Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:22]=[CH:21][C:20]3[CH:19]([N:23]4[CH:27]=[CH:26][N:25]=[CH:24]4)[CH2:18][CH2:17][C:16]([CH3:29])([CH3:28])[C:15]=3[CH:14]=2)=[CH:7][CH:6]=1.[OH-].[Na+]>C(O)C>[N:23]1([CH:19]2[CH2:18][CH2:17][C:16]([CH3:29])([CH3:28])[C:15]3[CH:14]=[C:13]([C:12]#[C:11][C:8]4[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:30])=[O:2])=[CH:10][CH:9]=4)[CH:22]=[CH:21][C:20]2=3)[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: COC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3n2ccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CCC(n2ccnc2)c2ccc(C#Cc3ccc(CC(=O)O)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
Using General Procedure I; a solution of methyl[4-(5-imidazol-1-yl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl-ethynyl)-phenyl]-acetate (Compound 136, 50.0 mg, 0.13 mmol) in ethanol (4 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 40.0 mg (83%) of the title compound as a pale-orange solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:27])=[C:4]([NH:10][C@H:11]([C@@H:24]([OH:26])[CH3:25])[C:12]([NH:14][NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].ClC1C(C)=C(N[C@H]([C@@H](O)C)[C:39](O)=[O:40])C=CC=1C#N.COC1C=C(C=CC=1)C(NN)=O>CO.CCOC(C)=O>[Cl:1][C:2]1[C:3]([CH3:27])=[C:4]([NH:10][C@H:11]([C@@H:24]([OH:26])[CH3:25])[C:12]([NH:14][NH:15][C:16](=[O:23])[C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([O:40][CH3:39])[CH:22]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccccc2)[C@H](C)O)ccc(C#N)c1Cl
Reactant: Cc1c(N[C@@H](C(=O)O)[C@H](C)O)ccc(C#N)c1Cl
Agent: COc1cccc(C(=O)NN)c1
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cccc(C(=O)NNC(=O)[C@H](Nc2ccc(C#N)c(Cl)c2C)[C@H](C)O)c1

Procedure:
Intermediate 6a was synthesized similarly to the procedure outlined for intermediate 1b described above using (2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (intermediate 1a) (530 mg, 2.0 mmol) and 3-methoxy-benzohydrazide (329 mg, 2.0 mmol). After column chromatography (2% methanol/EtOAc) the title compound was isolated as a white solid (471 mg, 57%). 1H NMR (500 MHz, d6-acetone, δ in ppm) 9.88 (br s, 1H), 9.53 (br s, 1H), 7.47 (m, 3H), 7.38 (at, J=8.0 Hz, 1H), 7.12 (m, 1H), 6.66 (d, J=8.7 Hz, 1H), 5.55 (d, J=7.0 Hz, 1H), 4.88 (br s, 1H), 4.40 (m, 1H), 4.12 (dd, J=3.3, 7.0 Hz, 1H), 3.83 (s, 3H), 2.34 (s, 3H), 1.35 (d, J=6.3 Hz, 3H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[CH:8]=[N:9][C:10]2[C:15]([C:16]=1[NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](O)=[O:25])=[CH:20][CH:19]=1)=[CH:14][CH:13]=[C:12]([Cl:27])[CH:11]=2)=[O:6])[CH3:3].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:58][CH:59]1[CH2:64][CH2:63][N:62]([CH2:65][C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[CH2:61][CH2:60]1>CN(C=O)C.C(Cl)Cl>[CH2:2]([O:4][C:5]([C:7]1[CH:8]=[N:9][C:10]2[C:15]([C:16]=1[NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]([NH:58][CH:59]3[CH2:64][CH2:63][N:62]([CH2:65][C:66]4[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=4)[CH2:61][CH2:60]3)=[O:25])=[CH:22][CH:23]=1)=[CH:14][CH:13]=[C:12]([Cl:27])[CH:11]=2)=[O:6])[CH3:3]
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: CCOC(=O)c1cnc2cc(Cl)ccc2c1Nc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2cc(Cl)ccc2c1Nc1ccc(C(=O)NC2CCN(Cc3ccccc3)CC2)cc1
Temperature: 85 °C
Yield: 96.9 %

Procedure:
4-[(4-Carboxyphenyl)amino]-7-chloro-3-quinolinecarboxylic acid ethyl ester hydrochloride (40.0 g, 98.2 mmol), 1-hydroxybenzotriazole hydrate (16.2 g, 120 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (24.5 g, 128 mmol) were stirred in 560 ml of DMF and treated with triethylamine (39.8 g, 54.8 ml, 393 mmol) followed by 4-amino-1-benzylpiperidine (20.6 g, 22.0 ml, 108 mmol). The reaction mixture was heated at 85° C. for 3.5 h, poured into 1.3 L of CH2Cl2 and washed with 3×500 ml of water. The organic phase was dried over Na2SO4 and concentrated in vacuo for 3 days. This afforded 51.7 g (95.2 mmol, 97% yield) of 7 -chloro-4-[[4 -[[[1-(phenylmethyl)-4-piperidinyl]amino]carbonyl]phenyl]amino]-3-quinolinecarboxylic acid ethyl ester as a yellow solid.
Reaction SMILES: [H-].[Na+].[C:3]1([S:9]([N:12]2[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13]2)(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:25]I.O>O1CCCC1>[CH3:25][N:17]([CH:14]1[CH2:15][CH2:16][N:12]([S:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)(=[O:10])=[O:11])[CH2:13]1)[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccccc2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)C1CCN(S(=O)(=O)c2ccccc2)C1
Reaction time: 8 h

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil) (49 mg) in tetrahydrofuran (10 ml) was added the product from part (a) (400 mg) as a solution in tetrahydrofuran (5 ml). After 30 minutes methyl iodide (90 ul) was added and the reaction stirred overnight. The mixture was poured into water and the organics extracted into ether. The ether extractions were combined, washed with brine, dried (MgSO4) and concentrated in vacuo to give crude product. Purification by column chromatography (eluent 20% EtOAc/Hexane) gave the subtitle compound as an oil (235 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([NH:26][CH3:27])=[O:25])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:28][N:29](C)[C:30](=O)OC(C)(C)C)[CH:9]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([NH:26][CH3:27])=[O:25])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:28][NH:29][CH3:30])[CH:9]=1
Reactant: CNC(=O)COc1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2ccccc2F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCc1cc(-c2ccccc2F)n(S(=O)(=O)c2ccc(OCC(=O)NC)cc2)c1
Reaction time: 1 h

Procedure:
tert-Butyl ((5-(2-fluorophenyl)-1-((4-(2-(methylamino)-2-oxoethoxy)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 4f (100 mg, 0.19 mmol) was dissolved in 3 mL of dichloromethane, followed by addition of 1 mL of trifluoracetic acid and then the reaction solution was stirred for 1 h. 10 mL of saturated sodium bicarbonate solution were added, and the reaction solution was extracted with dichloromethane (20 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with elution system A to obtain the title product 2-(4-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)-N-methylacetamide 4 (15 mg, a colorless oil), and the yield of the three steps was 16%.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[CH:16]=[N:17][CH:18]=[N:19][CH:20]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:26]>ClCCl>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[CH:16]=[N:17][CH:18]=[N+:19]([O-:26])[CH:20]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(-c2cncnc2)cc1OC1CCCC1
Solvent: ClCCl
Product: COc1ccc(-c2cnc[n+]([O-])c2)cc1OC1CCCC1
Reaction time: 120 h

Procedure:
A solution of 5-(3-Cyclopentyloxy-4-methoxyphenyl)pyrimidine (1.37 g) and 3-chloroperoxybenzoic acid (50.60%) (1.75 g) in dichloromethane (35 ml) was stirred at RT and the reaction followed by t.l.c. After 5 days, the reaction mixture was partitioned three times between dichloromethane (50 ml) and 10% aqueous Na2SO3 solution (50 ml).
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:11]=[CH:10][N:9]=[C:8]([NH:12][CH:13]3[CH2:18][CH2:17][N:16](CC4C=CC=CC=4)[CH2:15][CH2:14]3)[N:7]=2)=[CH:4][C:3]2[CH:26]=[CH:27][CH:28]=[CH:29][C:2]1=2>CCO.[Pd]>[S:1]1[C:5]([C:6]2[CH:11]=[CH:10][N:9]=[C:8]([NH:12][CH:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)[N:7]=2)=[CH:4][C:3]2[CH:26]=[CH:27][CH:28]=[CH:29][C:2]1=2
Reactant: c1ccc(CN2CCC(Nc3nccc(-c4cc5ccccc5s4)n3)CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: c1ccc2sc(-c3ccnc(NC4CCNCC4)n3)cc2c1
Reaction time: 5 h

Procedure:
Compound of Example 149 (4.0 g, 10.0 mmol) was dissolved in 100 ml of EtOH and hydrogenated in the presence of 200 mg palladium on charcoal 10% at room temperature and 1 bar for 5 hours. Then the mixture was filtered through Hyflo and evaporated. The crude was purified by chromatography on silicagel (DCM/MeOH/ammonia:8/2/0.2). Yield: 2.76 g (89%).
Reaction SMILES: [N-:1]=[C:2]=[O:3].[CH3:4][O:5][C:6](=[O:9])[CH2:7][NH2:8].N1C=CC=CC=1.Cl.NO.C(OC)(OC)OC>C1COCC1.CO>[CH3:4][O:5][C:6]([CH2:7][NH:8][C:2](=[O:3])[NH2:1])=[O:9]
Reactant: COC(=O)CN
Reactant: [N-]=C=O
Agent: Cl
Agent: NO
Solvent: CO
Solvent: COC(OC)OC
Solvent: C1CCOC1
Product: COC(=O)CNC(N)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.1 mol of p-aminobenzaldehyde ethylene glycol acetal in 100 mL of anhydrous THF is added dropwise over 10 minutes to a solution of 0.1mol glycine methyl ester isocyanate and 0.35 mol pyridine in 100 mL THF at room temperature under N2. The yellow reaction mixture is stirred at room temperature for 2 hours. After 1/2 hour a yellow-orange precipitate begins to form. After 2 hours the solvent is removed by rotary evaporator to give an orange, semisolid mass. A solution of 0.11 mmol hydroxylamine hydrochloride and 0.1 mol trimethyl orthoformate in CH3OH is added, and the reaction mixture is heated to reflux under N2 for 1 hour. Thereaction mixture is reduced to about 1/4 volume by rotary evaporator, and water is added. Pale yellow crystals of product form, which are isolated by filtration and dried overnight in a vacuum oven at 50°-55° C. The yield of crude product (mp 158°-161° C.): 70-75 %. The product is purified by recrystallization from a 10:6:1 solution of CH3OH:H2 0:compound. The product is washed with cold water and dried in a vacuum oven at 50° C. to give off-white crystals of N-[4-hydroxyiminomethyl)phenyl]-N'-methoxycarbonylmethylurea, mp. 167.5°-168.5° C. Elemental analysis: calcd. C 52.59, H 5.22,N 16.72; found C 52.38, H 5.16, N 16.65. 1H NMR (acetone-d6): δ10.15 s, 1H, --NOH; 8.4 s, 1H, --NH; 8.1 s/d, 1H, --CH=N; 7.55 bs, 4H, phenyl; 6.21 s/d, 1H, --NH--; 4.02 s/d, 2H, --CH2 --; 3.74 s,3H, CH3O--. 13C NMR (acetone-d6): δ172, --COO--; 156, --NCON--; 149, --CH;50 N--; 119, 128, 142, phenyl; 52, CH3O--; 42, --CH2 --. UV-vis (CH3OH): λmax =279 nm, ε=2.90×104.
Reaction SMILES: Cl.[CH2:2]([C:6]1[N:7]([CH2:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)[C:8](/[CH:11]=[C:12]2\[N:13]([CH2:22][CH2:23][CH2:24][CH3:25])[C:14](=[O:21])[N:15]([CH2:18][O:19][CH3:20])[C:16]\2=[O:17])=[CH:9][N:10]=1)[CH2:3][CH2:4][CH3:5].[OH-:37].[Na+].CO.Cl>C1COCC1>[CH2:2]([C:6]1[N:7]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:35][CH:36]=2)[C:8](/[CH:11]=[C:12](\[N:13]([CH2:22][CH2:23][CH2:24][CH3:25])[C:14]([NH:15][CH2:18][O:19][CH3:20])=[O:21])/[C:16]([OH:17])=[O:37])=[CH:9][N:10]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1ncc(/C=C2/C(=O)N(COC)C(=O)N2CCCC)n1Cc1ccc(C(=O)OC)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCc1ncc(/C=C(/C(=O)O)N(CCCC)C(=O)NCOC)n1Cc1ccc(C(=O)OC)cc1
Reaction time: 1.5 h

Procedure:
To a solution of methyl Z-4-[[2-butyl-5-[[3-butyl-1-(methoxymethyl)-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoate monohydrochlorde. (0.100 g, 0.193 mmol) in THF was added 1N NaOH (0.22 mL, 0.22 mmol) and then methanol (2 mL). The yellow solution was stirred for 1.5 hours and then 1N HCl (0.22 mL, 0.22 mmol) was added. The reaction mixture was evaporated in vacuo to a white solid. This solid was dissolved in ethyl acetate and water. The organic layer was dried briefly over MgSO4 and then concentrated to 1/6 original volume. An equal volume of hexane was added and the solid collected.
Reaction SMILES: [NH2:1][C@H:2]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:3][C:4]([N:6]1[CH2:29][CH2:28][CH2:27][C@H:7]1[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[C:16](Cl)[CH:15]=[CH:14][C:13]=1[O:19][CH2:20][C:21]([NH:23][CH:24]1[CH2:26][CH2:25]1)=[O:22])=[O:9])=[O:5].[H][H]>CO.[OH-].[OH-].[Pd+2]>[NH2:1][C@H:2]([CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:3][C:4]([N:6]1[CH2:29][CH2:28][CH2:27][C@H:7]1[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:19][CH2:20][C:21]([NH:23][CH:24]1[CH2:26][CH2:25]1)=[O:22])=[O:9])=[O:5]
Reactant: N[C@@H](CC(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1OCC(=O)NC1CC1)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: N[C@@H](CC(=O)N1CCC[C@H]1C(=O)NCc1ccccc1OCC(=O)NC1CC1)Cc1ccccc1
Yield: 71.5 %

Procedure:
Palladium hydroxide on activated charcoal (˜50 mg) was added to a solution of 15 mg of 1-[(3R)-3-amino-4-phenylbutanoyl]-N-{5-chloro-2-[2-(cyclopropylamino)-2-oxoethoxy]benzyl }-L-prolinamide in 1 mL methanol and the mixture was stirred under a balloon of hydrogen for 6 h. The reaction was diluted with methanol, filtered through a pad of Celite, and concentrated in vacuo. Purification using preparative TLC (silica gel, 13.5:1.5:85 methanol:concentrated ammonium hydroxide:methylene chloride) afforded 10 mg of the title compound. 1H NMR (400 MHz, CD3OD) δ 7.33–7.10 (m, 7H), 7.01–6.83 (d, 2H), 4.58–4.22 (m, 5H), 3.61–3.35 (m, 3H), 2.84–2.48 (m, 4H), 2.38–2.08 (m, 2H), 2.05–1.80 (m, 3H), 0.78–0.60 (m, 4H).
Reaction SMILES: [S:1]1[C:5]([CH2:6][CH2:7][N:8]([CH3:10])[CH3:9])=[CH:4][C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]1=2.[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C>[CH3:9][N:8]([CH3:10])[CH2:7][CH2:6][C:5]1[S:1][C:2]2[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=2[C:4]=1[C:20]([C:19]1[CH:23]=[CH:24][C:16]([F:15])=[CH:17][CH:18]=1)=[O:21]
Reactant: CN(C)CCc1cc2ccccc2s1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CN(C)CCc1sc2ccccc2c1C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 47 %

Procedure:
To a solution of (2-Benzo[b]thiophen-2-yl-ethyl)-dimethylamine (Compound 1a, 1.1 mmol) in dichloroethane (1 mL) under N2 at 0° C., p-fluorobenzoyl chloride (1.32 mmol) and aluminum chloride (3.3 mmol, 1M in nitrobenzene) were added. The mixture was warmed to RT and stirred for 5 hrs, quenched in sat. NaHCO3 and extracted with EtOAc (4×). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography in EtOAc with gradient to EtOAc:methanol (99:1) as required. Compound 3-1, [2-(2-Dimethylamino-ethyl)-benzo[b]thiophen-3-yl]-(4-fluoro-phenyl)-methanone, was isolated in 47% yield (170 mg); MS (MH+)=327.8.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:16][CH:15]=[C:14]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH:13]=2.[Cl:38][CH2:39][C:40](Cl)=O>ClCCl>[CH2:31]([O:30][C:14]1[CH:15]=[CH:16][C:17]2[C:18]3[N:19]([CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:40]([CH2:39][Cl:38])=[N:8][C:9]=3[CH:10]=[N:11][C:12]=2[CH:13]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)NCCNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCn1c(CCl)nc2cnc3cc(OCc4ccccc4)ccc3c21
Temperature: 25 °C
Yield: 15.5 %

Procedure:
Triethylamine (24.0 mL, 172.58 mmol) was added to a solution of tert-butyl 2-[(3-amino-7-benzyloxyquinolin-4-yl)amino]ethylcarbamate (35.25 g, 86.29 mmol) in dichloromethane (400 mL), and the reaction was stirred at ambient temperature. Chloroacetyl chloride (6.87 mL, 86.29 mmol) was quickly added at ambient temperature, and the reaction was stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethanol (500 mL) and stirred for two days at ambient temperature. The mixture was concentrated under reduced pressure and the residue was recrystallized from dichloromethane to afford 6.23 g of tert-butyl 2-[7-benzyloxy-2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethylcarbamate. The mother liquor was divided into two portions which were separately purified by normal phase prep HPLC on silica gel (eluting with 2 N ammonia in methanol/chloroform in a 33-minute gradient from 0:100 to 5:95) and combined to provide an additional 24.21 g of product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.CC(C)([O-])C.[K+].[Br:16][C:17]1[CH:18]=[C:19](F)[C:20]([C:23]#[N:24])=[N:21][CH:22]=1.Cl>C1COCC1>[Br:16][C:17]1[CH:18]=[C:19]([NH:1][C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=2)[C:20]([C:23]#[N:24])=[N:21][CH:22]=1
Reactant: Cc1cc(C)nc(N)c1
Reactant: N#Cc1ncc(Br)cc1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(C)nc(Nc2cc(Br)cnc2C#N)c1
Reaction time: 0.17 h

Procedure:
This example describes the conversion of (A6) to (A7) as illustrated in Scheme 1. To a solution of 2-amino-4,6-dimethylpyridine (30.4 g, 249 mmol) in THF (200 mL) at 0° C. was added potassium tert-butoxide (1.0 M in THF, 249 mL, 250 mmol) at such a rate to keep the internal temperature less then 10° C. After the addition was complete, the reaction mixture was stirred for 10 min, and then ˜60% of the reaction mixture was transferred via cannula to a cooled solution of 5-bromo-2-cyano-3-fluoropyridine (Manchester Organics, Ltd.; CAS: 886373-28-0, Runcorn, UK) (25.0 g, 124 mmol) in THF (200 mL). The reaction mixture was analyzed by LC which indicated near-complete consumption of the 5-bromo-2-cyano-3-fluoropyridine. The reaction mixture was diluted with water (400 mL) followed by hydrochloric acid (1.0 M in water, 50 mL, 50 mmol), and the resulting mixture was filtered. The collected solids were washed with water (2×50 mL). After 2 hours, the filtrate was filtered. The two collections of solids were combined, diluted with 4:1 hexanes/ethyl acetate (400 mL), and stirred. After 30 minutes, the mixture was filtered to afford 5-bromo-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carbonitrile. MS ESI calc'd. for C13H12BrN4 [M+H]+ 303 and 305. found 303 and 305. 1H NMR (600 MHz, CD3OD) δ 8.89 (d, J=2.4 Hz, 1H), 8.24 (d, J=1.8 Hz, 1H), 6.71 (s, 1H), 6.68 (s, 1H), 2.37 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: CNC1N=C(C2C=CC=CN=2)C=C(C2C=NC=C(C#CC3N(C)C=NC=3)C=2)C=1.Br[C:30]1[CH:31]=[C:32]([C:36]2[CH:41]=[C:40]([NH:42][CH:43]3[CH2:45][CH2:44]3)[N:39]=[C:38]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=3)[CH:37]=2)[CH:33]=[N:34][CH:35]=1.[C:52]([Si:54]([CH3:57])([CH3:56])[CH3:55])#[CH:53]>>[CH:43]1([NH:42][C:40]2[N:39]=[C:38]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=3)[CH:37]=[C:36]([C:32]3[CH:33]=[N:34][CH:35]=[C:30]([C:53]#[C:52][Si:54]([CH3:57])([CH3:56])[CH3:55])[CH:31]=3)[CH:41]=2)[CH2:45][CH2:44]1
Reactant: C#C[Si](C)(C)C
Reactant: Brc1cncc(-c2cc(NC3CC3)nc(-c3ccccn3)c2)c1
Agent: CNc1cc(-c2cncc(C#Cc3cncn3C)c2)cc(-c2ccccn2)n1
Product: C[Si](C)(C)C#Cc1cncc(-c2cc(NC3CC3)nc(-c3ccccn3)c2)c1

Procedure:
is prepared analogously to Methyl-[5″-(3-methyl-3H-imidazol-4-ylethynyl)-[2,2′;4′,3″]terpyridin-6′-yl]-amine (Example 2.182) by replacing (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-methyl-amine (Example 2.1; step 1) with (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-cyclopropyl-amine (Example 1.26) and by replacing 1-methyl-5-((trimethylsilyl)ethynyl)-1H-imidazole with ethynyl-trimethyl-silane to afford the title compound; [M+H]+ 385.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([CH:14]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[CH2:15][NH:16][C:17]2[N:25]=[C:24]([C:26](=[O:46])[NH:27][CH2:28][CH2:29][NH:30][C:31]([NH:33][CH:34]3[CH2:39][CH2:38][N:37]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=4)[CH2:36][CH2:35]3)=[O:32])[N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[C@@H:47]2[CH2:51][C@H:50]([NH:52][C:53]([CH2:55][O:56]C(=O)C)=[O:54])[C@@H:49]([OH:60])[C@H:48]2[OH:61])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:37]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[CH2:38][CH2:39][CH:34]([NH:33][C:31](=[O:32])[NH:30][CH2:29][CH2:28][NH:27][C:26]([C:24]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[C@@H:47]3[CH2:51][C@H:50]([NH:52][C:53](=[O:54])[CH2:55][OH:56])[C@@H:49]([OH:60])[C@H:48]3[OH:61])=[C:17]([NH:16][CH2:15][CH:14]([C:62]3[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:25]=2)=[O:46])[CH2:35][CH2:36]1
Reactant: CC(=O)OCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NC4CCN(c5ccccn5)CC4)nc32)[C@H](O)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NC4CCN(c5ccccn5)CC4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of acetic acid [(1S,2R,3S,4R)-4-(6-(2,2-diphenyl-ethylamino)-2-{2-[3-(3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-4-yl)-ureido]-ethylcarbamoyl}-purin-9-yl)-2,3-dihydroxy-cyclopentylcarbamoyl]-methyl ester trifluoroacetate (0.015 g, 16 μmol) in methanol (1 ml) is treated with potassium carbonate (0.01 g, 10 μmol) and the reaction mixture is allowed to stir at room temperature for 1 hour. The solvent is removed in vacuo and purification of the crude by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water −0.1% TFA) yields the title product. (MH+ 778.6)
Reaction SMILES: [C:1]([O:5][O:6][C:7]([O:16][O:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:15])[CH2:8][CH2:9][C:10](OCC)=[O:11])([CH3:4])([CH3:3])[CH3:2].[NH2:22][NH2:23].C(O)(C)C>O>[C:1]([O:5][O:6][C:7]([O:16][O:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:15])[CH2:8][CH2:9][C:10]([NH:22][NH2:23])=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CCC(C)(OOC(C)(C)C)OOC(C)(C)C
Reactant: NN
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)OOC(C)(CCC(=O)NN)OOC(C)(C)C
Reaction time: 20 h

Procedure:
4,4-Di-(t-butylperoxy)pentanohydrazide was prepared by reacting ethyl 4,4-di-(t-butyl-peroxy)pentanoate with 9 molar excess of 54% aqueous hydrazine. A 3-neck flask equipped with a magnetic stirrer, a thermometer and an addition funnel was charged with 125 mL of isopropanol (IPA), 15.3 g (0.05 mole) of 99% ethyl 4,4-di-(t-butylperoxy)pentanoate and 30 g (about 0.50 mole) of 54% aqueous hydrazine at 25° C. The solution was stirred for about 20 hours at 20°-25° C. Then the reaction mass was poured into 1000 mL of water and extracted once with 300 mL of methylene chloride. After drying over 10% by weight of anhydrous magnesium sulfate and separation of the spent desiccant by filtration, the methylene chloride was removed in vacuo leaving 14.4 g of liquid product. 30 mL of pentane were added and a solid was precipitated. The solid was separated by filtration and air dried, leaving 12.2 g (83.6% of theory, uncorrected) of a white solid having a melting point (mp) of 76°-78° C. An infrared (IR) spectrum of the product showed strong carbonyl absorption bands at 1640 cm-1 and at 1680 cm-1 and a strong NH band at 3300 cm-1. A DSC scan run on the product showed a peroxide decomposition exotherm at 170° C. These product data confirm that the product was 4,4-Di-(t-butylperoxy)pentano-hydrazide (I-1).