Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][C:8]([O-:10])=[N:9][C:4]2=[CH:3][CH:2]=1.[Na+]>C(O)(=O)C.O>[N:1]1[N:5]2[CH:4]=[N:9][C:8](=[O:10])[CH2:7][C:6]2=[CH:3][CH:2]=1
Reactant: [O-]c1ccn2nccc2n1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1Cc2ccnn2C=N1
Yield: 85.5 %

Procedure:
Sodium pyrazolo[1,5-a]pyrimidin-5-olate (13.47 g) was dissolved in 500 mL of acetic acid and 100 mL of water, stirred 15 minutes then evaporated to dryness under vacuum. The residue was suspended in 300 mL of 9:1 dichloromethane:methanol and vacuum filtered through silica gel to remove sodium acetate. The silica gel pad was washed with 700 mL of additional dichloromethane:methanol solution. The combined dichloromethane:methanol solution was concentrated to dryness. The solid product was suspended in 1:1 hexane:dichloromethane and filtered to yield 9.9 g (85%) pyrazolo[1,5-c]pyrimidin-5(4H)-one. LCMS (ESI) m+H=136.0; 1H NMR (400 MHz, DMSO-d6) δ: 12.1 (s broad exchangeable, 1H), 8.47 (d, 1H, J=7.9), 7.75 (d, 1H, J=1.9), 5.94 (d, 1H, J=7.5), 5.81 (d, 1H, J=1.7).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#N)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[OH-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]2[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: N#Cc1cccnc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Clc1ncccc1-c1ccccc1
Reaction time: 3 h
Yield: 48.5 %

Procedure:
A solution of 2-chloro-3-cyanopyridine (VII; 2.0 g, 0.01 mole) in methylene chloride was treated dropwise with a 1M solution of DABAL-H in methylene chloride (0.03 mole, 33 mL) at -78°. The solution turned from a colorless to a bright yellow-orange color during the addition, and the stirring was continued for 3 hr at -78°. The mixture was treated with 3N HCl (75 mL) which rapidly warmed the reaction to -10°. The rate of addition was regulated so as to maintain the reaction temperature below 0°. The solution was treated dropwise with 10% sodium hydroxide solution which formed a bright yellow emulsion which was filtered through sintered glass. The collected aluminum salts were exhaustively washed with methylene chloride, filtered, and the filtrate dried (MgSO4). Concentration of the organic solution in vacuo gave a yellow solid which was purified by Kugelrohr distillation (60°/0.4 Torr.) affording 0.46 g (33%) of 2-chloro-3-pyridinecarboxaldehyde (VI) as a white solid, m.p. 48°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:10][O:11][CH2:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[C:15]([O:17]C)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>[OH-].[Na+].CO>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:10][O:11][CH2:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccccc1COCC(Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NC(COCc1ccccc1C(=O)O)Cc1ccccc1
Temperature: 50 °C
Yield: 90 %

Procedure:
The suspension of compound 1a (39.9 g, 100 mmol) in 3.5N aqueous NaOH (130 mL) and MeOH (350 mL) was heated to 50° C. for 3 hr. Then the mixture was cooled to rt and acidified to pH=3 with 3.5N aqueous HCl, extracted with EA (2×300 mL). The organic extracts were combined and dried over anhydrous Na2SO4, concentrated under reduced pressure to get compound 1b as a white solid (34.7 g, 90% yield). 1H NMR (400 MHz, CDCl3): δ 8.08-8.06 (m, 1H), 7.73-7.53 (m, 2H), 7.42-7.40 (m, 1H), 7.30-7.19 (m, 5H), 4.95-4.84 (m, 2H), 4.05-4.02 (m, 1H), 3.55-3.48 (m, 2H), 2.93-2.91 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: [C:1]([NH:11][CH2:12][CH2:13][C:14]1[CH:21]=[CH:20][C:18]([OH:19])=[C:16]([OH:17])[CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].Cl.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=1>N1C=CC=CC=1>[C:23]([O:17][C:16]1[CH:15]=[C:14]([CH:21]=[CH:20][C:18]=1[O:19][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=1)[CH2:13][CH2:12][NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: O=C(NCCc1ccc(O)c(O)c1)OCc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(NCCc1ccc(OC(=O)c2cccnc2)c(OC(=O)c2cccnc2)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.6 %

Procedure:
19.0 g (66 mmol) of N-carbobenzoxydopamine obtained in Synthetic Example 1-(1) and 37.2 g (209 mmol) of hydrochloride of nicotinoyl chloride were added to 200 ml of pyridine. After stirring at room temperature for 12 hours, the mixture was allowed to react at 35°-40° C. for 2 hours. Then, the reaction mixture was poured into ice and a sodium carbonate solution followed by extraction with chloroform. The resulting extract was dried over anhydrous magnesium sulfate and the solvent was distilled off to obtain crude crystals. The thus-obtained crystals were recrystallized from ethyl acetate/diethyl ether (1:5 by volume) to obtain 23.5 g (yield: 71.6%) of the desired compound in the form of white crystals (m.p. 77°-78° C.).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:18][C:17](=O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1)[CH3:2].S(Cl)([Cl:22])=O>CN(C)C=O>[Cl:22][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[N:18]=1
Reactant: O=S(Cl)Cl
Reactant: CCc1ccc(-c2nc3ccccc3c(=O)[nH]2)cc1
Solvent: CN(C)C=O
Product: CCc1ccc(-c2nc(Cl)c3ccccc3n2)cc1

Procedure:
A mixture of 7.43 g of 2-(4-ethylphenyl)quinazolin-4(3H)-one and 50 ml of thionyl chloride was treated with 2.17 g of dimethylformamide as described in Example I. The solid was recrystallized twice from petroleum ether (60°-110° fraction) to give 4.23 g of light-colored 4-chloro-2-(4-ethylphenyl)quinazoline, m.p. 75.5°-76.5°; ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:5]([NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([N:18]2[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]2)[CH:9]=1)=[O:6].C(N(CC)C(C)C)C.[C:36]([C:38]1[N:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]2=[N:40][CH:39]=1)#[CH:37]>CN(C=O)C.[Cu]I>[N:40]1[CH:39]=[C:38]([C:36]#[C:37][C:2]2[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=2[CH3:27])[C:5]([NH:7][C:8]2[CH:13]=[C:12]([C:14]([F:16])([F:17])[F:15])[CH:11]=[C:10]([N:18]3[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]3)[CH:9]=2)=[O:6])[N:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=12
Reactant: C#Cc1cnc2ccccn12
Reactant: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(I)c3)cc(C(F)(F)F)c2)cn1
Agent: [Cu]I
Agent: CCN(CC)C(C)C
Solvent: CN(C)C=O
Product: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(C#Cc4cnc5ccccn45)c3)cc(C(F)(F)F)c2)cn1
Temperature: 25 °C
Reaction time: 28 h

Procedure:
To a solution of 3-iodo-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide (0.11 g, 0.22 mmol.) in DMF (1 mL) in a sealed tube was added Pd[(PPh3)4](0.013 g, 0.011 mmol), CuI (3 mg, 0.016 mmol), diethylisopropylamine (0.057 mL, 0.33 mmol.), followed by 3-ethynylimidazo[1,2-a]pyridine (0.040 g, 0.28 mmol.). The mixture was purged with argon for 15 minutes, sealed and stirred at rt for 28 h. The solvent was concentrated and the residue was taken up in methylene chloride (50 mL). The organic layer was washed with water, dried (Na2SO4) and evaporated to leave a brown residue which was purified by combiflash (hexane/ethyl acetate/methanol) to yield the desired material: MS (M+H)+ 500.
Reaction SMILES: C(O[C:4]([C:6]1[NH:7][N:8]=[C:9]([CH:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:12])[CH:10]=1)=[O:5])C.CC(OC([NH:27][CH2:28][CH2:29]O)=O)(C)C.C(OC(C1N(CC(NC(OC(C)(C)C)=O)C)N=C(COC2C=CC=CC=2)C=1)=O)C.O(CC1C=C2C(=O)NCCN2N=1)C1C=CC=CC=1>>[O:13]([CH:11]([C:9]1[CH:10]=[C:6]2[C:4](=[O:5])[NH:27][CH2:28][CH2:29][N:7]2[N:8]=1)[CH3:12])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1cc(C(C)Oc2ccccc2)n[nH]1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CCOC(=O)c1cc(COc2ccccc2)nn1CC(C)NC(=O)OC(C)(C)C
Agent: O=C1NCCn2nc(COc3ccccc3)cc21
Product: CC(Oc1ccccc1)c1cc2n(n1)CCNC2=O

Procedure:
The compound was prepared from (rac)-5-(1-phenoxy-ethyl)-2H-pyrazole-3-carboxylic acid ethyl ester and tert-butyl n-(2-hydroxyethyl)carbamate using the methods described in the preceding examples 7 ((rac)-2-(2-tert-butoxycarbonylamino-propyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester) and 6 (2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one).
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([CH2:21][C:22]([OH:24])=O)[C:6](=[O:25])[N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[C:4]=1[CH3:36])#[N:2].C[N:38](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([CH2:21][C:22]([NH2:38])=[O:24])[C:6](=[O:25])[N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=2)[C:4]=1[CH3:36])#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(CC(=O)O)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(CC(N)=O)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 0.33 h
Yield: 94.4 %

Procedure:
The reaction was carried out under argon. 2-[(6S)-5-Cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidin-1(2H)-yl]acetic acid (90 mg, 174 μmol; Example 21) was initially charged in DMF (3 ml), HATU (330 mg, 868 μmol, 5 eq.) was added at 0° C. and the mixture was stirred for 20 min. Ammonium chloride (18.1 mg, 340 μmol, 5 eq.) and N,N-diisopropylethylamine (224 mg, 1736 μmol, 10 eq.) were then added, and the mixture was stirred at RT until complete conversion had been achieved (after a number of hours; HPLC control). The reaction mixture was then concentrated under reduced pressure, and the crude product was purified by preparative HPLC (Column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave the title compound as a colorless solid (85 mg, 94% of theory).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24](COCC[Si](C)(C)C)[N:23]=[CH:22]4)=[CH:15][N:16]=[C:11]2[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[ClH:34]>O1CCOCC1>[ClH:34].[C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][N:23]=[CH:22]4)=[CH:15][N:16]=[C:11]2[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3cccc4cnn(COCC[Si](C)(C)C)c34)nc12
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3cccc4cn[nH]c34)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 21 %

Procedure:
To a stirred solution of N-tert-butyl-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (120 mg, 0.258 mmol) in dioxane (20 mL) was bubbled HCl gas until saturation and the reaction stirred at room temperature for 16 hours. Reaction mixture was concentrated and the residue purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 40% acetonitrile/60% water (0.1% trifluoroacetic acid V/V) initially, and then proceed to 50% acetonitrile/50% water (0.1% trifluoroacetic acid V/V) in a linear fashion after just 9 min.). Concentrated HCl was added to the combined fractions containing pure product, then solvents evaporated to afford N-tert-butyl-2-(1H-indazol-7-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide hydrochloride (20 mg, 21%) as a yellow solid. LCMS: (M+H)+=335; 1H NMR (300 MHz, CD3OD): δ 8.94 (s, 1H), 8.34 (s, 1H), 8.31 (s, 1H), 7.97 (s, 1H), 7.94 (s, 1H), 7.39 (t, 1H, J=6.9 Hz), 1.52 (s, 9H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][Br:8].[OH-].[Na+].[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[S:21][CH2:22][CH2:23][OH:24].CCCCCC>CCOCC.O>[Br:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:24][CH2:23][CH2:22][S:21][C:12]1[CH:13]=[CH:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]=1
Reactant: OCCSc1ccc2ccccc2c1
Reactant: BrCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: BrCCCCCCOCCSc1ccc2ccccc2c1
Reaction time: 4 h

Procedure:
A mixture of 1,6-dibromohexane (9 ml), 50% w/v sodium hydroxide (40 ml), 2-(2-naphthalenyl)thioethanol (4 g), TAB (0.8 g) and hexane (30 ml) was stirred vigorously at 20°, under nitrogen for 4 h. Water (100 ml) and ether (100 ml) were added and the mixture was further extracted with ether (100, 2×50 ml). The combined, dried ether extracts were evaporated in vacuo to give a yellow oil. Purification by FCC eluting with light petroleum (b.p. 60°-80°):ether (30:1→1:1) gave the title compound as a white crystalline solid (5.7 g), m.p. 38°-40° (softens 36°).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[Na+].[I-:16].Cl.N>O.C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][C:11]([I:16])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: Clc1ccc(-c2ccc(Cl)nn2)cc1
Agent: Cl
Agent: N
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Clc1ccc(-c2ccc(I)nn2)cc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
20 ml ACN are added to 0.50 g (1.11 mmol) 3-(4-chlorophenyl)-6-chloropyridazine and 3.33 g (22.2 mmol) NaI before 189 μl fuming conc. HCl are added and the mixture is stirred at 80° C. for 4 h. The mixture is alkalised with aq. Ammonia solution (32%) diluted with water and extracted with EtOAc. The org. phases are combined, dried with Na2SO4 and the solvent is removed in vacuo. The resulting crude product is triturated with TBME.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:24]([O:27][CH2:28][C:29]1[C:30]([N:44]2[CH2:55][CH2:54][N:53]3[C:46](=[CH:47][C:48]4[CH2:49][C:50]([CH3:57])([CH3:56])[CH2:51][C:52]=43)[C:45]2=[O:58])=[N:31][CH:32]=[CH:33][C:34]=1B1OC(C)(C)C(C)(C)O1)(=[O:26])[CH3:25].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O.O.O.C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[C:24]([O:27][CH2:28][C:29]1[C:30]([N:44]2[CH2:55][CH2:54][N:53]3[C:46](=[CH:47][C:48]4[CH2:49][C:50]([CH3:57])([CH3:56])[CH2:51][C:52]=43)[C:45]2=[O:58])=[N:31][CH:32]=[CH:33][C:34]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:26])[CH3:25]
Reactant: CN1CCC(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CC1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C4CCN(C)CC4)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 100 °C
Yield: 57.7 %

Procedure:
A 50-mL round-bottomed flask equipped with a reflux condenser was charged with 5-bromo-1-methyl-3-(5-(1-methylpiperidin-4-yl)pyridin-2-ylamino)pyridin-2(1H)-one 232d (160 mg, 0.40 mmol), {3-[(acetoxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (240 mg, 0.60 mmol), Pd(dppf)Cl2 (20 mg, 0.020 mmol), K3PO4 (180 mg, 0.80 mmol), sodium acetate trihydrate (120 mg, 0.80 mmol), water (0.5 mL), and acetonitrile (10 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 2 h. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified on silica-gel column chromatography eluting with 25:1 dichloromethane/methanol to afford 236a as a yellow solid (150 mg, 38%). MS-ESI: [M+H]+ 650.3
Reaction SMILES: [NH2:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=O)[C:3]=1[C:12]([OH:14])=O.Cl.[NH2:16][CH:17]1[CH2:22][CH2:21][C:20](=[O:23])[NH:19][C:18]1=[O:24]>>[NH2:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[C:4]2[C:3]=1[C:12](=[O:14])[N:16]([CH:17]1[CH2:22][CH2:21][C:20](=[O:23])[NH:19][C:18]1=[O:24])[C:5]2=[O:7]
Reactant: NC1CCC(=O)NC1=O
Reactant: Nc1c(O)ccc(C(=O)O)c1C(=O)O
Agent: Cl
Product: Nc1c(O)ccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O

Procedure:
reacting 3-amino-4-hydroxyphthalic acid with 3-aminopiperidine-2,6-dione hydrochloride, or an enantiomer or a mixture of enantiomers thereof; to form 4-amino-2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione.
Reaction SMILES: [N+:1]([C:4]1C=C([N+]([O-])=O)C=C[C:5]=1[O-])([O-])=O.[NH2:14][N+:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][OH:22])[CH:16]=1.[OH-].[Na+]>C(#N)C>[CH3:5][C:4]1[N:1]=[C:16]2[C:17]([CH2:21][OH:22])=[CH:18][CH:19]=[CH:20][N:15]2[N:14]=1
Reactant: N[n+]1cccc(CO)c1
Reactant: O=[N+]([O-])c1ccc([O-])c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: Cc1nc2c(CO)cccn2n1
Reaction time: 12 h
Yield: 26.6 %

Procedure:
To a solution of 1-amino-3-(hydroxymethyl)pyridinium 2,4-dinitrobenzenolate (100 g, 323 mmol) in acetonitrile (1.08 L), was added 2 N sodium hydroxide (485 mL) at room temperature, and the mixture was stirred for 12 hr. Acetonitrile was evaporated under reduced pressure, and the residual aqueous solution was extracted with 3 times with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by recrystallization (ethyl acetate/hexane) to give the title compound (14.0 g, yield 29%).
Reaction SMILES: [Si:1]([O:8][CH:9]1[C:13]2=[CH:14][C:15]3[CH:16]=[C:17]([C:21](=[N:25]C(C)(C)C)[CH2:22][CH2:23][CH3:24])[CH:18]=[CH:19][C:20]=3[N:12]2[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:30]([C:39](OC)=[O:40])([C:35](OC)=[O:36])[C:31]([O:33][CH3:34])=[O:32]>O(C1C=CC=CC=1)C1C=CC=CC=1>[Si:1]([O:8][CH:9]1[C:13]2=[CH:14][C:15]3[CH:16]=[C:17]([C:21]4[NH:25][C:35](=[O:36])[C:30]([C:31]([O:33][CH3:34])=[O:32])=[C:39]([OH:40])[C:22]=4[CH2:23][CH3:24])[CH:18]=[CH:19][C:20]=3[N:12]2[CH2:11][CH2:10]1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: COC(=O)C(C(=O)OC)C(=O)OC
Reactant: CCCC(=NC(C)(C)C)c1ccc2c(c1)cc1n2CCC1O[Si](C)(C)C(C)(C)C
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCc1c(-c2ccc3c(c2)cc2n3CCC2O[Si](C)(C)C(C)(C)C)[nH]c(=O)c(C(=O)OC)c1O
Temperature: 25 °C
Yield: 27.6 %

Procedure:
A solution of N-(1-(1-(tert-butyldimethylsilyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-7-yl)butylidene)-2-methylpropan-2-amine (3.8 g, 9.0 mmol) and trimethyl methanetricarboxylate (2.6 g. 13.5 mmol) in Ph2O (10 mL) was heated at 220° C. for 30 min. The reaction mixture was then cooled to room temperature and triturated with Et2O to afford the title compound as an off-white solid (1.2 g, 30%).
Reaction SMILES: [CH:1](=[C:8]1[CH2:13][CH2:12][CH2:11][NH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>[Ir].ClCCl>[CH2:1]([CH:8]1[CH2:13][CH2:12][CH2:11][NH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NCCCC1=Cc1ccccc1
Agent: [Ir]
Solvent: ClCCl
Solvent: CO
Product: O=C1NCCCC1Cc1ccccc1
Yield: 97.5 %

Procedure:
This example describes the preparation of I where n=2 and R1=phenyl. In a nitrogen-filled glove box, a Fisher-Porter tube was charged with iridium catalyst prepared as in Example 1 (10 mg, 0.012 mmol) and 3-(benzylidene)-2-piperidone (250 mg, 1.3 mmol). Methanol (3 mL) and dichloromethane (3 mL) were added and the system was flushed 4 times with hydrogen and pressured to 60 psi (0.5 MPa) H2. After 18 h the reaction mixture was filtered through a short pad of silica. The solvent was removed at reduced pressure to afford 3-benzyl-2-piperidone (240 mg, 96%) as a white crystalline solid. Chiral HPLC analysis (Chiralpak AS, 60% heptane, 39.2% isopropanol, 0.4% trifluoroacetic acid, 0.4% n-hexylamine, 40° C.) indicated that conversion was 100% and the enantiomeric excess was 83%. 13C NMR: δ 20.10, 24.33, 36.42, 41.31, 41.74, 125.11, 127.32, 128.21, 138.84, 173.69;
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2[C:14]([C:17]([OH:19])=O)=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.C[N:25](C=O)C>>[CH2:1]([N:8]1[CH2:16][C:15]2[C:14]([C:17]([NH2:25])=[O:19])=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc2c1CN(Cc1ccccc1)C2
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: NC(=O)c1cccc2c1CN(Cc1ccccc1)C2

Procedure:
A mixture of 35.0 g of 2-benzylisoindoline-4-carboxylic acid, 150 ml of thionyl chloride, and 1 ml of DMF was heated under reflux for 10 hours. After cooling, the reaction mixture was concentrated to the extent that the acid chloride crystals does not deposit. To the concentrate was added dropwise 28% aqueous ammonia under ice cooling and stirring After stirring for 3 hours crystals produced was collected by filtration and washed with water. The crystals were dissolved in chloroform, washed with 5% sodium hydroxide and water, and concentrated. The residue was recrystallized from ether to obtain 24.1 g of 2-benzylisoindoline-4-carboxamide.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.Cl.[CH2:8]([O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl.Cl>[CH2:8]([O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:20][C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])=[CH:21][CH:22]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(OCc2ccccc2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Cyclopropane carbonyl chloride (4.54 ml) was added dropwise over 5 min to a stirred solution of 4-benzyloxyaniline hydrochloride (11.8 g) and triethylamine (15.33 ml) in dichloromethane (60 ml). The reaction mixture was stirred at room temperature under nitrogen for 2 h. The solution was diluted with 2N hydrochloric acid (100 ml) and dichloromethane (200 ml). The organic layer was washed with 2N sodium carbonate (100 ml), water (100 ml), 10% brine (50 ml) and dried over anhydrous sodium sulphate. Concentration in vacuo gave a pale brown solid which was washed with diethyl ether (3×50 ml) to afford the title compound (12 g) as a white solid, m.p. 162°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[NH2:28])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:30]1[CH:35]=[CH:34][C:33]([CH:36]=O)=[CH:32][N:31]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl.CO>[C:1]([O:5][C:6]([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:28]=[CH:36][C:33]3[CH:34]=[CH:35][N:30]=[N:31][CH:32]=3)=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3ccccc3N)ccc2C(C)(C)C1
Reactant: O=Cc1ccnnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3ccccc3N=Cc3ccnnc3)ccc2C(C)(C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 7-(2-amino-benzoylamino)-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (512 mg, 1.3 mmol), pyridazine-4-carbaldehyde (140 mg, 1.3 mmol) and p-toluenesulfonic acid (10 mg) was heated at reflux in toluene (5 mL) for 1 h. The mixture was cooled to RT and diluted with CH2Cl2. NaBH4 (50 mg, 1.3 mmol) was added to the mixture followed by MeOH (2 mL). The mixture was stirred for 1 h. The crude material was purified with flash chromatography (SiO2, 5% MeOH/CH2Cl2) to give a yellow solid. MS (ES+): 488.0 (M+H)+. Calc'd for C28H33N5O3: 487.59.