Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][N:3]1[C:8](=[O:9])[NH:7][C:6](=[O:10])[CH:5]=[N:4]1.[CH3:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=1>N1C=CC=CC=1>[CH3:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([O:1][CH2:2][N:3]2[C:8](=[O:9])[NH:7][C:6](=[O:10])[CH:5]=[N:4]2)=[O:17])=[CH:14][CH:13]=1
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: O=c1cnn(CO)c(=O)[nH]1
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)OCn2ncc(=O)[nH]c2=O)cc1
Reaction time: 8 h

Procedure:
2-Hydroxymethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine (1.00 g), p-methylbenzoic acid (0.95 g) and N,N-dicyclohexylcarbodiimide (2.90 g) are dissolved in pyridine, and the mixture is allowed to stand overnight. The reaction mixture is then evaporated to dryness to give a residue, which is extracted with chloroform. The chloroform extract is condensed to give an oil, which is purified by thin layer chromatography with silica gel and recrystallized from a mixture of ethanol/n-hexane. 2-(p-Methylbenzoyloxymethyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine (Compound No. 42) is thus obtained. Yield, 1.01 g (56%). M.P. 139.3° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:11]=[CH:12][C:13]3[N:17]=[N:16][N:15](C)[C:14]=3[CH:19]=2)O)=[CH:4][CH:3]=1.[BrH:20]>C(O)(=O)C>[BrH:20].[Br:20][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[N:16][NH:15][C:14]=2[CH:19]=1
Reactant: Cn1nnc2ccc(C(O)c3ccc(Cl)cc3)cc21
Agent: Br
Solvent: CC(=O)O
Product: Clc1ccc(C(Br)c2ccc3nn[nH]c3c2)cc1
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 76.6 %

Procedure:
A mixture of 245 parts of α-(4-chlorophenyl)-1-methyl-1H-benzotriazole-6-methanol and 1500 parts of a hydrobromic acid solution in acetic acid was stirred for 2.5 hours at 40° C. The reaction mixture was evaporated at 60° C. and the residue was stirred in dichloromethane. After cooling to 10° C., the precipitated product was filtered off and dried, yielding 285 parts (76.6%) of 6-[bromo(4-chlorophenyl)methyl]-1H-benzotriazole monohydrobromide (int. 130).
Reaction SMILES: C[O:2][C:3](=[O:38])[C:4]([N:7]1[CH2:12][CH2:11][CH:10]([S:13][C:14]2[C:15]([F:37])=[CH:16][C:17]3[O:26][CH2:25][CH2:24][N:23]4[C:19](=[N:20][C:21]([C:27]5[N:28]([CH:33]([CH3:35])[CH3:34])[N:29]=[C:30]([CH3:32])[N:31]=5)=[CH:22]4)[C:18]=3[CH:36]=2)[CH2:9][CH2:8]1)([CH3:6])[CH3:5].[OH-].[Na+]>CO.O>[F:37][C:15]1[C:14]([S:13][CH:10]2[CH2:11][CH2:12][N:7]([C:4]([CH3:6])([CH3:5])[C:3]([OH:38])=[O:2])[CH2:8][CH2:9]2)=[CH:36][C:18]2[C:19]3[N:23]([CH2:24][CH2:25][O:26][C:17]=2[CH:16]=1)[CH:22]=[C:21]([C:27]1[N:28]([CH:33]([CH3:35])[CH3:34])[N:29]=[C:30]([CH3:32])[N:31]=1)[N:20]=3
Reactant: COC(=O)C(C)(C)N1CCC(Sc2cc3c(cc2F)OCCn2cc(-c4nc(C)nn4C(C)C)nc2-3)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nc(-c2cn3c(n2)-c2cc(SC4CCN(C(C)(C)C(=O)O)CC4)c(F)cc2OCC3)n(C(C)C)n1
Temperature: 100 °C

Procedure:
To a solution of 2-{4-[8-fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl]piperidin-1-yl}-2-methylpropionic acid methyl ester (0.394 mmol) in MeOH (3 mL) was added 2.0M NaOH in water (1 mL). The reaction mixture was heated at 100° C. for 1 h using microwave irradiation. The crude mixture was purified by column chromatography (C18, gradient 20-60% MeOH in 0.003M HCl/H2O) then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 0.5M NH3/MeOH. The product containing fractions were combined and concentrated under reduced pressure affording 2-{4-[8-Fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl]piperidin-1-yl}-2-methylpropionic acid as a yellow solid (177 mg, 85% over two steps). LCMS: RT 2.32, 2.37, 2.44 min [M−H]− 526.8
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][NH:11][CH2:12][CH2:13][NH2:14].[C:15]([NH:17][C:18](=[N:21][CH3:22])SC)#[N:16]>>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][NH:11][CH2:12][CH2:13][NH:14][C:18]([NH:17][C:15]#[N:16])=[N:21][CH3:22]
Reactant: CN=C(NC#N)SC
Reactant: NCCNCc1nc2ccccc2[nH]1
Product: CN=C(NC#N)NCCNCc1nc2ccccc2[nH]1

Procedure:
Reacting N-(2-benzimidazolylmethyl)ethylenediamine with N-cyano-N',S-dimethylisothiourea by the procedure of Example 36 gives a N-[2-(2-benzimidazolylmethylamino)ethyl]-N'-cyano-N"-methylguanidine. Treating with hydrobromic acid gives the hydrobromide salt. Hydrolysis of this compound by the procedure of Example 3(e) gives N-[2-(2-benzimidazolylmethylamino)ethyl]-N'-methylguanidine trihydrochloride.
Reaction SMILES: C[O-].[Na+].Cl[C:5]1[O:9][N:8]=[C:7]([C:10]2[N:14]3[N:15]=[C:16]([OH:23])[C:17]4[C:22]([C:13]3=[N:12][N:11]=2)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:6]=1.FC1C=CC(F)=C2C=1C(OCC1C=CC=CN=1)=NN1C(C3C=[C:42](C)[O:41]N=3)=NN=C12.O>CN(C)C=O>[OH:23][C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]2=[N:12][N:11]=[C:10]([C:7]3[CH:6]=[C:5]([O:41][CH3:42])[O:9][N:8]=3)[N:14]2[N:15]=1
Reactant: Oc1nn2c(-c3cc(Cl)on3)nnc2c2ccccc12
Reactant: Cc1cc(-c2nnc3c4c(F)ccc(F)c4c(OCc4ccccn4)nn23)no1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(-c2nnc3c4ccccc4c(O)nn23)no1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Sodium methoxide (165 mg, 0.3 mmol) was added to a stirred suspension of 3-(5-chloroisoxazol-3-yl)-6-hydroxy-1,2,4-triazolo[3,4-a]phthalazine (400 mg, 0.14 mmol) (prepared from Intermediate 7 using the procedure described in Example 15 part b) in N,N-dimethylformamide (20 ml) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 3 h then water was added (6 ml) and the solvents evaporated in vacuo. The residue was taken up in water and acidified to pH 2 using 2M hydrochloric acid. The resulting precipitate was filtered off, washed with hexane and azeotroped with ethanol to give crude 6-hydroxy-3(5-methoxyisoxazol-3-yl)-1,2,4-triazolo[3,4-a]phthalazine, MS (ES+) 284 [MH]+. The title-compound was prepared from this material using the procedure described in Example 103 part a, 1H NMR (250 MHz, CDCl3) δ 2.49 (3H, s, CH3), 4.15 (3H, s, CH3), 6.10 (1H, s, Ar—H), 7.45 (2H, d, J=8.5 Hz, Ar—H), 7.92 (1H, m, Ar—H), 8.06 (1H, m, Ar—H), 8.26-8.32 (3H, m, 3 of Ar—H), 8.64 (1H, d, Ar—H); MS (ES+) 438 [MH]+.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[F:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)=[CH:10][CH:9]=1
Reactant: Brc1cccs1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: Fc1ccc(-c2cccs2)cc1
Temperature: 80 °C
Yield: 95 %

Procedure:
To a solution of 2-bromothiophene (1.0 g, 6.14 mmol) in 1,2-dimethoxyethane (11 mL) was added 4-fluorophenylboronic acid (1.12 g, 7.99 mmol), followed by Pd(PPh3)4 (360 mg, 0.31 mmol) and a 2M Na2CO3 aq. solution (8 mL). The reaction mixture was heated at 80° C. for 4 h, then was poured onto a mixture of ice and CH2Cl2. The aqueous layer was extracted with CH2Cl2 (3×20 mL). The organic layers were dried (MgSO4) and concentrated under reduced pressure to yield a yellow oil. The crude product was filtered through a plug of silica with the aid of hexanes to give 4-fluorophenylthiphene (1.04 g, 95%). TLC (hex) Rf=0.40.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[NH2:6][CH:7]([C:9]1[CH:10]=[C:11]([NH:16][C:17]([C:19]2[N:23]([CH3:24])[N:22]=[C:21]([C:25]([F:31])([F:30])[C:26]([F:29])([F:28])[F:27])[C:20]=2[C:32]([F:35])([F:34])[F:33])=[O:18])[CH:12]=[CH:13][C:14]=1[Cl:15])[CH3:8].N1C=CC=CC=1>C1COCC1>[Cl:15][C:14]1[CH:13]=[CH:12][C:11]([NH:16][C:17]([C:19]2[N:23]([CH3:24])[N:22]=[C:21]([C:25]([F:30])([F:31])[C:26]([F:27])([F:28])[F:29])[C:20]=2[C:32]([F:35])([F:34])[F:33])=[O:18])=[CH:10][C:9]=1[CH:7]([NH:6][C:1](=[O:4])[CH2:2][CH3:3])[CH3:8]
Reactant: CC(N)c1cc(NC(=O)c2c(C(F)(F)F)c(C(F)(F)C(F)(F)F)nn2C)ccc1Cl
Reactant: CCC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCC(=O)NC(C)c1cc(NC(=O)c2c(C(F)(F)F)c(C(F)(F)C(F)(F)F)nn2C)ccc1Cl
Reaction time: 28 h
Yield: 90.4 %

Procedure:
Propionyl chloride (21 mg, 0.22 mmol, 1.3 eq.) in THF (1 ml) was added to a solution of N-[3-(1-aminoethyl)-4-chlorophenyl]-1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (80 mg, 0.17 mmol) and pyridine (18 mg, 0.22 mmol, 1.3 eq.) in THF (3 ml). After 28 h at room temperature, the mixture was concentrated under reduced pressure and purified by column chromatography (hexane/ethyl acetate) to give N-{4-chloro-3-[1-(propionylamino)ethyl]phenyl}-1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (80 mg, 89%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH:14]C(=O)OC(C)(C)C)[CH2:5][NH:6]C(=O)OC(C)(C)C.[ClH:22].CCOCC>CO>[ClH:22].[ClH:22].[CH3:1][O:2][CH2:3][C@@H:4]([NH2:14])[CH2:5][NH2:6]
Reactant: COC[C@H](CNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: COC[C@@H](N)CN
Temperature: 25 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
To a solution of di-tert-butyl [(2S)-3-methoxypropane-1,2-diyl]biscarbamate (895 mg, 2.94 mmol) in MeOH (30 mL), was added 2N HCl in Et2O (15 mL, 29.4 mmol). The reaction was stirred at rt for 18 h and the solvents evaporated to yield the title compound as a white solid (478 mg, 92%). LCMS: (FA) ES+ 105.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([OH:13])=[O:12])[NH:6]2.[C:14]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:14][O:12][C:11]([C:5]1[NH:6][C:7]2[C:3]([CH:4]=1)=[C:2]([F:1])[CH:10]=[CH:9][CH:8]=2)=[O:13]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)c1cc2c(F)cccc2[nH]1
Solvent: CO
Product: COC(=O)c1cc2c(F)cccc2[nH]1

Procedure:
25 4-Fluoroindole-2-carboxylic acid (0.65 g, 3.40 mmol) was dissolved in methanol (50 ml), and 4-toluenesulfonic acid (1.4 g, 7.36 mmol) was added under nitrogen. The solution was stirred at reflux for 24 hours. Most of the methanol was removed by evaporation, and the residue was dissolved in dicholoromethane (100 ml), washed with saturated sodium carbonate, and the organic layer was separated. The aqueous layer was extracted with dichloromethane (3×50 ml). The combined organic layers were washed with water, dried over sodium sulphate, and evaporated to yield a yellow crystalline material.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[Li]CCCC.[CH3:23][Sn:24](Cl)([CH3:26])[CH3:25]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([Sn:24]([CH3:26])([CH3:25])[CH3:23])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: C[Sn](C)(C)Cl
Reactant: Fc1ccc(-n2ccc3cc(Br)ccc32)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1ccc2c(ccn2-c2ccc(F)cc2)c1
Reaction time: 1 h

Procedure:
1-(4-Fluorophenyl)-5-bromo-1H-indole (5 g, 17.2 mmol) in THF (20 mL) was added during 3 minutes to a solution of n-BuLi (1.6 M, 26 mmol) in THF (200 mL) at −78° C. The solution was stirred for 4 minutes at −78° C. before addition of trimethylstannyl chloride (10 g, 50 mmol) in THF (10 mL). The reaction mixture was allowed to warn up to room temperature and stirred for 1 h. After evaporation of the solvent the crude product was purified by flash chromatography (EtOAc/Heptane 5/100). Yield: 3.6 g. Mp 61-63° C. (EtOAc/Heptane).
Reaction SMILES: [C:1]([NH:8][C:9]([N:18]1[CH:22]=[CH:21]C=N1)=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N)C[NH2:25]>C1COCC1>[C:11]([NH:10][C:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])=[N:18][CH2:22][CH2:21][NH2:25])([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Reactant: NCCN
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(=NCCN)NC(=O)OC(C)(C)C

Procedure:
With continued reference to Scheme J, a solution of the N,N′-bis-(Boc)-1H-Pyrazole-1-carboxamidine (2 g, 6.45 mmol) in THF (50 ml) was added dropwise to ethylene diamine (4 ml, 59.6 mmol) in THF (100 ml). After 30 min of mixing at room temperature solvent was evaporated then toluene (100 ml) was added and evaporated in order to remove remaining traces of the ethylene diamine. The resulting product (Compound XXIV) was treated immediately according to scheme K since it decomposes at room temperature. 1H NMR (CDCl3, 400 MHz) δ 1.40-1.61 (m, 18H), 2.87-2.90 (t, 2H,), 3.47-3.50 (m, 2H), 6.31-6.34 (t, 0.61H), 7.61-7.62 (d, 1H), 8.45-8.66 (broad s).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=O)[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:18])=O>CN(C)C=O.ClCCl>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([Cl:18])=[O:14])[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)Oc1cccc(CC(=O)O)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)Oc1cccc(CC(=O)Cl)c1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
Combine 3-isopropoxy-phenyl-acetic acid (0.5 g, 2.6 mmol) and dichloromethane (5 mL). Cool to -5° C. using a ice-salt bath. Add 2 drops of dimethylformamide followed by dropwise addition of oxalyl chloride (0.34 g, 2.7 mmol). after 1 hour, warm the reaction mixture to ambient temperature. After 2 hours, evaporate the reaction mixture in vacuo to give the title compound as a liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH2:18][CH2:17][CH:16]([NH:19][OH:20])[CH:15]=3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Si]([N:25]=[C:26]=[O:27])(C)(C)C.CCO>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH2:18][CH2:17][CH:16]([N:19]([OH:20])[C:26]([NH2:25])=[O:27])[CH:15]=3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: ONC1C=C(c2ccc(Sc3ccc(F)cc3)o2)CC1
Solvent: C1CCOC1
Solvent: CCO
Product: NC(=O)N(O)C1C=C(c2ccc(Sc3ccc(F)cc3)o2)CC1
Reaction time: 1 h
Yield: 32.3 %

Procedure:
To a stirred solution of N-[3-[5-(4-fluorophenylthio)-2-furyl]-2-cyclopenten-1-yl]-N-hydroxylamine (1.35 g; 4.64 mM) in THF (13 ml) was added TMSNCO (0.755 g; 5.56 mM) at room temperature under N2. After stirring for 1 hr, EtOH (20 ml) was added. Volatiles were removed, and the resulting residue was recrystallized from ethyl acetate-EtOH (20 ml-120 ml) to provide 0.5 g of the title compound as a colorless solid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)=[CH:13][C:12]3=[O:26])=[CH:7][N:6]2[C:27]=1[CH3:28].C[Si]([C:33]#[N:34])(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:17][C:14]2[CH:15]=[CH:16][N:11]([C:8]3[CH:9]=[CH:10][C:5]4[N:6]([C:27]([CH3:28])=[C:3]([CH2:2][C:33]#[N:34])[N:4]=4)[CH:7]=3)[C:12](=[O:26])[CH:13]=2)=[CH:20][CH:21]=1
Reactant: Cc1c(CCl)nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cn12
Reactant: C[Si](C)(C)C#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1c(CC#N)nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cn12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 1-(2-(chloromethyl)-3-methylimidazo[1,2-a]pyridin-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (150 mg) in THF (5 ml) were added trimethylsilyl cyanide (115 μl) and TBAF (1 M in THF, 1.13 ml) at room temperature, and the resulting mixture was stirred at room temperature for 4 h. The reaction mixture was then quenched with saturated FeSO4, and the organic layer was extracted with DCM. The extract was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (60 mg) as a white solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([O:12][CH3:13])=[CH:7][N:6]=1)=[O:4].[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.[K].[I-].[K+].O>CN(C)C=O>[Cl:11][C:10]1[C:5]([C:3](=[O:4])[CH2:2][N:18]2[C:17](=[O:19])[C:16]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]3[C:14]2=[O:24])=[N:6][CH:7]=[C:8]([O:12][CH3:13])[CH:9]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1cnc(C(=O)CBr)c(Cl)c1
Agent: [I-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cnc(C(=O)CN2C(=O)c3ccccc3C2=O)c(Cl)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 16.8 %

Procedure:
To 570 mg of 2-bromo-1-(3-chloro-5-methoxypyridin-2-yl)ethanone in 10 ml of N,N-dimethylformamide, 800 mg of potassium phthalimide and 36 mg of potassium iodide were added, and the mixture was stirred at 80° C. for 5 hours. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, mixed with 20 ml of water and extracted with ethyl acetate (40 ml×1), the resulting organic layer was dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:9 to 3:7) as the eluent to obtain 0.12 g of the desired product as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([N+:22]([O-])=O)[C:3]=1[CH3:25].O>C(O)(=O)C.[Fe]>[NH2:22][C:4]1[C:3]([CH3:25])=[C:2]([Cl:1])[CH:7]=[C:6]([F:8])[C:5]=1[N:9]1[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]1=[O:21]
Reactant: Cc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1N
Temperature: 25 °C
Reaction time: 14 h

Procedure:
3-(4-Chloro-6-fluoro-3-methyl-2-nitrophenyl)-methyl-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (2.0 g, 5.2 mmol) was dissolved in acetic acid (20 ml) and iron powder (1.2 g, 21.5 mmol) was added. Solution was stirred at ambient temperature for 14 hr. Water was added and product extracted with ethyl acetate followed by evaporation under reduced pressure. Title compound was separated by column chromatography on silica gel (eluent, hexane-ethyl acetate, 7:3; 1.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C@H:13]3[CH2:18][CH2:17][C@@H:16]([NH2:19])[CH2:15][CH2:14]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH:20]([C:22]1[CH:30]=[C:29]2[C:25]([CH:26]=[CH:27][NH:28]2)=[CH:24][CH:23]=1)=O.C([BH3-])#N.O1CCCC1>C(O)(=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C@H:13]3[CH2:14][CH2:15][C@@H:16]([NH:19][CH2:20][C:22]4[CH:30]=[C:29]5[C:25]([CH:26]=[CH:27][NH:28]5)=[CH:24][CH:23]=4)[CH2:17][CH2:18]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc2cc[nH]c2c1
Reactant: N[C@H]1CC[C@@H](Nc2ccnc3cc(Cl)ccc23)CC1
Agent: [BH3-]C#N
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Clc1ccc2c(N[C@H]3CC[C@@H](NCc4ccc5cc[nH]c5c4)CC3)ccnc2c1

Procedure:
A mixture of example 23A (30 mg, 0.11 mmol), 6-formylindole (19.2 mg, 0.132 mmol) and solid supported cyanoborohydride (0.22 mmol) was shaken in 1:1 mixture tetrahydrofuran and acetic acid for 15 hours, filtered and concentrated. The residue was purified with a high throughput HPLC system to provide the desired compound as its bis TRIFLUOROACETIC ACID salt. MS (ESI(+)Q1MS m/z 405 (M+H)+); 1H NMR (300 MHz, DMSO-D6) δ ppm 11.31 (s, 1 H), 8.74 (d, 1 H), 8.49-8.79 (m, 2 H), 7.96 (d, 1 H), 7.85 (dd, 1 H), 7.62 (d, 1 H), 7.56 (s, 1 H), 7.45 (t, 1 H), 7.13 (d, 1 H), 6.94 (d, 1 H), 6.47 (t, 1 H), 4.28 (br.s, 1 H), 4.08 (br.s, 1 H), 2.27 (s, 2 H), 1.73-2.13 (m, 9 H).
Reaction SMILES: CI.[C:3](=O)([O-])O.[Na+].[C:8]([O:12][C:13]([NH:15][C@@H:16]([CH2:33][S:34][C:35]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:17][NH:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]([O:31][CH3:32])=[O:30])=[O:14])([CH3:11])([CH3:10])[CH3:9]>CN(C)C=O>[C:8]([O:12][C:13]([NH:15][C@@H:16]([CH2:33][S:34][C:35]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH2:17][N:18]([C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]([O:31][CH3:32])=[O:30])[CH3:3])=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: COC(=O)c1cccc2c(NC[C@H](CSC(c3ccccc3)(c3ccccc3)c3ccccc3)NC(=O)OC(C)(C)C)cccc12
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cccc2c(N(C)C[C@H](CSC(c3ccccc3)(c3ccccc3)c3ccccc3)NC(=O)OC(C)(C)C)cccc12
Temperature: 20 °C
Reaction time: 20 h

Procedure:
3.6 cm3 of methyl iodide and 7 g of solid sodium hydrogen carbonate are added, with stirring, to a solution of 1.5 g of methyl 5-(2(R)-tert-butoxycarbonylamino-3-(triphenylmethylthio)-propylamino)-1-naphthoate in 25 cm3 of dimethyl-formamide. The reaction mixture is stirred for 20 hours at a temperature in the region of 20° C. and then poured onto 200 cm3 of ice. The aqueous phase is extracted 3 times with 150 cm3 of ethyl acetate. The organic phases are combined, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. The red oil obtained is purified by chromatography on silica [eluent: cyclohexane/ethyl acetate (90/10 by volume)]. 0.56 g of methyl 5-(2(R)-tert-butoxycarbonylamino-3-(triphenylmethylthio)propyl-N-methylamino)-1-naphthoate is obtained, the characteristics of which are the following:
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4](=[O:16])[O:5][C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][C:8]=1[OH:9].[H-].[Na+].[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[C:29](Cl)=[O:30]>C1COCC1>[OH:9][C:8]1[CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:5][C:4](=[O:16])[C:3]=1[NH:2][C:29]([C:20]1[CH:21]=[CH:22][C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=1)=[O:30]
Reactant: Nc1c(O)cc(-c2ccccc2)oc1=O
Reactant: O=C(Cl)c1ccc2ccccc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1c(O)cc(-c2ccccc2)oc1=O)c1ccc2ccccc2c1

Procedure:
The title compound was prepared by Method E using 3-amino-4-hydroxy-6-phenyl-2H-pyran-2-one hydrochloride (0.150 g, 0.626 mmol), THF (6 mL), 60% sodium hydride (0.028 mL, 0.688 mmol), 2-naphthoyl chloride (0.131 g, 0.688 mmol). m.p. dec. 219° C.; 1H NMR (250 MHz, DMSO-d6) δ 6.92 (s, 1 H), 7.61 (m, 5 H), 7.97 (m, 6 H), 8.62 (s, 1 H), 9.61 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]([CH2:20][CH:21]=[CH2:22])([C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([C:16]([F:19])([F:18])[F:17])[CH:7]=1)[C:3]([OH:5])=O.Cl.[O:24]=[C:25]1[CH2:30][CH2:29][C:28]([NH2:37])([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:27][CH2:26]1>>[O:24]=[C:25]1[CH2:26][CH2:27][C:28]([NH:37][C:3](=[O:5])[C:2]([CH3:1])([CH2:20][CH:21]=[CH2:22])[C:6]2[CH:7]=[C:8]([C:16]([F:17])([F:18])[F:19])[CH:9]=[C:10]([C:12]([F:14])([F:15])[F:13])[CH:11]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:29][CH2:30]1
Reactant: NC1(c2ccccc2)CCC(=O)CC1
Reactant: C=CCC(C)(C(=O)O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Product: C=CCC(C)(C(=O)NC1(c2ccccc2)CCC(=O)CC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
Prepared from (RS)-α-methyl-α-(2-propenyl)-3,5-bis(trifluoromethyl)benzeneacetic acid (Description 10) and 4-oxo-1-phenylcyclohexylamine hydrochloride (Description 3) according to the method of Description 11. 1H NMR (360 MHz, CDCl3) δ 7.81 (1H, s), 7.71 (2H, s), 7.35-7.27 (5H, m), 5.58 (1H, br s), 5.57-5.45 (1H, m), 5.09-5.03 (2H, m), 2.81-2.73 (2H, m), 2.66-2.60 (2H, m), 2.48-2.30 (6H, m), and 1.63 (3H, s).