Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Br:5][C:6]1[CH:15]=[C:14]2[C:9]([N:10]=[C:11]([O:18][CH3:19])[C:12]([O:16][CH3:17])=[N:13]2)=[C:8]([CH2:20]Br)[CH:7]=1.O>CN(C)C=O>[N:1]([CH2:20][C:8]1[CH:7]=[C:6]([Br:5])[CH:15]=[C:14]2[C:9]=1[NH:10][CH:11]([O:18][CH3:19])[CH:12]([O:16][CH3:17])[NH:13]2)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1nc2cc(Br)cc(CBr)c2nc1OC
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1Nc2cc(Br)cc(CN=[N+]=[N-])c2NC1OC
Reaction time: 3 h

Procedure:
743 mg (2 equiv.) of sodium azide are added at 20° C. to 2.07 g (5.72 mmol) of 7-bromo-5-bromomethyl-2,3-dimethoxy-quinoxaline in 25 ml of dimethylformamide. After 3 hours, the mixture is poured into water, extracted with diethyl ether, washed with water and brine and dried with magnesium sulfate. The solvent is concentrated by evaporation.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][CH3:15])=[CH:9][CH:8]=1)[CH3:2].Cl[CH2:18][C:19]1[S:23][C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)=[N:21][C:20]=1[CH3:34].[Na+].[I-].[H-].[Na+]>CN(C=O)C.CCOCC.O>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH2:14][CH3:15])[CH2:18][C:19]2[S:23][C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[N:21][C:20]=2[CH3:34])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCNc1ccc(OCC(=O)OCC)cc1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(N(CC)Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.7 %

Procedure:
To an ice-cooled and stirred solution of crude (4-ethylamino-phenoxy)-acetic acid ethyl ester (0.243 g, containing 0.214 g, 0.96 mmol), 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole (0.308 g, 1.05 mmol, WO02/28433) and NaI (0.144 g, 0.96 mmol) in DMF (3 ml) was added NaH (55% in oil, 0.063 g, 1.44 mmol). The reaction was stirred at RT for 4 h, water was added and diluted with Et2O and extracted with aqueous saturated NaHCO3/Et2O (3×). The organic phases were washed with aqueous saturated NaHCO3, dried (Na2SO4) and evaporated to give 0.32 g (70%) of crude (4-{ethyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-phenoxy)-acetic acid ethyl ester as an orange oil, MS: 479 (MH+).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2/[CH:11]=[CH:12]/[C:13]1[CH:14]=[C:15]([NH:20][C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH:16]=[CH:17][C:18]=1[CH3:19].[NH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:19][C:18]1[CH:17]=[CH:16][C:15]([NH:20][C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)=[CH:14][C:13]=1/[CH:12]=[CH:11]/[N:6]1[CH:5]=[N:4][C:3]2[C:7]1=[N:8][CH:9]=[N:10][C:2]=2[NH:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1
Reactant: Nc1cccnc1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1/C=C/n1cnc2c(Cl)ncnc21
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1/C=C/n1cnc2c(Nc3cccnc3)ncnc21
Temperature: 25 °C

Procedure:
(E)-N-(3-(2-(6-Chloro-9H-purin-9-yl)vinyl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (0.046 g, 0.10 mmol), 3-aminopyridine (0.022 g, 0.22 mmol), Pd2(dba)3 (5 mol %), 2-(dicyclohexylphosphino)biphenyl (7.5 mol %) and K3PO4 (0.032 g, 0.15 mmol) were mixed in DME. The mixture was heated at reflux under N2 for 15 h, cooled to rt, and partitioned between aq. Na2CO3 and EtOAc. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, concentrated on a rotavap, and then purified by RP HPLC (acetonitrile/water/0.1% TFA): MS [M+H]+ 515.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=O)[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.Cl.[CH3:15][NH:16][OH:17]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[N+:16]([O-:17])[CH3:15])[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: O=C(Cn1ccnc1)c1cccs1
Reactant: CNO
Agent: Cl
Product: C[N+]([O-])=C(Cn1ccnc1)c1cccs1

Procedure:
As illustrated in the following diagram, the thienyl compounds of this invention can be prepared by an initial bromination of 2-acetylthiophene 1, and reacting the resulting bromo derivative 2 with imidazole to produce the 1-(2-thienyl)-2-(1H-imidazol-1-yl)ethanone 3. Reaction of compound 3 with N-methylhyroxylamine hydrochloride provides the 1-(2-thienyl)-2-(1H-imidazol-1-yl)-N-methylethanimine N-oxide 4 which is included in the subject matter of our co-pending application Ser. No. 900,856 filed Aug. 27, 1986 entitled "α-Substituted Ketonitrone Derivatives" whose disclosure is incorporated herein by reference. The nitrone compound 4 is then treated with styrene or an appropriate styrene (or allyl phenyl ether or alkyl phenyl thioether) derivative 5 to give a diastereomeric mixture of the desired cis- and trans-5-(phenyl, phenoxymethyl or phenylthiomethyl)-3-(2-thienyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine 6. ##STR3##
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[C:8]([O-:12])(=[O:11])[CH:9]=[CH2:10]>>[C:1]([O:6][C:4](=[O:5])[CH:3]=[CH2:2])(=[O:7])/[CH:10]=[CH:9]\[C:8]([OH:12])=[O:11]
Reactant: O=C1C=CC(=O)O1
Reactant: C=CC(=O)[O-]
Product: C=CC(=O)OC(=O)/C=C\C(=O)O

Procedure:
U.S. Pat. No. 5,135,984 describes a method for modifying a chlorinated polyolefin with maleic anhydride and an acrylic-modified hydrogenated polybutadiene. This method involves the graft copolymerization of the chlorinated polyolefin with the maleic acid anhydride and acrylate modified hydrogenated polybutadiene by heating the mixture in the presence of a peroxide initiator. This results in an acrylic- and maleic anhydride-modified chlorinated polyolefin.
Reaction SMILES: [CH3:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6](=[O:18])[C:5]([C:19]([OH:21])=[O:20])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].I[CH2:29][CH3:30]>CN1C(=O)CCC1>[CH3:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:17])[F:15])[CH:9]=2)[C:6](=[O:18])[C:5]([C:19]([O:21][CH2:29][CH3:30])=[O:20])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1ccc(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 25 °C
Reaction time: 19 h
Yield: 87.5 %

Procedure:
A suspension of 6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylic acid (Example 1 (b), 13.1 g, 43.9 mmol), sodium carbonate (5.2 g, 48.3 mmol) and iodoethane (10.6 g, 67.7 mmol) in NMP (60 ml) was stirred at ambient temperature for 19 h under a nitrogen atmosphere. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was collected, washed with water and brine, dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica eluting with tert-butyl methyl ether/methanol (10:0.4) to give the title compound as a light brown solid (12.5 g, 87%).
Reaction SMILES: [NH2:1][C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[N:7]=1)([CH3:5])[CH2:3][OH:4].C([O-])([O-])=O.[K+].[K+].[Cl:19][CH2:20][C:21](Cl)=[O:22].CO>C(Cl)Cl.O>[Br:12][C:8]1[N:7]=[C:6]([C:2]([NH:1][C:21](=[O:22])[CH2:20][Cl:19])([CH3:5])[CH2:3][OH:4])[CH:11]=[CH:10][CH:9]=1
Reactant: CC(N)(CO)c1cccc(Br)n1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CC(CO)(NC(=O)CCl)c1cccc(Br)n1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of 2-amino-2-(6-bromo-pyridin-2-yl)-propan-1-ol (4.9 g, 21.2 mmol) in DCM (50 ml) was added K2CO3 (5.86 g, 42.4 mmol). The reaction mixture was cooled to 0° C. and 2-chloroacetyl chloride (2.55 ml, 3.59 g, 31.8 mmol) was added dropwise. The reaction mixture was allowed to warm to rt and to stir for 5 h. MeOH (20 ml) was added and stirring was continued at rt for 1 h. The reaction mixture was diluted with H2O and DCM, the phases were separated and the aq. phase was twice extracted with DCM. The combined org. phases were dried over Na2SO4, filtered and the solvent was removed to leave N-[1-(6-bromo-pyridin-2-yl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide as an orange oil. HPLC RtH4=0.73-0.77 min; ESIMS: 307, 309 [(M+H)+]; 1H NMR (400 MHz, DMSO-d6): δ 8.35 (s, 1H), 7.70-7.66 (m, 1H), 7.48 (dd, 1H), 7.38 (dd, 1H), 5.05-5.02 (m, 1H), 4.14 (s, 2H), 3.68-3.66 (m, 2H), 1.55 (s, 3H).
Reaction SMILES: Cl.[OH:2][C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[I-].C[N+]1C=CN([C:16](=[O:25])[N:17]([CH3:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)C=1.C(N(CC)CC)C>C(#N)C>[N:4]1[CH:5]=[CH:6][CH:7]=[N:8][C:3]=1[O:2][C:16](=[O:25])[N:17]([CH3:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Reactant: Oc1ncccn1
Agent: Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN(C(=O)Oc1ncccn1)c1ccccc1
Yield: 11.6 %

Procedure:
A solution of 2-hydroxypyrimidine hydrochloride (0.40 g, 3.00 mmol), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.83 ml, 6.00 mmol) in acetonitrile (15 ml) was stirred at room temperature overnight. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate) followed by crystallisation from ethyl acetate:heptane yielding the title compound (0.08 g, 12% yield) as a white solid.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]3([CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]3)[C:9](=[O:13])[NH:10]2)=[CH:6][CH:5]=1>CO>[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]3([CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]3)[C:9](=[O:13])[NH:10]2)=[CH:6][CH:5]=1
Reactant: O=C1CCC2(CC1)C(=O)Nc1cc(Br)ccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C1Nc2cc(Br)ccc2C12CCC(O)CC2

Procedure:
Sodium borohydride (77 mg, 2.0 mmol) was added portionwise to a stirred suspension of 6′-bromospiro[cyclohexane-1,3′-indoline]-2′,4-dione (preparation 21a, 0.30 g, 1.0 mmol) in methanol (14 mL) at room temperature. After 2.5 hours the mixture was concentrated in vacuo and water was added. The mixture was extracted with ethyl acetate and the organic layer was dried (MgSO4) and evaporated to give the title compound as a mixture of isomers. Separation of the isomers was achieved by reverse phase chromatography (C-18 silica from Waters©, water/acetonitrile/methanol as eluents [0.1% v/v formic acid buffered] 0% to 60%) to give, in order of elution, the pure minor isomer as a white solid (0.075 g, 25%):
Reaction SMILES: CS[CH:3]1[N:6]([CH2:7][C:8](=[O:15])[CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])[C:5](=[O:16])[CH2:4]1.[Cl:17]Cl>C(Cl)(Cl)(Cl)Cl>[Cl:17][CH:3]1[N:6]([CH2:7][C:8](=[O:15])[CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])[C:5](=[O:16])[CH2:4]1
Reactant: COC(=O)C(C)C(=O)CN1C(=O)CC1SC
Reactant: ClCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(C)C(=O)CN1C(=O)CC1Cl
Temperature: 0 °C
Reaction time: 0.05 h
Yield: 104.2 %

Procedure:
Methyl 4-(4-methylthio-2-oxoazetidin-1-yl)-2-methyl-3-oxobutyrate (280 mg, 1.14 mmole) was dissolved in dry carbon tetrachloride (15 ml) and to the stirred ice-cooled solution chlorine (80 mg, 1.13 mmole) in carbon tetrachloride (3.2 ml) was added in one portion. After addition of the chlorine, the cooling bath was removed and stirring was continued for 3 minutes. The solvent was evaporated under reduced pressure to yield methyl 4-(4-chloro-2-oxoazetidin-1-yl)-2-methyl-3-oxobutyrate as a pale yellow gum (275 mg). νmax (CHCl3): 1780 (β-lactam C=O), 1755 (ester C=O), 1725 (ketone C=O) cm-1.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[N:7][C:8]=2[Cl:12])[N:3]=1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>COC(O)C>[CH2:21]([NH:28][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[N:7][C:8]=2[Cl:12])[N:3]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc(-c2cc3nc(Cl)ccc3c(Cl)n2)cc1
Reactant: NCc1ccccc1
Agent: COC(C)O
Product: COc1ccc(-c2cc3nc(NCc4ccccc4)ccc3c(Cl)n2)cc1
Temperature: 80 °C
Reaction time: 72 h
Yield: 30.5 %

Procedure:
2,5-Dichloro-7-(4-methoxyphenyl)-[1,6]naphthyridine (147 mg, 0.48 mmol) and benzyl amine (0.055 mL, 0.5 mmol) were combined in methoxyethanol (2 mL) and stirred at 80° C. for 72 hours. The crude reaction mixture was concentrated, and column chromatography afforded benzyl-[5-chloro-7-(4-methoxyphenyl)-[1,6]naphthyridin-2-yl]-amine (55 mg, 30%).
Reaction SMILES: [O-:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K+].F[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1>CN1CCCC1=O.O>[CH:5]1[CH:6]=[CH:7][C:2]([O:1][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:3][CH:4]=1
Reactant: Fc1ccc(Cl)cc1
Reactant: [O-]c1ccccc1
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Clc1ccc(Oc2ccccc2)cc1
Yield: 54.2 %

Procedure:
A stirred solution containing 14.8 g (0.112 mole) of potassium phenoxide and 13.1 g (0.10 mole) of p-fluorochlorobenzene in 100 ml of N-methyl-2-pyrrolidinone is heated at reflux for a period of time necessary to effect complete reaction, as determined by vapor phase chromotography techniques. The crude reaction mixture is cooled and diluted to a volume of 400 ml with water, whereupon it is extracted with several portions of ether. The combined organic extracts are washed with a 5% sodium hydroxide solution, water, and a saturated sodium chloride solution, dried (magnesium sulfate), and concentrated in vacuo. Distillation at reduced pressure affords 11.1 g (54%) of material, b(0.05 mm) 73.5°-75.5°, whose spectral properties are in agreement with the desired structure.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C:13]([O:18][CH3:19])(=[O:17])[C@@H:14]([CH3:16])O.C(OCC)(=O)CO>>[CH3:19][O:18][C:13](=[O:17])[C@@H:14]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11])[CH3:16]
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: COC(=O)[C@@H](C)O
Agent: CCOC(=O)CO
Product: COC(=O)[C@H](C)Oc1ccc(C=O)cc1[N+](=O)[O-]

Procedure:
The title compound was synthesized in a manner analogous to intermediate 7 using 4-hydroxy-3-nitrobenzaldehyde and methyl (R)-(+)-lactate instead of 5-nitrovanillin and ethyl glycolate. MS: M+−87=166.1 Da.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5](N)=[N:6][CH:7]=1.[Br:10]Br.N([O-])=O.[Na+]>Br.[OH-].[Na+]>[Br:10][C:5]1[C:4]([CH3:9])=[CH:3][C:2]([I:1])=[CH:7][N:6]=1
Reactant: Cc1cc(I)cnc1N
Reactant: BrBr
Agent: Br
Agent: O=N[O-]
Agent: [Na+]
Product: Cc1cc(I)cnc1Br
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a suspension of 5-iodo-3-methyl-2-pyridinamine (7.0 g) in 47% hydrobromic acid was successively added bromine (2.31 mL) and aq solution of NaNO2 (5.16 g), the temperature being kept below 0° C. during addition. The reaction mixture was stirred for 1 hour at 5° C. and warmed to ambient temperature. The reaction was continued for 4 hours at ambient temperature and the mixture was diluted with NaOH(18 g in water 150 mL) and extracted with AcOEt. The organic phase was washed with 5% Na2S2O3 aq solution, water, and brine, and dried over Na2SO4. The solvent was removed in vacuo, and the residue was purified by silica gel column chromatography eluted with chloroform to give 2-bromo-5-iodo-3-methylpyridine (2.95 g) as pale yellow powder.
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.[NH2:9][C:10]1[CH:20]=[CH:19][C:13]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])=[CH:12][C:11]=1[Cl:21]>CC#N>[NH2:9][C:10]1[C:11]([Cl:21])=[CH:12][C:13]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])=[CH:19][C:20]=1[Cl:8]
Reactant: CN(C)C(=O)c1ccc(N)c(Cl)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CN(C)C(=O)c1cc(Cl)c(N)c(Cl)c1
Yield: 93.3 %

Procedure:
NCS (38 mg, 0.288 mmol) was added to a solution of 4-amino-3-chloro-N,N-dimethylbenzamide (52 mg, 0.262 mmol) in MeCN (520 mL). The reaction mixture was refluxed for 1 hour before being concentrated under vacuum. The residue was purified via Biotage silica gel column chromatography eluting with (cyclohexane/EtOAc 80/20 to 60/40) to afford the title product as a white solid (57 mg, 93%). 1H NMR (500 MHz, CDCl3) d 3.06 (s, 6H), 4.68 (br s, 2H), 7.34 (s, 2H). LC (Method D)-MS (ESI, m/z) tR 1.50 min, 233 [(M+H+), 100%].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([S:9]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C1COCCN1
Reactant: O=S(=O)(Cl)c1ccc(F)c(Br)c1
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(F)c(Br)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.3 %

Procedure:
3-Bromo-4-fluorobenzene-1-sulfonyl chloride (0.44 g, 1.609 mmol) in tetrahydrofuran (10 mL) was treated with morpholine (0.294 g, 3.38 mmol). The reaction mixture was stirred for 16 hours at ambient temperature. The solvent was removed, and the residue was loaded onto a silica gel column and eluted with 20% ethyl acetate in hexanes to give the title compound (0.45 g, 1.388 mmol, 86% yield).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].N1(O[C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)[C:18]([C:29]([NH2:31])=[O:30])=[CH:17][N:16]=2)C2C=CC=CC=2N=N1.C(#N)C>O>[NH2:3][CH2:2][CH2:1][NH:4][C:15]1[N:20]=[C:19]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=2)[C:18]([C:29]([NH2:31])=[O:30])=[CH:17][N:16]=1
Reactant: NCCN
Reactant: Cc1ccc(Nc2nc(On3nnc4ccccc43)ncc2C(N)=O)cc1
Solvent: O
Solvent: CC#N
Product: Cc1ccc(Nc2nc(NCCN)ncc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A 3.0 ml portion of ethylenediamine was added to a mixture of 1.0 g of 2-(benzotriazol-1-yloxy)-4-(4-methylanilino)pyrimidine-5-carboxamide and 30 ml of acetonitrile, followed by stirring at room temperature for 1 hour and 40 minutes. Water was added to the reaction mixture, followed by extraction with a chloroform-isopropanol mixed solution. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under a reduced pressure and then the thus obtained residue was purified by silica gel column chromatography (eluting solvent; chloroform:methanol:aqueous ammonia) . By recrystallizing the thus obtained colorless solid from an ethyl acetate-ethanol mixed solvent, 471 mg of 2-(2-aminoethylamino)-4-(4-methylanilino)pyrimidine-5-carboxamide was obtained (colorless crystals).
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C:6]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:11][C:5]=2[NH:4][C:3]1=[O:36].C(=O)([O-])[O-].[K+].[K+].Br[CH2:44][C:45]#[N:46]>CN(C=O)C.C(OCC)(=O)C>[C:31]([O:30][C:29](=[O:35])[NH:28][C:24]1([C:21]2[CH:22]=[CH:23][C:18]([C:9]3[C:10]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[CH:11][C:5]4[N:4]([CH2:44][C:45]#[N:46])[C:3](=[O:36])[CH:2]([CH3:1])[O:7][C:6]=4[N:8]=3)=[CH:19][CH:20]=2)[CH2:25][CH2:26][CH2:27]1)([CH3:32])([CH3:34])[CH3:33]
Reactant: C[C@H]1Oc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2NC1=O
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1Oc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2N(CC#N)C1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 50.9 %

Procedure:
A solution of (R)-tert-butyl 1-(4-(3-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (100 mg, 0.206 mmol) in DMF (2 ml) was added potassium carbonate (85 mg) and 2-bromoacetonitrile (44 μl, 0.618 mmol). The reaction mixture was stirred at room temperature for 48 h then was diluted with ethyl acetate (20 ml). Washed with water, brine, and dried with Na2SO4, filtered and concentrated to give crude product which was purified by column (biotage, 25 g) eluted with ethyl acetate and cyclohexane to afford product (55 mg). 1H NMR (500 MHz, CDCl3): 7.35 (s, 1H), 7.20-7.32 (m, 9H), 4.98 (q, 1H), 4.87 (dd, 2H), 2.44-2.49 (m, 4H), 2.06 (m, 1H), 1.80 (m, 1H), 1.75 (d, 3H), 1.24-1.36 (br, 9H).
Reaction SMILES: C(C1C=CC(C2/C(=C/C=C3/N(CCCS([O-])(=O)=O)C4C(C/3(C)C)=CC(S([O-])(=O)=O)=CC=4)/CCCC=2C=CC2C(C)(C)C3C(N=2)=[N+](CCCS([O-])(=O)=O)C=CC=3)=CC=1)(O)=O.[Na+:60].[Na+].Cl/[C:63](/[CH:90]=[CH:91]/[CH:92]=[C:93]1\[C:94]([CH3:112])([CH3:111])[C:95]2[C:96](=[N:110]\1)[N:97]([CH2:102][CH2:103][CH2:104][CH2:105][S:106]([O-:109])(=[O:108])=[O:107])[CH:98]=[C:99]([Cl:101])[CH:100]=2)=[CH:64]\[CH:65]=[CH:66]\[C:67]1[C:75]([CH3:77])([CH3:76])[C:74]2[C:69](=[CH:70][CH:71]=[C:72]([S:78]([O-:81])(=[O:80])=[O:79])[CH:73]=2)[N+:68]=1[CH2:82][CH2:83][CH2:84][CH2:85][S:86]([O-:89])(=[O:88])=[O:87].[Na+].[Na+].[C:115]([C:118]1[CH:119]=[C:120](B(O)O)[CH:121]=[CH:122][CH:123]=1)([OH:117])=[O:116]>>[C:115]([C:118]1[CH:119]=[C:120](/[C:63](/[CH:90]=[CH:91]/[CH:92]=[C:93]2\[C:94]([CH3:112])([CH3:111])[C:95]3[C:96](=[N:110]\2)[N:97]([CH2:102][CH2:103][CH2:104][CH2:105][S:106]([O-:109])(=[O:108])=[O:107])[CH:98]=[C:99]([Cl:101])[CH:100]=3)=[CH:64]\[CH:65]=[CH:66]\[C:67]2[C:75]([CH3:77])([CH3:76])[C:74]3[C:69](=[CH:70][CH:71]=[C:72]([S:78]([O-:81])(=[O:79])=[O:80])[CH:73]=3)[N+:68]=2[CH2:82][CH2:83][CH2:84][CH2:85][S:86]([O-:89])(=[O:87])=[O:88])[CH:121]=[CH:122][CH:123]=1)([OH:117])=[O:116].[Na+:60].[Na+:60]
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C/C(Cl)=C/C=C/C1=[N+](CCCCS(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc2C1(C)C
Agent: CC1(C)C(/C=C/C2=C(c3ccc(C(=O)O)cc3)/C(=C/C=C3/N(CCCS(=O)(=O)[O-])c4ccc(S(=O)(=O)[O-])cc4C3(C)C)CCC2)=Nc2c1ccc[n+]2CCCS(=O)(=O)[O-]
Agent: CC1(C)C(C=CC2=C(c3ccc(C(=O)O)cc3)/C(=C/C=C3/N(CCCS(=O)(=O)[O-])c4ccc(S(=O)(=O)[O-])cc4C3(C)C)CCC2)=Nc2c1ccc[n+]2CCCS(=O)(=O)[O-]
Agent: [Na+]
Product: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C/C(=C/C=C/C1=[N+](CCCCS(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc2C1(C)C)c1cccc(C(=O)O)c1

Procedure:
Compound 43 is prepared analogously to compound 17 (Example 17), except with compound 42 and m-carboxyphenyl boronic acid as starting materials.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][OH:12])[N:6]=1)=[O:4].[OH:13][C:14]1[C:19]([CH2:20][CH2:21][CH3:22])=[C:18](O)[CH:17]=[CH:16][C:15]=1[C:24](=[O:26])[CH3:25].C(P(CCCC)CCCC)CCC.[N+](C(OCC)=O)(C(OCC)=O)=[N-]>C1COCC1.C(OCC)(=O)C.C(OCC)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][O:12][C:18]2[CH:17]=[CH:16][C:15]([C:24](=[O:26])[CH3:25])=[C:14]([OH:13])[C:19]=2[CH2:20][CH2:21][CH3:22])[N:6]=1)=[O:4]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: COC(=O)c1cccc(CO)n1
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)[N+](=[N-])C(=O)OCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCCc1c(OCc2cccc(C(=O)OC)n2)ccc(C(C)=O)c1O
Reaction time: 12 h
Yield: 83.2 %

Procedure:
Combine 6-hydroxymethyl-pyridine-2-carboxylic acid methyl ester (2.20 g, 13.2 mmol), 1-(2,4-dihydroxy-3-propyl-phenyl)-ethanone (2.56 g, 13.2 mmol), and tri-n-butylphosphine (3.94 mL, 15.8 mmol) in THF (45 mL). Add diethyl diazodicarboxylate (3.98 g, 15.8 mmol). After 12 hours at ambient temperature, add diethyl ether (white precipitate forms) and filter, collect liquid and remove solvents under reduced pressure. Purify residue by flash chromatography eluting with 3:7 hexane:ethyl acetate to obtain the title compound as a white solid (3.769 g, 10.98 mmol): mass spectrum (m/e): 344 (M+1).