Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:5]([CH:14]([CH3:16])[CH3:15])[CH2:4][O:3]1.I([O-])(=O)(=O)=[O:18].[Na+]>C(#N)C.O.[Ru](Cl)(Cl)Cl>[O:1]=[S:2]1(=[O:18])[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@@H:5]([CH:14]([CH3:16])[CH3:15])[CH2:4][O:3]1
Reactant: CC(C)[C@H]1COS(=O)N1Cc1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)[C@H]1COS(=O)(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.7 %

Procedure:
To an ice-cooled solution of (4S)-2-oxo-3-benzyl-4-isopropyl-1,2,3-oxathiazolidine (6.00 g, 25.07 mmol) in acetonitrile (45 mL) and water (45.0 mL) was added ruthenium chloride (5.20 mg, 0.025 mmol) followed by sodium periodate (8.04 g, 37.6 mmol). The mixture was stirred for 1 h as ice bath melted and the reaction was gradually warmed to room temperature. The mixture was extracted with ether (3×50 mL). The combined organic extracts were washed with brine (100 mL), dried (MgSO4), filtered, then concentrated. The resulting oil was purified by silica gel flash column chromatography to give the title compound (1.9 g) as a colorless oil. LCMS m/z=256.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 0.86 (d, J=7.1 Hz, 3H), 0.90 (d, J=7.1 Hz, 3H), 1.83-1.95 (m, 1H), 3.41-3.45 (m, 1H), 4.23-4.28 (m, 2H), 4.39-4.44 (m, 2H), 7.35-7.43 (m, 5H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)C=C[C:2]=1C(C)C(O)=S.[CH:16]1[CH:17]=[CH:18][C:19]2N(O)N=[N:22][C:20]=2[CH:21]=1.O.O1CCCC1>CN(C)C=O>[CH2:17]1[CH2:16][CH2:21][CH:20]([N:22]=[C:2]=[N:1][CH:10]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)[CH2:19][CH2:18]1
Reactant: CC(C(O)=S)c1ccc2ccccc2n1
Reactant: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: C(=NC1CCCCC1)=NC1CCCCC1

Procedure:
The subtitled compound was prepared substantially in accordance with the procedure detailed in Example 1A using 1.8 g (5.2 mmol) of the subtitled compound of Preparation 1D, 1.8 g (5.2 mmol) of (2S)-2-N(t-butoxycarbonyl)amino-4-(quinolin-2-ylthiopropanoic acid, 0.70 g (5.2 mmol) of HOBT.H2O and 1.1 g (5.2 mmol) of DCC, in a 15 mL of tetrahydrofuran containing 2 mL of dimethylformamide, to provide 3.1 g of a yellow solid. This solid was purified using flash chromatography (eluent of 35% ethyl acetate in toluene) to provide 1.8 g of a white solid. Yield: 51%. 1H NMR (CDCl3): δ1.40 (s, 9 H), 1.45 (s, 9 H), 2.95 (m, 4 H) , 3.57 (d, J=4 Hz, 2 H), 3.65 (m, 1 H), 4.30 (m, 1 H), 4.52 (q, J=5 Hz, 1 H), 6.02 (br.s, 2 H), 6.85 (d, J=9 Hz, 1 H), 7.10-7.38 (m, 10 H), 7.46 (t, J=7 Hz, 1 H), 7.70 (m, 2 H), 7.90 (d, J=9 Hz, 1 H), 8.04 (d, J=8 Hz, 1 H). MS (FD): m/e 670 (M+). IR (KBr): 3292, 1715, 1637, 1594, 1518 cm-1. UV (EtOH): 210 nm (E=58,247), 257 nm (E=23,586), 327 nm (E=5,628), 339 nm (E=6,082).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[C:29]([C:36]([F:39])([F:38])[F:37])[CH:28]=1>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:9]=[C:4]([C:3]([OH:2])=[O:24])[C:5]([C:30]4[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][C:29]=4[C:36]([F:37])([F:38])[F:39])=[CH:6][CH:7]=3)[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: COc1ccc(B(O)O)c(C(F)(F)F)c1
Product: COc1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)c(C(F)(F)F)c1
Yield: 6.1 %

Procedure:
Using the conditions of General Procedure A for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted with 4-methoxy-2-(trifluoromethyl)phenylboronic acid (available from Combi-Blocks Inc.; 110 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-methoxy-2′-trifluoromethyl-biphenyl-2-carboxylic acid (8 mg, 6%). 1H NMR (300 MHz, DMSO-d6) δ 12.97 (br s, 1H), 8.54 (s, 1H), 8.48 (s, 1H), 8.34 (s, 1H), 8.23 (d, J=7.5 Hz, 1H), 8.09 (d, J=8.7 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.41 (d, J=7.9 Hz, 1H), 7.26 (s, 3H), 3.88 (s, 3H).
Reaction SMILES: C(Cl)(=O)C(C)(C)C.C(N(CC)CC)C.[C:15]([N:22]([CH3:31])[C@H:23]([C:28]([OH:30])=O)[CH2:24][CH:25]([CH3:27])[CH3:26])([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[NH2:32][C@H:33]([C:35]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:36])[CH3:34]>C(Cl)(Cl)Cl>[C:15]([N:22]([CH3:31])[C@H:23]([C:28]([NH:32][C@H:33]([C:35]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:36])[CH3:34])=[O:30])[CH2:24][CH:25]([CH3:26])[CH3:27])([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16]
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: C[C@H](N)C(=O)Cc1ccccc1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)C[C@@H](C(=O)N[C@@H](C)C(=O)Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
23.3 ml (18.9 g=157 mMol) pivaloyl chloride and 48 ml (28.9 g=286 mMol) triethylamine are added to a solution of 35 g (143 mMol) BOC-MeLeu-OH in 500 ml chloroform and the mixture stirred for 2 hrs. at room temperature under a nitrogen atmosphere. 30.7 g (171 mMol) H-Ala-Bzl dissolved in 300 ml chloroform are then added and the reaction mixture stirred for a further 2 hrs. at room temperature, again under a nitrogen atmosphere. The product is purified in accordance with the technique of example 1a) to yield the title compound: rotation, [α]D25 =-59.4° (c=1.0 in chloroform).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]#[CH:13].Cl[C:15]1[CH:20]=[CH:19][N:18]=[C:17](NC)[N:16]=1.[CH2:23]([N:25](CC)CC)C>CN(C)C=O.[Cu]I>[NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]#[C:13][C:19]1[CH:20]=[CH:15][N:16]([NH:25][CH3:23])[CH2:17][N:18]=1
Reactant: CCN(CC)CC
Reactant: C#Cc1cc(C(=O)OC)ccc1N
Reactant: CNc1nccc(Cl)n1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: CNN1C=CC(C#Cc2cc(C(=O)OC)ccc2N)=NC1
Temperature: 71 °C
Reaction time: 0.08 h
Yield: 84.8 %

Procedure:
3.0 g (17 mmol) of methyl 4-amino-3-ethynylbenzoate and 2.6 g (19 mmol) of 4-chloro-2-methylaminopyrimidine were initially charged in 20 ml of dimethylformamide (DMF) and 8.7 g (85 mmol) of triethylamine, and degassed with argon while stirring for 5 min. Subsequently, 65 mg of copper(I) iodide and 20 mg of tetrakis(triphenylamine)palladium(0) were added and the mixture was heated to 71° C. for 3 h. After aqueous workup, 4.1 g of methyl 4-amino-3-(1-methylaminopyrimidin-4-yl)ethynylbenzoate were obtained. (HPLC: 99.7 area %) HPLC method as in example 1.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12.C1(C)C=CC(S(O)=O)=CC=1.[Na].[C-:22]#[N:23].[K+]>CS(C)=O.O>[NH:8]1[C:4]2[N:5]=[CH:6][CH:7]=[C:2]([C:22]#[N:23])[C:3]=2[CH:10]=[N:9]1
Reactant: Ic1ccnc2[nH]ncc12
Reactant: [C-]#N
Agent: Cc1ccc(S(=O)O)cc1
Agent: [K+]
Agent: [Na]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccnc2[nH]ncc12
Temperature: 100 °C

Procedure:
4-Iodo-1H-pyrazolo[3,4-b]pyridine (802 mg, 3.27 mmol) was dissolved in DMSO (10 mL) then added p-toluenesulfinic acid, sodium salt (583 mg, 3.27 mmol) and KCN (319 mg, 4.90 mmol). The reaction was heated at 100° C. for 18 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine and dried over MgSO4 to yield 1H-pyrazolo[3,4-b]pyridine-4-carbonitrile as a light orange solid.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[O:14][CH2:15][C:16]#[N:17]>>[C:16]([CH2:15][O:14][C:13]1[CH:12]=[C:11]([NH:10][C:7]([C:5]2[O:6][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:9])[CH:20]=[CH:19][CH:18]=1)#[N:17]
Reactant: O=C(O)c1ccc(Br)o1
Reactant: N#CCOc1cccc(N)c1
Product: N#CCOc1cccc(NC(=O)c2ccc(Br)o2)c1

Procedure:
5-Bromo-furan-2-carboxylic acid (325 mg, 1.70 mmol) was coupled to (3-amino-phenoxy)-acetonitrile (172)(250 mg, 1.69 mmol) using Method C. The residue was purified by column chromatography eluting with a stepped gradient of 10-30% EtOAc in heptane to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([NH2:12])=[C:7]([Cl:13])[CH:6]=[CH:5][C:4]=2[N:3]=1.[CH:14]1([CH2:20][C:21](O)=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl>CN1CCCC1=O.O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[C:8]=2[NH:12][C:21](=[O:22])[CH2:20][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[N:3]=1
Reactant: Nc1c(Cl)ccc2nc(Cl)ccc12
Reactant: O=C(O)CC1CCCCC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Temperature: 50 °C
Yield: 31 %

Procedure:
To a stirred solution of 2,6-dichloroquinolin-5-amine (prepared as described in (d) below) (1 g) in N-methylpyrrolidinone (12 mL) was added 4-N,N-dimethylaminopyridine (1.2 g), cyclohexaneacetic acid (1 g) and PyBroP (4.4 g). The reaction mixture was heated to 50° C. for 10 hours. The mixture was cooled to room temperature and poured into water (10 mL) which was subsequently acidified to pH1 with aqueous 2M hydrochloric acid. The resulting solution was extracted with dichloromethane (3×20 mL). The combined organic extracts were dried, filtered and partially concentrated to give a white precipitate which was removed by filtration. Purification by chromatography (SiO2, methanol:dichloromethane 1:10 as eluant) gave the sub-title compound (490 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Cl)(=[O:27])=[O:26])[CH2:23][CH2:22]1>C(N(C(C)C)C(C)C)C>[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:12]2[CH2:11][CH2:10][N:9]([CH:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:14][CH2:13]2)(=[O:27])=[O:26])[CH2:23][CH2:22]1
Reactant: Clc1ccc(C(c2ccccn2)N2CCNCC2)cc1
Reactant: O=S(=O)(CCCCCCCl)NC1CC1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(CCCCCCN1CCN(C(c2ccc(Cl)cc2)c2ccccn2)CC1)NC1CC1
Yield: 46.6 %

Procedure:
1-[4-Chlorophenyl-(2-pyridyl)methyl]piperazine (7.90 g, 27.5 mmol) and N-cyclopropyl-6-chlorohexanesulfonamide (7.24 g, 30.2 mmol) were refluxed in N-ethyldiisopropylamine (20 ml) for 6 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1), to give N-cyclopropyl-6-[4-[4-chlorophenyl-(2-pyridyl)methyl]-1-piperazinyl]hexanesulfonamide (6.29 g) as an oil (yield based on 1-[4-chlorophenyl-(2-pyridyl)methyl]piperazine: 92.7%).
Reaction SMILES: Cl[Si](C)(C)[CH:3]1[C:14]2[C:6](=[CH:7][C:8]3CCC[C:12]=3[CH:13]=2)[C:5](C2C=CC=CC=2)=[CH:4]1.CCN(CC)CC.C(N)(C)(C)C>CCCCCC>[CH2:3]=[CH2:4].[CH2:4]=[CH:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:8][CH:7]=1
Reactant: C[Si](C)(Cl)C1C=C(c2ccccc2)c2cc3c(cc21)CCC3
Solvent: CCN(CC)CC
Solvent: CC(C)(C)N
Solvent: CCCCCC
Product: C=C
Product: C=Cc1ccccc1
Reaction time: 24 h
Yield: 485.2 %

Procedure:
Chlorodimethyl(1,5,6,7-tetrahydro-3-phenyl-s-indacen-1-yl)silane (10.8277 g, 0.03322 moles) was stirred in hexane (150 mL) as NEt3 (3.5123 g, 0.03471 moles) and t-butylamine (2.6074 g, 0.03565 moles) were added. This mixture was allowed to stir for 24 hours. After the reaction period the mixture was filtered and the volatiles removed resulting in the isolation of the desired product as a thick red-yellow oil (10.6551 g, 88.7% yield).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][CH2:25][C:26]1[S:27][CH:28]=[C:29]([C:31]#[N:32])[N:30]=1>>[C:31]([C:29]1[N:30]=[C:26]([CH2:25][NH:24][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)[S:27][CH:28]=1)#[N:32]
Reactant: N#Cc1csc(CN)n1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCc2nc(C#N)cs2)cn1
Yield: 68 %

Procedure:
As described for example 18, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64 mmol) was converted using 2-aminomethyl-thiazole-4-carbonitrile instead of aminomethyl-isoxazolidin-3-one to the title compound (SiO2, heptane:ethyl acetate=90:10 to 40:60, 188 mg, 68%) which was obtained as a white solid. MS: m/e=432.3 [M−H]+.
Reaction SMILES: [CH:1]1[C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]2[C:10]([O:12][C:13](=[O:14])[C:3]=2[CH:2]=1)=[O:11].C1(=O)[O:21]CCCCC1.N1C=CC=CC=1.[OH2:29]>CC(C)=O>[C:13]([OH:12])(=[O:14])[C:3]1[C:4](=[CH:5][C:6](=[CH:1][CH:2]=1)[C:7]([OH:21])=[O:8])[C:10]([OH:11])=[O:29]
Reactant: O
Reactant: O=C1CCCCCO1
Reactant: O=C(Cl)c1ccc2c(c1)C(=O)OC2=O
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: O=C(O)c1ccc(C(=O)O)c(C(=O)O)c1

Procedure:
Trimellitic acid anhydride chloride (50 g, 0.240 mol) is dissolved in 150 mL acetone in a 3-neck flask under nitrogen. The flask is cooled in an ice bath. A solution of AFM-caprolactone intermediate (82.05 g, 0.12 mol), and pyridine (19.0 g, 0.240 mol) in 80 ml of acetone is added slowly through a dropping funnel while continuously stirring the cold solution. After addition is completed, the flask contents are continuously stirred at room temperature for 4 hours. Water (4.32 g, 0.240 mol) is added and the solution is stirred continuously at room temperature overnight. The solids formed are removed by vacuum filtration and washed with acetone. The filtrate is concentrated and dried to yield the product
Reaction SMILES: O.O.[NH2:3][C@H:4]([C:10]([OH:12])=[O:11])[CH2:5][CH2:6][C:7]([OH:9])=O.[NH2:13][C@H:14]([C:20]([OH:22])=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][NH2:19].CO>CCCCCO>[NH2:3][C@H:4]([C:10]([OH:12])=[O:11])[CH2:5][CH2:6][C:7]([CH:18]([NH2:19])[CH2:17][CH2:16][CH2:15][C@@H:14]([C:20]([OH:22])=[O:21])[NH2:13])=[O:9]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Solvent: CO
Solvent: O
Solvent: CCCCCO
Product: NC(CCC[C@H](N)C(=O)O)C(=O)CC[C@H](N)C(=O)O

Procedure:
The 350 g of the L-lysine L-glutamate dihydrate, α-phase, previously prepared, still containing approximately 15% by weight of methanol, are suspended in 0.85 liter of n-amyl alcohol in a nitrogen atmosphere. The n-amyl alcohol is then heated, followed by the distillation at around 70° first of a ternary mixture containing n-amyl alcohol, methanol and water (approximately 0.1 liter) and then of a binary mixture of n-amyl alcohol and water (approximately 0.1 liter). Heating is terminated at the reflux temperature of the n-amyl alcohol i.e. at 138° C. After a total heating time of 20 hours, the precipitate formed is separated by filtration. This gives 400 g of crude product containing ε-(γ-L-glutamyl)-L-lysine and approximately 1 liter of amylic mother liquors from which 20 g of L-pyroglutamic acid are recovered from recycling after conversion into L-glutamic acid. The n-amyl alcohol is purified for recycling.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:22][C:23]1([CH3:41])[O:27][C@@H:26]([CH2:28]OS(C2C=C(Cl)C=CC=2Cl)(=O)=O)[CH2:25][O:24]1.Cl>CN(C)C=O.C(OCC)(=O)C.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:28][C@H:26]2[CH2:25][O:24][C:23]([CH3:41])([CH3:22])[O:27]2)=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(O)cc1
Reactant: CC1(C)OC[C@H](COS(=O)(=O)c2cc(Cl)ccc2Cl)O1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OC[C@H]2COC(C)(C)O2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of (R)-tert-butoxycarbonylamino-(4-hydroxy-phenyl)-acetic acid (1.4 g, 5.24 mmol) in dry N,N-dimethylformamide (25 mL) at 0° C. under an atmosphere of dry argon was added sodium hydride (60% suspension in mineral oil) (290 mg, 0.12 mmol) and the mixture stirred at 0° C. for 15 minutes. 2,5-Dichloro-benzenesulfonic acid (R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester (2.14 mmol, 6.29 mmol) was added to the reaction mixture to form a yellow solution which was stirred at ambient temperature for 5 minutes before warming to 100° C. for 10 minutes. The reaction mixture which by now contained a heavy precipitate was cooled to ambient temperature, diluted with ethyl acetate, cooled to 0° C. and treated with an equal volume of water. The stirred mixture was acidified to pH=4 with 1 M aqueous hydrochloric acid. The organic layer was separated and the aqueous layer extracted with ethyl acetate. The combined organic layers were washed with water (three times), dried over sodium sulfate, filtered through a thin pad of silica gel and concentrated in vacuo to give (R)-tert-butoxycarbonylamino-[4-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-acetic acid as a pale yellow solid foam which was of adequate purity for subsequent use in step 4 without additional purification (1.96 g, 96%).
Reaction SMILES: Cl[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[NH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][NH:10][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: NCc1ccccn1
Reactant: CC(C)(C)OC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)CNCc1ccccn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 57 %

Procedure:
tert-butyl 2-chloroacetate (0.83 g, 5.55 mmol) and 2-(Aminomethyl)pyridine (1.5 g, 8.32 mmol) were dissolved in 400 mL CH3CN. To this solution was added potassium carbonate (0.76 g, 5.55 mmol) and the mixture was stirred at room temperature for two days. The crude product was obtained as an oil after removal of the solvent and was purified on a silica gel preparative plate that was developed in with a 2% methanolic NH3 (7 M NH3 in methanol/98% CH2Cl2. The product was isolated as pale yellow oil (57%). 1H NMR (CDCl3) δ 8.414 (dd, 1H, Ar), 7.499 (dd, 1H, Ar), 7.200 (d, 1H, Ar), 7.013 (m, 1H, Ar), 3.806 (s, 2H, —CH2—), 3.242 (s, 2H, —CH2—), 2.458 (s, 1H, —CH—), 1.333 (s, 9H, —C(CH3)3).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[SH:11][C:12]1[CH:22]=[CH:21][C:15]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([S:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:21][CH:22]=2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=C(O)CCc1ccc(S)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CCc1ccc(Sc2ccc([N+](=O)[O-])cn2)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-5-nitropyridine (1.74 g, 11.0 mmol) and 4-mercaptohydrocinnamic acid (2.00 g, 11.0 mmol) in DMF (30 mL) was added potassium carbonate (4.55 g, 32.9 mmol), and the resulting solution was stirred for 1 hour at 80° C. To the reaction solution were added water and concentrated hydrochloric acid, and then cooled with ice. The precipitated solid matter was collected by filtration, to thereby yield 3.29 g of the title compound.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:8]=[C:9]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:10]=[N:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([F:21])[CH:14]=1.[I:27]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>C(O)(=O)C>[Cl:6][C:7]1[CH:8]=[C:9]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:10]=[N:11][C:12]=1[C:13]1[CH:18]=[C:17]([I:27])[C:16]([O:19][CH3:20])=[C:15]([F:21])[CH:14]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CCOC(=O)c1cnc(-c2ccc(OC)c(F)c2)c(Cl)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc(-c2cc(F)c(OC)c(I)c2)c(Cl)c1
Temperature: 25 °C

Procedure:
Sulfuric acid (2.5 mL) was added into a cold (ice bath) mixture of ethyl 5-chloro-6-(3-fluoro-4-methoxyphenyl)pyridine-3-carboxylate (500 mg, 1.614 mmol) and 1-iodopyrrolidine-2,5-dione (400 mg, 1.776 mmol) in acetic acid (7.5 mL). The reaction mixture was stirred in an ice bath and warmed up to room temperature in one hour before placed in a 55° C. oil bath overnight. The crude was combined with the crude from an identical probe reaction (33 mg scale). The combined crude was poured into an ice/water mixture and neutralized by NaHCO3. The resulting mixture was extracted with EtOAc. The separated organic phase was dried over Na2SO4, filtered and evaporated to afford a dark mixture. This dark crude mixture was purified by flash chromatography (SiO2, Biotage SNAP Cartridge, silica gel, KP-Sil, 100 g cartridge). The column was eluted by an EtOAc/hexanes mixture (0% to 30%). Related fractions were pooled and evaporated to afford a white solid as the titled compound. LCMS calc.=434.95. found=435.77 (M+H)+. 1H NMR (CDCl3, 500 MHz) δ 9.13 (d, J=2.0 Hz, 1H), 8.38 (d, J=1.5 Hz, 1H), 8.02 (s, 1H), 7.60 (dd, J=12.5, 2.0 Hz, 1H), 4.45 (q, J=7.0 Hz, 2H), 4.03 (s, 3H), 1.44 (t, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][C:23]([C:25]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[C:30]5[C:26]=4[CH:27]=[CH:28][NH:29]5)=[N:22][C:21]=3[C:38](O)=[O:39])=[CH:16][CH:15]=2)[CH2:10][C:9]1([CH3:42])[CH3:41])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[N:45]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.N.O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[O:24][C:23]([C:25]4[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:35])[F:37])=[C:30]5[C:26]=4[CH:27]=[CH:28][NH:29]5)=[N:22][C:21]=3[C:38](=[O:39])[NH2:45])=[CH:18][CH:19]=2)[CH2:10][C:9]1([CH3:41])[CH3:42])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3oc(-c4ccc(C(F)(F)F)c5[nH]ccc45)nc3C(=O)O)cc2)CC1(C)C
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3oc(-c4ccc(C(F)(F)F)c5[nH]ccc45)nc3C(N)=O)cc2)CC1(C)C
Reaction time: 2 h

Procedure:
A mixture of 4-{4-[4-carboxy-2-(7-trifluoromethyl-1H-indol-4-yl)-oxazol-5-yl]-phenyl}-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester, EDCI HCl (0.36 g, 0.002 mol) and HOBt (0.3 g, 0.002 mol) in 15 mL of DMF and 15 mL of NH3 in dioxane was stirred for 2 hrs. The solvents were removed in vacuo. The residue was partitioned between water and EtOAc, the organic phase dried over Na2SO4 and the solvent removed in vacuo to give the crude title compound product (0.18 g crude).
Reaction SMILES: [C:1]([N:3]([CH3:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=1)#[N:2].[C:12]1([NH2:22])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.Cl>>[C:12]1([NH:22][C:1]([N:3]([C:4]2[CH:5]=[C:6]([CH3:10])[CH:7]=[CH:8][CH:9]=2)[CH3:11])=[NH:2])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: Nc1cccc2ccccc12
Reactant: Cc1cccc(N(C)C#N)c1
Agent: Cl
Product: Cc1cccc(N(C)C(=N)Nc2cccc3ccccc23)c1
Temperature: 25 °C

Procedure:
A mixture of N-cyano-N-methyl-3-toluidine (0.47 g, 3.22 mmol) and 1-naphthylamine.HCl (0.54 g, 3 mmol) in a 5 ml round bottom flask was heated in a preheated oil bath at 170°-190° C. for 3 h under N2. The dark brown solution was allowed to cool to room temperature, and it became a rocky solid. The crude product was flash chromatographed on silica gel to yield N-(1-naphthyl)-N'-(m-tolyl)-N'-methylguanidine.HCl (40% yield) as a white powder. Elemental analysis: IR (CH2Cl2): 1625, 1600, 1560 cm-1. 1NMR (CDCl3): δ 2.135 (s, 3H), 3.536 (s, 3H), 6.847-7.972 (m, 11H). 13C -NMR (CDCl3): 20.9, 41.0, 122.6-141.6, 155.8. C19H2oN3OCl.1/256 H2O. (Cacl.) C: 70.02%, H: 6.19%, N: 12.89%; (Found) C: 70.33%, H: 6.20%, N: 12.90%