Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[CH:4][N:3]=1.S(=O)(=O)(O)[OH:24].N([O-])=O.[Na+]>O>[O:24]=[C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[CH:4][NH:3]1
Reactant: Nc1ncc(-c2c(-c3ccccc3)nn3ccccc23)cn1
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=c1ncc(-c2c(-c3ccccc3)nn3ccccc23)c[nH]1
Reaction time: 2 h

Procedure:
To a mixture of 3-(2-aminopyrimidin-5-yl)-2-phenylpyrazolo[1,5-a]pyridine (0.70 g) and 50% sulfuric acid (5.6 ml) was gradually added aqueous solution (5.6 ml) of sodium nitrite (1.68 g) at 5° to 10° C., and the resultant mixture was stirred for 3 hours at the same temperature and then for 2 hours at room temperature. To the reaction mixture was added water (14 ml). The precipitates were collected by filtration subjected to a column chromatography on silica gel (14 g) with a mixture of chloroform and methanol (10:1) as an eluent. The fractions containing the objective compound were combined and the solvent was evaporated in vacuo to give 3-(2-oxo-1,2-dihydropyrimidin-5-yl)-2-phenylpyrazolo[1,5-a]pyridine (0.44 g).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:5][N:6]=1.S(=O)(=O)(O)O.[CH3:17]O>>[CH3:1][C:2]1[S:3][C:4]([CH2:7][CH2:8][C:9]([O:11][CH3:17])=[O:10])=[CH:5][N:6]=1
Reactant: Cc1ncc(CCC(=O)O)s1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cnc(C)s1

Procedure:
A mixture of 31.7 g of 2-methyl-5-thiazolepropanoic acid, 3.2 ml of concentrated sulfuric acid and 300 ml of methanol was refluxed for 16 hours and was then concentrated to dryness. The residue was taken up in 100 ml of water and the pH was adjusted to 12-13 with addition of concentrated ammonium hydroxide. The mixture was extracted with methylene chloride and the extracts were dried over magnesium sulfate and was evaporated to dryness under reduced pressure to obtain 35 g of raw methyl 2-methyl-5-thiazolepropanoate. Its hydrochloride had a melting point of 115° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH:9]1(Br)[CH2:13][CH2:12][CH2:11][CH2:10]1.[OH-].[Na+].CN(C=O)C>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: BrC1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(OC2CCCC2)cc1
Temperature: 100 °C
Reaction time: 13.5 h
Yield: 83.3 %

Procedure:
A mixture of 4-bromophenol (40 g, 231 mmol), cyclopentylbromide (50 ml, 462 mmol), NaOH (18.5 g, 462 mmol) and DMF (150 mL) was stirred at 100° C. for 13.5 h, poured into water (300 mL) and extracted with t-BuOMe (4×100 mL). The combined organic extracts were washed with water (2×100 mL), brine, dried (Na2SO4), concentrated and distilled in vacuo to yield the sub-title compound (46.4 g, 94%).
Reaction SMILES: CS([C:5]1[N:9]=[C:8]([CH2:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[S:7][N:6]=1)(=O)=O.[CH2:17]([OH:21])[C:18]#[C:19][CH3:20].[H-].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[CH:11]1([CH2:10][C:8]2[S:7][N:6]=[C:5]([O:21][CH2:17][C:18]#[C:19][CH3:20])[N:9]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC#CCO
Reactant: CS(=O)(=O)c1nsc(CC2CCCCC2)n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCOc1nsc(CC2CCCCC2)n1
Reaction time: 0.5 h
Yield: 77 %

Procedure:
300 mg of 3-methylsulfonyl-5-(cyclohexyl)methyl-1,2,4-thiadiazole and 89 mg of 2-butyn-1-ol were dissolved in 2.5 g of N,N-dimethylformamide, 55 mg of sodium hydride (60% in oil) was added thereto, and the reaction mixture was stirred for 30 minutes under ice-cooling. Then, the reaction mixture was added to saturated brine, and extracted with t-butyl methyl ether. The organic layer was concentrated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography to give 222 mg of 5-(cyclohexyl)methyl-3-(2-butynyloxy)-1,2,4-thiadiazole (hereinafter referred to as the present invention compound (5)).
Reaction SMILES: [C:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([NH:17][C:18]([NH2:20])=[NH:19])#[N:16]>>[NH2:20][C:18]1[N:17]=[C:15]([NH2:16])[C:12]2[CH2:13][CH:8]([CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:9][CH2:10][C:11]=2[N:19]=1
Reactant: N#CNC(=N)N
Reactant: O=C1CCC(Cc2ccccc2)CC1
Product: Nc1nc(N)c2c(n1)CCC(Cc1ccccc1)C2

Procedure:
In an alternate method, when n is the bridging group --CH2 --, the 8-phenylmethylene-1,4-dioxaspiro[4.5]decane is treated with acetic acid and water as previously described, yielding the corresponding 4-phenylmethylenecyclohexanone. The cyclohexanone is then reduced with hydrogen gas in the presence of 10% palladium on charcoal (Degussa type), yielding the corresponding 4-phenylmethylcyclohexanol, which is in turn treated with sodium dichromate and sulfudc acid in water, affording the 4-phenylmethylcyclohexanone. The 4-phenylmethylcyclohexanone is then reacted with cyanoguanidine, as previously described, yielding the targeted 2,4-diamino-6-phenylmethyl-5,6,7,8-tetrahydroquinazoline. Example 3 provides a detailed description of how this reaction is conducted.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:46])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[C:35]([CH2:36][CH2:37][O:38]C3CCCCO3)=[CH:34][N:33]=[N:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:18])([F:20])[F:19])=[CH:10][C:9]2[NH:21][C:22](=[O:46])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[C:35]([CH2:36][CH2:37][OH:38])=[CH:34][N:33]=[N:32]4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3CCOC3CCCCO3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CCO)c1)=N2

Procedure:
The title compound was prepared from (RS)-{5-dimethylamino-2-[3-oxo-3-(3-{5-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-[1,2,3]triazol-1-yl}-phenyl) -propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert.-butyl ester (Example M72) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (179 mg).
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[N:13]=[C:12]([CH:14]=O)[CH:11]=[CH:10][CH:9]=1.[C:16]([CH2:18][C:19]([NH:21][CH:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:27][CH:26]=1)[CH2:23][CH3:24])=[O:20])#[N:17].O>CS(C)=O>[Br:7][C:8]1[N:13]=[C:12](/[CH:14]=[C:18](\[C:16]#[N:17])/[C:19]([NH:21][CH:22]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:29][CH:30]=2)[CH2:23][CH3:24])=[O:20])[CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: CCC(NC(=O)CC#N)c1ccc(OCCOC)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCC(NC(=O)/C(C#N)=C/c1cccc(Br)n1)c1ccc(OCCOC)cc1
Yield: 90 %

Procedure:
Potassium t-butoxide (0.014 g, 0.127 mmol) was added to a stirred solution of 6-bromo-2-pyridinecarboxaldehyde (0.094 g, 0.51 mmol) and 2-cyano-N-(1-(4-(2-methoxyethoxy)-phenyl)propyl)acetamide (0.07 g, 0.25 mmol) in dimethylsulfoxide (10 mL) under nitrogen at room temperature. After 26 hours the mixture was shaken with water and then extracted with ethyl acetate several times. The combined extracts were washed with water and then dried over sodium sulfate. The solvent was removed in vacuo leaving 0.10 g of a clear amber syrup, which was flash chromatographed on a column (5×10 cm) of silica gel with gradient elution utilizing dichloromethane/EtOAc (10:0 gradually changing to 12:1) to afford 0.040 g of the product as a clear pale yellow syrup; mass spec ES+m/z=444, 466 (m+1, m+23).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH:9]=[C:8]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH3:25])[N:19]=2)[CH:7]=1.[CH3:26][N:27]([CH3:32])[CH2:28][CH2:29][CH2:30][NH2:31]>>[CH3:17][O:16][C:13]1[CH:14]=[C:15]2[C:10]([CH:9]=[C:8]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH3:25])[N:19]=3)[CH:7]=[C:6]2[NH:5][CH2:4][CH2:3][CH2:2][NH:31][CH2:30][CH2:29][CH2:28][N:27]([CH3:32])[CH3:26])=[CH:11][CH:12]=1
Reactant: CN(C)CCCN
Reactant: CNc1nccc(-c2cc(NCCCBr)c3cc(OC)ccc3c2)n1
Product: CNc1nccc(-c2cc(NCCCNCCCN(C)C)c3cc(OC)ccc3c2)n1

Procedure:
N′-[3-({7-methoxy-3-[2-(methylamino)pyrimidin-4-yl]-1-naphthyl}amino)propyl]-N,N-dimethylpropane-1,3-diamine 189 was synthesized according to General Procedure H except in Step 2 4-(4-((3-bromopropyl)amino)-6-methoxynaphthalen-2-yl)-N-methylpyrimidin-2-amine and N1,N1-dimethylpropane-1,3-diamine were used. N′-[3-({7-methoxy-3-[2-(methylamino)pyrimidin-4-yl]-1-naphthyl}amino)propyl]-N,N-dimethylpropane-1,3-diamine 191 was isolated as a red-orange solid. M.p.=142-144° C. LCMS (m/z): 423 [M+H].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[NH:9][C:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:11][C:12](=[O:14])[CH:13]=2)[CH:3]=1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CC(O)(CC)C.[Cl-].[Zn+2].[Cl-]>[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]3[NH:9][C:10]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=4)=[CH:11][C:12](=[O:14])[CH:13]=3)[CH:3]=2)[CH2:24][CH2:23]1
Reactant: CN1CCNCC1
Reactant: O=c1cc(-c2ccccn2)[nH]c(-c2cc(Cl)ccn2)c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCC(C)(C)O
Product: CN1CCN(c2ccnc(-c3cc(=O)cc(-c4ccccn4)[nH]3)c2)CC1

Procedure:
A mixture of 5.22 g (18.4 mmol) of 4-chloro-1′H-[2,2′;6′,2″]terpyridin-4′-one, 18.36 g (184 mmol, 20.4 ml) of 1-methylpiperazine and 125 mg (0.92 mmol, 0.05 equivalent) of zinc(II) chloride in 80 ml of 2-methyl-2-butanol is boiled under reflux for 30 hours. The mixture is evaporated to dryness on a rotary evaporator. 100 ml of water are added and the mixture is rendered neutral with concentrated hydrochloric acid. Extracting the mixture four times with chloroform and combining and drying (sodium sulfate) the organic extracts gives the crude product which is subsequently recrystallized from acetonitrile. 4-(4-Methyl-piperazin-1-yl)-1′H-[2,2′;6′,2″]terpyridin-4′-one is obtained as a white solid. 1H-NMR (360 MHz, CDCl3): 8.69 (d, 1H, 4.5 Hz); 8.32 (d, 1H, J=5.9 Hz); 7.92-7.74 (m, 2H); 7.37-7.30 (m, 1H); 7.20 (d, 1H, J=2.3 Hz); 7.01 (s, 1H); 6.98 (s, 1H); 6.71-6.63 (m, 1H); 3.45-3.35(tm, 4H); 2.58-2.48 (tm, 4H); 2.32 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([O:12][CH3:13])=[CH:7][C:6]=1[Cl:14])=O.[NH2:15][C:16]([NH2:18])=[S:17]>CCO>[Cl:14][C:6]1[CH:7]=[C:8]([O:12][CH3:13])[CH:9]=[C:10]([Cl:11])[C:5]=1[C:3]1[N:15]=[C:16]([NH2:18])[S:17][CH:2]=1
Reactant: NC(N)=S
Reactant: COc1cc(Cl)c(C(=O)CBr)c(Cl)c1
Solvent: CCO
Product: COc1cc(Cl)c(-c2csc(N)n2)c(Cl)c1
Yield: 50.4 %

Procedure:
To a solution of 2-bromo-1-(2,6-dichloro-4-methoxyphenyl)ethanone (10-3, 1.3 g) and thiourea (0.42 g, 5.5 mmol) in 95% EtOH (15.0 mL) was heated at reflux for 60 min. The solution was concentrated under reduced pressure and the residue was re-dissolved in ethyl acetate. The solution was washed with saturated aqueous NaHCO3, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 4-(2,6-dichloro-4-methoxyphenyl)thiazol-2-ylamine (10-4, 0.60 g, 2.2 mmol) as yellow solids in 47% yield: 1H NMR (500 MHz, CDCl3) δ 7.08 (d, J=1.8 Hz, 1 H), 6.83 (d, J=1.8 Hz, 1 H), 6.49 (s, 1 H), 4.88 (brs, 2 H), 3.77 (s, 3 H); ESI-MS m/z 275.1 (M+H)+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([C@H:18]1[CH2:22][O:21][C:20](=[O:23])[N:19]1[C:24](=[O:52])[C@@H:25]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=1)/[CH:26]=[CH:27]/[CH2:28][C:29]([N:31]1[C@@H:35]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:34][O:33][C:32]1=[O:43])=[O:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:53](I)[CH:54]=[CH2:55]>C1COCC1>[CH2:55]([C@@H:28](/[CH:27]=[CH:26]/[C@H:25]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=1)[C:24]([N:19]1[C@@H:18]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:22][O:21][C:20]1=[O:23])=[O:52])[C:29]([N:31]1[C@@H:35]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:34][O:33][C:32]1=[O:43])=[O:30])[CH:54]=[CH2:53]
Reactant: O=C(C/C=C/[C@H](Cc1ccc(F)cc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: C=CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC[C@@H](/C=C/[C@H](Cc1ccc(F)cc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
A solution of NaHMDS (1.0 M in THF, 1.34 mL, 1.34 mmol) was slowly added dropwise over 10 min to a −78° C. solution of (S,E)-1,6-bis((S)-4-benzyl-2-oxooxazolidin-3-yl)-2-(4-fluorobenzyl)hex-3-ene-1,6-dione (763 mg, 1.34 mmol) in THF (4.8 mL). After the addition, the reaction mixture was allowed to stir for another 30 min at −78° C. and then a solution of allyl iodide (225 mg, 1.34 mmol) in THF (0.5 mL) was added dropwise. The reaction temperature was then warmed to −40° C. and stirred at −40° C. for 45 min. Then the reaction was warmed to 0° C. and stirred at 0° C. for an additional 1 hr. The reaction was quenched by the addition of saturated NH4Cl. The mixture was then partitioned between EtOAc and water. The organic phase was isolated, washed with saturated aqueous NaCl, dried over MgSO4 and concentrated. The crude product was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give (2S,5S,E)-2-allyl-1,6-bis((S)-4-benzyl-2-oxooxazolidin-3-yl)-5-(4-fluorobenzyl)hex-3-ene-1,6-dione (470 mg, 0.770 mmol, 57.6% yield) as a foam. Anal. Calcd. for C36H35FN2O6 m/z 610.2. found: 611.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C:5]([CH3:31])([CH3:30])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13](=O)[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])([CH3:23])[CH3:22])[CH:15]=2)[CH:8]=1)[CH3:2].[CH2:33]([SH:37])[CH2:34][CH2:35][SH:36].B(F)(F)F.CCOCC.[OH-].[Na+]>ClCCl>[CH2:1]([O:3][C:4](=[O:32])[C:5]([CH3:31])([CH3:30])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])([CH3:23])[CH3:22])[CH:15]=3)[S:37][CH2:33][CH2:34][CH2:35][S:36]2)[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(C)Cc1cccc(C(=O)c2cccc(CC(C)(C)C(=O)OCC)c2)c1
Reactant: SCCCS
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)C(C)(C)Cc1cccc(C2(c3cccc(CC(C)(C)C(=O)OCC)c3)SCCCS2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
To a solution of 3-{3-[3-(2-ethoxycarbonyl-2-methyl-propyl)-benzoyl]-phenyl}-2,2-dimethyl-propionic acid ethyl ester (6.2 g, 14 mmol) in dichloromethane (100 mL) was added 1,3-propanedithiol (1.9 g, 17.5 mmol) and borontrifluoride etherate (0.52 mL) solution was stirred at room temperature overnight and 5% sodium hydroxide solution (17.5 mL) was added. The organic layer was separated, washed with water (50 mL), dried over sodium sulfate, and evaporated to afford 3-(3-{2-[3-(2-ethoxycarbonyl-2-methyl-propyl)-phenyl]-[1,3]dithian-2-yl}-phenyl)-2,2-dimethyl-propanoic acid ethyl ester (6.5 g, 86%) as an oil. 1H NMR (300 MHz, CDCl3): δ (ppm): 7.58-6.96 (m, 8H), 4.10 (q, J=7.2 Hz, 4H), 2.85 (s, 4H), 2.76 (t, J=5.6 Hz, 4H), 1.98 (m, 2H), 1.25-1.14 (m, 18H). 13C NMR (75 MHz, CDCl3): δ (ppm): 177.2, 142.2, 138.1, 131.1, 129.3, 127.8, 127.3, 60.4, 46.2, 43.5, 29.4, 24.9, 24.5, 14.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1.[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([Cl:20])=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Cl:12][C:13]1[N:18]=[C:17]([NH:1][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][C:10]#[N:11])[CH:5]=[CH:6][CH:7]=2)[C:16]([Cl:20])=[CH:15][N:14]=1
Reactant: N#CCCc1cccc(N)c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCCc1cccc(Nc2nc(Cl)ncc2Cl)c1

Procedure:
3-(3-Amino-phenyl)-propionitrile (0.110 g, 0.000752 mol), 2,4,5-Trichloro-pyrimidine (0.152 g, 0.000828 mol), Potassium carbonate (0.125 g, 0.90 mmol), and DMF (1.0 mL, 0.014 mol) were heated at 85° C. for 90 min. The reaction mixture was diluted with H2O, extracted with CH2Cl2×3, dried over MgSO4, filtered, and concentrated under reduced pressure. Title compound isolated as a white solid. MP=111-112. HPLC purity: 95% LCMS: 295.10 (M+H) 1H-NMR (CDCl3, 400 MHz) δ 8.21 (d, J=0.8 Hz, 1H), 7.53-7.56 (m, 2H), 7.38 (dd, J=7.6 Hz, 7.8 Hz, 1H), 7.31 (s, 1H), 7.07 (d, J=7.6 Hz, 1H), 3.00 (dd, J=7.0 Hz, 7.3 Hz, 2H), 2.67 (dd, J=7.4 Hz, 7.2 Hz, 2H).
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH2:16][C:17](=S)[C:18]([OH:20])=[O:19])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:23][OH:24].[OH-].[K+].C(O)C>O>[C:1]1([C:7]2[C:15]([CH2:16][C:17](=[N:23][OH:24])[C:18]([OH:20])=[O:19])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=C(O)C(=S)Cc1c(-c2ccccc2)nn2ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C(Cc1c(-c2ccccc2)nn2ccccc12)=NO
Yield: 69.8 %

Procedure:
A mixture of 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2-thioxopropionic acid (3.74 g), hydroxylamine hydrochloride (2.63 g), 85% potassium hydroxide (2.50 g) and 80% aqueous ethanol (22.4 ml) was refluxed for 3 hours. After cooling, to the reaction mixture was added water (40 ml) and the resulting precipitates were filtered off. The filtrate was washed with methylene chloride (20 ml) twice, acidified with 10% aqueous hydrochloric acid (pH ≈2), and extracted with ethyl acetate (20 ml) twice. The organic layer was washed with water (10 ml) and a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was removed to give 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2-hydroxyiminopropionic acid (2.60 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:12]=1[CH3:13])[C:7]([O:9]CC)=O.[Li+].CC([N-]C(C)C)C.[C:22]([O:26][CH3:27])(=[O:25])[CH:23]=[CH2:24].CC(O)=O>C1COCC1>[Br:1][C:2]1[C:12]2[CH2:13][CH2:24][CH:23]([C:22]([O:26][CH3:27])=[O:25])[C:7](=[O:9])[C:6]=2[CH:5]=[N:4][CH:3]=1
Reactant: C=CC(=O)OC
Reactant: CCOC(=O)c1cncc(Br)c1C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C1CCc2c(Br)cncc2C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95.3 %

Procedure:
Ethyl 5-bromo-4-methylnicotinate (7.04 g, 28.8 mmol) in THF (28.8 mL) was added over a period of 20 min to a solution of LDA (31.7 mmol) [generated from N,N-diisopropylamine (4.52 ml, 31.7 mmol) and n-butyllithium (19.8 mL, 31.7 mmol, 1.6M in hexane) in 144 mL THF] at −78° C. The resulting dark red solution was stirred for 20 min, then methyl acrylate (6.21 g, 72.1 mmol) in THF (28.8 mL) was added over 15 min. The reaction was stirred an additional 1.5 h, then aq. 10% AcOH was added (resulting pH=4-5) and the reaction was allowed to warm to room temperature. After evaporation, the residue was poured on aq. sat. NaHCO3 and extracted with EtOAc (3×). The combined organic layers were dried (Na2SO4) and concentrated to afford the title compound (7.80 g, 95% in 70% purity with 30% starting material) as brown solid. MS: 284.0 (M+H+, 1Br).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(OC([NH:52][C@@H:53]([CH:81]([CH3:83])[CH3:82])[C:54]([O:56][CH2:57][O:58][C:59](=[O:80])[C@@:60]([CH2:78][OH:79])([CH3:77])[CH2:61][C@H:62]([NH2:76])[CH2:63][C:64]1[CH:69]=[CH:68][C:67]([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)=[CH:66][CH:65]=1)=[O:55])=O)C1C=CC=CC=1>CN(C=O)C>[NH2:52][C@@H:53]([CH:81]([CH3:83])[CH3:82])[C:54]([O:56][CH2:57][O:58][C:59](=[O:80])[C@@:60]([CH2:78][OH:79])([CH3:77])[CH2:61][C@H:62]([NH:76][C:6]([C:4]1[NH:3][N:2]=[N:1][CH:5]=1)=[O:8])[CH2:63][C:64]1[CH:65]=[CH:66][C:67]([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)=[CH:68][CH:69]=1)=[O:55]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCOC(=O)[C@](C)(CO)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1c[nH]nn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)[C@H](N)C(=O)OCOC(=O)[C@](C)(CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 29.8 %

Procedure:
1,2,3-Triazole-4-carboxylic acid (18 mg, 156 μmol), DIPEA (81.6 μL, 468 μmol) and HATU (59.3 mg, 156 μmol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid (S)-2-benzyloxycarbonylamino-3-methyl-butyryloxymethyl ester (90 mg, 160 μmol) dissolved in DMF (1 mL). The resulting mixture was stirred for 20 minutes and the solvent was evaporated. The remaining solid was dissolved in degassed 4.4% formic acid-methanol (5 mL) in a flask containing palladium black (˜100 mg) under nitrogen. The mixture was continuously stirred at room temperature. The mixture was filtered and washed with MeOH. The solvent was evaporated and the product purified by preparative HPLC to yield the title compound (25 mg; purity 95%). MS m/z [M+H]+ calc'd for C28H35N5O6, 538.26. found 538.4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[CH3:21][N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1.OP(O)(O)=O.[OH-].[NH4+]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:25]1[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH:24]=1
Reactant: CN1CCC(=O)CC1
Reactant: O=S(=O)(Oc1cc(Br)c2[nH]ccc2c1)c1ccccc1
Agent: O=P(O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CN1CC=C(c2c[nH]c3c(Br)cc(OS(=O)(=O)c4ccccc4)cc23)CC1
Temperature: 75 °C
Reaction time: 6 h

Procedure:
Combine benzenesulfonic acid 7-bromo-1H-indole-5-yl ester and 1-methyl-4-piperidone (4 eq.) in acetic acid. Heat to about 75° C. before adding 2.0 N H3PO4 (3 eq.). After about 6 hours, cool to room temperature and pour into a mixture of ammonium hydroxide in ice water. Separate the organic layer and dry over Na2SO4 and concentrated. Purify to give the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH2:16].C(OCC)(=O)C>CS(C)=O>[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH:16][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CN(C)CCN
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CN(C)CCNc1cc(F)ccc1[N+](=O)[O-]
Temperature: 23 °C
Reaction time: 1 h
Yield: 61.6 %

Procedure:
To a stirred solution of 2,4-difluoronitrobenzene (3.18 g., 20 mmole) In DMSO (5 ml) was added portion-wise N,N-dimethylethylene-diamine (3.52 g., 40 mmole). The mixture was stirred at 23° C. for 1 hour and poured into crushed ice. Ethyl acetate (200 ml) was added to dissolve the orange-yellow solid. The organic phase separated was washed with water and brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was chromatographed on a silica gel column eluting with CH2Cl2 /MeOH (20:1) to afford the compound (15) (2.8 g., 62%) which solidified on standing.