Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Cl:25])[C:9]=2[N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:12]2)[NH:4][CH:3]=1.[CH3:26][O:27][C@@H:28]([CH3:32])[C:29](O)=[O:30].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C.[Li+].[OH-]>CC#N.O.O.CN1C(=O)CCC1>[Cl:25][C:8]1[C:9]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH2:12]2)=[C:10]2[C:2]([NH:1][C:29](=[O:30])[C@@H:28]([O:27][CH3:26])[CH3:32])=[CH:3][NH:4][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Cl)cnc3[nH]cc(N)c23)C1
Reactant: CO[C@@H](C)C(=O)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CO[C@@H](C)C(=O)Nc1c[nH]c2ncc(Cl)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Reaction time: 0.17 h
Yield: 76.9 %

Procedure:
An NMP solution (2 mL) of (R)-tert-butyl 1-(3-amino-5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.200 g, 0.547 mmol; Example 91, Step A), (S)-2-methoxypropanoic acid (0.310 mL, 3.28 mmol), BOP-Cl (0.835 g, 3.28 mmol), and triethylamine (0.533 mL, 3.83 mmol) was stirred for 18 hours. 3M aqueous LiOH (3 mL) was then added. The reaction was stirred for 10 minutes, poured into water, and extracted with DCM. The combined organic fractions were dried (MgSO4), filtered, and concentrated to give the crude product, which was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 5-95 CH3CN/water) to give the product tert-butyl (R)-1-(5-chloro-3-((S)-2-methoxypropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.190 g, 77% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8](N)=[C:7]([O:15][CH2:16][CH3:17])[CH:6]=1)[CH3:2].[ClH:19].N([O-])=O.[Na+].[OH-].[Na+]>O.[Cu]Cl.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([Cl:19])=[C:7]([O:15][CH2:16][CH3:17])[CH:6]=1)[CH3:2]
Reactant: Cl
Reactant: CCOC(=O)c1cc(OCC)c(N)c(OCC)c1
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cc(OCC)c(Cl)c(OCC)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-amino-3,5-diethoxy-benzoic acid ethyl ester (5.1 g, 20.13 mmol, 1.0 equiv; prepared as described in I. Kompis and A. Wick Helv. Chim. Acta 1977, 60, 3025-3034) in water (40 mL) and 37% HCl (40 mL) at 0° C. was added sodium nitrite (1.67 g, 24.16 mmol, 1.2 equiv). After 10 min, copper(I) chloride (12.0 g, 120.81 mmol, 6.0 equiv) was added, the reaction mixture stirred for an additional 5 h at 0° C. and then the ice bath removed. After stirring for 18 h, the crude reaction mixture was adjusted to pH=8 by addition of a solution of 1 M NaOH and the aqueous layer extraced with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 5.0 g (91%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.32 (t, J=7.0 Hz, 4H), 1.40 (t, J=7.0 Hz, 6H), 4.09 (q, J=7.0 Hz, 4H), 4.30 (q, J=7.0 Hz, 2H), 7.18 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 13.33, 13.66, 60.29, 64.16, 105.75, 115.88, 128.25, 154.49, 165.01. MS (ISP): 273.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C@@H:8]2[CH2:10][C@H:9]2[C:11]([OH:13])=O)=[O:7])=[CH:4][CH:3]=1.[NH:16]1[CH2:21][CH2:20][CH:19]([N:22]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][C:23]2=[O:32])[CH2:18][CH2:17]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[K+].[Br-]>O.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C@H:8]2[CH2:10][C@H:9]2[C:11]([N:16]2[CH2:17][CH2:18][CH:19]([N:22]3[CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:32])[CH2:20][CH2:21]2)=[O:13])=[O:7])=[CH:14][CH:15]=1
Reactant: O=C(O)[C@@H]1C[C@H]1C(=O)c1ccc(Cl)cc1
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(c1ccc(Cl)cc1)[C@H]1C[C@H]1C(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 1.0 g (4.452 mmol) of trans-2-(4-chlorobenzoyl)cyclopropanecarboxylic acid, 0.97 g (4.194 mmol) of 3,4-dihydro-3-(4-piperidinyl)-2(1H)-quinazolinone, 1.4 g (4.36 mmol) of TBTU, 0.455 mg (4.5 mmol) of triethylamine, and 20 mL of dimethylformamide was stirred for 5 hours at ambient temperature. The reaction mixture was freed from solvent in vacuo, diluted with 300 mL of water, and made slightly acidic with citric acid. The precipitate formed was suction filtered and carefully washed with water, then with 5 mL of tetrahydrofuran, and finally dried in a circulating air drier at a temperature of 60° C. 1.3 g (71% of theoretical) of a colorless crystalline product was obtained: m.p. 272° C.-273° C.; Rf 0.24 (MP A); IR (KBr): 1674.1 cm−1 (C═O); MS: M+=437/439 (Cl).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:21][C:22]([CH3:27])([CH3:26])[C:23](Br)=[O:24].C(Cl)(Cl)Cl.O>C1COCC1>[C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:23](=[O:24])[C:22]([Br:21])([CH3:27])[CH3:26])=[CH:15][CH:16]=1)([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(N)cc1)C(=O)O
Reactant: CC(C)(Br)C(=O)Br
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(NC(=O)C(C)(C)Br)cc1)C(=O)O
Reaction time: 0.17 h
Yield: 65 %

Procedure:
Commercially available N-Boc 4-aminophenylalanine (3.62 g, 0.01447 mol) was dissolved in 50 mL of dry THF. 2-bromoisobutyryl bromide (1.757 mL, 0.01422 mol) was added dropwise over 30-60 seconds with vigorous stirring. The reaction was complete after 10 min (monitored by TLC). After approximately 20 min. the entire reaction mixture (including newly formed precipitate) was transferred to a separatory funnel with CHCl3, and approximately 100 mL of H2O. The reaction mixture was extracted with CHCl3 (3×50 mL). The organic phase was washed with distilled water (2×50 mL) and brine (50 mL). The organic phase was dried with MgSO4 and evaporated in vacuo to obtain the crude product (4.55 g). The crude solid product was recrystallized in 20-30 mL acetonitrile three times to purify the product. After three recrystallizations, N-Boc-4-(2′-bromoisobutyramido)phenylalanine was obtained in 65% yield (3.63 g). 1H NMR (500 MHz, DMSO): δ9.4 (s, 1H, COOH), δ7.8 (s, 1H, NH), δ7.5 (d, 2H, Ar H), δ7.1 (d, 2H, Ar H), δ6.0 (d, 1H, NH), δ4.2 (d, 1H, CH), δ3.05 (dd, 2H, CH2), δ2.0 (s, 6H, CH3), δ1.3 (s, 9H, CH3).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21](Cl)(=[O:23])=[O:22])([O-:14])=[O:13].N1C=CC=CC=1>C(Cl)Cl>[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[N:4]=[CH:3][CH:2]=[N:1]2)(=[O:23])=[O:22])([O-:14])=[O:13]
Reactant: Nc1cccc2nccnc12
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1cccc2nccnc12
Yield: 55.6 %

Procedure:
In a similar fashion using route 14 general procedure 26, quinoxalin-5-ylamine (Intermediate 482) (540 mg, 3.7 mmol), 2-nitro-benzenesulfonyl chloride (986 mg, 4.46 mmol), pyridine (0.9 ml, 7.44 mmol) and DCM (10 ml) gave the title compound (679 mg, 56%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: Br[C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.CC([O-])(C)C.[Na+].[C:17]([CH2:19][C:20](OC(C)(C)C)=O)#[N:18]>O1CCOCC1.ClCCl>[Cl:8][C:5]1[N:4]=[C:3]([O:9][CH3:10])[C:2]([CH:19]([CH3:20])[C:17]#[N:18])=[CH:7][CH:6]=1
Reactant: COc1nc(Cl)ccc1Br
Reactant: CC(C)(C)OC(=O)CC#N
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1nc(Cl)ccc1C(C)C#N
Temperature: 75 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
To a suspension of 3-bromo-6-chloro-2-methoxypyridine (99.9 g, 449 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (2.76 g, 3.38 mmol), and NaOtBu (105 g, 1090 mmol) in dioxane (805 mL) was added tert-butyl cyanoacetate (64.8 mL, 454 mmol) under nitrogen. The reaction mixture was heated for 235 min while maintaining the internal reaction temperature at 75° C. under nitrogen. After being cooled to 20° C., to the reaction mixture was added Mel (55.9 mL, 898 mmol) in one portion, and the resulting mixture was stirred overnight at r.t. Celite® (24 g) was added to the reaction mixture, and the resulting mixture was filtered through a 370 g silica plug. The plug was eluted with EtOAc/heptanes (1/3, 2.0 L), and the combined filtrate was concentrated. A solution of the crude residue (133.9 g) in DMSO (330 mL) and water (67 mL) was heated at 130° C. for 15.8 h. The reaction mixture was filtered through a plug of Celite®, and the filter cake was rinsed with MTBE and water. The filtrate was filtered again through a plug of Celite® and the filter cake was washed with MTBE and water. The filtrate was partitioned between MTBE (total volume=2.0 L), water (total volume=1.0 L) and brine (100 mL). The layers were separated and the organic layer was washed with water (1.0 L) and brine (750 mL), dried over Na2SO4, and concentrated to afford the crude 2-(6-Chloro-2-methoxypyridin-3-yl)propanenitrile (87.6 g, 99%) as a dark brown oil, which was used for the next step without any further purification. 1H NMR (600 MHz, CDCl3) δ 1.58 (d, 3H), 4.01 (s, 3H), 4.11 (q, 1H), 6.97 (d, 1H), 7.66 (d, 1H). MS (ES+)(M+H) 197.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH3:14])[N:8]=[CH:7][N:6]=1)[CH2:2][CH3:3].Cl.[CH3:16][NH:17][O:18][CH3:19].[OH-].[Na+]>O1CCOCC1.O>[CH2:1]([NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH3:14])[N:8]=[C:7]([N:17]([CH3:16])[O:18][CH3:19])[N:6]=1)[CH2:2][CH3:3]
Reactant: CNOC
Reactant: CCCNc1ncnc(NCCC)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCNc1nc(NCCC)nc(N(C)OC)n1
Temperature: 60 °C
Yield: 90 %

Procedure:
A mixture of 2-chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) (10.00 g, 43.53 mmol), N,O-dimethylhydroxylamine hydrochloride (8.49 g, 87.06 mmol) and NaOH (3.13 g, 78.35 mmol) in 1,4-dioxane (120 mL) and water (30 mL) was heated at 60° C. for 6 h, after which the volatiles were removed under reduced pressure. Saturated NaHCO3 solution (500 mL) was added to the residue and the mixture was extracted with EtOAc (3×200 mL). The combined organic extracts were washed with water (300 mL), then with a brine solution (300 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the resultant residue was filtered through silica gel using eluent CH2Cl2/EtOH (9/1 v/v) to yield N-(4,6-bis-n-propylamino[1,3,5]triazine-2-yl)-N,O-dimethyl-hydroxylamine (XXXV) (9.96 g, 90% yield).
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C@@H:9]([C:23]([OH:25])=O)[CH2:10][CH2:11][C@@H:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[F:22])[CH2:13][NH2:14])=O)(C)(C)C.ClCC(C)(O)C.C(N(C(C)C)CC)(C)C.C(Cl)CCl.[CH:52]1[CH:57]=[N:56][C:55]2N(O)N=N[C:54]=2[CH:53]=1.C([O-])(O)=O.[Na+]>CCO.C(Cl)Cl>[NH2:8][C@@H:9]1[CH2:10][CH2:11][C@@H:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])[CH2:13][N:14]([C:53]2[CH:52]=[CH:57][N:56]=[CH:55][CH:54]=2)[C:23]1=[O:25]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H](CC[C@H](CN)c1cccc(F)c1F)C(=O)O
Reactant: On1nnc2cccnc21
Agent: CC(C)(O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CCO
Product: N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(c2ccncc2)C1=O
Reaction time: 8 h
Yield: 53.4 %

Procedure:
A solution of (5S)—N2,N2-bis(tert-butoxycarbonyl)-5-(2,3-difluorophenyl)-D-lysine (0.569 g, 1.24 mmol), 1-chloro-2-methyl-2-propanol (0.202 g, 1.86 mmol) and diisopropylethylamine (0.529 g, 4.10 mmol) in EtOH (5 mL) was heated at 75° C. overnight. The reaction was concentrated to dryness, diluted with DCM (20 mL) and EDC (0.358 g, 1.87 mmol), HOAT (0.252 g, 1.87 mmol) were added followed by diisopropylethylamine (0.650 mL, 3.73 mmol). After stirring overnight, NaHCO3 was added, the layers separated and the aqueous phase backwashed with DCM. The combined organics were dried over magnesium sulfate, filtered, concentrated and the residue purified by silica gel chromatography (10%→35% EtOAc/hexanes) to give the title compound (0.21 g). MS 513.1 (M+1). 1H NMR (500 MHz, CD3OD) δ 7.1 (m, 3H), 5.24 (d, J=10.7 Hz, 1H), 4.02 (m, 1H), 3.69 (d, J=13.9 Hz, 1H), 3.60 (d, J=15.1 Hz, 1H), 3.39 (m, 1H), 3.24 (d, J=14.2 Hz, 1H), 2.4 (m, 1H), 2.1 (m, 3H), 1.5 (s, 18H), 1.20 (s, 3H), 1.16 (s, 3H).
Reaction SMILES: C[Si](C)(C)[O:3][C:4](=[CH2:18])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36](=[O:61])[C:37]#[C:38][CH2:39][C:40]2([CH2:46][CH2:47][C:48]3[CH:53]=[CH:52][C:51]([O:54][CH:55]4[CH2:60][CH2:59][CH2:58][CH2:57][O:56]4)=[CH:50][CH:49]=3)[S:45][CH2:44][CH2:43][CH2:42][S:41]2)=[CH:30][CH:29]=1.O.C(OCC)(=O)C>C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[O:56]1[CH2:57][CH2:58][CH2:59][CH2:60][CH:55]1[O:54][C:51]1[CH:52]=[CH:53][C:48]([CH2:47][CH2:46][C:40]2([CH2:39][CH:38]([CH2:18][C:4](=[O:3])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:37][C:36](=[O:61])[CH2:35][CH2:34][C:31]3[CH:32]=[CH:33][C:28]([O:27][CH:22]4[CH2:23][CH2:24][CH2:25][CH2:26][O:21]4)=[CH:29][CH:30]=3)[S:41][CH2:42][CH2:43][CH2:44][S:45]2)=[CH:49][CH:50]=1
Reactant: C=C(CCCCCCCCCCCCC)O[Si](C)(C)C
Reactant: O=C(C#CCC1(CCc2ccc(OC3CCCCO3)cc2)SCCCS1)CCc1ccc(OC2CCCCO2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCC(=O)CC(CC(=O)CCc1ccc(OC2CCCCO2)cc1)CC1(CCc2ccc(OC3CCCCO3)cc2)SCCCS1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Trimethyl-(1-methylene-tetradecyloxy)-silane (176 mg, 0.6 mmol) and the enone 21 (176 mg, 0.3 mmol) are dissolved in 2 mL of anhydrous THF and the solution is cooled down to −78° C. Two drops of tetrabutylammonium fluoride (1 M in THF) are injected. The mixture is stirred for 1 h at this temperature, then the solution is left to return to ambient temperature under stirring. After the addition of water and extraction with ethyl acetate, the product is dried and the solvent is evaporated off. The residue is purified by flash chromatography in order to produce compound 22.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6](CO)[CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][N:10]=[C:9]2[NH:14][CH2:15][C:16]1[CH:17]=[C:18]([NH:22]C(=O)OC(C)(C)C)[CH:19]=[CH:20][CH:21]=1)=[O:3].Cl.O1CCOC[CH2:34]1>CO>[NH2:22][C:18]1[CH:17]=[C:16]([C@H:15]([NH:14][C:9]2[C:8]3[C:13](=[C:4]([C:2]([NH2:1])=[O:3])[CH:5]=[CH:6][CH:7]=3)[N:12]=[CH:11][N:10]=2)[CH3:34])[CH:21]=[CH:20][CH:19]=1
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CNc2ncnc3c(C(N)=O)cc(CO)cc23)c1
Agent: Cl
Solvent: CO
Product: C[C@@H](Nc1ncnc2c(C(N)=O)cccc12)c1cccc(N)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl [3-({[8-(aminocarbonyl)-6-(hydroxymethyl)quinazolin-4-yl]amino}methyl)phenyl]carbamate (20 mg; 0.05 mmol; 1.00 eq.) in methanol (1 ml) was added 4.0M hydrogen chloride in dioxane (1 ml; 4.00 M; 4.00 mmol; 84.69 eq.). The reaction mixture was stirred at RT for 3 h. Concentrated to obtain title product. MS (M+1) 324.
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[C:13]2[CH:14]=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:6]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2[CH3:31])[N:5]=1)([CH3:3])[CH3:2].[OH-:32].[Na+].OO.O>CS(C)=O.C(O)C>[CH:1]([C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[C:13]2[CH:14]=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:6]([C:23]2[CH:30]=[CH:29][C:26]([C:27]([NH2:28])=[O:32])=[CH:25][C:24]=2[CH3:31])[N:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(C#N)ccc1-n1nc(C(C)C)c2c(-c3cnc4ccccc4c3)ccnc21
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCO
Product: Cc1cc(C(N)=O)ccc1-n1nc(C(C)C)c2c(-c3cnc4ccccc4c3)ccnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
4-Fluoro-3-methylbenzonitrile (0.077 g) and cesium carbonate (0.203 g) were added to a solution of compound (6c) (0.150 g) in DMF (1.73 mL), followed by stirring at 80° C. for 18 hr. The reaction solution was distributed between ethyl acetate and water. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled away, and the residue was purified by neutral silica gel column chromatography (hexane/ethyl acetate) to obtain 4-{(3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-3-methylbenzonitrile (0.154 g, 73%). This 4-{3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-3-methylbenzonitrile was dissolved in DMSO (5.0 mL) and ethanol (5.0 mL). A 4 N aqueous sodium hydroxide solution (0.195 mL) and a 30% hydrogen peroxide solution (0.088 mL) were added to the resulting solution, followed by stirring at room temperature for 30 min. Water was added to the reaction solution, and the precipitate was collected by filtration, washed with diethyl ether, and dried under reduced pressure to obtain compound (80) (0.135 g, 83%) as a white solid.
Reaction SMILES: C[O-].[Na+].Cl.Cl[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH2:13]([N:17]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[C:18]1[SH:28])[CH:14]([CH3:16])[CH3:15].O>CO>[CH2:13]([N:17]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[C:18]1[S:28][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)Cn1c(S)nc2ccccc2c1=O
Reactant: ClCc1ccccn1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)Cn1c(SCc2ccccn2)nc2ccccc2c1=O
Reaction time: 15 h
Yield: 46.1 %

Procedure:
5.4 ml Of 28% methanolic solution of sodium methoxide and 2.3 g of 2-chloromethylpyridine hydrochloride were added, in turn, to a solution of 3.0 g 3-isobutyl-2-mercapto-4(3H)-quinazolinone in 50 ml of methanol, and the stirring was continued at room temperature for 15 hours. The reaction solution was poured into about 300 ml of water and extracted with chloroform. The extract was dried over sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica column chromatography eluted with 10% ethyl acetate in chloroform. The fraction obtained from the eluent was further purified by crystallization from a mixture of ethyl acetate and diisopropylether to give 1.92 g of the title compound.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Si:7]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([Mg]Br)=[CH:28][C:27]=1[Cl:34])([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C)P(=O)(N(C)C)N(C)C.O1CCCC1>[Si:7]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:28][C:27]=1[Cl:34])([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCCCCI
Reactant: CC(C)(C)[Si](OCc1ccc([Mg]Br)cc1Cl)(c1ccccc1)c1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCCCCc1ccc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(Cl)c1
Temperature: 60 °C

Procedure:
Then, 1-iodopentane (910 mg) was added to a suspension of copper bromide-dimethyl sulfide complex (62 mg) in hexamethylphosphoric triamide (0.3 ml) under a nitrogen atmosphere, and the mixture was heated to 60° C. Thereto was dropwise added the above-mentioned solution (5 ml) of 4-((tert-butyldiphenylsilyloxy)methyl)-3-chlorophenyl magnesium bromide in tetrahydrofuran over 10 min after removal of unreacted magnesium. After completion of the dropwise addition, the reaction mixture was refluxed under heating for 2 hr. Aqueous ammonium chloride was added to the reaction mixture and the resulting product was extracted three times with hexane. The organic layers were combined, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was subjected to silica gel column chromatography (hexane) to give the objective compound (914 mg) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:9][OH:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[H-].[Na+].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1>CN(C=O)C.C(Cl)Cl>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][O:1][C:2]2[C:3]([CH2:9][OH:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=2)=[CH:17][CH:16]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Cc1ccc(O)c(CO)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(COc2ccc(C)nc2CO)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 59.8 %

Procedure:
1.39 g (10 mmol) of the commercial 3-hydroxy-6-methyl-2-pyridinemethanol in 15 ml DMF was cooled (0° C.), treated with 0.52 g (13.00 mmol) of NaH (55% in oil) and after 30 min, with 1.35 mL (10.00 mmol) p-methoxybenzylchlorid. The suspension was stirred 1 h at 0° C. and 2 h at RT. The reaction mixture was diluted with CH2Cl2 and washed with 1M NaOH and brine. The organic layers were dried over magnesium sulfate, evaporated, purified by silica gel column (AcOEt) and crystallized (AcOEt/n-n-heptane) to give 1.55 g (60%) of the title compound as a white solid. MS: 260.0 (MH+).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]#[N:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[NH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[NH2:14]>C(O)C>[NH2:12][C:11]1[N:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[N:14]=[CH:4][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: NNc1ccccn1
Reactant: CCOC=C(C#N)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2ccccn2)c1N
Temperature: 25 °C
Yield: 72.8 %

Procedure:
A solution of ethyl 2-(ethoxymethylene)-2-cyanoacetate (33.8 g, 200 mmol) and 2-hydrazinopyridine (21.8 g, 200 mmol) in ethanol (100 mL) was heated under reflux for 20 minutes. The solution was cooled to room temperature, and the resulting crystals were collected by filtration. The crystals were washed with ethanol and air dried to give the title compound (33.8 g, 73% yield).
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C:21]2=[N:22][C:5](=[CH:6][C:7]3[NH:11][C:10]([CH:12]=[C:13]4[CH:34]([CH3:35])[CH:33]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:15]([C:16]5[CH:27](C(OC)=O)[C:25](=[O:26])[C:24]6[C:17]=5[NH:18][C:19]([C:23]=6[CH3:32])=[CH:20]2)=[N:14]4)=[C:9]([CH3:42])[C:8]=3[CH:43]=[CH2:44])[C:4]=1[CH3:45].O.CCCCCC.CC(C)=O>N1C(C)=CC=CC=1C>[CH3:1][CH2:2][C:3]1[C:21]2=[N:22][C:5](=[CH:6][C:7]3[NH:11][C:10]([CH:12]=[C:13]4[C@@H:34]([CH3:35])[C@H:33]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:15]([C:16]5[CH2:27][C:25](=[O:26])[C:24]6[C:17]=5[NH:18][C:19]([C:23]=6[CH3:32])=[CH:20]2)=[N:14]4)=[C:9]([CH3:42])[C:8]=3[CH:43]=[CH2:44])[C:4]=1[CH3:45]
Reactant: C=Cc1c(C)c2cc3nc(c4c5[nH]c(cc6nc(cc1[nH]2)C(C)=C6CC)c(C)c5C(=O)C4C(=O)OC)C(CCC(=O)OC)C3C
Solvent: CC(C)=O
Solvent: Cc1cccc(C)n1
Solvent: CCCCCC
Product: C=Cc1c(C)c2cc3nc(c4c5[nH]c(cc6nc(cc1[nH]2)C(C)=C6CC)c(C)c5C(=O)C4)[C@@H](CCC(=O)OC)[C@@H]3C
Temperature: 25 °C
Yield: 83.6 %

Procedure:
To a solution of methyl pheophorbide-a (100 mg, 0.17 mmol) in 2,6-lutidine (25 mL) was added distilled water (48 μL, 2.7 mmol, 16 equiv.) and the mixture was refluxed under argon with stirring. The reaction was monitored by HPLC (hexane-acetone, 90:10-mobile phase, LiChrospherCN-column, detection at 425 and 410 nm). The HPLC of reaction aliquot after 30 min showed 100% completion (by peak area). The solution was cooled to room temperature and solvent removed under reduced pressure. The residue was crystallized from methylene chloride-methanol to give methyl pyropheophorbide-a (78 mg, 87%).