Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CN(C=O)C>[CH2:26]([O:11][C:10](=[O:12])[C@H:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:9][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:15][CH:14]=1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](C(=O)OCc1ccccc1)c1ccc(OCc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 17 h
Yield: 184 %

Procedure:
To a solution of (S)-tert-butoxycarbonylamino-(4-hydroxy-phenyl)-acetic acid (32.03 g, 120 mmol) in DMF (300 ml) was added potassium carbonate (35 g, 252 mmol) and benzylbromide (30 ml, 252 mmol). The reaction mixture was stirred at 50° C. under a nitrogen atmosphere for 17 h. The mixture was poured into water (1l) and extracted with EtOAc (3×600 ml). The combined organic extracts were washed with water (3×600 ml), brine (600 ml), dried over magnesium sulfate, filtered and evaporated in vacuo to yield a yellow oil (49.4 g, 92%). LCMS purity 100%, m/z 470 [M++Na]+.
Reaction SMILES: [H-].[Na+].[C:3]([O:6][CH2:7][C:8](=[O:17])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(=[O:5])[CH3:4].I[CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1COCC1>[C:3]([O:6][CH2:7][C:8]([CH:9]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:17])(=[O:5])[CH3:4]
Reactant: CC(=O)OCC(=O)CC(=O)OC(C)(C)C
Reactant: CCOC(=O)CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CCC(C(=O)COC(C)=O)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.4 %

Procedure:
To a suspension of 60% NaH (1.02 g) in THF (50 mL) was added tert-butyl 4-(acetyloxy)-3-oxobutanoate (5.00 g) under ice-water cooling and the mixture was stirred at 0° C. for 0.5 hour. To this added ethyl 3-iodopropanoate (5.54 g) and the mixture was stirred at 50° C. for 8 hours. The mixture was partitioned between AcOEt and water. The organic layer was separated, washed with brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and AcOEt (20:1-3:1) to give 1-tert-butyl 5-ethyl 2-[(acetyloxy)acetyl]pentanedioate as yellow oil (4.27 g).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)[CH:18]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:37][C:38]1[CH:46]=[C:45]([Cl:47])[CH:44]=[C:43]([Cl:48])[C:39]=1[C:40](Cl)=[O:41]>C(Cl)Cl>[Cl:37][C:38]1[CH:46]=[C:45]([Cl:47])[CH:44]=[C:43]([Cl:48])[C:39]=1[C:40]([N:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[CH:10][CH:11]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH:18]=1)=[O:41]
Reactant: c1cc(CNc2ccc(OCCN3CCCC3)cc2)cc(OC2CCCCO2)c1
Reactant: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1c(Cl)cc(Cl)cc1Cl)N(Cc1cccc(OC2CCCCO2)c1)c1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-[3-(tetrahydro-pyran-2-yloxy)-benzyl]-amine (0.050 g, 0.13 mmol) in 0.5 mL methylene chloride was added triethylamine (0.035 mL, 0.25 mmol), 2,4,6-trichlorobenzoyl chloride (0.061 g, 0.25 mmol), and catalytic N,N-dimethylaminopyridine (DMAP). The reaction mixture was stirred overnight at room temperature. The reaction was concentrated to give the title compound of Step A which was used in Step B without further purification. MS 605.4 (M+1)+
Reaction SMILES: C([CH:5]([O:34][SiH](C1C=CC=CC=1)C1C=CC=CC=1)[CH2:6][C:7]1[CH:8]=[C:9]([N:13]2[C:18]3=[N:19][C:20]([S:23][CH3:24])=[N:21][CH:22]=[C:17]3[CH2:16][N:15]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[Cl:32])[C:14]2=[O:33])[CH:10]=[CH:11][CH:12]=1)(C)(C)C.ClC1C=C(Cl)C=CC=1N.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[Cl:32][C:26]1[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:25]=1[N:15]1[CH2:16][C:17]2[C:18](=[N:19][C:20]([S:23][CH3:24])=[N:21][CH:22]=2)[N:13]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([CH2:6][CH2:5][OH:34])[CH:8]=2)[C:14]1=[O:33]
Reactant: CSc1ncc2c(n1)N(c1cccc(CC(O[SiH](c3ccccc3)c3ccccc3)C(C)(C)C)c1)C(=O)N(c1ccc(Cl)cc1Cl)C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Nc1ccc(Cl)cc1Cl
Agent: [F-]
Product: CSc1ncc2c(n1)N(c1cccc(CCO)c1)C(=O)N(c1ccc(Cl)cc1Cl)C2
Yield: 99.6 %

Procedure:
1.97 g (2.83 mmol) of 1-[3-(2-tertbutyldiphenylsilyloxyethyl)phenyl]-3-(2,4-dichlorophenyl)-3,4-dihydro-7-methylthio-pyrimido[4,5-d]pyrimidin-2(1H)-one (prepared in a manner analogous to that described in Example 53(a)-(b) using 2,4-dichloroaniline in place of 2-chloro-6-methylaniline) was reacted with a 1M solution of tetrabutylammonium fluoride in a manner analogous to that described in Example 69. 1.3 g (100%) of 3-(2,4-dichlorophenyl)-3,4-dihydro-1-[3-(2-hydroxyethyl)phenyl]-7-methylthio-pyrimido[4,5-d]pyrimidin-2(1H)-one was isolated as a yellow solid. [Mass spectrum (ESI) MH+ =461].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:20]([OH:22])=O)[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][OH:29].ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[C:20]([NH:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][OH:29])=[O:22])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCCOCCO
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCCOCCO
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
To a solution of N-t-butoxycarbonyl-L-tryptophan, (128 g, 0.42 mol), 2-(2-aminoethoxy)ethanol (46.42 g, 0.44 mol), 1-hydroxybenzotriazole (60.0 g, 0.44 mol) in 700 mL of DMF at 0° C. was added DCC (100 g, 0.48 mol). After stirring at 0° C. for 15 minutes, the mixture was stirred at room temperature overnight. The white solids were filtered and washed with EtOAc. The filtrate was concentrated under reduced pressure. The residue was taken up in ether and a small amount of EtOAc, washed with it HCl (3×500 mL), saturated NaHCO3 (3×500 mL), and brine (3×500 mL). The organic layer was dried (MgSO4), filtered and concentrated to give 2-(S)-t-butoxycarbonylamino-N-[2-(2-hydroxy-ethoxy)ethyl]-3-(1H-indol-3-yl)-propionamide, 150 g (yield 91%), MS: 392.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:24][CH:25]1[NH:29][C:28](=[O:30])[CH2:27][CH2:26]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[N:6]=[N:7][C:2]([N:29]4[CH:25]([CH3:24])[CH2:26][CH2:27][C:28]4=[O:30])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CC1CCC(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)nn3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CCC4C)nn3)CC2)c(C)c1
Yield: 10.1 %

Procedure:
Using (6-chloropyridazin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 230 and 5-methylpyrrolidin-2-one (54 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (18 mg) was obtained.
Reaction SMILES: [C@H:1]1([OH:8])[CH2:6][CH2:5][CH2:4][C@@H:3]([OH:7])[CH2:2]1.CC(C)([O-])C.[K+].Br[CH2:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:18]=1[C:19]([O:21][CH3:22])=[O:20].BrCC1C=CC=C(C)C=1C(Br)=O.CC1C=CC=C(C)C=1C(OC)=O>C(OC)(C)(C)C.O>[OH:7][C@@H:3]1[CH2:4][CH2:5][CH2:6][C@H:1]([O:8][CH2:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:18]=2[C:19]([O:21][CH3:22])=[O:20])[CH2:2]1
Reactant: COC(=O)c1c(C)cccc1CBr
Reactant: O[C@@H]1CCC[C@H](O)C1
Agent: CC(C)(C)[O-]
Agent: COC(=O)c1c(C)cccc1C
Agent: Cc1cccc(CBr)c1C(=O)Br
Solvent: COC(C)(C)C
Solvent: O
Product: COC(=O)c1c(C)cccc1CO[C@H]1CCC[C@@H](O)C1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 14.2 %

Procedure:
10.0 g (86 mmol) of cis-1,3-cyclohexanediol were taken up in 150 ml of methyl tert-butyl ether (MTBE), admixed at approx. 20° C. with 6.72 g (59.9 mmol) of potassium tert-butoxide (KOtBu) and stirred. After about 30 minutes, the suspension was cooled to 5° C. and admixed dropwise with 7.4 g (approx. 50%) of methyl 2-bromomethyl-6-methylbenzoate, which may be prepared, for example, by methanolyzing the acid bromide (2-bromomethyl-6-methylbenzoyl bromide) or by brominating methyl 2,6-dimethylbenzoate. The mixture was stirred at 0–5° C. for 1 h, heated to 20–23° C. and left to stir overnight. Water was added, the mixture was stirred vigorously, the phases were separated, the organic phase was washed once more with water and then the organic phase was concentrated under reduced pressure. The residue (4.6 g) was chromatographed on silica gel (1:1 ethyl acetate/n-heptane). 1.2 g of the desired compound were obtained as a light yellow oil, 1H NMR (CDCl3), δ =1.27 (m, 1H), 1.45 (m, 1H), 1.55 (m, 1H), 1.74 (m, 1H), 1.82 (m, 1H), 2.05 (m, 1H), 2.34 (s, 3H), 3.46 (m, 1H), 3.72 (m, 1H), 3.91 (s, 3H), 4.58 (dd, 2H), 7.15 (d, 1H), 7.20 (d, 2H), 7:27 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([C:11]([O:13][C@H:14]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:16]([C:26]([O:28]C)=[O:27])[CH2:15]1)=[O:12])[CH2:6]2.O[Li].O>C1COCC1.CO.O>[C:22]([O:21][C:19]([N:17]1[CH2:18][C@H:14]([O:13][C:11]([N:5]2[CH2:4][C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[Cl:1])[CH2:6]2)=[O:12])[CH2:15][C@H:16]1[C:26]([OH:28])=[O:27])=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: COC(=O)[C@@H]1C[C@@H](OC(=O)N2Cc3cccc(Cl)c3C2)CN1C(=O)OC(C)(C)C
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](OC(=O)N2Cc3cccc(Cl)c3C2)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
This ester product, (2S,4R)-1-tert-butyl 2-methyl 4-(4-chloroisoindoline-2-carbonyloxy)pyrrolidine-1,2-dicarboxylate (0.78 g, 1.8 mmol) was then dissolved in a mixture of solvent THF:MeOH:water 2:2:1 (v/v) (5.4 mL), followed by addition of LiOH—H2O (0.15 g, 3.7 mmol). After stirring at rt for overnight, the reaction was concentrated to near dryness. The resulting solid residue was re-dissolved in water (40 mL) and washed with ether (2×30 mL). The aqueous layer was acidified with 1N HCl to pH ˜2 and the combined EtOAc extracts (3×30 mL) was washed with brine and dried (Na2SO4), giving the titled product as a white foamy solid after evaporation of solvent.
Reaction SMILES: C(OC(=O)[N:7]([CH2:23][CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([NH:34][C:35]3[O:36][C:37]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:38][N:39]=3)[CH:32]=2)[NH:27][C:26]=1[C:46]1[CH:51]=[C:50]([CH3:52])[CH:49]=[C:48]([CH3:53])[CH:47]=1)[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:14][CH:13]=1)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[CH3:52][C:50]1[CH:51]=[C:46]([C:26]2[NH:27][C:28]3[C:33]([C:25]=2[CH2:24][CH2:23][NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][S:19]([CH3:22])(=[O:20])=[O:21])=[CH:16][CH:17]=2)=[CH:32][C:31]([NH:34][C:35]2[O:36][C:37]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:38][N:39]=2)=[CH:30][CH:29]=3)[CH:47]=[C:48]([CH3:53])[CH:49]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(Nc4ncc(-c5ccccc5)o4)cc3c2CCN(CCCCc2ccc(NS(C)(=O)=O)cc2)C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Cc1cc(C)cc(-c2[nH]c3ccc(Nc4ncc(-c5ccccc5)o4)cc3c2CCNCCCCc2ccc(NS(C)(=O)=O)cc2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 92.4 %

Procedure:
To a solution of {2-[2-(3,5-dimethylphenyl)-5-(5-phenyloxazol-2-ylamino)-1H-indol-3-yl]-ethyl}-[4-(4-methanesulfonylaminophenyl)butyl]-carbamic acid tert-butyl ester (10 mg in 0.80 mL methylene chloride) at 0° C. was added 0.050 mL anisole followed by 0.20 mL trifluoroacetic acid and the mixture stirred at 0° C. After 3 hours, the mixture was concentrated in vacuo and the residual acid removed by azeotrope with toluene. Purification of the concentrate by flash chromatography on silica gel (methylene chloride:methanol:ammonium hydroxide, 90:7:1) gave the title compound (8 mg). m/e 648 (M+H)
Reaction SMILES: [CH3:1][N:2]([CH2:18][C:19]([OH:21])=O)[NH:3][C:4](=[O:17])[NH:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[NH2:22][C@@H:23]([CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[CH:49][CH:48]=1)[C:24]([N:26]([CH2:36][C:37]1[C:38]2[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=2[S:40][CH:41]=1)[C@@H:27]([CH3:35])[CH:28]([O:32][CH2:33][CH3:34])[O:29][CH2:30][CH3:31])=[O:25]>>[S:40]1[CH:41]=[C:37]([CH2:36][N:26]([C@@H:27]([CH3:35])[CH:28]([O:29][CH2:30][CH3:31])[O:32][CH2:33][CH3:34])[C:24](=[O:25])[C@@H:23]([NH:22][C:19](=[O:21])[CH2:18][N:2]([CH3:1])[NH:3][C:4]([NH:5][CH2:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][CH:8]=2)=[O:17])[CH2:46][C:47]2[CH:48]=[CH:49][C:50]([O:53][C:54]([CH3:55])([CH3:57])[CH3:56])=[CH:51][CH:52]=2)[C:38]2[CH:45]=[CH:44][CH:43]=[CH:42][C:39]1=2
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Reactant: CN(CC(=O)O)NC(=O)NCc1cccc2ccccc12
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)CN(C)NC(=O)NCc1cccc2ccccc12

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(1-methyl-2-(naphthalen-1-ylmethylcarbamoyl)hydrazinyl)acetic acid (Compound VI-8) 84 mg (0.29 mmol) was coupled with (S)-2-amino-N-(benzo[b]thiophen-3-ylmethyl)-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxypropan-2-yl)propanamide (Compound IV-6) 100 mg (0.20 mmol) to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:4]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])[C:3]=1[CH3:30].O.CCO>C1COCC1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[C:4]([CH:19]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[C:20]([OH:22])=[O:21])[C:3]=1[CH3:30]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)c(Br)c2ccccc2c1-c1ccc(Cl)cc1
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccccc2c1Br
Temperature: 100 °C
Yield: 34.9 %

Procedure:
A solution of ethyl 2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate (30 mg, 71.4 μmol), LiOH monohydrate (15 mg, 0.357 mmol), H2O (500 μL), EtOH (absolute, 500 μL), and THF (500 μL) was placed in a sealed tube and heated to 100° C. Once the reaction was complete, it was cooled to 23° C., filtered through a 0.45 micron filter, and directly purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA). The product-containing fractions were combined and lyophilized, giving the title compound (parent form) (11.5 mg, 40%). 1H NMR (400 MHz, CD3OD) δ 8.38 (d, J=8.6 Hz, 1H), 7.63-7.47 (m, 4H), 7.38-7.20 (m, 3H), 5.30 (s, 1H), 2.69 (s, 3H), 1.00 (s, 9H). LCMS-ESI− (m/z): [M—CO2—H]− calcd for C22H21BrClO: 415.2; Found: 415.0.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13](OC)=[O:14])=[C:11](F)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:21][NH2:22]>C(O)CCC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:12]([C:13](=[O:14])[NH:21][NH:22]2)=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1F
Solvent: CCCCO
Solvent: O
Product: O=c1[nH][nH]c2cc(OCc3ccccc3)ccc12
Temperature: 160 °C
Reaction time: 1 h

Procedure:
Methyl 4-(benzyloxy)-2-fluorobenzoate (52.4 mg) which can be prepared according to the method described in Reference example 30, etc. was dissolved in n-butanol (1 mL; manufactured by Kanto Chemical Co., Inc.), added with hydrazine monohydrate (96 μL; manufactured by Sigma-Aldrich Co.), and stirred in a sealed tube under microwave for 1 hour at 160° C. Precipitates from the reaction solution were filtered and washed with n-butanol to obtain the title compound (39.6 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:12]3[CH:13]=[N:14][C:15]([NH2:17])=[CH:16][C:11]=3[N:10]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[Xe](F)[F:38]>C1COCC1>[F:38][C:16]1[C:11]2[N:10]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:9]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)[C:12]=2[CH:13]=[N:14][C:15]=1[NH2:17]
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3cc(N)ncc23)ccn1
Reactant: F[Xe]F
Solvent: C1CCOC1
Product: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3c(F)c(N)ncc23)ccn1
Temperature: 0 °C

Procedure:
A 200 mL round bottom flask was charged with 3-(2-methylpyridin-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-amine (0.76 g, 1.625 mmol) and the flask was put under an atmosphere of argon. The reaction was charged with 10 mL THF and the slurry was cooled to 0° C. in an ice bath. Xenon Difluoride (0.056 ml, 1.418 mmol) was added with vigorous stirring in several portions. Then stirring was continued with warming to ambient temperature.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]2[CH2:15][O:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:16]=[N+:17]=[N-:18].[Na+].[Cl-].[NH4+]>CO.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([OH:14])[CH2:15][N:16]=[N+:17]=[N-:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]([C@H]2CO2)C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H]([C@H](O)CN=[N+]=[N-])C1
Yield: 103.5 %

Procedure:
A solution of (S)—(S)-3-oxiranylpyrrolidine-1-carboxylic acid t-butyl ester (1.1 g, 4.9 mmol, 1.0 eq.), sodium azide (800 mg, 12.3 mmol, 2.5 eq.), and ammonium chloride (474 mg, 8.9 mmol) in MeOH (25 mL) was stirred at reflux overnight. The white solid residue obtained on removal of solvent was dissolved in EtOAc (25 mL) and washed with water and saturated aqueous NaCl (1×25 mL each). The organic layer was then dried over Na2SO4 and concentrated to yield (S)-3-((S)-2-azido-1-hydroxyethyl)pyrrolidine-1-carboxylic acid t-butyl ester (1.3 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[CH3:21][N:22]([CH3:31])[C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=O>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:26]([C:25]3[CH:28]=[CH:29][CH:30]=[C:23]([N:22]([CH3:31])[CH3:21])[CH:24]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: CN(C)c1cccc(C=O)c1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Product: CN(C)c1cccc(-c2nc3c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)c(Br)cnc3[nH]2)c1
Yield: 58 %

Procedure:
In a similar fashion to Compound LXXVI, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (1.30 mg, 0.386 mmol) and 3-(dimethylamino)benzaldehyde were reacted to produce 105 mg (58%) of the title compound. mp: 220-221° C., 1H NMR (300 MHz, DMSO-d6): 13.02 (s, 1H), 7.90 (d, 1H), 7.66 (s, 1H), 7.50 (s, 1H), 7.47 (d, J=8 Hz, 1H), 7.30 (t, J=8 Hz, 1H), 7.15 (s, 1H), 6.86 (m, 1H), 6.81 (d, J=8 Hz, 1H), 6.40 (d, J=5 Hz, 1H), 6.33 (s, 2H), 2.98 (s, 6H), 2.87 (s, 1H), 2.77 (s, 1H), 2.60 (d, J=8 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 1.42 (d, J=8 Hz, 1H). MS: 467, 469 (M+H), HPLC: 2.13 min (G method).
Reaction SMILES: O=[C:2]([CH3:10])[CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[CH3:11][NH2:12]>[Pt]=O.C(O)C>[CH3:11][NH:12][CH:2]([CH3:10])[CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: CC(=O)CCn1ccnc1
Reactant: CN
Agent: O=[Pt]
Solvent: CCO
Product: CNC(C)CCn1ccnc1
Reaction time: 1 h

Procedure:
A suspension of 0.35 g. of platinum oxide in 30 ml. of absolute ethanol is hydrogenated at 50 p.s.i. for one hour. To this is added a mixture of 13.8 g. of 1-(3-oxobutyl)-imidazole, 6.2 g. of methylamine and 60 ml. of ethanol. The mixture is shaken under ca. 50 p.s.i. of hydrogen until one equivalent is absorbed. Filtration of the catalyst and removal of solvent in vacuo gives 1-(3-methylaminobutyl)-imidazole.
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH:25]([CH3:27])[CH3:26])[C:12]2[CH:13]=[C:14]([CH2:23][CH3:24])[C:15]3[O:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]=3[CH:22]=2)=[CH:7][CH:6]=1)C.[OH-].[K+]>C(O)C>[CH:25]([N:11]([C:12]1[CH:13]=[C:14]([CH2:23][CH3:24])[C:15]2[O:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]=2[CH:22]=1)[C:8]1[CH:7]=[CH:6][C:5]([C:4]([OH:28])=[O:3])=[CH:10][CH:9]=1)([CH3:27])[CH3:26]
Reactant: CCOC(=O)c1ccc(N(c2cc(CC)c3c(c2)C(C)(C)CO3)C(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cc(N(c2ccc(C(=O)O)cc2)C(C)C)cc2c1OCC2(C)C
Yield: 82.3 %

Procedure:
Following general procedure I and using 4-[isopropyl-(3,3-dimethyl-7-ethyl-2,3-dihydro-benzofuran-5-yl)-amino]-benzoic acid ethyl ester (Compound 38, 0.21 g, 0.55 mmol) and 2 mL of 5M potassium hydroxide solution in 10 mL of ethanol, the title compound (0.16 g, 88%)was obtained as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.86 (d, 2H, J=9.1 Hz), 6.69 (d, 1H, J=2.0 Hz), 6.65 (d, 1H, J=2.0 Hz), 6.51 (d, 2H, J=9.1 Hz), 4.35 (heptet, 1H, J=6.5 Hz), 4.30 (s, 2H), 2.60 (q, 2H, J=7.5 Hz), 1.33 (s, 6H), 1.21 (t, 3H, J=7.5 Hz), 1.15 (d, 6H, J=6.5 Hz).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:7]=1)=[O:5])C.[OH-].[Na+]>C1COCC1.CO.CCOC(C)=O>[O:14]1[CH2:15][CH2:16][CH:11]([N:8]2[CH:9]=[CH:10][C:6]([C:4]([OH:5])=[O:3])=[N:7]2)[CH2:12][CH2:13]1
Reactant: CCOC(=O)c1ccn(C2CCOCC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccn(C2CCOCC2)n1
Reaction time: 8 h
Yield: 80.3 %

Procedure:
1-(Tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylic acid ethyl ester (1.14 g, 5.09 mmol) was dissolved in a mixture of THF (5.0 mL) and MeOH (5.0 mL). To this was added NaOH (20% aqueous, 5.0 mL). The reaction mixture was stirred overnight and was then diluted with EtOAc and washed with 1 M NaHSO4. The aqueous layer was extracted with EtOAc and the combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure to give the product as a white solid (802 mg, 80%).