Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([OH:7])[CH:2]=1.[H-].[Na+].[Cl:10][C:11]1[CH:16]=[C:15]([N+]([O-])=O)[CH:14]=[CH:13][N:12]=1>>[Cl:10][C:11]1[CH:16]=[C:15]([O:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:14]=[CH:13][N:12]=1
Reactant: Oc1cccnc1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: Clc1cc(Oc2cccnc2)ccn1
Yield: 96 %

Procedure:
Using the method of Example 3, Step A, pyridin-3-ol (0.450 g, 4.73 mmol), 60% sodium hydride in mineral oil (189 mg, 4.73 mmol), and 2-chloro-4-nitropyridine (0.750 g, 4.73 mmol) were reacted to provide 2-chloro-4-(pyridin-3-yloxy)pyridine (0.938 g, 96% yield) as a clear oil. 1H NMR (CDCl3) δ 8.57 (d, 1H), 8.49 (d, 1H), 8.28 (d, 1H), 7.39-7.48 (m, 2H), 6.86 (s, 1H), 6.82 (d, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[N:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=4)=[CH:13][C:12]3=[O:24])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:25][NH:26][CH2:27][CH2:28][C:3]1=2.[C:29]1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:41].Cl>>[ClH:41].[ClH:41].[CH3:29][N:26]1[CH2:27][CH2:28][C:3]2[N:2]([CH3:1])[C:10]3[CH:9]=[C:8]([N:11]4[CH:16]=[CH:15][C:14]([C:17]5[N:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=5)=[CH:13][C:12]4=[O:24])[CH:7]=[CH:6][C:5]=3[C:4]=2[CH2:25]1
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Reactant: Cc1ccc(-c2ccn(-c3ccc4c5c(n(C)c4c3)CCNC5)c(=O)c2)nn1
Agent: Cl
Product: Cc1ccc(-c2ccn(-c3ccc4c5c(n(C)c4c3)CCN(C)C5)c(=O)c2)nn1
Yield: 74 %

Procedure:
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(6-methylpyridazin-3-yl)pyridin-2(1H)-one (77 mg, 0.21 mmol) was reacted according to the procdure of Example 47 to provide the free-base. Conversion to the dihydrochloride salt using the procedure of Example 30 (step g) provided the title compound (60 mg, 74%) as a yellow solid: mp 285-288° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.9 (s, 1H), 8.32 (d, J=8.8 Hz, 1H), 7.85 (d, J=7.2 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.64 (d, J=1.5 Hz, 1H), 7.56 (d, J=8.3 Hz, 1H), 7.25 (d, J=1.7 Hz, 1H), 7.14-7.11 (m, 2H), 4.65 (d, J=12.1 Hz, 1H), 4.31 (dd, J=14.2, 7.5 Hz, 1H), 3.81-3.74 (m, 1H), 3.71 (s, 3H), 3.55-3.45 (m, 1H), 3.26-3.15 (m, 2H), 2.98 (s, 3H), 2.72 (s, 3H); ESI MS m/z 386 [M+H]+; HPLC (Method B)>99% (AUC), tR=9.4 min.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([C@@:10]12[CH2:17][CH2:16][C:15](=[O:18])[C@@H:14]1[C:13](=[O:19])[N:12]([C@@H:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:21])[CH2:11]2)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:28]I>CN(C)C=O>[C:3]([O:7][C:8]([C@@:10]12[CH2:17][CH2:16][C:15](=[O:18])[C@:14]1([CH3:28])[C:13](=[O:19])[N:12]([C@@H:20]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH3:21])[CH2:11]2)=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: CI
Reactant: C[C@H](c1ccccc1)N1C[C@]2(C(=O)OC(C)(C)C)CCC(=O)[C@@H]2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](c1ccccc1)N1C[C@]2(C(=O)OC(C)(C)C)CCC(=O)[C@]2(C)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
N,N-Dimethylformamide (2.0 mL) was added to sodium hydride (152 mg, 3.48 mmol) in an argon atmosphere. A solution of (1S,5R)-4,6-dioxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octan-1-ylcarboxylic acid tert-butyl ester (1.00 g, 2.91 mmol) in N,N-dimethylformamide (8.0 mL) was added dropwise to this suspension under ice-cooling, and the mixture was stirred at 0° C. for 30 minutes. Subsequently, methyl iodide (0.217 mL, 3.49 mmol) was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was ice-cooled and then the reaction was quenched with water, followed by extraction with ethyl acetate. Then, the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and filtered. Thereafter, the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=2:1→1:1) to give 0.79 g of the title compound as a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].[O:15]1[CH2:20][CH2:19][CH:18]([CH2:21][NH2:22])[CH2:17][CH2:16]1.O1CCOCC1>CCOC(C)=O>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:22]([CH2:21][CH:18]1[CH2:19][CH2:20][O:15][CH2:16][CH2:17]1)[C:9]2=[O:14])([O-:3])=[O:2]
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Reactant: NCC1CCOCC1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=c1c2cccc([N+](=O)[O-])c2ccn1CC1CCOCC1

Procedure:
5-Nitro-isochromen-1-one (1.0 g, 0.0052 mol) and C-(tetrahydro-pyran-4-yl)-methylamine (0.72 g, 0.0063 mol) were stirred in 1,4-dioxane (3 mL, 0.04 mol) at 120° C. for 18 hours. The mixture was diluted with EtOAc (200 mL), washed with 1 N HCl (30 mL×2), brine (30 mL) and dried over Na2SO4. After the filtration the solvent was removed and the residue was purified via flash chromatography (40 g of silica gel, 40% EtOAc/Hexanes) to give a yellow oil. MS m/z (M+H) 289.1.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][CH2:11][CH2:12][N:13]([C@H:29]1[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]1)[C:14](=[O:28])[NH:15][C:16]1[S:17][C:18]([S:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[CH:19][N:20]=1.[CH2:36]([O:38]C(=O)C(SC1SC(N)=NC=1)(C)C)C.COC1C=CC(S)=CC=1>>[CH3:36][O:38][C:7]1[CH:6]=[CH:5][C:4]([S:9][CH2:10][CH2:11][CH2:12][N:13]([C@H:29]2[CH2:30][CH2:31][C@H:32]([CH3:35])[CH2:33][CH2:34]2)[C:14](=[O:28])[NH:15][C:16]2[S:17][C:18]([S:21][C:22]([CH3:26])([CH3:27])[C:23]([OH:25])=[O:24])=[CH:19][N:20]=2)=[CH:3][CH:8]=1
Reactant: COc1ccccc1SCCCN(C(=O)Nc1ncc(SC(C)(C)C(=O)O)s1)[C@H]1CC[C@H](C)CC1
Reactant: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Agent: COc1ccc(S)cc1
Product: COc1ccc(SCCCN(C(=O)Nc2ncc(SC(C)(C)C(=O)O)s2)[C@H]2CC[C@H](C)CC2)cc1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis 2-{2-[3-[3-(2-methoxy-phenylsulfanyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid using 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester and 4-methoxy-thiophenol.
Reaction SMILES: Br[CH2:2][CH:3]([OH:13])[CH2:4][O:5][C:6]1[C:11]([Cl:12])=[N:10][CH:9]=[CH:8][N:7]=1.[CH:14]([NH2:17])([CH3:16])[CH3:15]>CO>[Cl:12][C:11]1[C:6]([O:5][CH2:4][CH:3]([OH:13])[CH2:2][NH:17][CH:14]([CH3:16])[CH3:15])=[N:7][CH:8]=[CH:9][N:10]=1
Reactant: CC(C)N
Reactant: OC(CBr)COc1nccnc1Cl
Solvent: CO
Product: CC(C)NCC(O)COc1nccnc1Cl

Procedure:
53 g of 2-(3'-bromo-2'-hydroxy-propoxy)-3-chloropyrazine and 59 g of isopropylamine in 500 ml of methanol are boiled for 15 hours under reflux. The reaction mixture is then evaporated in a waterpump vacuum. The residue is partitioned between 2 N hydrochloric acid and ether. The hydrochloric acid phase is rendered alkaline with concentrated sodium hydroxide solution and extracted by shaking with ether. The ether extracts are washed with water, dried over sodium sulphate and evaporated in a waterpump vacuum. The residue crystallises from ether. 3-Chloro-2-(3'-isopropylamino-2'-hydroxy-propoxy)-pyrazine, melting point 99°-100° C., is thus obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][C@H:4]1[C:6]([CH3:8])([CH3:7])[C@H:5]1[C:9]([OH:11])=[O:10].N(C(C)(C)C#N)=NC(C)(C)C#N.BrBr>C1(C)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]([CH3:12])=[CH:3][CH:4]1[C:6]([CH3:7])([CH3:8])[CH:5]1[C:9]([OH:11])=[O:10]
Reactant: CC(C)=C[C@@H]1[C@H](C(=O)O)C1(C)C
Agent: BrBr
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Cc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)=CC1C(C(=O)O)C1(C)C
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 95.5 %

Procedure:
2.0 g of cis-chrysanthemic acid and 23 mg of azobisisobutyronitrile were dissolved in 20 ml of toluene and thereto was added dropwise a solution of bromine (21 mg) in carbon tetrachloride with stirring at 80° C. over a period of 20 minutes. Thereafter, a treatment similar to Example 1 was carried out to obtain 1.91 g of chrysanthemic acid. Gas chromatographic assay thereof showed the composition: cis, 9.8% and trans, 90.2%.
Reaction SMILES: [N:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH:19]=C)[CH:17]=3)[NH:12][C:11]=2[C:21]([NH2:23])=[O:22])(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.I([O-])(=O)(=O)=[O:25].[Na+].O.C([O-])(O)=O.[Na+]>CC(C)=O.[Os](=O)(=O)(=O)=O>[CH:19]([C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:21]([NH2:23])=[O:22])=[C:10]2[S:7]([N:1]1[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1)(=[O:8])=[O:9])=[O:25]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1ccc2[nH]c(C(N)=O)c(S(=O)(=O)N3CCOCC3)c2c1
Agent: O=[Os](=O)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: NC(=O)c1[nH]c2ccc(C=O)cc2c1S(=O)(=O)N1CCOCC1

Procedure:
3-(Morpholin-4-ylsulfonyl)-5-vinyl-1H-indole-2-carboxamide (207 mg, 0.617 mmol, 1.0 equiv), sodium periodate (660 mg, 3.09 mmol, 5.0 equiv) and osmium tetraoxide (16 mg, 0.062 mmol, 0.1 equiv) were dissolved in 18 mL of a 5:1 solution of acetone:water and stirred for 18 hours. The mixture was poured into aqueous saturated NaHCO3 and extracted three times with dichloromethane. The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The title compound was obtained by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. ESI+MS: 338.1 [M+H]+.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2([C:31]3[CH:36]=[C:35]([CH3:37])[C:34]([O:38][Si](C(C)(C)C)(C)C)=[C:33]([CH3:46])[CH:32]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([C:23]3[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=3)[C:15]2=[O:30])=[CH:9][C:8]=1[CH3:47])(C)(C)C.C[O-].[Na+].C1C[O:56][CH2:55]C1>CO>[OH:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2([C:31]3[CH:32]=[C:33]([CH3:46])[C:34]([OH:38])=[C:35]([CH3:37])[CH:36]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([O:56][CH3:55])[N:24]=3)[C:15]2=[O:30])=[CH:9][C:8]=1[CH3:47]
Reactant: Cc1cc(C2(c3cc(C)c(O[Si](C)(C)C(C)(C)C)c(C)c3)C(=O)N(c3ccnc(Cl)n3)c3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Reactant: C1CCOC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nccc(N2C(=O)C(c3cc(C)c(O)c(C)c3)(c3cc(C)c(O)c(C)c3)c3ccccc32)n1

Procedure:
Under an N2 atmosphere, combine 3,3-Bis-[4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethyl-phenyl]-1-(2-chloro-pyrimidin-4-yl)-1,3-dihydro-indol-2-one and sodium methoxide solution (0.5 M) in methanol (2.0 mL). Add THF (5.0 mL) and stir for 3 h at room temperature. Quench the reaction with saturated aqueous ammonium chloride (25 mL). Add ethyl acetate (25 mL) and separate the layers. Dry the organic layer with sodium sulfate and concentrate in vacuo. Dissolve the crude residue in THF (2 mL), and add a solution of tetrabutylammonium fluoride (1.0 M) in THF (0.84 mL). Stir the reaction at room temperature for 1 h. Quench the reaction with saturated aqueous ammonium chloride (25 mL). Add ethyl acetate (25 mL) and separate the layers. Dry the organic layer with sodium sulfate and concentrate in vacuo. Purify by flash column chromatography eluting with a gradient from 25% to 50% ethyl acetate in hexanes to give 0.289 g (%) of the title compound: mass Spectrum (ion spray): m/z=482(M+1); 1H NMR (DMSO-d6): δ8.67 (d, 1H), 8.29 (s, 2H), 8.21 (d, 1H), 7.36 (td, 1H), 7.30, (dd, 1H), 7.22 (td, 1H), 6.69 (s, 4H), 3.97 (s, 3H), 2.05 (s, 12H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([OH:9])=O)=[CH:2]1.CCN(C(C)C)C(C)C.Cl.[C:20]1([CH2:26][CH2:27][C:28]2[N:29]=[C:30]([CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[S:31][CH:32]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[C:20]1([CH2:26][CH2:27][C:28]2[N:29]=[C:30]([CH:33]3[CH2:38][CH2:37][N:36]([C:7](=[O:9])[CH2:6][C:3]4[CH:4]=[CH:5][S:1][CH:2]=4)[CH2:35][CH2:34]3)[S:31][CH:32]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc(CCc2csc(C3CCNCC3)n2)cc1
Reactant: O=C(O)Cc1ccsc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccsc1)N1CCC(c2nc(CCc3ccccc3)cs2)CC1
Reaction time: 0.5 h

Procedure:
Thiophen-3-ylacetic acid (156 mg) and Hünig base (323 mg) are dissolved in dichloromethane (10 ml) and stirred for 30 min. 4-[4-(2-Phenylethyl)-1,3-thiazol-2-yl]piperidine hydrochloride (II-1, 309 mg), prepared according to Process 1.2, is added, and the mixture is stirred for a further 5 min before bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (599 mg) is added. The reaction mixture is stirred at room temperature overnight. After removal of the solvent under reduced pressure, the residue is purified chromatographically. This gives 1-{4-[4-(2-phenylethyl)-1,3-thiazol-2-yl]piperidin-1-yl}-2-(thiophen-3-yl)ethanone (99 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3([O:19][C:7]=2[C:6]([C:20]([OH:22])=[O:21])=[CH:5][CH:4]=1)[CH2:15][CH2:14][N:13](C(=O)C)[CH2:12][CH2:11]3.[Li+].[OH-].Cl.[CH3:26]O>O>[CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3([O:19][C:7]=2[C:6]([C:20]([O:22][CH3:26])=[O:21])=[CH:5][CH:4]=1)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3
Reactant: CO
Reactant: COc1ccc(C(=O)O)c2c1OC1(CCN(C(C)=O)CC1)O2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1ccc(OC)c2c1OC1(CCNCC1)O2
Yield: 57 %

Procedure:
A solution of 7-methoxy-1′-acetyl-spiro[1,3-benzodioxole-2,4′-piperidine]-4-carboxylic acid (143 mg, 0.467 mmol) and LiOH (224 mg, 9.34 mmol) in water (3 mL) and MeOH (3 mL) was heated to 75° C. for five hours. At room temperature the mixture was neutralized with 2M HCl and evaporated to dryness under reduced pressure. The crude 7-methoxy-spiro[1,3-benzodioxole-2,4′-piperidine]-4-carboxylic acid [LC/MS (METHOD B): (m/z) 266.2 (MH+); RT=1.57 min; purity (UV)=82%] was refluxed overnight in 1.7 M methanolic HCl (5 mL). At room temperature water (20 mL) was added. The aqueous phase was washed with Et2O (10 mL), made basic by addition of Na2CO3 and extracted with dichloromethane (3×10 mL). The organic phase was dried over MgSO4 and evaporation under reduced pressure afforded methyl 7-methoxy-spiro[1,3-benzodioxole-2,4′-piperidine]-4-carboxylate (75 mg, 57%). 1H NMR (DMSO) δ 7.31 (d, 1H), 6.72 (d, 1H), 3.87 (s, 3H), 3.78 (s, 3H), 2.96-2.77 (m, 4H), 1.94-1.83 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([CH3:29])[N:12]2[C:13](=[O:28])[C:14]([NH:17][C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[CH:15][N:16]=[C:11]2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:30](OC(NC1C(=O)N2[C@H](C(OC(C)(C)C)=O)CCC2=NC=1)=O)[C:31]1C=CC=CC=1.C(I)C=C>>[C:1]([O:5][C:6]([C:8]1([CH2:29][CH:30]=[CH2:31])[N:12]2[C:13](=[O:28])[C:14]([NH:17][C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[CH:15][N:16]=[C:11]2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1(C)CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Reactant: CC(C)(C)OC(=O)[C@@H]1CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Agent: C=CCI
Product: C=CCC1(C(=O)OC(C)(C)C)CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Yield: 55 %

Procedure:
According to the procedure for the preparation of intermediate 19a, alkylation of intermediate 1g (250 mg, 0.649 mmol) with allyl iodide afforded 153 mg (55%) of intermediate 20a. MS (ESI) 426.4 (M+H+), 448.4 (M+Na+).
Reaction SMILES: [NH:1]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C@H:2]([C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10](O)=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:53][C@H:54]([C:58]([N:60]1[CH2:71][CH2:70][CH2:69][C@H:61]1[C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])=[O:59])[CH:55]([CH3:57])[CH3:56].Cl.C(N(CC)CC)C>ClCCl>[NH:1]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C@H:2]([C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([NH:53][C@H:54]([C:58]([N:60]1[CH2:71][CH2:70][CH2:69][C@H:61]1[C:62]([O:64][C:65]([CH3:66])([CH3:68])[CH3:67])=[O:63])=[O:59])[CH:55]([CH3:57])[CH3:56])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
A solution of Z-Val-Pro-OH (681.3 mg, 1.95 mmol) in dichloromethane (6 mL), was successively treated at room temperature. with (benzotriazol-1-yloxy)tris(dimethylamino)phosphoniun hexafluorophale (BOP) (865.1 mg, 1.95 mmol), H-Val-Pro-OtBu.HCl (500 mg, 1.63 mmol) and triethylamine (TEA) (500 μL, 3.58 mmol). The mixture was stirred overnight at room temperature. Then, the solvent was evaporated, the residue was dissolved in dichloromethane and washed with citric acid (10%), NaHCO3 (10%) and brine. The organic layer was dried (Na2SO4) and evaporated to dryness leaving a residue that was purified on a column chromatography with hexane-ethyl acetate, 2:1 to give X (68% yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([NH:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:8])=[CH:5][CH:4]=1.[CH2:17]([CH:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1)[CH2:18][CH3:19].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:17]([CH:20]1[CH2:25][CH2:24][CH:23]([NH:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([C:7]([NH:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:8])=[CH:15][CH:16]=2)[CH2:22][CH2:21]1)[CH2:18][CH3:19]
Reactant: CCCC1CCC(=O)CC1
Reactant: NCc1ccc(C(=O)NCCC(=O)O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCCC1CCC(NCc2ccc(C(=O)NCCC(=O)O)cc2)CC1
Temperature: 25 °C

Procedure:
The resulting resin bound 3-(4-aminomethylbenzoylamino)propionic acid was treated with 98 mg 4-propylcyclohexanone (700 μmol) dissolved in 500 μL 1,2-dichloroethane, 50 μL acetic acid and a slurry of 148 mg NaBH(OAc)3 (700 μmol) in 1 mL 1,2-dichloroethane. Over night shaking at 25° C. followed by filtration and washing with 2×1 mL dichloromethane, 2×1 mL CH3OH:DMF 1:1 and 3×1 mL DMF afforded resin bound 3-{4-[(4-propylcyclohexylamino)-methyl]benzoylamino}propionic acid.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH2:4]([O:6][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[N:10][C:9]=1Cl)[CH3:5]>CO>[CH2:4]([O:6][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[N:10][C:9]=1[O:2][CH3:1])[CH3:5]
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1cccnc1OC
Temperature: 25 °C
Yield: 79 %

Procedure:
Sodium methoxide (18 mL, 25 wt % in methanol) was added slowly to a solution of ethyl-2-chloronicotinate (11.14 g 60 mmol) in anhydrous methanol (60 mL). The reaction mixture was stirred under reflux for 15 h, then cooled to rt. The methanol was removed in vacuo. The residue was dissolved in EtOAc (200 mL) and sat. ammonium chloride solution (50 mL) was added. The organic layer was separated and dried over anhydrous Na2SO4. Removal of solvent gave ethyl-2-methoxynicotinate (8.58 g, 79%) as yellow oil. Sodium hydride (0.21 g, 60% in mineral oil, 5.16 mmol) was mixed with anhydrous DMF (5 mL). A solution of 3′-bromo-4′-methoxyacetophenone (0.99 g, 4.3 mmol) in anhydrous DMF (3 mL) was added drop-wise at 0° C. under nitrogen. The mixture was stirred at 0° C. for 5 min. and then at rt for 30 min. The mixture was cooled to 0° C. A solution of ethyl 2-methoxy nicotinate (1.81 g, 10 mmol) in anhydrous DMF (3 mL) was added slowly. The ice bath was removed and the stirring continued at rt under nitrogen for 20 h. Water (20 mL) was added and the mixture was extracted with EtOAc (2×100 mL). The organic layer was washed with brine and dried over anhydrous Na2SO4. Removal of the solvent gave a dark solid. Triturating with ether gave a yellow solid (1.32 g, 84%). The solid (1.31 g, 3.6 mmol) and pyridinium hydrochloride (6.24 g, 54 mmol) were mixed together and stirred at 190° C. for 3 h, The reaction mixture was then cooled to rt, followed by the addition of water (200 mL). The solid was isolated by filtration, washed with water and dried under vacuum. The crude compound was purified by column chromatography (Silica Gel 230-400 mesh; 5:4:1 hexanes, EtOAc and methanol as an eluent) to give 2-(3-bromo-4-hydroxyphenyl)-4H-pyrano[2,3-b]pyridin-4-one (0.453 g, 40%) of as yellow solid. MS (ES) m/z: 317.84, 239.9; Mp. 267-272° C.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([Cl:7])[S:4][C:3]=1[CH3:8].C1C(=O)N([Br:16])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CCCCCC.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:16][CH2:8][C:3]1[S:4][C:5]([Cl:7])=[CH:6][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1sc(Cl)cc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Product: Clc1cc(Cl)c(CBr)s1
Temperature: 0 °C
Yield: 55.3 %

Procedure:
A solution of 3,5-Dichloro-2-methyl-thiophene (1.3 grams, 7.8 mmole), NBS (1.4 grams, 7.8 mmole) and benzoyl peroxide (0.065 g) in carbon tetrachloride (40 ml) was refluxed for 18 hours. The mixture was cooled to 0° C., diluted with 40 ml hexane and filtered. The filtrate was concentrated to an oil which was purified via flash chromatography on silica using hexane as eluent to give an oil (1.06 g). MW 245.95; MS (m/e) 246 (M++1).
Reaction SMILES: [C:1](#[N:3])[CH3:2].[Li]CCCC.[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16]Br>O1CCCC1>[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH2:2][C:1]#[N:3]
Reactant: CC#N
Reactant: BrCc1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CCCc1ccccc1Br
Temperature: -78 °C

Procedure:
Into a 500-mL 3-necked round-bottom flask, was placed a solution of acetonitrile (49 g, 1.20 mol, 9.96 equiv) in tetrahydrofuran (150 mL). This was followed by the addition of BuLi (72 mL, 1.50 equiv) dropwise with stirring at −78° C. Stirred at −78° C. for 1 h. To this was added a solution of 1-bromo-2-(bromomethyl)benzene (30 g, 120.00 mmol, 1.00 equiv) in tetrahydrofuran (100 mL) dropwise with stiffing at −78° C. The resulting solution was stirred for 1 h at −78° C. The reaction was quenched by the addition of 100 mL of water at −78° C. The resulting aqueous solution was extracted with 3×100 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20). The crude product was purified by distillation under reduced pressure (2 mm Hg) and the fraction was collected at 98-107° C. This resulted in 13.21 g (52%) of 3-(2-bromophenyl)propanenitrile as colorless oil.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C@H:16]([C:17](O)=[O:18])[CH2:15][C:14]2[C:9](=[CH:10][C:11]([OH:23])=[C:12]([N+:20]([O-:22])=[O:21])[CH:13]=2)[CH2:8]1)=[O:6])([CH3:3])[CH3:2].Cl.[CH3:25][O:26][C:27](=[O:45])[C@@H:28]([NH2:44])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][CH:37]=2)=[CH:32][CH:31]=1>>[CH:1]([O:4][C:5]([N:7]1[C@H:16]([C:17](=[O:18])[NH:44][C@H:28]([C:27]([O:26][CH3:25])=[O:45])[CH2:29][C:30]2[CH:31]=[CH:32][C:33]([C:36]3[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][CH:37]=3)=[CH:34][CH:35]=2)[CH2:15][C:14]2[C:9](=[CH:10][C:11]([OH:23])=[C:12]([N+:20]([O-:22])=[O:21])[CH:13]=2)[CH2:8]1)=[O:6])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: CC(C)OC(=O)N1Cc2cc(O)c([N+](=O)[O-])cc2C[C@H]1C(=O)O
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc([N+](=O)[O-])c(O)cc2CN1C(=O)OC(C)C
Yield: 79.7 %

Procedure:
(S)-7-Hydroxy-6-nitro-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid 2-isopropyl ester 3-methyl ester (2.4 mmol) was hydrolyzed according to general procedure B to provide the acid (0.704 g). (S)-7-Hydroxy-6-nitro-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid 2-isopropyl ester (2.16 mmol) was coupled with (S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester-hydrochloride (2.38 mmol) according to general procedure A to provide the amide (1.01 g) LC/MS: m/z 588.