Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]([C:16]2[CH:28]=[CH:27][C:19]([C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=2)[N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl>[CH2:25]([N:22]([CH2:23][CH3:24])[C:20]([C:19]1[CH:27]=[CH:28][C:16]([CH:9]([N:10]2[CH2:11][CH2:12][N:13]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:14][CH2:15]2)[C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]#[N:2])=[CH:17][CH:18]=1)=[O:21])[CH3:26]
Reactant: O=Cc1ccccc1
Reactant: CCN(CC)C(=O)c1ccc(C(c2cccc(C#N)c2)N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(C(c2cccc(C#N)c2)N2CCN(Cc3ccccc3)CC2)cc1
Yield: 57 %

Procedure:
To a solution of INTERMEDIATE 3 (606 mg) in 1,2-dichloroethane (15 mL) was added benzaldehyde (220 μL, 1.3 eq) and sodium triacetoxyborohydride (480 mg, 1.4 eq). After 3 days the reaction was diluted with dichloromethane (50 mL) and washed with saturated aqueous sodium bicarbonate. The aqueous layer was washed with dichloromethane (2×25 mL) and the combined organic extracts were dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography, eluting 5% methanol in dichloromethane to yield INTERMEDIATE 4a as a colorless foam (428mg, 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:24])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH3:21])=[N:19][N:18]=[C:17]1[CH2:22]Cl.[I-:25].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:24])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH3:21])=[N:19][N:18]=[C:17]1[CH2:22][I:25]
Reactant: [I-]
Reactant: Cc1nnc(CCl)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1nnc(CI)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 7, 2',5-dichloro-2-[3-(chloromethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone is treated with potassium iodide in acetone to give 2',5-dichloro-2-[3-(iodomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone of melting point 185°-195° C. (decomposition).
Reaction SMILES: [CH:1](=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([NH:14][CH2:15][CH2:16][CH3:17])[CH2:12][CH3:13]>ClCCCl>[CH2:11]([N:14]([CH2:1][CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:15][CH2:16][CH3:17])[CH2:12][CH3:13]
Reactant: CCCNCCC
Reactant: O=CC=Cc1ccccc1
Solvent: ClCCCl
Product: CCCN(CC=Cc1ccccc1)CCC
Reaction time: 3 h

Procedure:
Cinnamaldehyde (0.504 cm3, 4.0 mmol), di-propylamine (0.548 cm3, 4.0 mmol) and [Ir(COD)(dppb)][PF6] (0.070 g, 2 mol %) were treated as stated above, with 1,2-dichloroethane as solvent, and at approx. 1 bar H2 for 3 hours. The yield of product (N,N-di-n-propylcinnamylamine) obtained was 80.9%.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[H-].[Na+].[CH2:16](I)[CH3:17].O>CN(C=O)C>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]([CH2:16][CH3:17])[C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1
Reactant: CCI
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)oc(=O)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
To a solution of 1 g (5.06 mmol) of 6-chloro-1H-benzo[d][1,3]oxazine-2,4-dione in DMF (20 ml) were carefully added 265 mg of sodium hydride (55% in mineral oil) at 0° C. This mixture was stirred for 30 min at RT and then 1.18 ml (7.59 mmol) of ethyl iodide were added. Stirring was continued for 16 h at RT, then water was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated. The remaining residue was purified by crystallization from heptane to obtain 682 mg (60%) of 6-chloro-1-ethyl-1H-benzo[d][1,3]oxazine-2,4-dione as an off-white solid. 1HNMR (DMSO-d6, 300 MHz): δ 1.21 (t, J=7.0 Hz, 3H), 4.05 (q, J=7.0 Hz, 2H), 7.54 (d, J=9.1 Hz, 1H), 7.88 (dd, J=9.1 and 2.5 Hz, 1H), 7.96 (d, J=2.5 Hz, 1H).
Reaction SMILES: [CH2:1]([NH:5][CH2:6]C)[CH2:2][CH2:3][CH3:4].[CH3:8][O:9][CH2:10][CH2:11]Cl>>[CH2:1]([N:5]([CH3:6])[CH2:11][CH2:10][O:9][CH3:8])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNCC
Reactant: COCCCl
Product: CCCCN(C)CCOC
Reaction time: 48 h

Procedure:
In an autoclave of 100 mL, N-butyl-N-ethylamine (34.0 g, 390 mmol) was made reacted with chloroethyl methyl ether (18.5 g, 196 mmol) at 130 deg C. for 48 hours. Solid salt that was formed was removed by filtration, and residue (filtrate) was subjected to reduced-pressure distillation by using a Vigreux column of 25 cm. Then 1H-NMR measurement of obtained amine is performed, and it was confirmed that chemical shifts, δ (ppm), are 3.45-3.42 (t, 2H), 3.31(s, 3H), 2.52-2.50(t, 2H), 2.34-2.31(t, 2H), 2.22(s, 3H), 1.45-1.38(m, 2H), 1.31-1.22(m, 2H), and 0.89-0.85(t, 3H), and that N-butyl-N-methyl-N-2-methoxyethylamine was synthesized.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11](=[O:31])[NH:12][C:13]([S:29][CH3:30])=[N:14][C:15]=1[NH:16][C@H:17]1[C@H:24]2[C@H:20]([O:21]C(C)(C)[O:23]2)[C@@H:19]([CH2:27][OH:28])[CH2:18]1.Cl>CO>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11](=[O:31])[NH:12][C:13]([S:29][CH3:30])=[N:14][C:15]=1[NH:16][C@@H:17]1[CH2:18][C@H:19]([CH2:27][OH:28])[C@@H:20]([OH:21])[C@H:24]1[OH:23]
Reactant: CSc1nc(N[C@@H]2C[C@H](CO)[C@H]3OC(C)(C)O[C@H]32)c(-c2nc3ccccc3s2)c(=O)[nH]1
Agent: Cl
Solvent: CO
Product: CSc1nc(N[C@@H]2C[C@H](CO)[C@@H](O)[C@H]2O)c(-c2nc3ccccc3s2)c(=O)[nH]1

Procedure:
Compound 13 (15 mg, 0.033 mmol) was dissolved in MeOH (1 ml) and 3 M HCl (1 ml) and stirred at room temperature for 18 h. The solvents were evaporated to give the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:3]2[S:23][CH2:22][CH2:21][C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[N:7]=1.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C)C=O>[N:24]([C:2]1[C:3]2[S:23][CH2:22][CH2:21][C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[N:7]=1)=[N+:25]=[N-:26]
Reactant: Oc1ccc(N2CCN(c3nc(Cl)c4c(n3)CCS4)CC2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1nc(N2CCN(c3ccc(O)cc3)CC2)nc2c1SCC2
Temperature: 100 °C
Reaction time: 4.5 h
Yield: 81.8 %

Procedure:
1.18 g (2.75 mmol) of 4-[4-(4-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperazin-1-yl]phenol (III) is placed in 25 mL of dimethylformamide, and 1.20 g (18.46 mmol) of sodium azide is added. The reaction mixture is stirred for 4.5 hours at 100° C. Then it is concentrated by evaporation, and the residue is cooled in the ice bath and combined with water. The precipitate formed is suction filtered, washed, and dried. 0.800 g of product IV is obtained and used further as a crude product.
Reaction SMILES: [CH2:1]([C:3]1([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[OH:16])[CH3:2].Br[CH2:23][C:24]#[C:25][Si](C)(C)C.[OH-].[Na+]>CS(C)=O.O>[CH2:1]([C:3]1([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[O:16][CH2:25][C:24]#[CH:23])[CH3:2]
Reactant: CCC1(CC(=O)OC)OCCc2c1[nH]c1c(O)cccc21
Reactant: C[Si](C)(C)C#CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: C#CCOc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3
Yield: 82.2 %

Procedure:
A mixture of methyl 1-ethyl-1,3,4,9-tetrahydro-8-hydroxy-pyrano[3,4-b]indole-1-acetate (6 g, 20.8 mmol), 3-bromo-1-trimethylsilyl-1-propyne [4.8 g, 25 mmol, prepared according to R. B. Miller, Synth. Comm., 2, 267 (1972)] and 2.5N--NaOH (10 mL, 25 mmol) in DMSO (60 mL) was heated under nitrogen for 30 minutes at 120° C. Upon cooling, the micture was diluted with 2 volumes of water, acidified with 2N--KHSO4 solution and extracted with ether. The extracts were dried (Na2SO4) and concentrated in vacuo. The residual oil (7 g) was flash-chromatographed (silica Merck-60, chloroform) to provide methyl 1-ethyl-1,3,4,9-tetrahydro-8-[(2-propynyl)oxy]-pyrano[3,4-b]indole-1-acetate (5.6 g, 83%) as an oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[CH:10]=[C:11]([O:20][CH3:21])[CH:12]=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[C:14]2[CH3:19].[CH2:22]([S:24]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)(=[O:26])=[O:25])[CH3:23]>ClCCl.O>[CH2:22]([S:24]([N:27]1[CH2:28][CH2:29][N:30]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]2[CH:10]=[C:11]([O:20][CH3:21])[CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[C:14]3[CH3:19])[CH2:31][CH2:32]1)(=[O:26])=[O:25])[CH3:23]
Reactant: CCS(=O)(=O)N1CCNCC1
Reactant: COc1cc(NCCCCCCCl)c2nccc(C)c2c1
Solvent: ClCCl
Solvent: O
Product: CCS(=O)(=O)N1CCN(CCCCCCNc2cc(OC)cc3c(C)ccnc23)CC1
Yield: 68.2 %

Procedure:
A mixture of 1.5 g. (0.0049 mole) of N-(6-chlorohexyl)-6-methoxy-4-methyl-8-quinolinamine and 2.7 g (0.015 mole) of 1-(ethylsulfonyl)-piperazine was heated at 130° for 50 min, allowed to cool and taken up in dichloromethane and water. The organic layer was washed again, dried, and concentrated to dryness in vacuo. The residue was chromatographed over 70 g of silica gel first with ethyl acetate and then with 2% methanol in ethyl acetate. The eluant containing product, Rf(silica--ethyl acetate)=0.05, was concentrated to dryness in vacuo. Recrystallization of the residue from 2-propanol afforded 1.5 g (68%) of the title compound, mp 72°-74°.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([NH:15][C:16]3[C:21]([N+:22]([O-])=O)=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].C(O)C.O1CCOCC1>[NH2:22][C:21]1[C:16]([NH:15][C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:8]=2)=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: COc1ccc(Nc2ncccc2[N+](=O)[O-])cc1OC1CCCC1
Agent: [Pd]
Solvent: CCO
Solvent: C1COCCO1
Product: COc1ccc(Nc2ncccc2N)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A mixture of 2-[(3-cyclopentyloxy-4-methoxyphenyl)amino]-3-nitropyridine (1.30 g) and 10% palladium on carbon (0.3 g) in ethanol (20 ml) and 1,4-dioxane (20 ml) was stirred under hydrogen (3 atm) at room temperature for 1 hours. The catalyst was removed by filtration and the solvent was evaporated. The resulting solid was collected and washed with isopropyl ether to give 3-amino-2-[(3-cyclopentyloxy-4-methoxyphenyl)amino]pyridine (992 mg).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Li+].CC([N-]C(C)C)C.Cl[C:19]1[C:20]([C:28]([OH:30])=[O:29])=[CH:21][N:22]([CH3:27])[C:23](=[O:26])[C:24]=1[CH3:25]>C1COCC1>[F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:19]1[C:20]([C:28]([OH:30])=[O:29])=[CH:21][N:22]([CH3:27])[C:23](=[O:26])[C:24]=1[CH3:25]
Reactant: Nc1ccc(I)cc1F
Reactant: Cc1c(Cl)c(C(=O)O)cn(C)c1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(Nc2ccc(I)cc2F)c(C(=O)O)cn(C)c1=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 52 %

Procedure:
To the stirred solution of 2-fluoro-4-iodoaniline (470 mg, 1.94 mmol) in dry THF (4 mL) cooled to −78° C., was added LDA (2M in THF) (1.35 mL, 2.70 mmol) After vigorous stirring for 10 minutes at this temperature, a solution of 4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (160 mg, 0.792 mmol) dissolved in dry THF (8 mL) was added dropwise through a syringe. The dry-ice bath was removed after 1 hour, and the reaction was stirred for 16 hours at room temperature At this time, LC/MS indicated 23% of the title product and 33% of unreacted chloride in the reaction mixture. The same reaction mixture was continued to stir at room temperature for additional 24 hours. The mixture was then re-cooled to −78° C. under a dry-ice/acetone bath. Additional LDA (1.35 mL, 2.70 mmol) (2M in THF) was added to the reaction mixture and slowly warmed to room temperature in 16 hours until LC/MS showed the consumption of chloride material. The mixture was cooled to −5° C., and aqueous HCl (1N) (15 mL) was added. The solution was extracted with EtOAc (15 mL×3). The combined organic layers was dried (MgSO4) and concentrated to give a residue which was triturated with DCM to give a solid. The title compound was used for the next reaction without further purification. (165 mg, 52% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:9]([CH2:12][CH:13]3[CH2:15][CH2:14]3)=[N:10][N:11]=2)[CH:5]=[CH:6][C:7]=1I.[NH2:16][CH2:17][CH:18]1[CH2:20][CH:19]1[C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[C:23]#[N:24]>>[Cl:1][C:2]1[C:3]2[N:4]([C:9]([CH2:12][CH:13]3[CH2:15][CH2:14]3)=[N:10][N:11]=2)[CH:5]=[CH:6][C:7]=1[NH:16][CH2:17][CH:18]1[CH2:20][CH:19]1[C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[C:23]#[N:24]
Reactant: Clc1c(I)ccn2c(CC3CC3)nnc12
Reactant: N#Cc1ccccc1C1CC1CN
Product: N#Cc1ccccc1C1CC1CNc1ccn2c(CC3CC3)nnc2c1Cl
Yield: 35.3 %

Procedure:
A mixture of 8-chloro-3-(cyclopropyl methyl)-7-iodo-[1,2,4]triazolo[4,3-a]pyridine (60 mg, 0.180 mmol), 2-(2-(aminomethyl)cyclopropyl)benzonitrile (31.0 mg, 0.180 mmol) was reacted in a manner similar to Example 1 to give 2-(2-(((8-chloro-3-(cyclopropylmethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)amino)methyl)cyclopropyl)benzonitrile (24 mg, 32.5%) as a film. 1H NMR (400 MHz, METHANOL-d4) δ 8.15 (d, J=7.5 Hz, 1H), 7.62 (dd, J=7.8, 1.0 Hz, 1H), 7.53 (td, J=7.8, 1.3 Hz, 1H), 7.29 (td, J=7.7, 1.0 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 6.97 (d, J=7.8 Hz, 1H), 3.65 (dd, J=14.6, 6.0 Hz, 1H), 3.51 (dd, J=14.6, 6.5 Hz, 1H), 2.98 (d, J=6.8 Hz, 2H), 2.28-2.20 (m, 1H), 1.55 (ddd, J=8.7, 6.1, 4.8 Hz, 1H), 1.26-1.08 (m, 3H), 0.65-0.54 (m, 2H), 0.36-0.25 (m, 2H). LCMS: M+1=378.0.
Reaction SMILES: [H-].[Na+].P(=O)([O-])O[C:5]([CH2:17][CH3:18])(CC)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[C:13]#[N:14].[F:21][C:22]1[CH:29]=[CH:28]C(C=O)=[CH:24][CH:23]=1.[Na+].[Cl-]>CN(C=O)C.O>[F:21][C:22]1[CH:29]=[CH:28][C:18]([CH:17]=[CH:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[C:13]#[N:14])=[CH:24][CH:23]=1
Reactant: CCC(CC)(O[PH](=O)[O-])c1ccc(F)cc1C#N
Reactant: O=Cc1ccc(F)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(F)ccc1C=Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 23.2 %

Procedure:
Sodium hydride (60% in mineral oil; 1.66 g [0.993 g NaH], 41.4 mmol, 1.10 equiv) was added to a solution of diethyl-2-cyano-4-fluorobenzyl phosphonate (10.2 g-equiv, 37.6 mmol, 1.0 equiv) in DMF (40 mL) over a period of 2 min. The reaction was stirred for 20 min at room temperature. 4-Fluorobenzaldehyde (4.67 g, 38 mmol, 1.0 equiv) was then added over a period of 2 min. After stirring for 18 h, H2O (200 mL) and satd. NaCl (50 mL) were added and the resulting mixture was extracted with EtOAc (2×100 mL). The combined organic layers were washed with 1N NaOH (1×100 mL) and H2O (2×100 mL), dried (anhyd. Na2SO4), and rotary evaporated (>100° C., heat gun). The crude, dark-red crystalline/oil (7.49 g, 82.7%) was chromatographed twice on silica gel (50×250 mm, dry pack), eluting first with hexane/EtOAc [4:1] and the second chromatography with [30:1] to provide a TLC-pure, yellow compound (2.1 g, 23.2%).
Reaction SMILES: [NH2:1][C@H:2]([C:11]([NH:13][C@@H:14]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl.C(N1CCOCC1)C.[N:33]([C:48]([O:50][CH2:51][CH:52]1[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[C:58]2[C:53]1=[CH:54][CH:55]=[CH:56][CH:57]=2)=[O:49])([CH3:47])[C@H:34]([C:44](O)=[O:45])[CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[N:33]([C:48]([O:50][CH2:51][CH:52]1[C:53]2[C:58](=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:59]2[C:64]1=[CH:63][CH:62]=[CH:61][CH:60]=2)=[O:49])([CH3:47])[C@H:34]([C:44]([NH:1][C@H:2]([C:11]([NH:13][C@@H:14]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:45])[CH2:35][O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CCOC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: CN(C(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](COCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](CC(C)C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](COCc1ccccc1)N(C)C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of Tyr-D-Leu-OEt hydrochloride (1.649 g) in DMF (10 ml) cooled to 0° C. was added N ethylmorpholine (0.59 ml) in DMF (1 ml), followed by a solution of FMOC-N-Me-Ser(O-Bzl)-OH (2.18 g) in DMF (5 ml), followed by a solution of HOBt (0.9315 g) in DMF (5 ml), and followed by a solution of DCC (0.947 g) in DMF (2 ml). The reaction solution was stirred at 0° C. for 1 hour and then at room temperature for 4 hours. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography eluting with (95:5) methylene chloride:methanol. The product was obtained as a semisolid. Rf 0.35. Fab Mass spec. m/e 736 (M+ +H).
Reaction SMILES: C([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)C.C([O-])([O-])=O.[K+].[K+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>C(O)C>[CH2:19]([O:11][C:8]1[CH:7]=[CH:6][C:5]([C:4]([OH:3])=[O:12])=[CH:10][CH:9]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: ClCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(O)c1ccc(OCc2ccccc2)cc1
Reaction time: 18 h

Procedure:
A mixture of 132.5 g ethyl-4-hydroxybenzoate, 135 g K2CO3 and 110 ml benzyl chloride in 900 ml of ethanol was refluxed under stirring for 18 hrs. The mixture was warm filtered, and the filtrate evaporated. The residue was dissolved in 700 ml of water, 98 g of KOH was added, whereafter the mixture was refluxed with stirring for 2 hrs, or until a clear solution was obtained. The pH of the solution was adjusted to pH 1 with conc. HCl, and the crystalline material formed was filtered off. The identity of the product was confirmed with NMR.
Reaction SMILES: N[C:2]1[C:7]2[N:8]3[CH:16]([CH3:17])[CH2:15][N:14]([CH2:18][CH3:19])[C:13](=[O:20])[C:9]3=[C:10]([O:11][CH3:12])[C:6]=2[C:5](=[O:21])[N:4]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=2)[N:3]=1.N([O-])=O.[Na+].N1C=CC=CC=1.[FH:41]>>[Cl:30][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[F:29])[CH2:22][N:4]1[C:5](=[O:21])[C:6]2[C:10]([O:11][CH3:12])=[C:9]3[C:13](=[O:20])[N:14]([CH2:18][CH3:19])[CH2:15][CH:16]([CH3:17])[N:8]3[C:7]=2[C:2]([F:41])=[N:3]1
Reactant: CCN1CC(C)n2c(c(OC)c3c(=O)n(Cc4ccc(F)c(Cl)c4)nc(N)c32)C1=O
Reactant: F
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CCN1CC(C)n2c(c(OC)c3c(=O)n(Cc4ccc(F)c(Cl)c4)nc(F)c32)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred, cold (0° C.) solution of 4-amino-2-(3-chloro-4-fluorobenzyl)-10-methoxy-8-ethyl-6-methyl-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (0.55 g, 1.26 mmol) in hydrogen fluoride-pyridine (9.5 mL) in a polyethylene tube, solid sodium nitrite (96 mg, 1.38 mmol) was added in small portions over a period of 10 minutes. The reaction mixture was stirred at room temperature for 1 hour. The product mixture was added dropwise into an ice-cold saturated aqueous sodium bicarbonate solution. The resultant mixture was extracted with ethyl acetate. The combined organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford the title material.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([CH3:47])=[C:14]([C:18]2[C:30]3[C:29]4[C:24](=[CH:25][C:26]([N:31]5[CH2:35][CH2:34][CH:33]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH2:32]5)=[CH:27][CH:28]=4)[NH:23][C:22]=3[C:21]([C:44](O)=[O:45])=[N:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].F[P-](F)(F)(F)(F)F.[N:57]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.CN1CCOCC1>CN(C=O)C.O>[Si:37]([O:36][CH:33]1[CH2:34][CH2:35][N:31]([C:26]2[CH:25]=[C:24]3[C:29]([C:30]4[C:18]([C:14]5[C:13]([CH3:47])=[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]6[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=6)[CH:17]=[CH:16][CH:15]=5)=[CH:19][N:20]=[C:21]([C:44](=[O:45])[NH2:57])[C:22]=4[NH:23]3)=[CH:28][CH:27]=2)[CH2:32]1)([C:40]([CH3:43])([CH3:41])[CH3:42])([CH3:39])[CH3:38]
Reactant: Cc1c(NC(=O)OCc2ccccc2)cccc1-c1cnc(C(=O)O)c2[nH]c3cc(N4CCC(O[Si](C)(C)C(C)(C)C)C4)ccc3c12
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1c(NC(=O)OCc2ccccc2)cccc1-c1cnc(C(N)=O)c2[nH]c3cc(N4CCC(O[Si](C)(C)C(C)(C)C)C4)ccc3c12
Yield: 88.2 %

Procedure:
A burgundy, homogeneous solution of 4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-(3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)-9H-pyrido[3,4-b]indole-1-carboxylic acid (0.1323 g, 0.203 mmol), ammonium chloride (0.043 g, 0.813 mmol), BOP (0.117 g, 0.264 mmol), DIPEA (0.170 mL, 0.976 mmol) and N-methylmorpholine (0.087 mL, 0.793 mmol) in DMF (1.694 mL) was stirred for 1 h. Water (20 mL) was added, and the precipitate was filtered and dried over Drierite to give benzyl the desired product (0.1164 g, 0.179 mmol, 88% yield) as a brown solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.OO.C([O-])([O-])=[O:16].[K+].[K+]>CS(C)=O>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:10]=[CH:9][C:6]([C:7]([NH2:8])=[O:16])=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(C(F)(F)F)cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 1 h
Yield: 182.3 %

Procedure:
To a cold solution of 4-(trifluoromethyl)benzonitrile (0.500 g, 2.92 mmol) in DMSO (6.0 mL) was added H2O2 (50%) (5 mL) at 0° C., followed by portion-wise addition of K2CO3 (0.121 g, 0.87 mmol). The reaction mass was allowed to attain RT and stirred for 1 h. The reaction mass was quenched in ice water and extracted with DCM and concentrated to afford 0.300 g of product. 1H NMR (400 MHz, DMSO d6): δ 7.60 (br s, 1H), 7.82 (d, J=7.5 Hz, 2H), 8.05 (d, J=6.6 Hz, 2H), 8.17 (br s, 1H); MS (m/z): 190.11 (M+H+).
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]1[CH2:20][CH2:19][C:14]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:13][C@@H:12]1[CH2:21][OH:22])C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[NH2:10][C@H:11]1[CH2:20][CH2:19][C:14]2([O:15][CH2:16][CH2:17][O:18]2)[CH2:13][C@@H:12]1[CH2:21][OH:22]
Reactant: O=C(N[C@H]1CCC2(C[C@@H]1CO)OCCO2)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: N[C@H]1CCC2(C[C@@H]1CO)OCCO2

Procedure:
Preparation A4, Step 4: A solution of (7R,8S)-8-(S-1-Phenyl-ethylamino)-1,4-dioxa-spiro[4.5]decane-7-carboxylic acid ethyl ester (55 g, 0.165 mol) in ether (300 ml) is cooled to 0° C. in an ice bath and treated slowly with LAH (12.5 g, 0.32 mol). After the addition is complete the mixture is stirred for an additional 45 mins and then quenched by drop-wise addition of 12 ml of water followed by 50 ml of 1 N NaOH (caution: vigorous foaming). The resultant suspension is stirred in the ice bath for 1-2 hours to give a granular white suspension which is filtered on a buchner funnel. The solid is washed with ether and the combine ether filtrates are concentrated to give 48 g of the alcohol as a colorless syrup. This is used without further purification. A solution of this alcohol (42 g, 0.14 mol) in 500 ml of MeOH was treated with 13 g of 20% Pd(OH)2/C and hydrogenated overnight at 55 psi. The mixture was filtered through Celite and concentrated on a rotary evaporator to give ((7S,8S)-8-Amino-1,4-dioxa-spiro[4.5]dec-7-yl)-methanol as a syrup. This was used without further purification. 1H NMR (300 MHz, CDCl3) δ (TMS): 3.99-3.92 (bm, 4 H), 3.84 (dd, J=3 Hz, J=12 Hz, 1 H), 3.67 (dd, J=5 Hz, J=12 Hz, 1 H), 3.27 (m, 1 H), 2.51 (bs, 3 H), 1.67-1.55 (m, 7 H).