Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH:6]1[CH2:11][C:10]2[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][C:9]=2[S:8](=[O:21])(=[O:20])[NH:7]1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30].C(OCC)(=O)C>O1CCCC1>[O:21]=[S:8]1(=[O:20])[C:9]2[CH:15]=[C:14]([C:16]([F:18])([F:17])[F:19])[CH:13]=[CH:12][C:10]=2[CH2:11][CH:6]([CH2:5][N:4]([CH2:3][CH2:2][OH:1])[C:29](=[O:30])[O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[NH:7]1
Reactant: O=S1(=O)NC(CNCCO)Cc2ccc(C(F)(F)F)cc21
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N(CCO)CC1Cc2ccc(C(F)(F)F)cc2S(=O)(=O)N1
Reaction time: 0.42 h
Yield: 51.4 %

Procedure:
To a solution of 3,4-dihydro-N-(2-hydroxyethyl)-7-(trifluoromethyl)-2H-1,2-benzothiazine-3-methanamine 1,1-dioxide (124 mg, 0.382 mmol) in tetrahydrofuran (4 mL) was added, sequentially, 0.5 N aqueous sodium carbonate (2 mL, 1 mmol) and benzyl chloroformate (0.066 mL, 0.46 mmol). The reaction was stirred for 25 min. The layers were separated and the aqueous layer was extracted with dichloromethane (5 mL). The combined organic layers were washed with saturated sodium chloride (5 mL) and were concentrated in vacuo. To the residue taken up in methanol (5 mL) was added 2 N potassium hydroxide (0.5 mL). After 15 min, the reaction was brought to pH 4 with 1 N HCl. The reaction was concentrated in vacuo to remove the methanol. The residue was partitioned between dichloromethane (10 mL) and water (5 mL). The organic layer was dried (magnesium sulfate) and concentrated in vacuo to provide a yellow oil. Chromatography of this residue (silica, 30% ethyl acetate/hexanes to ethyl acetate gradient) provided 90 mg (51%) of a phenylmethyl [(3,4-dihydro-1,1-dioxido-7-(trifluoromethyl)-2H-1,2-benzothiazin-3-yl)methyl](2-hydroxyethyl)carbamate as a white solid: LCMS (neg. ion spectrum) m/z 457.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH2:10])=[O:4].C(=O)([O-])[O-].[K+].[K+].[C:17](Cl)(=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1>C(#N)C.O>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1)=[O:4]
Reactant: COC(=O)c1sccc1N
Reactant: COc1cccc(C(=O)Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1sccc1NC(=O)c1cccc(OC)c1

Procedure:
To a solution of methyl-3-amino-2-thiophenecarboxylate, 20, (8.0 g) in acetonitrile (100 mL) was added potassium carbonate (7.73 g) followed by m-anisoyl chloride, 23, (7.51 mL). The reaction mixture was heated to reflux, then cooled and diluted with water. 3-(3-Methoxy-benzoylamino)-thiophene-2-carboxylic acid methyl ester, 24, (12.78 g) was subsequently collected as a white solid.
Reaction SMILES: [C:1]1([N:7]([CH2:30][CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])(C)C)=[O:34])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:40].C(O)C.C(=O)([O-])[O-].[NH4+:48].[NH4+]>ClCCl.C(O)C>[ClH:40].[ClH:40].[C:1]1([N:7]([CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:39])=[O:34])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:20]=[CH:21][C:22]([C:25](=[NH:26])[NH2:48])=[CH:23][CH:24]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(=O)N(CCCC(=O)OC(C)(C)C)c3ccccc3)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CCCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Yield: 68 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-tert-butyloxycarbonylpropyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 68% of theory, C29H32N6O3 (512.6); Rf value: 0.12 (silica gel; dichloromethane/ethanol=4:1); EKA mass spectrum: (M+H)+=513; (M+H+Na)++=268.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9])[CH:2]=[CH2:3].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1CCCC1.[C:25]1([Se:31]Cl)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[CH2:1]([CH:4]1[CH2:8][CH2:7][CH:6]([Se:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:5]1=[O:9])[CH:2]=[CH2:3]
Reactant: C=CCC1CCCC1=O
Reactant: Cl[Se]c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC1CCC([Se]c2ccccc2)C1=O
Temperature: -65 °C
Yield: 70.5 %

Procedure:
While under a nitrogen, a solution of 2-allylcyclopentanone (12.4 g, 100 mmol) in anhydrous tetrahydrofuran (100 mL) was cooled to −70° C. and treated with 1 N lithium bis(tri-methylsilyl)amide/tetrahydrofuran (200 mL, 200 mmol) at a rate to keep pot temperature below −55° C. Once the addition was complete, the mixture was stirred at −60 to −70° C. for one additional hour. A second solution of phenylselenyl chloride (19.5 g, 102 mmol) in anhydrous tetrahydrofuran (50 mL) was added dropwise and the mixture stirred at −60 to −70° C. for 30 min, then allowed to warm to 0° C. The reaction was quenched by addition of the solution to a rapidly stirred mixture of ethyl acetate (500 mL) and 5% aqueous citric acid (200 mL), and the organic layer was separated. The aqueous solution was extracted with ethyl acetate (2×100 mL) and the combined organic solution was washed with saturated aqueous sodium chloride (200 mL), dried (MgSO4), and concentrated in vacuo. The residue was dissolved in heptane and loaded onto a silica gel column (˜600 cc) and eluted with 2:1 heptane/dichloromethane, then with 1:1 heptane/dichloromethane to afford 2-allyl-5-(phenylselanyl)cyclopentanone (19.7 g, 71%) as a pale yellow oil. NMR (CDCl3): δ 7.40-7.50 (m, 2 H), 7.05-7.25 (m, 3 H), 5.50-5.70 (m, 1 H), 4.80-4.95 (m, 2 H), 3.45-3.75 (m, 1 H), 2.30-2.50 (m, 1 H), 1.80-2.25 (m, 5 H), 1.50-1.75 (m, 1 H). MS (M+1): 279.1/280.9 (for 2 major isotopes of Se).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[C:17]([F:23])[C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:24])[N:7]=1)=[O:5])[CH3:2].Br[C:26]1[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[C:17]([F:23])[C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:26]3[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=3)[C:14]=2[CH3:24])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)n1
Reactant: CCn1cc(Br)cn1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(CC)c3)c3c(F)c(Cl)ccc23)n1

Procedure:
Prepared according to the procedure described in Example 9, Step 4, using the following starting materials: 6-(6-chloro-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-pyridine-2-carboxylic acid ethyl ester and 4-bromo-1-ethyl-1H-pyrazole.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13](CC3C=C(F)C=CC=3Br)[C:12](=[O:23])[N:11]([CH3:24])[C:10](=[O:25])[CH:9]=2)[CH2:3]1.[Cl:26][C:27]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:28]=1[CH2:29]Br>>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:29][C:28]3[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:27]=3[Cl:26])[C:12](=[O:23])[N:11]([CH3:24])[C:10](=[O:25])[CH:9]=2)[CH2:3]1
Reactant: Cn1c(=O)cc(N2CCC[C@@H](N)C2)n(Cc2cc(F)ccc2Br)c1=O
Reactant: Clc1ccc(Cl)c(CBr)c1
Product: Cn1c(=O)cc(N2CCC[C@@H](N)C2)n(Cc2cc(Cl)ccc2Cl)c1=O

Procedure:
The title compound was prepared from compound 1 using the same procedures as in the preparation of compound 10, except that 2,5-di-chloro-benzyl bromide was used in the place of 2-bromo-5-fluoro-benzyl bromide. 1H-NMR (400 MHz, CDCl3-CD3OD 10:1): 6 ppm 7.50 (d, J=8.6 Hz, 1 H), 7.39 (dd, J=8.3, 2.526 Hz, 1 H), 7.22 (d, J=2.5 Hz, 1 H), 5.41 (s, 1 H), 5.01-4.93 (ABq, J=41.9, 16.2 Hz, 2H), 3.25 (m, 2 H), 3.10 (s, 3H), 2.85 (m, 1 H), 2.76 (m, 1 H), 2.67 (m, 1 H), 1.91 (m, 1 H), 1.75 (m, 1 H), 1.45 (m, 2 H). MS (ES) [m+H] calc'd for C17H21Cl2N4O2, 383.1. found 383.1.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:15])=[C:9]([NH:11][C:12](=[O:14])C)[CH:10]=1)[CH3:2].[H-].[Na+].ClC1O[C:21]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([Cl:30])[CH:25]=2)=[CH:22][N:23]=1>CN(C=O)C>[Cl:30][C:26]1[CH:25]=[C:24]([C:21]2[O:14][C:12]([NH:11][C:9]3[CH:10]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[CH:6]=[CH:7][C:8]=3[CH3:15])=[N:23][CH:22]=2)[CH:29]=[CH:28][N:27]=1
Reactant: CCOCc1ccc(C)c(NC(C)=O)c1
Reactant: Clc1cc(-c2cnc(Cl)o2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCc1ccc(C)c(Nc2ncc(-c3ccnc(Cl)c3)o2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
A solution of N-(5-(ethoxymethyl)-2-methylphenyl)ethanamide (344 mg, 1.66 mmol) in DMF (5 mL) was added to a suspension of NaH (133 mg, 3.32 mmol, 60% dispersion in mineral oil) in DMF (5 mL) at 0° C. under an atmosphere of argon. The mixture was stirred for 1 h at room temperature and cooled to 0° C. A solution of 2-chloro-5-(2-chloropyridin-4-yl)oxazole (357 mg, 1.66 mmol) in DMF (5 mL) was added dropwise to the mixture. After 1 h at 0° C., the reaction was poured into ice water (20 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and filtered. After removal of solvent the residue was silica gel column chromatographed (CH2Cl2/Ethanol:98/2) to give 474 mg of 5-(2-chloropyridin-4-yl)-N-(5-(ethoxymethyl)-2-methylphenyl) oxazol-2-amine (83%) as a beige solide.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[CH2:14]([N:16]([CH2:27][CH3:28])[CH2:17][CH2:18][O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)[CH3:15]>>[CH2:5]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:24][C:23]1[CH:22]=[CH:21][C:20]([O:19][CH2:18][CH2:17][N:16]([CH2:14][CH3:15])[CH2:27][CH3:28])=[CH:26][CH:25]=1)=[O:13])=[CH:5]2)[C:4]1[CH:8]=[CH:9][CH:10]=[CH:2][CH:3]=1
Reactant: CCN(CC)CCOc1ccc(N)cc1
Reactant: O=C(O)c1cc2cc(O)ccc2[nH]1
Product: CCN(CC)CCOc1ccc(NC(=O)c2cc3cc(OCc4ccccc4)ccc3[nH]2)cc1

Procedure:
The entitled compound was obtained as a white solid in the same manner as in Example 1-1 but using 5-hydroxyindole-2-carboxylic acid and 4-[2-(diethylamino)ethoxy]aniline.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([CH:30]([NH:35][S:36]([C:39]([CH3:42])([CH3:41])[CH3:40])(=O)=[O:37])[C:31]([F:34])([F:33])[F:32])=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[CH3:43][Si]([N-][Si](C)(C)C)(C)C.[Li+]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([CH:30]([N:35]([CH3:43])[S:36]([C:39]([CH3:42])([CH3:40])[CH3:41])=[O:37])[C:31]([F:33])([F:34])[F:32])=[N:9][N:10]([C:11]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:4]=2[CH:3]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)S(=O)(=O)NC(c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12)C(F)(F)F
Agent: [Li+]
Product: CN(C(c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12)C(F)(F)F)S(=O)C(C)(C)C
Temperature: 25 °C
Yield: 49.7 %

Procedure:
N-(1-(6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfonamide (108 mg, 0.181 mmol) was cooled to 0° C. and charged with lithium bis(trimethylsilyl)amide (0.217 ml, 0.217 mmol) followed by iodomethahe (0.011 ml, 0.181 mmol) (˜2 drops). The reaction was allowed to warm to rt overnight. Quenched excess LiHMDS with methanol and evaporated solvents on the V-10. The residue was purified on silica, 10-50% DCM/EtOAc to provide N-(1-(6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2-sulfinamide (53 mg, 0.09 mmol, 48% yield) MS ESI Calc'd for C32H30ClF3N4OS [M+H]+ 611, found 611.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C:22]3[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=3)[CH:15]=2)=[C:9]([CH3:30])[CH:8]=1.C(N(CC)CC)C>C(OCC)(=O)C>[CH3:1][S:2]([O:6][C:7]1[CH:8]=[C:9]([CH3:30])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C:22]3[CH:23]=[CH:24][C:25]([CH:26]=[O:27])=[CH:28][CH:29]=3)[CH:15]=2)=[C:11]([CH3:13])[CH:12]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(O)cc(C)c1-c1cccc(COc2ccc(C=O)cc2)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(OS(C)(=O)=O)cc(C)c1-c1cccc(COc2ccc(C=O)cc2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Methanesulfonyl chloride was dropwise added under ice-cooling to a mixture of 4-[(4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methoxy]benzaldehyde, triethylamine and ethyl acetate, followed by stirring at 0° C. for 2 hours to obtain 3′-[(4-formylphenoxy)methyl]-2,6-dimethylbiphenyl-4-yl methanesulfonate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Br:8])=[N:6][CH:7]=1.[CH3:9][C:10](=O)[CH2:11][CH2:12][C:13](=O)[CH3:14]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:4]=[CH:3][C:2]([N:1]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:9])=[CH:7][N:6]=1
Reactant: Nc1ccc(Br)nc1
Reactant: CC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1ccc(Br)nc1
Yield: 75.1 %

Procedure:
To a 25 mL round bottom flask was added 5-amino-2-bromopyridine (600 mg, 3.5 mmol, 1.0 equiv), hexane-2,5-dione (420 mg, 4.2 mmol, 1.2 equiv), p-toluenesulfonic acid (5 mg), and toluene (3.5 mL). A Dean-Stark trap was fitted on top of the round bottom flask and the reaction mixture was heated to reflux for 2 h. The reaction was then concentrated and purified by silica gel column chromatography (5% ethyl acetate/hexanes) to give 660 mg (76%) of 2-bromo-5-(2,5-dimethyl-1H-pyrrol-1-yl)pyridine.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:29]=[CH:28][C:7]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)[C:10]([O:12]C)=[O:11])=[CH:6][CH:5]=1.O>CO>[Cl:3][C:4]1[CH:29]=[CH:28][C:7]([O:8][CH:9]([C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[CH:18][CH:19]=2)[C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1
Reactant: COC(=O)C(Oc1ccc(Cl)cc1)c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C(Oc1ccc(Cl)cc1)c1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 94.3 %

Procedure:
To a solution of 10 g of KOH in 80 ml of 50% methanol is added 30.2 g of methyl (p-chlorophenoxy)-[p-(p-chlorophenoxy)phenyl]acetate. The mixture is refluxed for 3 hours, cooled, poured into 100 ml of water. The solution is extracted with two 100-ml portions of ether. The aqueous layer is acidified with concentrated hydrochloric acid. The mixture is extracted with two 100-ml portions of ether and the extracts are washed with water, brine and dried (MgSO4). Evaporation of the solvent yields an oil which is triturated with petroleum ether to give 27.5 g of product as white crystals. Recrystallization from hexane-chloroform gives white plates, mp 141°-142° C.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][N:5]([C:16](=[O:24])[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:8][CH:7]=1.[C:25](Cl)(=[O:27])[CH3:26].CCN(CC)CC>C(Cl)Cl>[CH3:1][S:2][CH2:3][CH2:4][N:5]([C:16](=[O:24])[C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)[C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:25](=[O:27])[CH3:26])(=[O:13])=[O:14])=[CH:8][CH:7]=1
Reactant: CSCCN(C(=O)c1ccc(F)cc1)c1ccc(S(N)(=O)=O)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSCCN(C(=O)c1ccc(F)cc1)c1ccc(S(=O)(=O)NC(C)=O)cc1
Yield: 80.3 %

Procedure:
A solution of 4-[(2-methylthio-ethyl)-(4-fluoro-benzoyl)-amino]-benzenesulfonamide (0.32 g, 0.88 mmol), acetyl chloride (0.069 mL, 76 mg, 0.97 mmol), and Et3N (0.13 mL, 97 mg, 0.96 mmol) in CH2Cl2 (9 mL) was heated at reflux for 2 h. After cooling, the mixture was evaporated in vacuo, and the residue was purified by MPLC (CH2Cl2 to 60:40 CH2Cl2/EtOAc) to afford 0.29 g (81%) of 4-[(2-methylthio-ethyl)-(4-fluoro-benzoyl)-amino]-N-acetyl-benzenesulfonamide as a colorless glass; 1H NMR δ 2.03 (s, 3H), 2.15 (s, 3H), 2.77 (m, 2H), 4.15 (m, 2H), 6.90 (dd, 2H, J=7.5, 7.5), 7.24 (d, 2H, J=9.0), 7.32 (dd, 2H, J=3.0, 9.0), 7.92 (d, 2H, J=9.0), 9.1 (br s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([O:23][CH3:24])[CH:17]=3)=[N:10][N:11]([CH2:13][C:14]#[N:15])[CH:12]=2)[CH:5]=[C:4]([NH:25][CH2:26][C@@H:27]([OH:29])[CH3:28])[N:3]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:29][C@@H:27]([CH3:28])[CH2:26][NH:25][C:4]1[N:3]=[C:2]([C:32]2[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=2)[N:7]=[C:6]([C:8]2[C:9]([C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([O:23][CH3:24])[CH:17]=3)=[N:10][N:11]([CH2:13][C:14]#[N:15])[CH:12]=2)[CH:5]=1
Reactant: COc1cc(C)cc(-c2nn(CC#N)cc2-c2cc(NC[C@H](C)O)nc(Cl)n2)c1
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cc(C)cc(-c2nn(CC#N)cc2-c2cc(NC[C@H](C)O)nc(-c3cccnc3)n2)c1
Temperature: 75 °C
Reaction time: 0.17 h
Yield: 66.8 %

Procedure:
In a two-necked round-bottom flask, [4-[2-chloro-6-(2(S)-hydroxy-propylamino)-pyrimidin-4-yl]-3-(3-methoxy-5-methylphenyl)pyrazol-1-yl]acetonitrile (370 mg, 0.9 mmol), 3-pyridine boronic acid (143.27 mg, 1.17 mmol), bis(triphenylphosphine)palladium (II) dichloride (18.88 mg, 0.027 mmol), and potassium carbonate (75.98 mg, 0.72 mmol) were dissolved in a mixture of acetonitrile and water (10 mL, 1:1, v/v) through which nitrogen gas was then flowed for 10 min and heated at 75° C. for 3 hours. After completion of the Suzuki coupling reaction, the reaction mixture was dissolved in water and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and distilled under vacuum. The purification of the concentrate by chromatography produced the title compound (274 mg, 67.1%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH2:14])=[CH:5][N:4]=1)#[N:2].[N+:15]([CH:18]=[C:19](SC)SC)([O-:17])=[O:16]>C(O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[CH2:11][CH2:12][CH2:13][NH:14][C:19]2=[CH:18][N+:15]([O-:17])=[O:16])=[CH:5][N:4]=1)#[N:2]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: N#Cc1ccc(CNCCCN)cn1
Solvent: CCO
Product: N#Cc1ccc(CN2CCCNC2=C[N+](=O)[O-])cn1
Temperature: 25 °C
Yield: 63.7 %

Procedure:
A mixture of N-(2-cyano-5-pyridylmethyl)trimethylenediamine (1.9 g), 1-nitro-2,2-bis(methylthio)ethylene (1.6 g) and ethanol (30 ml) was refluxed for 5 hours with stirring. The reaction mixture was cooled to room temperature. The precipitated crystals were collected by filtration, and washed with ethanol to give pale yellow 1-(2-cyano-5-pyridylmethyl)-2-(nitromethylene)tetrahydropyrimidine (1.6 g). mp. 214°-216° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](=[O:11])[N:8]([CH3:10])[CH:9]=1)([O-])=O>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7](=[O:11])[N:8]([CH3:10])[CH:9]=1
Reactant: Cn1cc([N+](=O)[O-])ccc1=O
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cn1cc(N)ccc1=O
Reaction time: 8 h

Procedure:
To a suspension of 5-nitro-1-methyl-2(1H)-pyridone (154 mg, 0.999 mmol) in ethyl acetate (3 mL) and ethanol (3 mL) was added 5% Pd—C (36 mg), and the resulting mixture was stirred under hydrogen atmosphere overnight. The reaction mixture was filtered and the filtrate was concentrated in vacuo to obtain the title compound as light-green oil. 1H NMR (CD3OD 400 MHz): δ=3.53 (s, 3H), 6.49 (d, 1H, J=9.6 Hz), 7.07 (d, 1H, J=3.2 Hz), 7.28 (dd, 1H, J=2.8 & 9.6 Hz). MS (ES+): m/z 125.04 (100) [MH+]. HPLC: tR=0.43 min (ZQ2000, polar—5 min).
Reaction SMILES: [CH:1]([C:4]1[C:9](=[O:10])[NH:8][C:7](=[O:11])[NH:6][C:5]=1[O:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([CH3:21])[CH:20]=1)[CH:16]=O)([CH3:3])[CH3:2].[C:22]([CH2:24]P(=O)(OCC)OCC)#[N:23].CC(C)([O-])C.[K+]>C1COCC1.CC(=O)OCC>[CH:1]([C:4]1[C:9](=[O:10])[NH:8][C:7](=[O:11])[NH:6][C:5]=1[O:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:24][C:22]#[N:23])[CH:18]=[C:19]([CH3:21])[CH:20]=1)([CH3:3])[CH3:2]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: Cc1cc(C=O)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C=CC#N)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reaction time: 1 h
Yield: 40 %

Procedure:
To a stirred mixture of 3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yloxy)-5-methyl-benzaldehyde (788 mg, 2.73 mmol) and diethyl cyanomethyl-phosphonate (451 μl, 2.79 mmol) in THF (15 ml) at 0° C. (ice bath) under nitrogen atmosphere, was added potassium t-butoxide (920 mg, 8.2 mmol). After stirring for 1 hr., the mixture was stirred for overnight at room temperature. The mixture was then diluted with EA, washed with aqueous saturated ammonium chloride solution, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, EA: hexanes (from 2:3 to 1:1)) to afford 340 mg (40%) of a white solid. m.p. 279-280° C.; 1H NMR (200 MHz, DMSO-d6) δ 1.05 (6H, d, J=7.0 Hz), 2.33 (3H, s), 2.78 (1H, m), 6.55 (1H, d, J=16.8 Hz), 7.03 (1H, s), 7.21 (1H, s), 7.25 (1H, s), 7.62 (1H, d, J=16.8 Hz), 11.05 (1H, s), 11.31 (1H, s); m/z (LC/Mass, EI) 312 (M+H+).
Reaction SMILES: Cl.O1CCOCC1.[NH2:8][C:9]1[N:10]=[CH:11][C:12]([C:26]2[CH2:27][CH2:28][N:29](C(OC(C)(C)C)=O)[CH2:30][CH:31]=2)=[N:13][C:14]=1[C:15]1[N:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:17][N:16]=1>CO>[C:20]1([C:18]2[O:17][N:16]=[C:15]([C:14]3[C:9]([NH2:8])=[N:10][CH:11]=[C:12]([C:26]4[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=4)[N:13]=3)[N:19]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cnc(N)c(-c3noc(-c4ccccc4)n3)n2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Nc1ncc(C2=CCNCC2)nc1-c1noc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.6 %

Procedure:
A solution of HCl in dioxane (505.5 μL of 4 M, 2.022 mmol) was added to a solution of tert-butyl 4-[5-amino-6-(5-phenyl-1,2,4-oxadiazol-3-yl)pyrazin-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (170 mg, 0.4043 mmol) in methanol (5 mL) at rt and the reaction mixture stirred at room temperature for 48 h. The reaction mixture was concentrated in vacuo to give the title compound (129 mg, 99% yield); MS (ES+) 321.03
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([NH:9][CH2:10][CH2:11][N:12]2[C:17](=[O:18])[CH:16]=[CH:15][C:14]([C:19]([OH:21])=O)=[CH:13]2)=[O:8])[CH:2]=1.[CH3:22][N:23](C)C=O.C(N(CC)CC)C>C(OCC)(=O)C>[CH3:22][NH:23][C:19]([C:14]1[CH:15]=[CH:16][C:17](=[O:18])[N:12]([CH2:11][CH2:10][NH:9][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:8])[CH:13]=1)=[O:21]
Reactant: O=C(O)c1ccc(=O)n(CCNC(=O)c2cccnc2)c1
Reactant: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc(=O)n(CCNC(=O)c2cccnc2)c1
Temperature: -8 °C
Reaction time: 2.25 h

Procedure:
To a 100 ml round bottomed flask fitted with a magnetic stirrer bar and nitrogen inlet was added 1,6-dihydro-l-[2-(3-pyridinylcarbonylamino)ethyl]-6-oxo-3-pyridinecarboxylic acid (0.22 g, 0.77 mmol) methylamine hydrochloride (0.104 g, 1.54 mmol), and dimethylformamide (25.5 ml). The reaction mixture was cooled in a -8° C. ice bath and treated with triethylamine (1.07 ml, 7.7 mmol) and propylphosphonic acid anhydride (0.55 ml, added as a 0.55 ml ethyl acetate solution, Angew. Chemie 1980, 92(2), 129). The flask was allowed to warm slowly to room temperature and stirred for 2.25 hours. The mixture was concentrated, slurried in aqueous sodium bicarbonate, and again concentrated. The residue was slurried in methanol and filtered. Further purification of the solid recovered from filtration via flash column chromotography (silica gel, 15-20% methanol/dichloromethane) gave the product, MP: 208°-210° C.