Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[CH3:4][C:5]1[O:10][CH2:9][N:8]([C:11]([CH3:17])([CH3:16])[C:12](=[O:15])[CH:13]=[CH2:14])[C:7](=[O:18])[C:6]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([S:3][CH2:14][CH2:13][C:12](=[O:15])[C:11]([N:8]1[C:7](=[O:18])[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:5]([CH3:4])[O:10][CH2:9]1)([CH3:17])[CH3:16])[CH3:2]
Reactant: CCS
Reactant: C=CC(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCSCCC(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Ethanethiol (0.0389 ml) was added to a mixture of 4-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-4-methylpent-1-en-3-one (100 mg) and potassium carbonate (4.85 mg) in N,N-dimethylformamide, and then stirred overnight at 20° C., and for 24 hours at 40° C. The mixture was purified by silica gel column chromatography eluting with isohexane/ethyl acetate (4:1) to give 5-ethylthio-2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpentan-3-one (Compound 1083, 45 mg), NMR 1.2(t,3H), 1.4(s,6H), 1.9(s,3H), 2.5(q,2H), 2.8(s,4H), 5.3(s,2H),7.2-7.4(m,5H).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([CH2:18]O)[C:13]=1[CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].S(Cl)([Cl:23])=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:1]([O:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][Cl:23])[C:13]=1[CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCOc1ccnc(CO)c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCOc1ccnc(CCl)c1C
Yield: 91.5 %

Procedure:
19.8 g (0.058 mol, 1.0 eq.) of 4-decyloxy-2-hydroxymethyl-3-methylpyridine was dissolved in 300 mL of ethyl acetate, and 7.6 g (0.064 mol, 1.1 eq.) of thionyl chloride was added dropwise at 12 to 18° C. Subsequently, the mixture was allowed to react for 0.5 hours at room temperature, and then a 7% aqueous solution of sodium bicarbonate (220 g) was added to adjust the reaction liquid to pH 7.5. The organic layer was washed with a 5% aqueous solution of sodium bicarbonate (160 g), dried over anhydrous magnesium sulfate, and then concentrated to dryness under reduced pressure, to obtain 15.8 g of 4-decyloxy-2-chloromethyl-3-methylpyridine as a black oily matter.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]([CH2:15][OH:16])([CH3:14])[NH:10][C:9]2=[O:17])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]([CH2:15][O:16][S:23]([CH3:22])(=[O:25])=[O:24])([CH3:14])[NH:10][C:9]2=[O:17])=[CH:4][C:3]=1[C:18]([F:19])([F:21])[F:20]
Reactant: CC1(CO)NC(=O)N(c2ccc(Cl)c(C(F)(F)F)c2)C1=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC1(COS(C)(=O)=O)NC(=O)N(c2ccc(Cl)c(C(F)(F)F)c2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
3-(4-Chloro-3-trifluoromethyl-phenyl)-5-hydroxymethyl-5-methyl-imidazolidine-2,4-dione from Example 10 (1.01 g, 3.14 mmoL) in DCM (10 mL) was treated with TEA (0.66 mL, 4.70 mmoL) followed by MsCl (360 mg, 3.14 mmoL) at 0° C. The reaction was slowly warmed to room temperature and stirring for another 2 hrs. The crude product was partitioned between DCM and water. The organic layer was washed with sat. NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated, then purified by silica gel column chromatography using heptane and ethyl acetate as eluent to afford the title compound as a white solid (1.05 g, yield 85%).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[CH:5][CH:4]=1)=O.[S:19]1[CH:23]=[C:22]([CH2:24][CH2:25][NH2:26])[C:21]2[CH:27]=[CH:28][CH:29]=[CH:30][C:20]1=2>>[S:19]1[CH:23]=[C:22]([CH2:24][CH2:25][NH:26][CH2:1][C:3]2[CH:18]=[CH:17][C:6]([O:7][C:8]3[CH:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=3)=[CH:5][CH:4]=2)[C:21]2[CH:27]=[CH:28][CH:29]=[CH:30][C:20]1=2
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)cn1
Reactant: NCCc1csc2ccccc12
Product: NC(=O)c1ccc(Oc2ccc(CNCCc3csc4ccccc34)cc2)cn1
Yield: 50.2 %

Procedure:
Using a method similar to Example 405, a reaction of 5-(4-formylphenoxy)pyridine-2-carboxamide (Example 388, Part D) (0.0366 g, 0.151 mmol) and 2-benzo[b]thiophen-3-ylethylamine (0.0295 g, 0.166 mmol) gives the title compound (0.0306 g, 50.2%): TOF MS ES+ 404.1 (M+H)+, HRMS calcd for C23H22N3O2S 404.1433 (M+H)+, found 404.1423, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=8.9 min. 100% purity.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[CH2:3][C:4](O)=[O:5].CO>C1COCC1>[NH2:1][CH:2]([C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1)[CH2:3][CH2:4][OH:5]
Reactant: NC(CC(=O)O)c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CO
Product: NC(CCO)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
Borane-tetrahydrofuran complex (94.0 mL, 93.92 mmol) was added dropwise to a stirred suspension of 3-amino-3-(4-chlorophenyl)propionic acid (2.50 g, 12.52 mmol) in THF (75 mL) at 0° C. over a period of 20 minutes under nitrogen. The resulting suspension was stirred at 0° C. for 30 minutes then at 22° C. for 5 hours. The reaction mixture was added portionwise to methanol (500 mL). The mixture was concentrated, redissolved in methanol (250 mL) and reconcentrated (this process was repeated three times). The residue was dissolved in DCM (200 mL) and washed with 1N NaOH (150 mL). The aqueous layer was extracted with DCM (5×100 mL) and the extracts combined with the organic layer. The combined organics were washed with saturated brine (2×150 mL), dried over MgSO4 and concentrated to afford a white semi-solid. The crude product was purified by flash silica chromatography, elution gradient 5 to 7% (10:1 MeOH/conc. NH3 (aq)) in DCM. Pure fractions were evaporated to dryness to afford 3-amino-3-(4-chlorophenyl)propan-1-ol (1.320 g, 56.8%) as a white solid.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH2:10][C:11]([O:13][CH3:14])=[O:12].Cl[CH:16](Cl)[O:17]C.Cl>ClCCl.O>[CH:16]([C:9]1[S:5][C:6]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:8]=1)=[O:17]
Reactant: COC(=O)Cc1cccs1
Reactant: COC(Cl)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)Cc1ccc(C=O)s1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 90.4 %

Procedure:
To a suspension of aluminium trichloride (853 mg, 6.4 mmol) in dichloromethane (4 mL) at −10° C. was added a solution of methyl 2-(2-thienyl)acetate (500 mg, 3.2 mmol) in dichloromethane (3 mL). The resulting solution was stirred at −10° C. for 10 minutes. A solution of dichloro(methoxy)methane (434 μL, 4.8 mmol) in dichloromethane (3 mL) was then added dropwise over 30 minutes. The reaction mixture was stirred at −10° C. for 1 h. The resulting solution was poured into a flask containing water (20 mL), crushed ice and concentrated HCl (1 mL) and stirred vigorously for 30 minutes. The solution was washed with dichloromethane (3×20 mL) and the combined organic phases washed with aqueous saturated sodium bicarbonate (30 mL) followed by brine (30 mL). The phases were separated over a hydrophobic frit and concentrated in vacuo to give the title compound as a red oil (533 mg, 91%) which was used in the next step without further purification.
Reaction SMILES: [CH:1]1[C:2]([I:10])=[CH:3][C:4]([I:9])=[C:5]([OH:8])[C:6]=1[I:7].[C:11](Cl)(=[O:16])[CH:12]=[CH:13][CH2:14][CH3:15].C(N(CC)CC)C>ClCCl>[C:11]([O:8][C:5]1[C:6]([I:7])=[CH:1][C:2]([I:10])=[CH:3][C:4]=1[I:9])(=[O:16])[CH2:12][CH2:13][CH:14]=[CH2:15]
Reactant: Oc1c(I)cc(I)cc1I
Reactant: CCC=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCCC(=O)Oc1c(I)cc(I)cc1I

Procedure:
First, 9 g of triiodophenol was dissolved in 150 mL dichloromethane under argon. Then, 3.15 mL of pentenoyl chloride was added while stirring. Triethylamine was then added slowly and stirred for 4 hr. The solution was washed with 100 mL of water and evaporated to dryness, leaving 2,4,6-triiodophenyl penta-4-enoate.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:20])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[OH:19])[CH2:6][CH2:5]1)(=O)C.[ClH:21]>>[ClH:21].[OH:19][C:12]1[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:11]=1[C:10]([CH:7]1[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]1)=[O:20]
Reactant: COc1ccc(C(=O)C2CCN(C(C)=O)CC2)c(O)c1
Agent: Cl
Product: COc1ccc(C(=O)C2CCNCC2)c(O)c1
Temperature: 25 °C

Procedure:
To a round-bottom flask, equipped with a condenser and mechanical stirrer, was added 25.0 g of 1-acetyl-4-(2-hydroxy-4-methoxybenzoyl)piperidine and 148 ml of 6 N hydrochloric acid. The reaction mixture was stirred under reflux for 6 hrs and overnight at ambient temperature. The precipitate was collected, washed with acetone and recrystallized twice from ethanol to yield 16.70 g of product, mp, 264°-266°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][C:10]=1[OH:11])=[O:5])[CH3:2].C(N=C(O)N(C(C)C)[C:21]([CH3:24])([CH3:23])[CH3:22])(C)C>C(Cl)Cl>[C:21]([O:11][C:10]1[CH:9]=[C:8]([C:12]([O:14][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:13])[S:7][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)N=C(O)N(C(C)C)C(C)(C)C
Reactant: CCOC(=O)c1sc(C(=O)O)cc1O
Solvent: ClCCl
Product: CCOC(=O)c1sc(C(=O)OC(C)(C)C)cc1OC(C)(C)C
Reaction time: 12 h
Yield: 33 %

Procedure:
A solution of ethyl-3-hydroxy-5-carboxy-2-thiophenecarboxylate(25 g, 0.115 mmol) in dry (25 g, 0.115 mmol) in dry CH2Cl2 (200 ml) was treated, at ambient temperature, with diisopropyl-tert-butylisourea (175 ml) added dropwise. This caused an exotherm which heated the mixture to reflux. The reaction mixture was then stirred for 12 hours, the solid removed by filtration, and the CH2Cl2 evaporated. The residual oil was purified by subjecting to silica gel chromatography, eluting with petroleum ether: ether (90:10) to give a mixture of two products (28.5 g). These two products were separated by flash chromatography, eluting with CH2Cl2 : petroleum ether (1:1), to give title compound (12.6 g, 33%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:17][CH:16]=1.[OH-].[Na+].Cl>CO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(OCCCN4CCOCC4)cc3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(OCCCN4CCOCC4)cc3)cc12

Procedure:
A solution of methyl 6-chloro-5-{4-[3-(morpholin-4-yl)propoxy]phenyl}-1H-indole-3-carboxylate (24 mg, 0.056 mmol) in methanol (0.5 mL) and 1 M sodium hydroxide (0.17 mL, 0.17 mmol) was heated at 75° C. for 24 hours. The reaction was acidified with 1 M HCl to pH=2 then diluted with ethyl acetate. The layers were separated and the aqueous layer was back-extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified using reverse-phase chromatography to give the title compound as the formic acid salt. MS (ES+) 415.129 (M+H)+ Retention time: 2.2 min; Waters Atlantis dC18 5 μm 4.6×50 mm, 95% H2O/5% MeCN linear to 5% H2O/95% MeCN over 4.0 min, HOLD at 5% H2O/95% MeCN to 5.0 min. (0.05% TFA) Flow: 2.0 mL/min.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CC(C)=O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:4]([CH3:9])[CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1cc(I)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(I)cc1C
Yield: 103.2 %

Procedure:
4-Iodo-2-methylphenol (3.0 g, 12.9 mmol) was dissolved in acetone (250 ml) at room temperature, and then potassium carbonate (2.67 g, 19.4 mmol, 1.5 eq.) was added thereto and vigorously stirred. Ethyl bromoacetate (1.56 ml, 14.1 mmol, 1.5 eq.) was quickly added to the mixture, and then reacted further at room temperature for 4 hours. After completion of the reaction, the reaction mixture was extracted with aqueous ammonium chloride solution and ethyl acetate, and dried over magnesium sulfate. The crude product was purified on silica flash column. The solvent was evaporated under reduced pressure to thereby yield 4.26 g of the title compound (yield: 98.5%).
Reaction SMILES: I.[NH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:7]([C:11]2[N:15]([C:16]3[CH:17]=[CH:18][C:19]([F:24])=[C:20]([CH:23]=3)[C:21]#[N:22])C(=O)[O:13][N:12]=2)=[N:8][O:9][N:10]=1.[S:26](N)([NH2:29])(=[O:28])=[O:27].[OH-].[Na+].O>N1C=CC=CC=1>[NH2:29][S:26]([NH:2][CH2:3][CH2:4][NH:5][C:6]1[C:7]([C:11](=[N:12][OH:13])[NH:15][C:16]2[CH:17]=[CH:18][C:19]([F:24])=[C:20]([C:21]#[N:22])[CH:23]=2)=[N:8][O:9][N:10]=1)(=[O:28])=[O:27]
Reactant: N#Cc1cc(-n2c(-c3nonc3NCCN)noc2=O)ccc1F
Reactant: NS(N)(=O)=O
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: N#Cc1cc(NC(=NO)c2nonc2NCCNS(N)(=O)=O)ccc1F
Temperature: 120 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
In a microwave vial, 5-[3-{4-[(2-aminoethyl)amino]-1,2,5-oxadiazol-3-yl}-5-oxo-1,2,4-oxadiazol-4(5H)-yl]-2-fluorobenzonitrile hydroiodide (20.0 mg, 0.044 mmol) and sulfamide (25 mg, 0.26 mmol) were suspended in pyridine (0.5 mL). The reaction was heated to 120° C. for 10 minutes in a microwave reactor. The solvent was removed and the residue dissolved in methanol (0.17 mL). A solution of 2.0 N NaOH in water (0.22 mL, 0.44 mmol) was added in one portion. The reaction was stirred at room temperature overnight. After neutralization with acetic acid (50 μL), the product was purified using preparative LCMS to give the title compound (4.9 mg, 29%). LCMS for C12H14FN8O4S (M+H)+: m/z=385.0. 1H NMR (400 MHz, DMSO-d6): δ 11.65 (s, 1H), 9.08 (s, 1H), 7.34 (t, J=9.1 Hz, 1H), 7.22 (dd, J=5.4, 2.8 Hz, 1H), 7.13 (m, 1H), 6.70 (t, J=5.9 Hz, 1H), 6.59 (s, 2H), 6.20 (t, J=6.1 Hz, 1H), 3.34 (m, 2H), 3.09 (m, 2H).
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[C:10]([CH3:21])=[C:11]([C:14]([O:19][CH3:20])=[C:15]([CH3:18])[C:16]=1[CH3:17])[CH2:12]Cl.[CH3:22][NH:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[CH:34]([CH3:36])[CH3:35]>CN(C)C=O>[OH:8][C:9]1[C:10]([CH3:21])=[C:11]([C:14]([O:19][CH3:20])=[C:15]([CH3:18])[C:16]=1[CH3:17])[CH2:12][N:23]([CH2:24][CH2:25][O:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[CH:34]([CH3:36])[CH3:35])[CH3:22]
Reactant: CNCCOc1cc(C)ccc1C(C)C
Reactant: COc1c(C)c(C)c(O)c(C)c1CCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1c(C)c(C)c(O)c(C)c1CN(C)CCOc1cc(C)ccc1C(C)C
Temperature: 25 °C
Yield: 93.6 %

Procedure:
Triethylamine (7.0 ml) was added dropwise to a solution of 3-hydroxy-6-methoxy-2,4,5-trimethylbenzyl chloride (10.73 g) and N-methyl-2-(2-isopropyl-5-methylphenoxy)ethylamine (10.37 g) in N,N-dimethylformamide (60 ml) while stirring the mixture at room temperature. Immediately after the dropwise addition, heat was developed and salt was precipitated. The mixture was stirred at room temperature for 2 hours and triethylamine (2.0 ml) was added. The mixture was stirred for 1 hour. The reaction mixture was poured on ice water and extracted with ethyl acetate to give a crude product. The product was purified by silica gel chromatography (eluent; ethyl acetate/benzene=1/1) to give 18.03 g of the title compound (pale brown solid).
Reaction SMILES: [Cl:1][C:2]1[C:6]([S:7]([N:10]=[C:11]=[O:12])(=[O:9])=[O:8])=[CH:5][S:4][N:3]=1.[CH3:13][C:14]1[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([NH2:21])[N:15]=1>C(Cl)Cl>[Cl:1][C:2]1[C:6]([S:7]([NH:10][C:11]([NH:21][C:16]2[N:17]=[C:18]([CH3:20])[CH:19]=[C:14]([CH3:13])[N:15]=2)=[O:12])(=[O:8])=[O:9])=[CH:5][S:4][N:3]=1
Reactant: O=C=NS(=O)(=O)c1csnc1Cl
Reactant: Cc1cc(C)nc(N)n1
Solvent: ClCCl
Product: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2csnc2Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 10 ml portion of the methylene chloride solution of 3-chloro-4-isothiazolesulfonyl isocyanate, prepared in Example 2, was added to 0.2 g of 4.6-dimethyl-2-pyrimidinamine, and the mixture stirred 0.5 hour at ambient temperature. The solvent was evaporated and the residual solid triturated with ether, collected and dried giving 0.5 g of the title compound, m.p. 136°-140°. IR: 1720 and 1700 cm-1 (C=O).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:10][NH:11][C:5]=2[NH:4][C:3]1=O.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:3]1[N:2]([CH3:1])[C:7](=[O:8])[C:6]2[C:9]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:10][NH:11][C:5]=2[N:4]=1
Reactant: Cn1c(=O)[nH]c2[nH]nc(Nc3ccccc3)c2c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: Cn1c(Cl)nc2[nH]nc(Nc3ccccc3)c2c1=O
Yield: 72 %

Procedure:
5-methyl-3-(phenylamino)-1H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (4.3 g, 16.7 mmol) is refluxed in POCl3 (120 mL) for 2 days, and then POCl3 is removed under reduced pressure. The residue is suspended in 100 mL of water and carefully adjusted to pH=1˜2 with 7% NH4OH upon cooling. The mixture is then extracted with CH2Cl2 and MeOH (10:1, v/v) five times. The combined organic phase is washed with water, dried over Na2SO4, and then evaporated under reduced vacuum to give 3.3 g of crude product (Yield: 72%). MS (ESI) m/z 276.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:31][O:32][CH2:33]Cl.[Cl-].[NH4+]>ClCCl>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][O:21][CH2:31][O:32][CH3:33])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCl
Reactant: COC(=O)c1cc(CCO)ccc1OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOCCc1ccc(OCc2ccccc2)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a stirred solution of methyl 2-benzyloxy-5-(2-hydroxyethyl)benzoate (1.43 g) in dichloromethane (20 ml) were added N,N-diisopropylethylamine (1.0 ml) and chloromethyl methyl ether (460 μl) under ice-cooling, and the mixture was stirred for 17 hours at room temperature. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with dichloromethane. The extract was washed with brine and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, purification of the residue by flash column chromatography on silica gel (eluent: hexane/ethyl acetate=4/3) gave methyl 2-benzyloxy-5-(2-methoxymethoxyethyl)benzoate (1.19 g).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25](SC)[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([Cl:34])=[CH:16][C:15]=2[F:35])=[O:12])[N:7]([CH3:36])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:37][NH2:38].C1COCC1>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25]([NH:38][CH3:37])[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([Cl:34])=[CH:16][C:15]=2[F:35])=[O:12])[N:7]([CH3:36])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)(C)C)nn4C)c(F)cc3Cl)c(=O)n(C)c2n1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)(C)C)nn4C)c(F)cc3Cl)c(=O)n(C)c2n1
Yield: 23 %

Procedure:
Using a procedure analogous to example A1, 1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(4-chloro-2-fluoro-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.2, 0.38 mmol) and 2 M methylamine in THF (3 eq) were combined and purified via C-18 chromatography to provide 1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3(4-chloro-2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea as a white solid (0.045 g, 23% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.95 (brs, 2H), 8.61 (s, 1H), 8.17 (d, J=8.8 Hz, 1H), 7.87 (brs, 1H), 7.75 (s, 1H), 7.55 (d, J=10.8 Hz, 1H), 6.04 (s, 1H), 3.58-3.51 (m, 6H), 2.90 (s, 3H), 1.16 (s, 9H); MS (ESI) m/z: 513.3 (M+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=1.[Li+].CC([N-]C(C)C)C.Br[CH2:23][C:24]#[C:25][Si:26]([CH3:29])([CH3:28])[CH3:27]>C1COCC1>[CH3:27][Si:26]([CH3:29])([CH3:28])[C:25]#[C:24][CH2:23][CH:7]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: C[Si](C)(C)C#CCBr
Reactant: c1cncc(Cc2cccnc2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CCC(c1cccnc1)c1cccnc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In an oven-dried 100-mL round-bottom flask was placed di(pyridin-3-yl)methane (0.100 g, 0.58 mmol) in dry THF (10 mL) under N2. The solution was cooled to 0° C. and LDA (0.580 mL of a 1.5 M solution, 0.87 mmol) was slowly added to form a dark red suspension. The suspension was stirred for 15 min at 0° C. and then 3-bromo-1-(trimethylsilyl)-1-propyne (0.164 mL, 1.16 mmol) was added via syringe. The reaction was warmed to rt, quenched with water (1 mL), and extracted with dichloromethane (2×25 mL). The organic layers were combined and dried over Na2SO4, filtered and concentrated to give the crude product 3-(4-(trimethylsilyl)-1-(pyridin-3-yl)but-3-ynyl)pyridine. This material was dissolved in methanol (5 mL), K2CO3 (0.500 g, 3.6 mmol) was added, and the mixture was stirred at rt for 48 h. The reaction was filtered and washed with dichloromethane (2×10 mL), then concentrated and dried. Purification by reverse phase chromatography gave 0.119 g (47%) of 3-(1-(pyridin-3-yl)but-3-ynyl)pyridine as a TFA salt. Analytical LCMS: single peak (214 nm), 0.416 min. ESIMS m/z 209.1 (C14H12N2+H+ requires 209.1079).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[F:13])[CH:5]=[CH:6][C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[CH3:20][N:21]([CH3:37])[CH:22]1[CH2:26][CH2:25][N:24]([C:27]2[S:28][C:29]3[CH:35]=[C:34]([NH2:36])[CH:33]=[CH:32][C:30]=3[N:31]=2)[CH2:23]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]([NH:36][C:34]2[CH:33]=[CH:32][C:30]3[N:31]=[C:27]([N:24]4[CH2:25][CH2:26][CH:22]([N:21]([CH3:37])[CH3:20])[CH2:23]4)[S:28][C:29]=3[CH:35]=2)=[O:9])[CH:10]=[CH:11][C:12]=1[F:13]
Reactant: O=C(O)C=Cc1ccc(F)c(F)c1
Reactant: CN(C)C1CCN(c2nc3ccc(N)cc3s2)C1
Agent: O=C(Cl)C(=O)Cl
Product: CN(C)C1CCN(c2nc3ccc(NC(=O)C=Cc4ccc(F)c(F)c4)cc3s2)C1
Yield: 77 %

Procedure:
Prepare according to Method C (Example 9), using 3,4-difluorocinnamic acid (107 mg, 0.581 mmol), oxalyl chloride (250 μL, 2.87 mmol), and 2-(3-dimethylamino-pyrrolidin-1-yl)-benzothiazol-6-ylamine (100 mg, 0.382 mmol) to afford the title compound (126 mg, 77%). mass spectrum (m/e): 429.0 [M+H], 427.0 [M−H]. 1H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.25 (d, 1H, J=0.9 Hz), 7.72 (m, 1H), 7.55 (d, 1H, J=15.3 Hz), 7.52-7.48 (m, 2H), 7.43-7.41 (m, 2H), 6.80 (d, 1H, J=15.8 Hz), 3.70 (dd, 1H, J=9.7, 7.0 Hz), 3.61 (m, 1H), 3.47 (m, 1H), 3.26 (dd, 1H, J=9.9, 8.1 Hz), 2.88 (m, 1H), 2.21-2.17 (m, 7H), 1.90 (m, 1H).