 Hz, 1H), 6.62 (d, J=8.5 Hz, 1H), 5.08 (broad singlet, 2H), 4.41 (broad singlet, 2H), 4.07 (broad singlet, 2H), 3.37 (s, 3H), 3.29 (s, 3H), 2.75 (m, 1H), 1.16 (d, J=7.5 Hz, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([O:7][CH2:8][C@@H:9]2[CH2:11][N:10]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:5][CH:4]=1)#[N:2].[CH2:21]([N:28]([CH3:37])[CH:29]1[CH:34]2[CH2:35][CH2:36][CH:30]1[CH2:31][NH:32][CH2:33]2)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(O)C>[CH2:21]([N:28]([CH3:37])[CH:29]1[CH:34]2[CH2:35][CH2:36][CH:30]1[CH2:31][N:32]([CH2:11][C@H:9]([NH:10][C:12](=[O:13])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[CH2:8][O:7][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:20][CH:19]=1)[CH2:33]2)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CN(Cc1ccccc1)C1C2CCC1CNC2
Reactant: CC(C)(C)OC(=O)N1C[C@H]1COc1ccc(C#N)cc1
Solvent: CC(C)O
Product: CN(Cc1ccccc1)C1C2CCC1CN(C[C@@H](COc1ccc(C#N)cc1)NC(=O)OC(C)(C)C)C2
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl (2S)-2-[(4-cyanophenoxy)methyl]-1-aziridinecarboxylate (see step (iii) above; 1.26 g, 4.6 mmol) and N-benzyl-N-methyl-3-azabicyclo[3.2.1]octan-8-amine (see step (vii) above; 1.05 g, 4.6 mmol) in IPA (15 mL) was stirred at 60° C. overnight. The solvent was evaporated and the residue purified by chromatography on silica gel, eluting with DCM:MeOH (20:1). This gave 1.8 g (78%) of the subtitle compound
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[N:15]4[CH2:16][CH2:17][S:18][C:19]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])([CH3:21])[CH2:20][C:14]4=[N:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][N:34]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:24]([O:23][CH2:22][C:19]1([CH3:21])[S:18][CH2:17][CH2:16][N:15]2[C:11]([C:8]3([C:5]4[CH:6]=[CH:7][C:2]([C:36]5[CH:35]=[N:34][C:33]([O:32][CH3:31])=[CH:38][CH:37]=5)=[CH:3][CH:4]=4)[CH2:10][CH2:9]3)=[N:12][N:13]=[C:14]2[CH2:20]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(Br)cc4)CC3)n2CCS1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)cn1
Temperature: 25 °C
Yield: 37.3 %

Procedure:
A solution of the compound (508 mg, 1.0 mmol) obtained in Example 16-4), 2-methoxypyridine-5-boronic acid pinacol ester (352 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 130° C. for 1.5 h under microwave irradiation. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (200 mg, 37%) as a light yellow oily substance.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[CH2:53]([O:60][C:61]1[CH:76]=[CH:75][C:74](Br)=[CH:73][C:62]=1[C:63]([O:65][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)=[O:64])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.[NH:78]1[CH2:83][CH2:82][CH2:81][CH2:80][CH2:79]1>CCOCC.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].C1(C)C=CC=CC=1>[C:54]1([CH2:53][O:60][C:61]2[CH:76]=[CH:75][C:74]([N:78]3[CH2:83][CH2:82][CH2:81][CH2:80][CH2:79]3)=[CH:73][C:62]=2[C:63]([O:65][CH2:66][C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)=[O:64])[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: O=C(OCc1ccccc1)c1cc(Br)ccc1OCc1ccccc1
Reactant: C1CCNCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=C(OCc1ccccc1)c1cc(N2CCCCC2)ccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
Caesium carbonate (689 mg, 2.11 mmol) was finely ground in a nitrogen-filled glovebox and weighed into an oven-dried Schlenk flask. The flask was quickly capped with a rubber septum and purged with argon. Pd2(dba)3 (3.46 mg, 3.78 μmol) and BINAP (7.05 mg, 0.01 mmol) were added into the flask, followed by benzyl 2-(benzyloxy)-5-bromobenzoate (may be prepared as described in Description 4; 600 mg, 1.51 mmol), piperidine (129 mg, 1.510 mmol), and toluene (10 ml). The solution was refluxed for 10 h. The solution was then cooled to room temperature, diluted with ether, filtered, and concentrated in vacuo to yield the title compound.
Reaction SMILES: [C:1]([NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([F:25])=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16]([C:17]#[N:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].OO.S([O-])([O-])(=[O:32])=S.[Na+].[Na+]>CO.O.C(OCC)(=O)C>[F:25][C:14]1[N:11]2[CH2:12][CH2:13][N:8]([C:6]([NH:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][C:10]2=[C:16]([C:17]([NH2:18])=[O:32])[C:15]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)NC(=O)N1CCn2c(F)c(-c3ccccc3)c(C#N)c2C1
Reactant: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)N1CCn2c(F)c(-c3ccccc3)c(C(N)=O)c2C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 15.8 %

Procedure:
To a solution of 0.360 g (1.06 mmol) of N-tert-butyl-6-fluoro-8-cyano-7-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxamide in 4.2 ml of methanol is added 0.1 ml (1.1 mmol) of aqueous 35% sodium hydroxide solution and then 0.28 ml (3.2 mmol) of 35-volumes aqueous hydrogen peroxide solution. After stirring for 2 hours at 60° C., a further 0.05 ml (0.5 mmol) of 35-volumes aqueous hydrogen peroxide solution is added and the mixture is stirred for 16 hours at 60° C. After cooling, 0.25 g of sodium thiosulfate dissolved in 0.5 ml of water is added and the heterogeneous mixture is diluted with 75 ml of ethyl acetate. The organic phase is separated out, washed twice with 25 ml of water and then with 25 ml of saturated aqueous sodium chloride solution, after which it is dried over sodium sulfate. The solvent is evaporated off under reduced pressure to give a yellow oil, which is purified by chromatography on a column of silica gel, eluting with a mixture of 2 to 6% methanol in dichloromethane, to give 0.06 g of 6-fluoro-7-phenyl-N2-(tert-butyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide in the form of a solid after triturating in diisopropyl ether, filtering off and drying.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:13])(=[O:3])[CH3:2].[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19](Cl)=[O:20].Cl>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:19]([OH:20])[C:15]2[O:14][CH:18]=[CH:17][CH:16]=2)[C:5]1=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C(=O)Cc2ccccc21
Reactant: O=C(Cl)c1ccco1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=O)N1C(=O)C(=C(O)c2ccco2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
An ice-cooled solution of 7.0 g 1-acetyl-2-indolinone and 10.8 g DMAP in 60 ml DMF is combined with 4.4 ml of furan-2-carboxylic acid chloride. The mixture is stirred for 1 hour at ambient temperature, then poured onto 40 ml of conc. hydrochloric acid and 500 ml ice water. The precipitate is suction filtered, washed successively with ethanol and diethyl ether and dried.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(N(CCCC)CCCC)CCC.[C:22]([NH:30][C:31]1[CH:43]=[C:42]([CH:44]=[CH2:45])[CH:41]=[CH:40][C:32]=1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.CN(C)C(=O)C>[C:22]([NH:30][C:31]1[CH:43]=[C:42](/[CH:44]=[CH:45]/[C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)[CH:41]=[CH:40][C:32]=1[C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])(=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Oc1ccc(I)cc1
Reactant: C=Cc1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2ccccc2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCCCN(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)c1ccc(/C=C/c2ccc(O)cc2)cc1NC(=O)c1ccccc1
Temperature: 110 °C
Reaction time: 6 h
Yield: 64.9 %

Procedure:
0.12 g of 4-iodophenol, 0.18 mL of tributylamine and 4.2 mg of palladium acetate were added do 2.4 mL of N,N-dimethylacetamide solution containing 0.12 g of tert-butyl 2-(benzamido)-4-vinylbenzoate sequentially at room temperature and stirred under nitrogen atmosphere at 110° C. for 6 hours. After the reaction mixture was cooled to room temperature, 10% citric acid aqueous solution and ethyl acetate were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 10% citric acid aqueous solution, a saturated sodium thiosulfate aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia Chemical Ltd., eluent; hexane:ethyl acetate=1:1] to obtain 0.10 g of tert-butyl 2-(benzamido)-4-((E)-2-(4-hydroxyphenyl)vinyl)benzoate as yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10](Cl)=[O:11])=[CH:6][CH:5]=1.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(CC)CC)C>ClCCl>[N:14]1([C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:13])=[CH:5][CH:6]=2)=[O:11])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: C1CCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)N2CCCC2)cc1

Procedure:
29.0 g (0.146 mol) of 4-chlorocarbonyl benzoic acid monomethyl ester, 14.2 g (200 mmol) of pyrrolidine and 21.0 g (208 mmol) of triethylamine were reacted in 350 ml of dichloromethane. After the treatment in an ordinary manner, methyl 4-(1-pyrrolidylcarbonyl)benzoate was obtained. 29.0 g of this ester compound was hydrolyzed with 12.0 g of sodium hydroxide in a mixed solvent comprising 70 ml of water, 70 ml of methanol and 70 ml of tetrahydrofuran. After the completion of the reaction, the solvent was distilled off. After the addition of 1 N hydrochloric acid followed by the treatment with dichloromethane as the extractant in an ordinary manner, the title compound was obtained.