Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](OCC)=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[N:15]=2)[CH:3]=1.CO.[NH3:25]>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:25])=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[N:15]=2)[CH:3]=1
Reactant: CCOC(=O)c1nnc(Cl)cc1Nc1cccc(OCC)n1
Reactant: N
Solvent: CO
Product: CCOc1cccc(Nc2cc(Cl)nnc2C(N)=O)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
Ethyl 6-chloro-4-(6-ethoxypyridin-2-ylamino)pyridazine-3-carboxylate (40.3 mg, 125 mmol) was dissolved in 7 N ammonia in methanol solution (7.01 g, 9 mL, 63.0 mmol) and stirred at 25° C. for 18 h. The reaction mixture was concentrated in vacuo to give 6-chloro-4-(6-ethoxypyridin-2-ylamino)pyridazine-3-carboxamide (33 mg, 112 μmol, 90%) as a light yellow solid that was used directly without further purification. MS (EI/CI) m/z: 294.1 [M+H].
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:35])[C:11]([C:28](=[O:34])[C:29]([CH3:33])([CH3:32])[CH2:30][CH3:31])=[CH:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[C:15](=[O:27])[C:14]=12)C1C=CC=CC=1>FC(F)(F)C(O)=O>[Cl:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[CH2:19][N:16]1[CH2:17][CH2:18][N:13]2[CH:12]=[C:11]([C:28](=[O:34])[C:29]([CH3:32])([CH3:33])[CH2:30][CH3:31])[C:10](=[O:35])[C:9]([OH:8])=[C:14]2[C:15]1=[O:27]
Reactant: CCC(C)(C)C(=O)c1cn2c(c(OCc3ccccc3)c1=O)C(=O)N(Cc1cccc(Cl)c1)CC2
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)(C)C(=O)c1cn2c(c(O)c1=O)C(=O)N(Cc1cccc(Cl)c1)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
9-Benzyloxy-2-(3-chlorobenzyl)-7-(2,2-dimethylbutyryl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (55 mg) was dissolved in trifluoroacetic acid (0.5 ml) and the mixture was stirred at room temperature for 30 min. The solvent was evaporated and toluene was added, and the mixture was concentrated, which operations were performed twice. Crystallization from chloroform-diisopropyl ether gave 2-(3-chlorobenzyl)-7-(2,2-dimethylbutyryl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (32 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:18])[CH:11]=[C:12]([C:15]([OH:17])=[O:16])O[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][NH2:20].CO.Cl>>[CH2:1]([O:8][C:9]1[C:10](=[O:18])[CH:11]=[C:12]([C:15]([OH:17])=[O:16])[N:20]([CH3:19])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(=O)c(OCc2ccccc2)co1
Reactant: CN
Agent: Cl
Solvent: CO
Product: Cn1cc(OCc2ccccc2)c(=O)cc1C(=O)O
Temperature: 0 °C
Yield: 90 %

Procedure:
A mixture of 5-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid (20.0 g, 81.2 mmol) and a solution of 2M MeNH2 in methanol (162.5 mL, 325 mmol) was stirred at RT for 16 h. Volatiles were removed under reduced vacuum, and the residue was dissolved in 70 mL of de-ionized water. To the ice-cold mixture was added a 6N HCl solution (13.5 mL, 81.0 mmol) dropwise. The precipitated solid was collected via filtration, and washed with water and acetone to give the title compound as a light yellow solid (18.9 g, 90% yield). 1H NMR (400 MHz, DMSO-D6) δ (ppm): 7.82 (s, 1H), 7.45-7.33 (m, 5H), 6.72 (s, 1H), 5.05 (s, 2H) and 3.84 (s, 3H); MS-ESI (m/z): 259.8 [M+1]+, 91.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([CH2:14][OH:15])[CH2:12][O:11][C@@H:10]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.S(=O)(=O)=O.N1C=CC=CC=1>CS(C)=O.ClCCl>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([CH:14]=[O:15])[CH2:12][O:11][C@@H:10]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)CO[C@H]1CN(C(=O)OC(C)(C)C)[C@@H](CO)CO1
Agent: O=S(=O)=O
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)CO[C@H]1CN(C(=O)OC(C)(C)C)[C@@H](C=O)CO1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 92.4 %

Procedure:
Dissolve (2R,5S)-2-(2,2-dimethylpropoxy)-5-hydroxymethylmorpholine-4-carboxylic acid tert-butyl ester (3.67 g, 12.1 mmol) in anyhydrous dimethylsulfoxide (25 mL) and dichloromethane (4 mL) and cool to 0° C. under nitrogen. Add diisopropylethylamine (7.4 mL, 42.3 mmol) then pyridine sulfur trioxide (3.47 g, 21.8 mmol) in 2 portions. Stir at 0° C. for 20 minutes and then remove from the cooling bath to allow all solids to dissolve. Pour into ice cold saturated aqueous sodium chloride, extract with 10% ethyl acetate/hexanes, wash with 0.1 N aqueous citric acid (30 mL), saturated aqueous sodium chloride (30 mL), dry (magnesium sulfate), filter and concentrate to give the desired compound as a colorless oil (3.37 g, 92%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH:9][NH2:10])=[O:8])=[CH:5][CH:4]=1.[CH3:15][N:16]1[C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=[N:17]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>O.CN(C)C=O>[CH3:15][N:16]1[C:20]([C:21]([NH:10][NH:9][C:7](=[O:8])[C:6]2[CH:11]=[CH:12][C:3]([C:2]([F:13])([F:14])[F:1])=[CH:4][CH:5]=2)=[O:22])=[CH:19][CH:18]=[N:17]1
Reactant: Cn1nccc1C(=O)O
Reactant: NNC(=O)c1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nccc1C(=O)NNC(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 19 h
Yield: 80.5 %

Procedure:
4-(Trifluoromethyl)benzohydrazide (583 mg) was added to a dimethylformamide (6.8 mL) solution that contained 1-methyl-1H-pyrazol-5-carboxylic acid (300 mg), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.09 g) and diisopropylethylamine (830 μL) at a room temperature, and the obtained solution was then stirred for 19 hours. Thereafter, water was added to the reaction solution, and the obtained mixture was then extracted with ethyl acetate. The organic layer was washed with water and a saturated saline, and was then dried over anhydrous magnesium sulfate, followed by vacuum concentration. The obtained solid was washed with ethyl acetate/hexane (1:1), so as to obtain the title compound (598 mg) in the form of a colorless solid. The filtrate was concentrated under a reduced pressure, and the residue was then purified by column chromatography (silica gel cartridge, chloroform:methanol=10:0 to 9:1), so as to further obtain the title compound (109 mg) in the form of a colorless solid.
Reaction SMILES: C([Li])CCC.[N:6]1([C:11]2[N:12]=[C:13]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[NH:16][C:15]=3[N:23]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1.Br[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>C1COCC1>[N:6]1([C:11]2[N:12]=[C:13]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)[C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]([CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:15]=3[N:23]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: c1ccc2c(c1)[nH]c1nc(N3CCCC3)nc(N3CCCC3)c12
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cn1c2ccccc2c2c(N3CCCC3)nc(N3CCCC3)nc21
Reaction time: 1 h

Procedure:
n-Butyllithium (4.26 mL; 1.6 M in hexane) is added to a mixture of 2,4-di-1-pyrrolidinyl-9H-pyrimido[4,5-b]indole (III, EXAMPLE 2, 2.0 g) in THF (50 mL) at -15°. After 1 hr, t-butyl bromoacetate (1.27 g) in THF (20 mL) is added, and the mixture is stirred for 2 hr at 20-25°. The mixture is partitioned between aqueous sodium bicarbonate and methylene chloride, and the organic layer is dried and concentrated. Chromatography of the crude product (silica gel; hexane/methylene chloride/ethyl acetate (70/25/5) gives the title compound, mp=131-133°; NMR (CDCl3) 7.87, 7.15, 4.92, 3.92, 3.61, 1.96 and 1.43 δ; MS (m/z=421 (M+).
Reaction SMILES: [S:1](Cl)(Cl)(=[O:3])=[O:2].[N:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][NH2:18])=[CH:8][CH:7]=1.C(N(CC)CC)C>ClCCl>[N:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][N:14]2[CH2:15][CH2:16][CH2:17][NH:18][S:1]2(=[O:3])=[O:2])=[CH:8][CH:7]=1
Reactant: NCCCNCCc1ccncc1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S1(=O)NCCCN1CCc1ccncc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of sulphuryl chloride (7.5 g) in dichloromethane (20 cm3) was added dropwise over 15 minutes to a stirred solution of N-[2-(4-pyridyl)ethyl]-1,3-diaminopropane (10.0 g) in dichloromethane (100 cm3) and triethylamine (11.2 g) at -20°. The mixture was allowed to warm slowly to room temperature over 1 hour. After stirring for 16 hours the solution was filtered and sodium carbonate solution (50 cm3) was added. The aqueous phase was extracted with methylene chloride (2×50 cm3) and the dried (MgSO4) extracts were evaporated in vacuo to give an oil which was chromatographed on silica ("Merck 60. 9385") eluting with methanol:ethyl acetate, 1:19, to give a solid which was recrystallised from ethanol to afford 2-[2-(4-pyridyl)ethyl] tetrahydro-1,2,6-thiadiazine-1,1-dioxide, m.p. 124°-125° (2.0 g).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].[CH3:6][N:7]([CH2:9][C:10]1[O:14][C:13]([CH2:15]O)=[C:12]([CH3:17])[CH:11]=1)[CH3:8].[OH-].[K+]>Cl>[CH3:8][N:7]([CH2:9][C:10]1[O:14][C:13]([CH2:15][S:5][CH2:4][CH2:3][NH2:2])=[C:12]([CH3:17])[CH:11]=1)[CH3:6]
Reactant: NCCS
Reactant: Cc1cc(CN(C)C)oc1CO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: Cc1cc(CN(C)C)oc1CSCCN
Reaction time: 0.25 h
Yield: 91.1 %

Procedure:
To a solution of 2-aminoethanethiol hydrochloride (2.27 g; 20.0 mmoles) in 20 ml of concentrated HCl that was cooled in an ice-salt bath to -10° was added dropwise 5-dimethylaminomethyl-3-methyl-2-furanmethanol (3.38 g; 20.0 mmoles) [prepared in Step A], and the mixture stirred for 15 minutes then allowed to stand in the cold (0°) overnight. After 17 hours the cold solution was made strongly basic with aqueous KOH solution and then extracted with five portions of methylene chloride. The combined organic phase was dried, filtered and evaporated under reduced pressure to yield the title compound (4.16 g), bp 110°-120°/0.1 mm Hg.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:29])[CH:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[N:10]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)(=[O:19])=[O:18])[C:9]=1[CH3:28])[CH3:7]>C1COCC1.CO>[Cl:27][C:22]1[CH:21]=[C:20]([S:17]([N:10]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:16]3[C:8]([CH:6]([CH3:7])[C:5]([OH:29])=[O:4])=[C:9]2[CH3:28])(=[O:18])=[O:19])[CH:25]=[CH:24][C:23]=1[Cl:26]
Reactant: COC(=O)C(C)c1c(C)n(S(=O)(=O)c2ccc(Cl)c(Cl)c2)c2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C(C)C(=O)O)c2cccnc2n1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 4 h

Procedure:
1M Aqueous NaOH (0.25 mL) is added to a stirring solution of 2-[1-(3,4-dichloro-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-propionic acid methyl ester (17 mg, 0.04 mmol) in 1:1 THF/MeOH (1 mL). After 4 hours, the reaction is evaporated and the residue dissolved in water. The aqueous solution is acidified to pH 1, and resulting solid is collected by filtration. The crude product is purified by flash chromatography (10:1 EtOAc/MeOH), followed by trituration with iso-hexane, to afford 2-[1-(3,4-dichloro-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-propionic acid; MH+=413.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH2:9])[CH:5]=[C:4]([C:10]#[N:11])[CH:3]=1.[C:12](Cl)(=[O:14])[CH3:13].O>N1C=CC=CC=1>[C:12]([NH:9][NH:8][C:6]1[CH:5]=[C:4]([C:10]#[N:11])[CH:3]=[C:2]([Cl:1])[N:7]=1)(=[O:14])[CH3:13]
Reactant: N#Cc1cc(Cl)nc(NN)c1
Reactant: CC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)NNc1cc(C#N)cc(Cl)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A suspension of 5.0 g of 6-chloro-2-hydrazinopyridine-4-carbonitrile in 50 ml of pyridine was cooled to 0° C. in an ice bath and 3.1 g of acetyl chloride was added dropwise over a 10 minute period. The mixture became homogeneous after the addition and it was allowed to warm to ambient temperature. After 2 hours, the reaction mixture was poured into 180 ml of water and the precipitate which formed was separated by filtration and dried to give N-acetyl-N'-(6-chloro-4-cyano-2-pyridyl)hydrazine which was purified by recrystallization from ethanol.
Reaction SMILES: [P:1](=[O:5])([OH:4])([OH:3])[OH:2].[OH-].[Mg+2:7].[OH-].OC(CCCCCCCCC)=O.OCC(CO)O.OCC(CO)O>O>[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Mg+2:7].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Mg+2:7].[Mg+2:7]
Reactant: O=P(O)(O)O
Agent: CCCCCCCCCC(=O)O
Agent: [Mg+2]
Agent: [OH-]
Solvent: OCC(O)CO
Solvent: O
Product: O=P([O-])([O-])[O-]

Procedure:
A solution obtained by diluting 2.7 kg of a 85% by weight solution of phosphoric acid with ion-exchanged water to a total quantity of 100 kg was gradually added with stirring to a solution obtained by adding 2 kg of magnesium hydroxide to 300 kg of ion-exchanged water, and then further adding and dissolving therein 2 kg of diglycerol monocaprate (trade name: “SUNSOFT Q-10 D”; HLB=9.5; monoester content: 85% by weight; specific gravity: 0.9; manufactured by Taiyo Kagaku Co., Ltd.). The pH of the resulting mixture was adjusted to 8 using a handy pH meter manufactured by HORIBA, Ltd. After forming of the salt of magnesium phosphate by neutralization reaction was terminated, the resulting reaction mixture was subjected to solid-liquid separation by centrifugation (3000×g, for 10 minutes), and 4 kg (dry weight basis) of magnesium phosphate of the solid phase portion was collected (average particle size of fine metal particles: about 0.31 μm). The magnesium phosphate was resuspended in ion-exchanged water, to give a magnesium phosphate dispersion composition having a solid content of 10% by weight (20 parts by weight of an emulsifier were contained based on 100 parts by weight of the metal salt). The resulting composition was filled in a clear container, and stored with leaving it at rest for 1 month at normal temperatures. As a result, the composition was excellent in dispersion stability, with no occurrence of separation and precipitation of the constituents.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[CH3:12][NH:13][O:14][CH3:15].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(=O)([O-])O.[Na+].C(N(CC)CC)C>[Cl:1][C:2]1[C:7]([C:8]([N:13]([O:14][CH3:15])[CH3:12])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CNOC
Reactant: O=C(O)c1cccnc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
2-Chloropyridine-3-carboxylic acid (13 g), N,O-dimethylhydroxylamine hydrochloride (8.85 g), HOBt (5.57 g), EDCI (15.37 g) and triethylamine (34.5 ml) were dissolved in DMF (150 ml), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate) to give the title compound (10.5 g).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:20])[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]([OH:19])[CH:5]=2.BrC1C(=O)C2C(C=1C1C=CC=CC=1)=CC=C(O)C=2.O[CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:44][CH2:43]1>>[Br:1][C:2]1[C:3](=[O:20])[C:4]2[C:9]([C:10]=1[C:11]1[CH:12]=[C:13]([F:18])[CH:14]=[C:15]([F:17])[CH:16]=1)=[CH:8][CH:7]=[C:6]([O:19][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:52])([CH3:54])[CH3:53])=[O:49])[CH2:44][CH2:43]1)[CH:5]=2
Reactant: O=C1C(Br)=C(c2cc(F)cc(F)c2)c2ccc(O)cc21
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(O)cc21
Product: CC(C)(C)OC(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2cc(F)cc(F)c2)CC1
Reaction time: 96 h

Procedure:
The procedure of Step 6 of Example 1 was repeated except for using 2-bromo-3-(3,5-difluorophenyl)-6-hydroxy-1H-inden-1-one obtained in Step 5 of Example 36 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, t-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate instead of 4-(2-hydroxyethyl)morpholine, being stirred for 4 d, and being purified by silica gel column chromatography (EtOAc/hexanes=1:4) to obtain the title compound.
Reaction SMILES: C(=O)([O-])O.[Na+].Cl[C:7]1[N:8]=[CH:9][C:10]([C:13]([O:15]C)=[O:14])=[N:11][CH:12]=1.CC1(C)C(C)(C)OB([C:25]2[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH:30]=2)O1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>COCCOC.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:37][C:34]([O:33][C:31]([N:28]1[CH2:27][CH:26]=[C:25]([C:7]2[N:8]=[CH:9][C:10]([C:13]([OH:15])=[O:14])=[N:11][CH:12]=2)[CH2:30][CH2:29]1)=[O:32])([CH3:35])[CH3:36]
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2cnc(C(=O)O)cn2)CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
Saturated aqueous sodium hydrogen carbonate solution (5.00 ml) was added to methyl 5-chloropyrazine-2-carboxylate (173 mg, 1.00 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (371 mg, 1.20 mmol), palladium(II) acetate (11 mg, 0.05 mmol) and triphenylphosphine (52 mg, 0.20 mmol) in 1,2-dimethoxyethane (5.00 ml) at 25° C. under nitrogen. The resulting mixture was stirred at 80° C. for 4 h. The reaction mixture was diluted with water (50 mL) and washed with EtOAc (50 mL). The aqueous layer was adjusted to pH 1 using HCl (2M aqueous solution) and extracted with EtOAc (2×50 mL). The combined organics were dried over MgSO4 and concentrated under reduced pressure to afford 5-[1-[(2-methylpropan-2-yl)oxycarbonyl]-3,6-dihydro-2H-pyridin-4-yl]pyrazine-2-carboxylic acid (305 mg, 100%) as a yellow solid. This was used directly in the next reaction, with no further purification.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[NH:28]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[C@H:29]([C:45]([NH:47][C@H:48]([C:61](O)=[O:62])[CH2:49][CH2:50][CH2:51][CH2:52][NH:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])=[O:46])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:33][CH:32]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CN(C=O)C>[NH:28]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[C@H:29]([C:45]([NH:47][C@H:48]([C:61]([NH:1][C@H:2]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)=[O:62])[CH2:49][CH2:50][CH2:51][CH2:52][NH:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])=[O:46])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)OC(=O)NCCCCNC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCCNC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Yield: 65.8 %

Procedure:
compound SP308P. Same procedure as above with Trp-NH(CH2)4NHBoc (152.4 mg, 0.407 mmol), N-Boc-Tyr(Bn)-Lys(Boc)-OH (247.3 mg, 0.407 mmol), EDC (85.8 mg, 0.45 mmol) and HOBt (60.7 mg, 0.45 mmol) in CH2Cl2/DMF (1.8 mL, 1/1). The crude residue was triturated with MeOH/pentane to afford a white solid (255.9 mg, 65%). 1H NMR (300 MHz, DMSO-d6) δ 1.29-1.57 (m, 10H, 3 CH2 Lys, 2 CH2 putrescine), 1.29 (s, 9H, (CH3)3), 1.36 (s, 9H, (CH3)3), 2.64 (m, 1H, CH2 Tyr), 2.86-3.11 (m, 9H, CH2 Lys, CH2 Tyr, CH2 Trp, 2 CH2 putrescine), 4.10 (m, 1H, CHα), 4.26 (m, 1H, CHα), 4.46 (m, 1H, CHα), 5.03 (s, 2H, CH2 (Bn)), 6.70 (broad s, 1H), 6.87-7.4 (m, 15H), 7.56 (d, J=7.6 Hz, 1H), 7.81-7.97 (m, 3H), 10.8 (s, 1H). 13C NMR (75 MHz, DMSO-d6) δ 22.4, 29.2, 32 (3 CH2 Lys), 26.2, 26.7 (2 CH2 putrescine), 27.8 (CH2 Trp), 28, 28.1, 28.2 (3 (CH3)3), 36.3 (CH2 Tyr), 38.2, 39.5, 39.8 (2 CH2 putrescine, CH2 Lys), 52.4, 53.4, 55.8 (CHα Tyr, Lys, Tip), 69 (CH2 (Bn)), 77.2, 78 (2 C(CH3)3), 109.8, 111.1, 114.2, 118.1, 118.4, 120.7, 123.4, 127.3, 127.5, 127.6, 128.3, 130.1, 135.9, 137.1 (19 aromatic C), 154.7, 155.5, 156.7 (Car-O, 2 CO carbamate), 170.7, 171.1, 171.5 (3 CO amide). Anal. Calcd. for C52H73N7O10: C, 65.32; H, 7.70; N, 10.25. Found: C, 65.30; H, 7.64; N, 10.04.
Reaction SMILES: O.Cl.[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][CH2:9]2)([O-])=O>CCO.N.CO.[Fe]>[NH2:3][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][CH2:9]2
Reactant: O=C1NCc2cc([N+](=O)[O-])ccc21
Agent: [Fe]
Agent: Cl
Agent: N
Solvent: O
Solvent: CO
Solvent: CCO
Product: Nc1ccc2c(c1)CNC2=O
Temperature: 95 °C

Procedure:
Iron powder (158 mg, 2.83 mmol), water (61 μL), and HCl (37%, 5 μL, 0.566 mmol) were added into the suspension of 5-nitro-2,3-dihydroisoindol-1-one (50.4 mg, 0.283 mmol) in EtOH (754 μL). The above mixture was heated at 95° C. for 2 h. After that time, several drops of 7N NH3 in MeOH were added to basify the solution, and the solid was filtered off. The filtrate was concentrated in vacuo to obtain a light-yellow solid that was purified by preparative TLC eluting with 10% MeOH/CH2Cl2 to give a light-yellow solid of 5-amino-2,3-dihydroisoindol-1-one. 1H NMR (CD3OD, 400 MHz): δ=7.48 (s, 1H), 8.08 (s, 2H), 9.91 (s, 1H), 10.66 (d, 1H, J=8.8 Hz). MS (ES+): m/z 149.21 (100) [MH+]. HPLC: tR=1.20 min (ZQ2000, polar—5 min).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[CH2:14][C:13]([CH3:16])([CH3:15])[O:12][CH2:11][C:10](=[S:17])[NH:9]2)[CH:7]=1.[F:20][CH:21]([F:32])[O:22][C:23]1[CH:24]=[CH:25][C:26]([C:29](O)=[O:30])=[N:27][CH:28]=1>>[F:19][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:29]([C:26]2[CH:25]=[CH:24][C:23]([O:22][CH:21]([F:32])[F:20])=[CH:28][N:27]=2)=[O:30])=[CH:7][C:6]=1[C@:8]1([CH3:18])[CH2:14][C:13]([CH3:16])([CH3:15])[O:12][CH2:11][C:10](=[S:17])[NH:9]1
Reactant: O=C(O)c1ccc(OC(F)F)cn1
Reactant: CC1(C)C[C@@](C)(c2cc(N)ccc2F)NC(=S)CO1
Product: CC1(C)C[C@@](C)(c2cc(NC(=O)c3ccc(OC(F)F)cn3)ccc2F)NC(=S)CO1
Yield: 82 %

Procedure:
The compound was prepared in an analogous manner as described for intermediate B14A from (S)-5-(5-amino-2-fluoro-phenyl)-5,7,7-trimethyl-[1,4]oxazepane-3-thione (intermediate A17A) (75 mg, 0.26 mmol) and 5-difluoromethoxy-pyridine-2-carboxylic acid [CAS No. 1174323-34-2, described in example 48] (50 mg, 0.26 mmol). The compound was obtained as white foam (99 mg, 82%). MS (ISP): m/z=454.1 [(M+H)+].
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][C:30]=1[NH:31][CH:32]=[O:33])[NH:27][C:26](=[O:34])[CH2:25]2>>[CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=[C:25]3[C:24]4[C:28](=[CH:29][C:30]([NH:31][CH:32]=[O:33])=[C:22]([F:21])[CH:23]=4)[NH:27][C:26]3=[O:34])=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2]
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Reactant: O=CNc1cc2c(cc1F)CC(=O)N2
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4cc(NC=O)c(F)cc43)c(C)c2C1=O
Yield: 69.4 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-formamide as starting materials to give N-{3-[5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-ylmethylene]-5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl}-formamide (51 mg, 69.4%) as a red solid.