Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]#[CH:18])[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]#[CH:18])[N:12]=[CH:11][N:10]=1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCO
Reactant: C#CCOc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CCOc1cc(OCC#CC)ncn1
Temperature: 25 °C
Yield: 187.6 %

Procedure:
In 4 ml of tetrahydrofuran was suspended 0.12 g of sodium hydride (60% in oil), to which 0.7 ml of a tetrahydrofuran solution containing 0.18 g of 2-butyn-1-ol was slowly added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 20 minutes and then cooled to 0° C., to which 0.7 ml of a tetrahydrofuran solution containing 0.4 g of 4-chloro-6-(2-propynyloxy)pyrimidine was slowly added dropwise. The mixture was further stirred at 0° C. for 4.5 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.9 g of 4-(2-butynyloxy)-6-(2-propynyloxy)pyrimidine (the present compound (2)).
Reaction SMILES: [C:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[C:10]([C:23]([NH:25][NH:26][C:27](=O)[C:28]([CH3:31])([CH3:30])[CH3:29])=O)[CH:9]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>C1COCC1>[C:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[C:10]([C:23]2[S:42][C:27]([C:28]([CH3:31])([CH3:30])[CH3:29])=[N:26][N:25]=2)[CH:9]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: COc1ccc(F)c(-c2ccc(OC(=O)C(C)(C)C)cc2C(=O)NNC(=O)C(C)(C)C)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(OC(=O)C(C)(C)C)cc2-c2nnc(C(C)(C)C)s2)c1
Yield: 97 %

Procedure:
A solution of 2′-fluoro-5′-methoxy-2-(2-pivaloylhydrazinecarbonyl)-[1,1′-biphenyl]-4-yl pivalate (203 mg) and the Lawesson's reagent (194 mg) in THF (6.0 mL) was stirred at 80° C. for 50 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (196 mg) as a colorless oil.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:8][O:7][CH2:6][C@H:5]1[O:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=[N+]=[N-]>CC(C1C=C(C(C)(C)C)C(=O)/C(=C/N[C@@H]2[C@@H](N/C=C3/C=C(C(C)(C)C)C=C(C(C)(C)C)C/3=O)CCCC2)/C=1)(C)C.[Co]>[CH3:11][Si:10]([CH3:13])([CH3:12])[O:9][C@@H:5]1[CH2:6][O:7][CH2:8][C@H:4]1[NH2:1]
Reactant: C[Si](C)(C)O[C@@H]1COC[C@H]1N=[N+]=[N-]
Agent: [Co]
Agent: CC(C)(C)C1=C/C(=C/N[C@H]2CCCC[C@@H]2N/C=C2\C=C(C(C)(C)C)C=C(C(C)(C)C)C2=O)C(=O)C(C(C)(C)C)=C1
Product: C[Si](C)(C)O[C@@H]1COC[C@H]1N

Procedure:
The title compound is prepared by essentially following the procedure described in Preparation 31 using [(3S,4R)-4-azidotetrahydrofuran-3-yl]oxy-trimethyl-silane (9.34 g, 46.4 mmol; prepared in opposing stereochemical configuration compared to the procedure found in Jacobsen, E. N.; Larrow, J. F.; Schaus, S. E. J. Org. Chem. 1997, 62, 4197-4199; except using commercially available (1S,2S)-(+)-1,2-cyclohexanediamino-N,N′-bis(3,5-di-t-butylsalicylidene)cobalt (II) as catalyst) to provide a colorless oil (7.55 g, 93%). LC-ES/MS m/z 176 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:20](=[O:22])[CH2:19][CH:18]([CH2:23][CH2:24][CH3:25])[CH2:17][C:16]=3[NH:15][C:14]([CH3:26])=[C:13]2[C:27]#[N:28])[CH:5]=[C:6]([N+:9]([O-])=O)[C:7]=1[OH:8].C(O)(=O)C>C1COCC1.[Zn]>[NH2:9][C:6]1[CH:5]=[C:4]([CH:12]2[C:21]3[C:20](=[O:22])[CH2:19][CH:18]([CH2:23][CH2:24][CH3:25])[CH2:17][C:16]=3[NH:15][C:14]([CH3:26])=[C:13]2[C:27]#[N:28])[CH:3]=[C:2]([Br:1])[C:7]=1[OH:8]
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(O)c([N+](=O)[O-])c1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(N)c(O)c(Br)c1
Reaction time: 2 h

Procedure:
To a solution of 4-(3-bromo-4-hydroxy-5-nitro-phenyl)-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydro-quinoline-3-carbonitrile (15.8 g) and acetic acid (30 ml) in THF (300 ml), zinc dust (46 g) was added in portions, under vigorous stirring. After 2 h, the mixture was filtered and concentrated until a precipitate formed. This precipitate was collected by filtration and washed with ethanol.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:17]#[C:18][Si](C)(C)C)[CH:8]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].CO>CCCCCC>[C:13]([C:9]1[CH:8]=[C:7]([C:17]#[CH:18])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]=1[O:11][CH3:12])([CH3:16])([CH3:14])[CH3:15]
Reactant: COc1c(C(C)(C)C)cc(C#C[Si](C)(C)C)cc1C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CO
Product: C#Cc1cc(C(C)(C)C)c(OC)c(C(C)(C)C)c1

Procedure:
Following General Procedure E and (3,5-di-tert-butyl-4-methoxy-phenylethynyl)-trimethyl-silane (Intermediate 168, 0.28 g, 0.9 mmol), potassium carbonate (0.98 g, 7.1 mmol) and methanol (10 mL) followed by flash column chromatography over silica gel (230-400 mesh) using hexane as the eluent, the title compound was obtained (0.23 g, 100%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:18]3[C:13](=[C:14]([NH:19]C(=O)C)[N:15]=[CH:16][CH:17]=3)[CH2:12][O:11][C:9]=2[CH:10]=1.[OH-].[K+]>C(O)C.O>[NH2:1][C@@H:2]([CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:18]3[C:13](=[C:14]([NH2:19])[N:15]=[CH:16][CH:17]=3)[CH2:12][O:11][C:9]=2[CH:10]=1
Reactant: CC(=O)Nc1nccc2c1COc1cc(OC[C@@H](N)CC(C)C)ccc1-2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)C[C@H](N)COc1ccc2c(c1)OCc1c-2ccnc1N
Temperature: 70 °C
Yield: 12.8 %

Procedure:
To a stirred solution of (S)-N-(8-((2-amino-4-methylpentyl)oxy)-5H-chromeno[3,4-c]pyridin-4-yl)acetamide (20 mg, 0.056 mmol) (prepared as in Example 12, Part H) in a mixture of ethanol (10 mL) and water (2 mL) was added KOH (31.6 mg, 0.563 mmol) and the reaction was heated at 70° C. for 14 h. After completion of the reaction, the volatile organic solvent was removed under reduced pressure, water (20 mL) was added and the solution extracted with dichloromethane (2×20 mL). The combined organic extracts were washed with water (1×20 mL), dried over sodium sulfate and concentrated under reduced pressure to obtain (S)-8-((2-amino-4-methylpentyl)oxy)-5H-chromeno[3,4-c]pyridin-4-amine (2.31 mg, 7.15 umol, 13% yield) as an off-white solid. 1H NMR (400 MHz, MeOD) δ 7.90 (d, J=5.6 Hz, 1 H), 7.69 (d, J=8.7 Hz, 1 H), 6.98 (d, J=5.6 Hz, 1 H), 6.72 (m, 1 H), 6.6 (d, J=2.5 Hz, 1 H), 5.07 (s, 2 H), 4.10 (m, 1 H), 3.92 (m, 1 H), 3.40 (m, 1 H), 1.82 (m, 1 H), 1.49 (m, 2 H), 1.01 (m, 6 H); LCMS (ESI) m/e 314.2 [(M+H)+, calcd for C18H24N3O2 314.2]; LC/MS retention time (Method C): tR=1.21 min; HPLC retention time (method A): tR=7.52 min; HPLC retention time (method B): tR=8.68 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.[NH:17]1[C:25]2[C:20](=[CH:21][C:22]([NH2:26])=[CH:23][CH:24]=2)[CH2:19][CH2:18]1.CCN(CC)CC>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:26][C:22]1[CH:21]=[C:20]2[C:25](=[CH:24][CH:23]=1)[NH:17][CH2:18][CH2:19]2
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Reactant: Nc1ccc2c(c1)CCN2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(Br)cc2/C1=C/Nc1ccc2c(c1)CCN2

Procedure:
6-Bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (250 mg, 0.89 mmol), 2,3-dihydro-1H-indol-5-ylamine×2HCl (184 mg, 0.89 mmol) and Et3N (0.37 mL, 2.67 mmol) in N,N-dimethylformamide (DMF) (10 mL) is stirred for 4 days. The reaction mixture is concentrated in vacuo and the residue is triturated in H2O for 24 hours. The precipitate is filtered, washed with H2O and dried in vacuo to give 370 mg of the title compound as a brown solid. HRMS (ESI) m/z calcd for C18H14BrN3O2 (M+H)+1 384.03422. found: 384.03553. The compound is contains 29% of 4-(5-amino-2,3-dihydro-indol-1-ylmethylene)-6-bromo-4H-isoquinoline-1,3-dione.
Reaction SMILES: Cl.[NH:2]1[CH2:6][C@H:5]([OH:7])[C@@H:4]([OH:8])[CH2:3]1.[Cl:9][C:10]1[N:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[C:12](Cl)[N:11]=1.CCN(C(C)C)C(C)C>C(#N)C>[Cl:9][C:10]1[N:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[C:12]([N:2]2[CH2:6][C@H:5]([OH:7])[C@@H:4]([OH:8])[CH2:3]2)[N:11]=1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Reactant: O[C@H]1CNC[C@@H]1O
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(N2C[C@H](O)[C@@H](O)C2)nc(Cl)n1
Temperature: 50 °C
Yield: 82.6 %

Procedure:
A mixture of the (3S,4S)-pyrrolidine-3,4-diol hydrochloride (0.773 g, 5.54 mmol), methyl 2,6-dichloropyrimidine-4-carboxylate (1.038 g, 5.01 mmol), and iPr2NEt (2.00 mL, 11.5 mmol) in acetonitrile (25 mL) was heated at 50° C. for 3 h. The reaction mixture was evaporated in vacuo and the residue chromatographed over silica gel with 25-75% acetone in hexanes. The product fractions were evaporated in vacuo to give methyl 2-chloro-6-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)pyrimidine-4-carboxylate as a light tan powder (1.132 g, 4.14 mmol, 83% yield). LC/MS: m/z=274.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:4]=1[CH2:5]O.C(N(CC)CC)C.CS(Cl)(=O)=O.[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12.[K]>C(Cl)Cl.CN(C=O)C.CCOC(C)=O.[Cl-].[Na+].O.O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:4]=1[CH2:5][C:33]1[CH:32]=[CH:31][CH:30]=[C:26]2[C:27]([NH:28][C:24](=[O:34])[C:25]=12)=[O:29]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1cccc(C)c1CO
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cccc(C)c1Cc1cccc2c1C(=O)NC2=O
Temperature: 25 °C
Yield: 66.4 %

Procedure:
To a solution of 2-methoxy-6-methylbenzyl alcohol (0.96 g, 6.32 mmol) in CH2Cl2 (35 mL) was added triethylamine (2.00 mL, 14.35 mmol) followed by methanesulfonyl chloride (0.90 mL, 11.63 mmol) and the resultant solution was heated at 40° C. for 45 minutes then cooled to room temperature. The mixture was diluted with CH2Cl2 (35 mL), washed with brine (3×15 mL), dried (Na2SO4), and concentrated to provide a pale yellow solid. The solid (1.12 g) was dissolved in DMF (35 mL), treated with potassium phthalimide (2.62 g, 14.15 mmol), and heated at 80° C. overnight. The mixture was cooled to room temperature and diluted with EtOAc (70 mL), brine (35 mL), and water (20 mL). The phases were separated and the organic phase was washed with 1.0 N NaOH (6×10 mL) and brine (2×20 mL). The organic phase was dried (MgSO4) and concentrated to provide an pale yellow solid. The solid was rinsed with hexanes (3×10 mL) and provided 1.18 g (66%) of (2-methoxy-6-methylbenzyl)phthalimide as a white solid. 1H NMR (CDCl3) δ 2.53 (s, 3H), 3.75 (s, 3H), 4.89 (s, 2H), 6.70 (d, 1H, J=8.4 Hz), 6.80 (d, 1H, J=7.5 Hz), 7.15 (dd, 1H, J=7.5, 8.4 Hz), 7.66-7.68 (m, 2H), 7.76-7.80 (m, 2H); 13C NMR (CDCl3) δ 20.27, 34.95, 55.90, 108.61, 122.38, 123.17, 123.41, 128.97, 132.60, 134.07, 139.55, 158.70, 168.36.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:5]([CH3:7])[N:6]=1.Cl[CH2:14][C:15]1[CH:34]=[CH:33][C:18]([O:19][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:7][C:5]1[N:6]=[C:2]([S:1][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:19][CH2:20][C:21]3[N:22]=[C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[O:24][C:25]=3[CH3:26])=[CH:33][CH:34]=2)[S:3][C:4]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: COC(=O)Cc1sc(S)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1sc(SCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
A mixture of methyl (2-mercapto-4-methylthiazol-5-yl)acetate (385 mg), 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (600 mg), potassium carbonate (400 mg) and N,N-dimethylformamide (20 ml) was stirred at room temperature for 2 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl [4-methyl-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylthio]thiazol-5-yl]acetate (750 mg, yield 82%) was obtained as an oil from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9]([NH:12][C:13]2[CH:14]=[C:15]([S:31]([OH:34])(=[O:33])=[O:32])[CH:16]=[C:17]3[C:22]=2[C:21]([S:23]([OH:26])(=[O:25])=[O:24])=[CH:20][C:19]([S:27]([OH:30])(=[O:29])=[O:28])=[CH:18]3)(=[O:11])=[O:10])=[CH:4][CH:3]=1.C1C(N=NC2C(=O)N(C3C=CC(S([O-])(=O)=O)=CC=3)N=C2C([O-])=O)=CC=C(S([O-])(=O)=O)C=1.[Na+].[Na+].[Na+].O.O.O.C([O-])(=O)C.[Na+].[N+](C1C=CC(C([O:86][C:87](=O)[C:88]2[CH:93]=[CH:92][C:91]([N+:94]([O-:96])=[O:95])=[CH:90][C:89]=2[S:97]([OH:100])(=[O:99])=[O:98])=O)=C(S(O)(=O)=O)C=1)([O-])=O>O>[N+:94]([C:91]1[CH:92]=[CH:93][C:88]([C:87]([NH:1][C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([S:9]([NH:12][C:13]3[CH:14]=[C:15]([S:31]([OH:34])(=[O:33])=[O:32])[CH:16]=[C:17]4[C:22]=3[C:21]([S:23]([OH:26])(=[O:25])=[O:24])=[CH:20][C:19]([S:27]([OH:30])(=[O:28])=[O:29])=[CH:18]4)(=[O:11])=[O:10])=[CH:4][CH:3]=2)=[O:86])=[C:89]([S:97]([OH:100])(=[O:98])=[O:99])[CH:90]=1)([O-:96])=[O:95]
Reactant: O=C(OC(=O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)O
Reactant: Cc1cc(N)ccc1S(=O)(=O)Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)cc(S(=O)(=O)O)c12
Agent: CC(=O)[O-]
Agent: O=C([O-])C1=NN(c2ccc(S(=O)(=O)[O-])cc2)C(=O)C1N=Nc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: O
Product: Cc1cc(NC(=O)c2ccc([N+](=O)[O-])cc2S(=O)(=O)O)ccc1S(=O)(=O)Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)cc(S(=O)(=O)O)c12
Temperature: 0 °C
Yield: 166.9 %

Procedure:
To a stirred solution of 9.0 g of 8-(5-amino-o-toluenesulfonamido)-1,3,6-naphthalenetrisulfonic acid, trisodium salt, and 3.34 g of sodium acetate trihydrate in 47.0 ml of water chilled to 0° C. in an ice bath is added 4.29 g of 4-nitro-2-sulfobenzoic acid anhydride in one portion. The mixture is stirred for a total of 10 minutes in the ice bath and the undissolved material is separated. The solution, at 0° C., is acidified with 1.38 ml of concentrated hydrochloric acid, then is added dropwise, with vigorous stirring, to 750 ml of absolute ethanol. The product is collected, washed with 85% aqueous ethanol, ethanol and ether and is dried to yield 11.75 g of 8-[5-(4-nitro-2-sulfobenzamido)-o-toluenesulfonamido]-1,3,6-naphthalenetrisulfonic acid, tetrasodium salt.
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:15]([N:17]1[CH2:24][CH2:23][CH2:22][C@@H:18]1[C:19]([NH2:21])=[O:20])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8].[H][H]>CO.[Pd]>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:15]([N:17]1[CH2:24][CH2:23][CH2:22][C@@H:18]1[C:19]([NH2:21])=[O:20])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8]
Reactant: [H][H]
Reactant: CC(C)C[C@H](NC(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1)C(=O)N1CCC[C@@H]1C(N)=O
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@@H]1CCC(=O)N1)C(=O)N1CCC[C@@H]1C(N)=O
Yield: 79.1 %

Procedure:
1.5 g (3.25 mmoles) of Z-Glp-Leu-D-Pro-NH2 are dissolved in 70 ml of methanol, 0.3 g of a 10% palladium-on-carbon catalyst are added to the solution, and hydrogen is bubbled through the mixture for one hour. The catalyst is filtered off, the filtrate is evaporated, and the amorphous residue is triturated with ether. The resulting 0.94 g of crude product are dissolved in water, the solution is decolourized, filtered, and the clear filtrate is freeze-dried. 0.87 g (79%) of Glp-Leu-D-Pro-NH2 are obtained; Rf5 =0.47, [α]D25 =+8.4° (c=1%, in acetic acid).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]([NH:18][CH2:19][CH2:20][NH:21]C(=O)OC(C)(C)C)=[O:17])[CH:13]=[CH:14][CH:15]=2)[C:5]([C:29]#[N:30])=[C:4]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:3]=1[C:37]#[N:38].[ClH:39]>O1CCOCC1>[ClH:39].[NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]([NH:18][CH2:19][CH2:20][NH2:21])=[O:17])[CH:13]=[CH:14][CH:15]=2)[C:5]([C:29]#[N:30])=[C:4]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:3]=1[C:37]#[N:38]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1cccc(CSc2nc(N)c(C#N)c(-c3ccccc3)c2C#N)c1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1c(N)nc(SCc2cccc(C(=O)NCCN)c2)c(C#N)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
79 mg (0.15 mmol) of tert-butyl (2-{[(3-{[(6-amino-3,5-dicyano-4-phenylpyridin-2-yl)sulfanyl]-methyl}phenyl)carbonyl]amino}ethyl)carbamate Example 57A were initially charged in 1 ml of dioxane. After addition of 21.6 mg (0.6 mmol) of 4 N hydrochloric acid in dioxane, the mixture was stirred at RT overnight. The reaction mixture was evaporated. The residue was purified by preparative HPLC (Chromasil, water/acetonitrile).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:27]=[O:28])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[C:16]([C:23]([F:26])([F:25])[F:24])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH2:12][CH2:13][CH2:14][N:7]21.[F:29][C:30]([Si](C)(C)C)([F:32])[F:31].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([C:23]([F:24])([F:26])[F:25])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:27]([OH:28])[C:30]([F:32])([F:31])[F:29])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C=O)c23)c(C(F)(F)F)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(O)C(F)(F)F)c23)c(C(F)(F)F)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
To a solution of 9-chloro-1-[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (336 mg, 0.82 mmol) and (trifluoromethyl)trimethylsilane (0.36 mL, 2.44 mmol) in tetrahydrofuran (10 mL) was added tetrabutylammonium fluoride (1.0M solution in tetrahydrofuran 0.082 mL, 0.082 mmol) at 0° C. The mixture was stirred at 0° C. for 0.5 hr. 1N HCl (2.0 mL) was added to the reaction mixture at 0° C. and the mixture was stirred at 0° C. for 0.5 hr. The mixture was basified with aqueous sodium hydrogen carbonate and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture to give the title compound (372.5 mg, 0.775 mmol, 94%) as a pale yellow solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:10]=[C:11]([NH:20][C:21]([C@@H:23]2[N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30][C:29]3[N:28]=[C:27]([O:40][CH3:41])[CH:26]=[CH:25][C:24]2=3)=[O:22])[CH:12]=[C:13]([F:19])[C:14]=1[Si:15]([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])O.[Na+]>>[F:19][C:13]1[CH:12]=[C:11]([NH:20][C:21]([C@@H:23]2[NH:32][CH2:31][CH2:30][C:29]3[N:28]=[C:27]([O:40][CH3:41])[CH:26]=[CH:25][C:24]2=3)=[O:22])[CH:10]=[C:9]([F:8])[C:14]=1[Si:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: COc1ccc2c(n1)CCN(C(=O)OC(C)(C)C)[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(n1)CCN[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 95.3 %

Procedure:
Cooled TFA (10.5 mL) was added to tert-butyl (R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (747 mg, 1.52 mmol) at room temperature, and the mixture was stirred at room temperature for 3 min. The reaction mixture was poured into ice and aqueous sodium hydrogencarbonate solution, and the pH of the mixture was adjusted to 8 with aqueous sodium hydrogencarbonate solution. Then, the mixture was extracted with ethyl acetate (×3). The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give (R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide (567 mg, 1.448 mmol, 95%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14](OCC)=[O:15].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[Cl-].[NH4+]>C1COCC1>[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14](=[O:15])[CH2:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH3:1]
Reactant: CCOC(=O)c1ccco1
Reactant: Cc1ccncc1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cnccc1CC(=O)c1ccco1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83 %

Procedure:
3,4-Dimethylpyridine (2.25 mL, 20.0 mmol) and ethyl furan-2-carboxylate (5.02 mL, 40.0 mmol) were dissolved in THF (20 mL), and at 0° C., a 1.0 mol/L solution of lithium hexamethyldisilazide in THF (40.0 mL, 40.0 mmol) was added dropwise thereto, followed by stirring at room temperature for 1.5 hours. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride, followed by extraction with ethyl acetate. The organic layer was washed successively with a saturated aqueous solution of ammonium chloride and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:2) to afford 1-(2-furyl)-2-(3-methylpyridin-4-yl)ethanone (3.34 g, 16.6 mmol).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[F:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37](O)=[O:38])=[CH:29][CH:28]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37]([NH:1][CH:2]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([C:22]([F:24])([F:25])[F:23])(=[O:21])=[O:20])[CH:14]=2)[CH:3]([C:5]2[CH:6]=[CH:7][C:8]([F:11])=[CH:9][CH:10]=2)[OH:4])=[O:38])=[CH:29][CH:28]=1
Reactant: NC(Cc1cccc(S(=O)(=O)C(F)(F)F)c1)C(O)c1ccc(F)cc1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1cccc(S(=O)(=O)C(F)(F)F)c1)C(O)c1ccc(F)cc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-{3-[(trifluoromethyl)sulfonyl]phenyl}propan-1-ol (260 mg, 0.69 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (131 mg, 0.69 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (198 mg, 1.03 mmol) and 1-hydroxybenzotriazole hydrate (105 mg, 0.69 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-2:1). Recrystallization from ethyl acetate-hexane gave the objective substance (218 mg, 58%).