Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[C:9]([C:13]3[CH:14]=[C:15]4[C:20](=[N:21][CH:22]=3)[N:19]([C:23]([NH2:25])=[O:24])[CH2:18][CH2:17][CH2:16]4)[CH:10]=[N:11][CH:12]=2)[CH2:3][CH2:2]1.O[O:27][S:28]([O-:30])=O.[K+]>O1CCOCC1.O>[O:27]=[S:28]1(=[O:30])[CH2:2][CH:3]=[C:4]([C:7]2[CH:8]=[C:9]([C:13]3[CH:14]=[C:15]4[C:20](=[N:21][CH:22]=3)[N:19]([C:23]([NH2:25])=[O:24])[CH2:18][CH2:17][CH2:16]4)[CH:10]=[N:11][CH:12]=2)[CH2:5][CH2:6]1
Reactant: O=S([O-])OO
Reactant: NC(=O)N1CCCc2cc(-c3cncc(C4=CCSCC4)c3)cnc21
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)N1CCCc2cc(-c3cncc(C4=CCS(=O)(=O)CC4)c3)cnc21
Reaction time: 2 h
Yield: 101.8 %

Procedure:
To 6-[5-(3,6-dihydro-2H-thiopyran-4-yl)-pyridin-3-yl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (57 mg, 0.16 mmol) in 2 mL of 1:1 dioxane/H2O is added oxone (266 mg, 0.32 mmol). The mixture is stirred for 2 h. The mixture is quenched by addition of sodium sulfite and concentrated. The residue is suspended into MeOH and filtered. The filtrate is concentrated and purified via the Preparative HPLC (5%-70% CH3CN/H2O) to give 62.6 mg of the titled product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:14])[N+:9]=2[O-])[CH:4]=1.C1(C)C=CC(S([Cl:24])(=O)=O)=CC=1>ClC(Cl)C>[Cl:24][CH2:14][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc2c(ccc(C)[n+]2[O-])c1
Solvent: CC(Cl)Cl
Product: COc1ccc2nc(CCl)ccc2c1
Temperature: 100 °C
Yield: 34.1 %

Procedure:
6-Methoxyquinaldine N-Oxide (6.94 g, 36.71 mmol) was added to a stirring solution of p-toluenesulfonylchloride (7.0 g, 36.84 mmol) in dichloroethane (100 mL). The reaction was heated to 100° C. overnight, partitioned between 10% K2CO3 /ethyl acetate, dried over MgSO4, and evaporated under reduced pressure. The crude solid was purified by HPLC to afford 2.6 g (37%) of chloride.
Reaction SMILES: [C:1]1(=[O:17])[N:5]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13](O)=[O:14])=[CH:8][CH:7]=2)[C:4](=[O:16])[CH:3]=[CH:2]1.C(Cl)(=O)C([Cl:21])=O>ClCCl>[C:1]1(=[O:17])[N:5]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13]([Cl:21])=[O:14])=[CH:8][CH:7]=2)[C:4](=[O:16])[CH:3]=[CH:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1ccc(N2C(=O)C=CC2=O)cc1
Solvent: ClCCl
Product: O=C(Cl)Cc1ccc(N2C(=O)C=CC2=O)cc1
Temperature: 35 °C
Reaction time: 15 h
Yield: 59 %

Procedure:
1.0 g (4.33 mmol) of p-maleinimidophenylacetic acid were suspended in 25 ml of dichloromethane and diluted with a 2.5-fold excess of oxalic acid dichloride (1.37 g, 945 μl; 10.82 mmol). The reaction mixture was heated to 30-40° C. with the exclusion of moisture and stirred for 15 h. Then the solvent was removed under a vacuum and dried under a high vacuum. Crystallization from toluene yielded a yellow powder (yield: 59%); melting point: 154° C.; Rf-value: 0.29 (acetic ester/hexane 4/1)
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2].[N:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[CH:28][CH:27]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.CS(C)=O>O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:33][CH2:32][C:29]4[CH:28]=[CH:27][C:26]([O:25][CH2:24][CH2:23][N:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)=[CH:31][CH:30]=4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2]
Reactant: NCc1ccc(OCCN2CCOCC2)cc1
Reactant: CCn1ncc2c(Cl)c3ccccc3nc21
Solvent: CS(C)=O
Solvent: O
Product: CCn1ncc2c(NCc3ccc(OCCN4CCOCC4)cc3)c3ccccc3nc21
Temperature: 25 °C
Yield: 77.2 %

Procedure:
A mixture of 1-ethyl-4-chloro-1H-pyrazolo[3,4-b]quinoline (0.7 g, 3 mmol), 4-[2-(4-morpholinyl)ethoxy]phenylmethylamine (0.75 g, 3.2 mmol) and DMSO (3 mL) was heated on a steam bath for 8 hours. Additional 1-ethyl-4-chloro-1H-pyrazolo[3,4-b]quinoline (0.7 g, 3 mmol) was then added and the reaction mixture was heated on a steam bath for another 4 hours. The reaction mixture was cooled to room temperature and then was poured into water. The mixture was extracted with CH2Cl2 (3×100 mL) and then CH2Cl2 layers were combined, dried over MgSO4 and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with CH2Cl2 /methanol (95/5), followed by recrystallization from ethyl acetate, to afford 1.0 g of 1-ethyl-N-[4-[2-(4-morpholinyl)ethoxy]phenylmethyl]-1H-pyrazolo[3,4-b]quinolin-4amine, as a yellow solid, m.p. 170°-172° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][CH:10]=1.[OH-].[K+]>O1CCOCC1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[S:15][C:12]1[CH:13]=[CH:14][C:9]([NH2:8])=[CH:10][CH:11]=1
Reactant: Clc1ccccn1
Reactant: Nc1ccc(S)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1ccc(Sc2ccccn2)cc1
Temperature: 60 °C
Yield: 84.7 %

Procedure:
A mixture of 22.7 g of 2-chloropyridine, 25 g of 4-aminothiophenol, 12.4 g of potassium hydroxide and 100 ml of dioxane was heated at 60° C. for about 2 hours to react them, and the product was purified to obtain 34.2 g of 4-(pyridine-2-ylthio) aniline. A mixture of 10 g of 4-(pyridine-2-ylthio) aniline, 5.6 g of triethylamine and 70 ml of chloroform was cooled at lower 5° C. in nitrogen gas atmosphere and 17 g of trifluoromethanesulfonic anhydride was added dropwise to the mixture. After the addition, the mixture was further stirred at 40° to 50° C. for about 1 hour to react them.
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][C:6]1[CH:15]=[CH:14][C:13]2[CH2:12][CH2:11][CH2:10][CH:9](O)[C:8]=2[N:7]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[Br:2][CH:9]1[C:8]2[N:7]=[C:6]([CH3:5])[CH:15]=[CH:14][C:13]=2[CH2:12][CH2:11][CH2:10]1
Reactant: Cc1ccc2c(n1)C(O)CCC2
Reactant: BrP(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1ccc2c(n1)C(Br)CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
Phosphorus tribromide (0.0105 mol) was added dropwise at 0° C./5° C. under N2 flow to a mixture of (±)-5,6,7,8-tetrahydro-2-methyl-8-quinolinol (intermediate 17) (0.03 mol) in toluene (20 ml). The mixture was brought to room temperature and stirred at room temperature overnight. Ice water was added. The mixture was basified with a concentrated NaOH solution and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue (6 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 99/1; 20–45 μm). The pure fractions were collected and the solvent was evaporated, yielding 2 g (29%) of (±)-8-bromo-5,6,7,8-tetrahydro-2-methylquinoline (interm. 18).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[F:23])[NH2:19].C(=O)(O)[O-].[Na+]>C(O)C.[Cl-].[Na+].O>[Cl:15][C:16]1[CH:17]=[C:18]([NH:19][C:2]2[C:11]3[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:13]#[N:14])[CH:20]=[CH:21][C:22]=1[F:23]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: N#Cc1cnc2cnc(F)cc2c1Cl
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(F)c(Cl)c1
Yield: 83.6 %

Procedure:
To 600 mg of 4-chloro-6-fluoro-[1.7]naphthyridine-3-carbonitrile in 15 mL of absolute ethanol was added 500 mg of 3-chloro-4-fluoroaniline. After refluxing the reaction under an inert atmosphere for 2 hours, the reaction mixture was poured into a mixture of brine and saturated aqueous sodium bicarbonate and the resultant crystals were filtered and washed with water. The product was then recrystallized from chloroform/hexanes. Drying in vacuo yielded 765 mg (83%) of 4-(3-chloro-4-fluoro-phenylamino)-6-fluoro-[1.7]naphthyridine-3-carbonitrile as yellow needles: melting point 108-111° C.; mass spectrum (m/e): M+H 316.8.
Reaction SMILES: [CH:1]1([CH2:4][C:5](=O)/[C:6](/[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:12]=2)=[CH:7]\N(C)C)[CH2:3][CH2:2]1.[OH:25][CH2:26][CH2:27][NH:28][C:29]([NH2:31])=[NH:30].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:1]1([CH2:4][C:5]2[C:6]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]4[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=4)[N:12]=3)=[CH:7][N:31]=[C:29]([NH:28][CH2:27][CH2:26][OH:25])[N:30]=2)[CH2:3][CH2:2]1
Reactant: CN(C)/C=C(\C(=O)CC1CC1)c1ccnc(Nc2ccncc2)n1
Reactant: N=C(N)NCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCNc1ncc(-c2ccnc(Nc3ccncc3)n2)c(CC2CC2)n1
Temperature: 120 °C
Reaction time: 2 h
Yield: 16.2 %

Procedure:
To a solution (3Z)-1-cyclopropyl-4-(dimethylamino)-3-[2-(pyridin-4-ylamino)pyrimidin-4-yl]but-3-en-2-one (9) (50 mg, 0.155 mmol) in DMF (1288 μl), 1-(2-hydroxyethyl)guanidine (23.92 mg, 0.232 mmol) and potassium carbonate (107 mg, 0.773 mmol) were added dropwise, and the reaction mixture was stirred at 120° C. for 2 hours. The crude product was purified by reverse-phase HPLC [30-90% organic phase over 15 minutes] followed by Biotage™ silica gel chromatography [10 g SNAP column, 100% DCM to 12% MeOH/DCM] to obtain the desired product (9.13 mg, 16.3%).
Reaction SMILES: [N+:1]([C:4]1[N:8]2[CH:9]=[C:10]([S:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:11]=[CH:12][C:7]2=[N:6][CH:5]=1)([O-])=O.[H][H]>[Pd].O1CCOCC1>[NH2:1][C:4]1[N:8]2[CH:9]=[C:10]([S:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:11]=[CH:12][C:7]2=[N:6][CH:5]=1
Reactant: O=[N+]([O-])c1cnc2ccc(Sc3ccccn3)cn12
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: Nc1cnc2ccc(Sc3ccccn3)cn12

Procedure:
A solution of 0.542 gm. (0.002 mole) of 3-nitro-6-(2-pyridylthio) imidazo [1,2-a] pyridine in 20 ml. of dioxane is reduced at 40 psi. under a hydrogen atmosphere with 0.500 g. of 5% palladium on carbon as catalyst. When the uptake of hydrogen is complete, the catalyst is removed by filtration. The filtrate is evaporated in vacuo to yield 3-amino-6-(2-pyridylthio) imidazo [1,2-a] pyridine.
Reaction SMILES: Cl[C:2]1[C:3]([Cl:16])=[N:4][C:5]2[CH:6]=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=[CH:9][C:10]=2[N:11]=1.[CH2:17]([NH2:20])[C:18]#[CH:19]>O1CCOCC1>[Cl:16][C:3]1[C:2]([NH:20][CH2:17][C:18]#[CH:19])=[N:11][C:10]2[CH:9]=[C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]3=[CH:6][C:5]=2[N:4]=1
Reactant: Clc1nc2cc3ccccc3cc2nc1Cl
Reactant: C#CCN
Solvent: C1COCCO1
Product: C#CCNc1nc2cc3ccccc3cc2nc1Cl
Yield: 72.7 %

Procedure:
A mixture of 2,3-dichlorobenzo[g]quinoxaline (0.634 g, 2.55 mmol), propargylamine (0.21 ml, 3.05 mmol) and TEA (0.53 mL, 3.83 mmol) in 15 mL of dioxane was heated to reflux for 4.5 hours. After evaporating the resulting mixture under vacuum, the crude product was chromatographed (CH2Cl2) to afford the title compound as a yellow solid (0.496 g, 73%); mp 169-172° C.; IR (KBr, cm−1) 3412, 3283, 3235, 1570, 1508, 1335; −1H NMR (DMSO) δ 8.44 (s, 1H), 8.26 (s,1H), 8.16-8.06 (m, 3H), 7.58-7.54 (m, 1H), 7.51-7.48 (m, 1H), 4.28 (dd, J=6.1, 2.5, 2H), 3.12 (t, J=2.5, 1H); LC/MS 97.8% (220 nm), m/z (M+H+) 268.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11].C([O-])([O-])=O.[K+].[K+].[CH3:29][O:30][CH2:31]Cl>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:29][O:30][CH3:31])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: COCCl
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCN(c1ccc(Cl)cc1Br)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(2-bromo-4-chloro-phenyl)-4-tert-butyl-benzenesulfonamide (1.00 g, 2.49 mmol) and K2CO3 (1.72 g, 12.4 mmol) in 8 mL anhydrous THF was added chloromethyl methyl ether (299 mg, 3.73 mmol). The resultant heterogeneous solution was stirred for 60 minutes at ambient temperature and the solids were subsequently removed via filtration. The filtrate was subsequently concentrated in vacuo and the residue was dissolved in EtOAc. The organics were washed with saturated Na2CO3, dried over MgSO4, and evaporated in vacuo. The resultant residue was then purified via automated silica gel chromatography to afford the desired protected sulfonamide: MS (ES) M+H expected 446.0, found 446.0.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[ClH:13].[CH2:14]=O>CO>[ClH:13].[NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH2:14][Cl:13])[CH:7]=1)[C:3]([OH:5])=[O:4]
Reactant: C=O
Reactant: NC(C(=O)O)c1ccc(O)cc1
Agent: Cl
Solvent: CO
Product: NC(C(=O)O)c1ccc(O)c(CCl)c1
Reaction time: 0.12 h

Procedure:
To a solution of (-)-α-amino-4-hydroxybenzeneacetic acid (100 g, 0.6 mole) in a minimum amount of concentrated hydrochloric acid at 35°-40° C. is added 50 ml of aqueous formaldehyde (35-37%) (0.6 mole). The addition of hydrogen chloride gas is begun. After 5-10 minutes, a solid begins to precipitate. Stirring is continued for 30 minutes, and the solid is then collected. The crude product is washed with ether and with acetone. A second crop is obtained from the filtrate after standing at room temperature overnight. Total yield is 102 g (67%) m.p.>300° C., [α]D18 =-134° (c 4.75, CH3OH) MNR (DMSO-D6) ppm (δ) 4.68 (s,2), 4.9 (broad s,1), 6.9-7.6 (superimposed q and s,3).
Reaction SMILES: BrC1C=CC(S(O[CH2:12][C@@H:13]2[O:27][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]4)(=O)=O)=CC=1.[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1[N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>CS(C)=O.C(=O)(O)[O-].[Na+]>[CH3:26][C:21]1[CH:20]=[CH:19][C:18]2[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14][C@H:13]([CH2:12][N:41]4[CH2:40][CH2:39][N:38]([C:29]5[CH:30]=[CH:31][C:32]6[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=6)[CH:28]=5)[CH2:43][CH2:42]4)[O:27][C:17]3=2)[N:22]=1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Reactant: c1ccc2cc(N3CCNCC3)ccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc2c3c(ccc2n1)OC[C@H](CN1CCN(c2ccc4ccccc4c2)CC1)O3
Temperature: 50 °C
Yield: 69.8 %

Procedure:
A mixture of [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl 4-bromobenzenesulfonate (2.73 g, 6.06 mmol) and 1-naphthalen-2-yl-piperazine (3.86 g, 18.2 mmol) in anhydrous dimethylsulfoxide (60 mL) was heated at 50° C. overnight. The cooled reaction was diluted with saturated aqueous sodium bicarbonate (200 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography on silica gel (2/2/95 methanol/ammonium hydroxide/methylene chloride) did not provide clean product. Re-chromatography on silica gel (90/5/5 ethyl acetate/hexane/triethylamine) afforded 1.80 g (69%) of the title compound as a beige solid: mg 134–137° C.; MS (ES) m/z426 [M+H]+.
Reaction SMILES: [N:1]#[N:2].[S:3]([NH:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:27])[NH2:26])([C:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:11]([N:12]([CH3:14])[CH3:13])[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4].O.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38]([OH:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1.[CH:43]1[CH:48]=CC=[CH:45][CH:44]=1>C(O)CCC>[N:1]#[N:2].[C:32]1([CH3:42])[CH:33]=[CH:34][C:35]([S:38]([OH:41])(=[O:39])=[O:40])=[CH:36][CH:37]=1.[C:32]1([CH3:42])[CH:33]=[CH:34][C:35]([S:38]([OH:41])(=[O:39])=[O:40])=[CH:36][CH:37]=1.[CH2:48]([O:29][C:28](=[O:30])[C@H:20]([CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:26])[NH2:27])[NH:19][S:3]([C:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:11]([N:12]([CH3:13])[CH3:14])[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:4])=[O:5])[CH2:43][CH2:44][CH3:45]
Reactant: c1ccccc1
Reactant: CN(C)c1cccc2c(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)O)cccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#N
Solvent: CCCCO
Solvent: O
Product: CCCCOC(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1cccc2c(N(C)C)cccc12
Temperature: 100 °C
Yield: 95 %

Procedure:
A mixture of 1.0 gram of N2 -dansyl-L-arginine and 1.0 gram of p-toluenesulfonic acid monohydrate in 10 ml of n-butyl alcohol was heated for 30 minutes at 100° C. To the thus obtained clear solution, 100 ml of benzene was added, and the mixture was refluxed for 3 hours, removing water by azeotropic distillation. After the solvent was removed by distillation, 50 ml of ethyl ether and 50 ml of petroleum ether were added to the residue to give a crystalline mass. Crystallization from acetone gave N2 -dansyl-L-arginine n-butyl ester di(p-toluenesulfonate) in 95% yield: mp. 160°-164° C.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][OH:13])[CH2:8]1)=[O:6])[CH:2]=[CH2:3].[CH3:14]C(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C.C(OCC)(=O)C>CC(C)=O>[C:12]([CH:9]1[CH2:10][CH2:11][N:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH2:8]1)(=[O:13])[CH3:14]
Reactant: C=CCOC(=O)N1CCC(CO)C1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1CCC(C(C)=O)C1
Reaction time: 1 h

Procedure:
To a solution of 1-allyloxycarbonyl-3-hydroxymethylpyrrolidine (2.6 g) in acetone was added Jones reagent (1.25N, 20 ml) at ambient temperature. After stirring for 1 hour, isopropyl alcohol (10 ml) was added thereto. The resulting precipitate was removed by filtration and the filtrate was evaporated in vacuo. The residue was dissolved in dichloromethane, dicyclohexylcarbodiimide (0.79 g), Meldrum's acid (0.55 g), 4-methylaminopyridine (0.47 g) to the solution at 0° C. After stirring for 24 hours at ambient temperature, the resulting precipitate was removed by filtration. The filtrate was washed with 1N hydrochloric acid and evaporated in vacuo. The residue was dissolved in a mixture of acetic acid (10 ml) and water (7 ml), and the mixture was refluxed for 1 hour. Evaporation of the solvent gave a residue, which was taken up into ethyl acetate. The solution was washed in turn with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of n-hexane and ethyl acetate (2:1, V/V) to give 3-acetyl-1-allyloxycarbonylpyrrolidine (2.01 g).
Reaction SMILES: OC(C)(C)C[C@@:4]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H](C2C=CC(C3C=CN=C(OC)C=3)=CC=2)C)[CH2:6][CH2:5]1.C(=O)([O-])[O-].[K+].[K+].IC.Cl>C(#N)C>[C:27]1([CH:4]2[O:9][C:8](=[O:10])[NH:7][CH2:6][CH2:5]2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)ccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: O=C1NCCC(c2ccccc2)O1
Temperature: 25 °C
Yield: 133.2 %

Procedure:
(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(2-methoxypyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (28 mg, 0.061 mmol), potassium carbonate (17 mg, 2 equiv), and Iodomethane (40 μL, 10 equiv) were mixed with acetonitrile (2.5 mL) and heated at reflux for 4 h. After being cooled to rt, the mixture was acidified with 5% aq HCl and purified by prep HPLC to afford (S)-6-(2-hydroxy-2-methylpropyl)-3-(S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (14.4 mg. 52%). LC-MS and 1H NMR (CD3OD) were the same as those of product made by Method 1.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[CH2:10][C@H:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[C:28]([Si:32](Cl)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([CH3:31])([CH3:30])[CH3:29]>CN(C)C=O.O>[CH2:1]([O:8][C:9](=[O:22])[CH2:10][C@H:11]([NH:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:12][O:13][Si:32]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC(=O)OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (S)-3-tert-butoxycarbonylamino-4-hydroxy-butyric acid benzyl ester (1.34 g, 4.37 mmol) (prepared using the method of Rodriguez, Marc; Linares, Muriel; Doulut, Sylvie; Heitz, Annie; Martinez, Jean; Tetrahedron Lett. (1991), 32(7), 923-6) and imidazole (0.88 g, 13.01 mmol in dimethylformamide (7 ml) is treated with tertbutyldiphenylsilyl chloride (1.69 ml, 6.5 mmol). The reaction mixture is stirred together at room temperature for 1 hour, then diluted with water and extracted into ethylacetate. The ethylacetate phase is dried over MgSO4 and evaporated. The crude product is purified by flash silica chromatography (elution with 1:1 ethylacetate/hexane) to afford (S)-3-tert-butoxycarbonylamino-4-(tert-butyl-diphenyl-silanyloxy)-butyric acid benzyl ester. [M-BOC] 448.0.
Reaction SMILES: [OH-].[Na+].O.[CH:4]1([NH:7][C:8]2[N:18]=[C:17]([OH:19])[C:16]([F:20])=[CH:15][C:9]=2[C:10]([O:12]CC)=[O:11])[CH2:6][CH2:5]1>C(O)C>[CH:4]1([NH:7][C:8]2[N:18]=[C:17]([OH:19])[C:16]([F:20])=[CH:15][C:9]=2[C:10]([OH:12])=[O:11])[CH2:5][CH2:6]1
Reactant: CCOC(=O)c1cc(F)c(O)nc1NC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(F)c(O)nc1NC1CC1
Yield: 70.5 %

Procedure:
To a solution of 95% ethanol (20 ml) and 2N NaOH/H2O (40 ml) was added 2.65 g of ethyl 2-cyclopropylamino-5-fluoro-6-hydroxynicotinate. The inital suspension was refluxed for a total of six hours, then cooled, and evaporated to a solid. The solid was dissolved in 30 ml of H2O and acidified to pH=1 with 2N HCl solution. The solid formed upon acidification was collected by filtration and washed with H2O to give the crude acid product. This product was triturated with hot 95% ethanol, filtered, and dried to give 1.65 g of a beige colored solid, 2-cyclopropyl-5-amino-6-hydroxynicotinic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[C:4]([Cl:25])[CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[C:36]3[C:40](=[CH:41][CH:42]=2)[NH:39][CH:38]=[CH:37]3)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:25][C:4]1[CH:3]=[C:2]([C:34]2[CH:35]=[C:36]3[C:40](=[CH:41][CH:42]=2)[NH:39][CH:38]=[CH:37]3)[CH:7]=[CH:6][C:5]=1[N:8]1[C:12]([CH2:13][C@@H:14]2[CH2:18][CH2:17][N:16]([C:19]([CH:21]3[CH2:23][CH2:22]3)=[O:20])[CH2:15]2)=[N:11][NH:10][C:9]1=[O:24]
Reactant: CC1(C)OB(c2ccc3[nH]ccc3c2)OC1(C)C
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2Cl)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4[nH]ccc4c3)cc2Cl)C1
Temperature: 120 °C
Yield: 48 %

Procedure:
A mixture of 4-(4-bromo-2-chlorophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (140 mg, 0.329 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (80 mg, 0.329 mmol), potassium carbonate (182 mg, 1.315 mmol), and tetrakis(triphenylphosphine)palladium(0) (19.0 mg, 0.016 mmol) in 1,4-dioxane (5 mL) and water (2 mL) was heated at 120° C. for 3.5 hr. The reaction mixture was cooled and loaded onto a silica gel pre-column and purified by flash chromatography (dichloromethane to 6% methanol in dichloromethane) to afford the title product (73 mg, 0.158 mmol, 48% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.96-8.78 (m, 1H), 8.37 (br. s, 1H), 7.92-7.82 (m, 2H), 7.76-7.64 (m, 1H), 7.56-7.47 (m, 1H), 7.47-7.39 (m, 2H), 7.36-7.30 (m, 1H), 6.76-6.61 (m, 1H), 4.04-3.02 (m, 4H), 2.80-2.39 (m, 3H), 2.34-2.03 (m, 1H), 1.84-1.60 (m, 1H), 1.07-0.94 (m, 2H), 0.76 (dd, J=3.3, 7.8 Hz, 2H).