Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1C2C=C(C=NC)C=CC=2N=C1N)C(C)C.C1(C)C=CC([S:24]([CH:27]([N+]#[C-])C2C=CC(F)=CC=2)(=[O:26])=[O:25])=CC=1.CN.[CH2:40]([N:44]1[C:48]2[CH:49]=[C:50]([C:53]3[N:57]([CH3:58])[CH:56]=[N:55][C:54]=3[C:59]3[CH:64]=[CH:63][C:62]([F:65])=[CH:61][CH:60]=3)[CH:51]=[CH:52][C:47]=2[N:46]=[C:45]1[NH2:66])[CH:41]([CH3:43])[CH3:42].C[OH:68]>>[CH3:27][S:24]([OH:25])(=[O:26])=[O:68].[CH3:27][S:24]([OH:25])(=[O:26])=[O:68].[CH2:40]([N:44]1[C:48]2[CH:49]=[C:50]([C:53]3[N:57]([CH3:58])[CH:56]=[N:55][C:54]=3[C:59]3[CH:60]=[CH:61][C:62]([F:65])=[CH:63][CH:64]=3)[CH:51]=[CH:52][C:47]=2[N:46]=[C:45]1[NH2:66])[CH:41]([CH3:43])[CH3:42]
Reactant: CO
Reactant: [C-]#[N+]C(c1ccc(F)cc1)S(=O)(=O)c1ccc(C)cc1
Agent: CC(C)Cn1c(N)nc2ccc(-c3c(-c4ccc(F)cc4)ncn3C)cc21
Agent: CN
Agent: CN=Cc1ccc2nc(N)n(CC(C)C)c2c1
Product: CS(=O)(=O)O

Procedure:
Beginning with 1-isobutyl-2-amino-6-(methyliminomethyl)-1H-benzimidazole (142 mg, 0.52 mmol), α-(p-toluenesulfonyl)-4-fluorobenzylisocyanide (302 mg, 1.05 mmol), methanol (2.5 ml), and methylamine (1.3 ml, 2M in tetrahydrofuran), 1-(isobutyl)-2-amino-6-(1-methyl-4 (4-fluorophenyl)-1H-imidazol-5-yl)-1H-benzimidazole may be prepared essentially as described in EXAMPLE 72. Treatment with 1 equivalent of methanesulfonic acid provides the title compound (114 mg).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[F:12][C:13]1([F:19])[CH2:16][CH:15]([CH2:17]O)[CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[F:12][C:13]1([F:19])[CH2:16][CH:15]([CH2:17][O:1][C:2]2[CH:10]=[C:9]3[C:5]([CH2:6][CH2:7][C:8]3=[O:11])=[CH:4][CH:3]=2)[CH2:14]1
Reactant: OCC1CC(F)(F)C1
Reactant: O=C1CCc2ccc(O)cc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CCc2ccc(OCC3CC(F)(F)C3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.9 %

Procedure:
To a solution of 6-hydroxy-2,3-dihydro-1H-inden-1-one (3.6 g, 24.3 mmol) in THF (60 mL) were (3,3-difluorocyclobutyl)methanol (2.97 g, 24.3 mmol) and triphenylphosphine (9.56 g, 36.45 mmol) added. Diisopropyl azodicarboxylate (7.18 mL, 36.5 mmol) was added dropwise. The reaction mixture was stirred at r.t. overnight. The material was purified by flash column chromatography using a gradient of 0-100% EtOAc in heptane, providing 3.67 g (60% yield) of the title compound. 1H NMR (500 MHz, DMSO-d6) ppm 2.30 (br. s., 1H) 2.42-2.52 (m, 6H) 2.54-2.62 (m, 1H) 2.63-2.66 (m, 2H) 2.67-2.76 (m, 2H) 2.98-3.04 (m, 2H) 4.08 (d, 2H) 7.10 (d, 1H) 7.26 (dd, 1H) 7.48 (d, 1H); MS (ES+) m/z 253 [M+H]+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:25][N:26]1[C:30]2[CH:31]=[C:32]([C:35]([OH:37])=O)[CH:33]=[CH:34][C:29]=2[N:28]=[N:27]1.CN(C=O)C.[F:43][C:44]([F:72])([C:68]([F:71])([F:70])[F:69])[CH2:45][O:46][C:47](=[O:67])[C@H:48]([OH:66])[CH2:49][C@H:50]([NH2:65])[CH2:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([Cl:64])[CH:59]=2)=[CH:54][CH:53]=1.CCN(C(C)C)C(C)C>>[F:72][C:44]([F:43])([C:68]([F:69])([F:70])[F:71])[CH2:45][O:46][C:47](=[O:67])[C@H:48]([OH:66])[CH2:49][C@H:50]([NH:65][C:35]([C:32]1[CH:33]=[CH:34][C:29]2[N:28]=[N:27][N:26]([OH:25])[C:30]=2[CH:31]=1)=[O:37])[CH2:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([Cl:64])[CH:59]=2)=[CH:54][CH:53]=1
Reactant: N[C@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C[C@@H](O)C(=O)OCC(F)(F)C(F)(F)F
Reactant: O=C(O)c1ccc2nnn(O)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C[C@@H](O)C(=O)OCC(F)(F)C(F)(F)F)c1ccc2nnn(O)c2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 7.1 %

Procedure:
HATU (37.9 mg, 99.6 μmol) was added to a solution of 1-hydroxy-1H-1,2,3-benzotriazole-6-carboxylic acid (14.9 mg, 83 μmol) in DMF (0.5 mL, 6.4 mmol) and the resulting mixture was stirred at room temperature for 5 minutes. (2R,4R)-4-Amino-5-(3′-chlorobiphenyl-4-yl)-2-hydroxypentanoic acid 2,2,3,3,3-pentafluoropropyl ester (30.0 mg, 66.4 μmol) was added to the mixture, followed by DIPEA (35 μL, 0.2 mmol) dropwise over 5 minutes, and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated in vacuo to yield a yellow liquid, which was purified by preparative HPLC to yield the title compound as a white solid (2.9 mg, purity 100%). MS m/z [M+H]+ calc'd for C27H22ClF5N4O5, 613.12. found 613.0.
Reaction SMILES: C(N(C(C)C)C(C)C)C.Br.Br.[NH2:12][C:13]1[C:17]([NH2:18])=[CH:16][S:15][CH:14]=1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=1[N:27]=[C:28]=[S:29]>C1COCC1>[NH2:12][C:13]1[C:17]([NH:18][C:28]([NH:27][C:21]2[C:22]([CH3:26])=[CH:23][CH:24]=[CH:25][C:20]=2[Cl:19])=[S:29])=[CH:16][S:15][CH:14]=1
Reactant: Cc1cccc(Cl)c1N=C=S
Reactant: Nc1cscc1N
Agent: Br
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(Cl)c1NC(=S)Nc1cscc1N

Procedure:
was obtained in a similar manner to the method specified in Example 6a) by reacting a mixture prepared from 0.74 g (=1.01 ml) of N-ethyl-N,N-diisopropylamine in 40 ml of THF, 0.8 g of 3,4-diaminothiophene dihydrobromide and 0.473 g of 2-chloro-6-methylphenyl isothiocyanate.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[S:8])[O:5][C:6]=1[CH3:7].C(N1C(=O)C2=CC=CC=[C:13]2[C:12]1=[S:21])C>>[CH3:1][C:2]1[N:3]=[C:4]([S:8][S:21][CH2:12][CH3:13])[O:5][C:6]=1[CH3:7]
Reactant: CCN1C(=O)c2ccccc2C1=S
Reactant: Cc1[nH]c(=S)oc1C
Product: CCSSc1nc(C)c(C)o1

Procedure:
Starting from 4,5-dimethyl-2-thiono-4-oxazoline and N-ethylthiophthalimide there is obtained (4,5-dimethyl-2-oxazolyl)ethyl-disulphide. nD20 =1.5467. IR (liq.): bands inter alia at 3020, 2970, 1640, 1450, 1175, 1105, 950, 745 cm-1.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].Cl.[N:13]([O-])=O.[Na+].[CH3:17][C:18]1[NH:19][N:20]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[C:21](=[O:23])[CH:22]=1.C(=O)([O-])O.[Na+]>O.C(O)C>[OH:11][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[N:1]=[N:13][C:22]1[C:18]([CH3:17])=[N:19][N:20]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[C:21]=1[OH:23])[C:6]([OH:8])=[O:7]
Reactant: Nc1ccc(C(=O)O)cc1O
Reactant: Cc1ccc(-n2[nH]c(C)cc2=O)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(-n2nc(C)c(N=Nc3ccc(C(=O)O)cc3O)c2O)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 4-amino-3-hydroxybenzoic acid (0.77 g, 0.005 mol.) in 1N aqu. hydrochloric acid (15.0 mL) was cooled to 0° C. and treated slowly with a solution of sodium nitrite (0.38 g; 0.0055 mol.) in water (5.0 mL). After addition the solution was stirred at 0° C. for 10 min. then 3-methyl-1-(4-methylphenyl)-3-pyrazolin-5-one (0.94 g; 0.005 mol.) was added in one portion. Ethanol (15.0 mL) was added followed by sat. aqu. sodium hydrogen carbonate until the pH of the solution was 8 (ca. 10 mL needed). The red solution was then stirred at room temperature for 16 h.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1>>[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][CH2:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH2:5][CH2:13][C:12]2[CH:15]=[CH:16][C:9]([Cl:8])=[CH:10][CH:11]=2)=[CH:11][CH:10]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CC(=O)CC(C)=O
Product: O=C(CCc1ccc(Cl)cc1)CC(=O)CCc1ccc(Cl)cc1

Procedure:
Using 2,4-pentanedione (20.0 g, 0.2 mol) and 4-chlorobenzyl chloride (74.7 g), the reaction was carried out in the same manner as described in Example 17, (1), and the residual orange red semisolid (69 g) was recrystallized from methanol to give the title compound as s white prisms which was an ca 3:17 mixture of Keto/Enol as seen by the methylene singlet at δ3.51 ppm and the methine singlet at δ5.37 ppm in the 1HNMR spectrum; yield: 24.7 g; mp 74.6°-76.1° C.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@@H:9]([C:18](=[O:21])[NH:19][CH3:20])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)C)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[F:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][C@@H:9]([NH:7][CH3:6])[C:18]([NH:19][CH3:20])=[O:21])=[CH:16][CH:15]=1
Reactant: CNC(=O)[C@@H](Cc1ccc(F)cc1)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)[C@@H](Cc1ccc(F)cc1)NC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
((1R)-2-(4-Fluorophenyl)-1-(methylcarbamoyl)ethyl)-methylcarbamic acid tert-butylester (1.0 g; 3.22 mmol) was dissolved in methylene chloride (5 mL). Trifluoroacetic acid (5 mL) was added and the reaction mixture was stirred for 30 min at room temperature. Methylene chloride (30 mL), an aqueous solution of sodium hydrogen carbonate/sodium carbonate (pH 9; 30 mL) and sodium hydrogen carbonate (solid), were added to the reaction mixture, until pH 9. The organic phase was dried (magnesium sulfate) and evaporated in vacuo to afford 0.62 g of (2R)-3-(4-fluorophenyl)-N-methyl-2-methylaminopropionamide.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][CH2:8][CH:7]2[CH:5]([O:6]2)[CH2:4][O:3]1.O.O.O.O.O.O.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C(#N)C>[OH:6][CH:5]1[CH2:4][O:3][C:2]([CH3:1])([CH3:10])[O:9][CH2:8][CH:7]1[N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: C1CNCCN1
Reactant: CC1(C)OCC2OC2CO1
Solvent: CC#N
Solvent: O
Product: CC1(C)OCC(O)C(N2CCNCC2)CO1
Yield: 20.4 %

Procedure:
14.4 g (0.1 mol) of 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane (J. Org. Chem. 41, 2469 [1976]) are heated under reflux in 100 ml of acetonitrile with 20 g (0.1 mol) of piperazine hexahydrate for 8 hours and the 1,4-bis-(6-hydroxy-2,2-dimethyl-1,3-dioxepan-5-yl)-piperazine precipitated [melting point: 235°-237° (from isopropanol)] is filtered off with suction. The mother liquor is concentrated and the residue is purified by chromatography on 200 g of silica gel with methylene chloride/methanol (9:1) as the mobile phase, the main component being eluted towards the end of the chromatography with methylene chloride/methanol (4:1). 4.7 g of 1-(6-hydroxy-2,2-dimethyl-1,3-dioxepan-5-yl)-piperazine are obtained as an oil; Rf value=0.05 (on silica gel; methylene chloride/methanol (9:1)].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N+:12]([O-])=O)[N:8]([C:15](=[O:24])[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:7][CH2:6]2.O.O.[Sn](Cl)Cl.Cl>C(O)C.CC(N(C)C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[NH2:12])[N:8]([C:15](=[O:24])[CH2:16][CH2:17][N:18]1[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1)[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CCN1CCOCC1)CC2
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCO
Product: COc1cc2c(cc1N)N(C(=O)CCN1CCOCC1)CC2
Reaction time: 8 h

Procedure:
To a solution of 5-(methyloxy)-1-[3-(4-morpholinyl)propanoyl]-6-nitro-2,3-dihydro-1H-indole (0.44 g, 1.31 mmols) in absolute ethanol (150 mL) and DMA (20 mL) was added tin(II)chloride dihydrate (1.77 g, 7.84 mmols) and 1M HCl (3.0 mL). After overnight stirring, reaction was quenched with excess saturated Na HCO3 solution, stirred for one hr. and filtered through celite which was rinsed with methanol. After organic solvent removal, the aqueous layer was extracted with dichloromethane (2×200 mL), the organic layers were combined, adsorbed to silica gel and purified by column chromatography (DCM to 5% MeOH/DCM+0.1% NH4OH) to afford 5-(methyloxy)-1-[3-(4-morpholinyl)propanoyl]-2,3-dihydro-1H-indol-6-amine. ESIMS (M+H)+=306.
Reaction SMILES: [H-].[Na+].O1CC[CH2:5][CH2:4]1.[NH2:8][C:9]1[CH:10]=[C:11]([SH:15])[CH:12]=[CH:13][CH:14]=1.ICC>O.CN(C)C=O>[CH2:4]([S:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[NH2:8])[CH3:5]
Reactant: C1CCOC1
Reactant: Nc1cccc(S)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCI
Solvent: O
Product: CCSc1cccc(N)c1
Reaction time: 0.08 h
Yield: 82 %

Procedure:
Sodium hydride (60% in oil, 2.3 g) was suspended in a mixed solvent of tetrahydrofuran (35 mL) and N,N-dimethylformamide (15 mL), and 3-aminobenzenethiol (5.0 g) was added dropwise at room temperature. The mixture was stirred at the same temperature for 5 min, iodoethane (6.86 g) was added, and the mixture was stirred for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→4:1) to give the title compound as a yellow oil (yield 5.0 g, 82%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH:11]2[C:16](=O)[CH2:15][CH2:14][S:13][CH2:12]2)=O)=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([NH:32][C:33]([NH2:35])=[NH:34])[CH:23]=[CH:24][C:25]=1[N:26]1[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CCO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:11]3[CH2:12][S:13][CH2:14][CH2:15][C:16]=3[N:35]=[C:33]([NH:32][C:22]3[CH:23]=[CH:24][C:25]([N:26]4[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]4)=[C:20]([O:19][CH3:18])[CH:21]=3)[N:34]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCSCC1C(=O)Cc1ccc(F)cc1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: COc1cc(Nc2nc3c(c(Cc4ccc(F)cc4)n2)CSCC3)ccc1-n1cnc(C)c1
Temperature: 60 °C

Procedure:
3-(2-(4-Fluorophenyl)acetyl)dihydro-2H-thiopyran-4(3H)-one (200 mg, 0.79 mmol), 1-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)guanidine (194 mg, 0.79 mmol) and potassium carbonate (200 mg, 1.45 mmol) was slurrified in EtOH (5 mL) and heated to 60° C. for 16 h. DCM and water were added to the cooled reaction mixture. The organic phase was separated and dried with Mg2SO4 and then the solvent was evaporated. The crude product was used as such in next step. MS (ES+) m/z 462.2 (M+H)+
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:7][CH:6]=1)(=O)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:7][CH:6]=1)(=[S:29])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)Nc1ccc(-c2nc3ccccc3s2)cc1
Solvent: O
Product: CC(=S)Nc1ccc(-c2nc3ccccc3s2)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 101.6 %

Procedure:
A mixture of 2-(4'-acetamidophenyl)benzothiazole (0.4 g, 1.49 mmol) and Lawesson's reagent (0.37 g, 0.9 mmol) in hexamethyl-phosphoamide (HMPA) (10 ml) was stirred at 100° C. for 6 hours. The reaction mixture was poured into water. The precipitate formed was filtered off, washed with water and dried. The crude product was purified by chromatography on silica gel, eluting with ethyl acetate-hexane (5:6)to give pale yellow crystals (0.26 g, 61%), m.p. 221.6-222.8° C.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11]C=1.[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](Cl)=[O:26].C(=O)(O)[O-].[Na+]>ClCCl>[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([NH:8][CH2:9][CH2:14][CH2:13][CH:12]([C:15]([F:16])([F:17])[F:18])[CH3:11])=[O:26]
Reactant: O=C(Cl)CCCCCBr
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(CCCNC(=O)CCCCCBr)C(F)(F)F
Temperature: 20 °C
Reaction time: 0.33 h

Procedure:
Triethylamine (1.30 mL) and 4-aminobenzotrifluoride (1.21 g) were stirred in dichloromethane (35 mL) at 0° C. under nitrogen and treated with 6-bromohexanoyl chloride (1.15 mL). After 20 minutes, the reaction was allowed to warm to 20° C. and stirred an additional 40 minutes. The reaction was treated with aqueous saturated sodium bicarbonate (40 mL), and extracted with dichloromethane. The extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to a solid. This solid was dissolved ethyl acetate and the title compound was precipitated out as fine white needles by addition of hexanes (2.35 g). M.p. 96°-98° C. Anal. Calc. for C13H15BrF3NO: C, 46.17;H, 4.47;N, 4.14. Found: C, 46.25;H, 4.59;N, 4.12.
Reaction SMILES: CON(C)[C:4]([CH:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:7])=[O:5].[C:17]1([Mg]Br)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[O:5]=[C:4]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH3:7]
Reactant: CON(C)C(=O)C(C)NC(=O)OC(C)(C)C
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: CC(NC(=O)OC(C)(C)C)C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
tert-butyl 1-(N-methoxy-N-methylcarbamoyl)ethylcarbamate (39) (2.3 g, 10.0 mmol, 1.0 equiv.) was added to a 250 mL RBF followed by THF (100 mL). The mixture was cooled to 0° C. via an ice bath and a 1.0 M solution of PhMgBr in THF (30.0 mL, 30.0 mmol, 3.0 equiv.) was added over 8 min. The reaction stirred for 1.0 h at 0° C. and the ice bath was removed. The reaction stirred for an additional 1.0 h at rt. and was again cooled to 0° C. via an ice bath. Next, the reaction was quenched by addition of 1.0 M HCl (60 mL). The solution was transferred to a separatory funnel with additional 1.0 M HCl (40 mL) and extracted with EtOAc (3×75 mL). The organic layers were combined, washed with sat. NaCl (1×50 mL), and dried over Na2SO4. The solution was then concentrated on a rotary evaporator and dried under vacuum to give 3.1 g of crude material. The residue was purified by flash column chromatography (15% EtOAc/Hexanes) to give 2.2 g (86%) of 40 as a colorless oil.10 Rf=0.25 (15% EtOAc/Hexanes); IR (film) 3356, 2977, 1680, 1164 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.96 (d, J=7.5 Hz, 2H, Ph-H), 7.59 (t, J=7.5 Hz, 1H, Ph-H), 7.48 (t, J=7.5 Hz, 2H, Ph-H), 5.62 (br d, J=6.5 Hz, 1H, carbamate-NH), 5.30 (t, 1H, Boc-NH—CH), 3.78 (s, 3H, N—OCH3), 3.19 (s, 3H, N—CH3), 1.46 (s, 9H, Boc-t-butyl-CH3, 1.40 (d, J=7.0 Hz, 3H, CH—CH3); 13C NMR (125 MHz, CDCl3) δ 199.6, 155.5, 134.3, 133.9, 129.0, 128.8, 80.0, 51.3, 28.6, 20.1; LRMS (ESI-MS m/z): Mass calcd for C14H19NO3 [2M]+, 498.62. Found 499. Spectroscopic data were consistent with the literature data for this compound.
Reaction SMILES: Cl[C:2]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][CH3:16])=[CH:11][CH:12]=2)[C:7]([CH3:17])=[CH:6][C:5]1([CH3:19])[CH3:18])=[O:3].[CH4:20].C[OH:22]>>[C:2]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][CH3:16])=[CH:11][CH:12]=2)[C:7]([CH3:17])=[CH:6][C:5]1([CH3:19])[CH3:18])([O:22][CH3:20])=[O:3]
Reactant: CCOc1ccc2c(c1)C(C)=CC(C)(C)N2C(=O)Cl
Reactant: C
Reactant: CO
Product: CCOc1ccc2c(c1)C(C)=CC(C)(C)N2C(=O)OC
Reaction time: 1 h

Procedure:
1-Chlorocarbonyl-6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline (2.8 g) was dissolved with stirring in abs. methanol (10 ml). Stirring continued at room temperature for 1 hour. The solution was then treated with active charcoal, filtered and evaporated to dryness, yielding colourless, oily material which crystallized on standing. Pure 1-carbomethoxy-6-ethoxy-1,2-dihydro2,2,4-trimethylquinoline (2.2 g) was obtained by recrystallisation from methanol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH3:13])([CH3:12])[CH2:10][CH3:11])=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1.[NH2:17][C:18]1[N:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][N:19]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.CCOC(C)=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>[CH3:12][C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([C:21]2[CH:20]=[N:19][C:18]([NH2:17])=[N:23][CH:22]=2)=[CH:3][C:4]=1[N+:14]([O-:16])=[O:15])([CH3:13])[CH2:10][CH3:11]
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: CCC(C)(C)Nc1ccc(Br)cc1[N+](=O)[O-]
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: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 82.4 %

Procedure:
A reaction mixture of crude (4-bromo-2-nitro-phenyl)-(1,1-dimethyl-propyl)-amine (600 mg, 2.09 mmol), 2-aminopyrimidine-5-boronic acid pinacol ester (330 mg, 1.49 mmol), Pd(PPh3)4 (160 mg), K2CO3 (600 mg, 4.34 mmol) in DMF (7.0 mL) and H2O (2.0 mL) is heated under microwave conditions at 100° C. for 1 hour. The reaction mixture is allowed to cool to room temperature, diluted with EtOAc (100 mL), washed with H2O (75 mL×2), dried with Na2SO4 and filtered. The filtrate is concentrated under reduced pressure and the residue is purified by silica gel flash column chromatography with 50% EtOAc in heptane as the eluent to afford 5-[4-(1,1-dimethyl-propylamino)-3-nitro-phenyl]-pyrimidin-2-ylamine (370 mg, 82%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([CH:11]=[CH2:12])=[C:9]([NH2:13])[N:8]=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([O:21][CH3:22])[C:15]=2[F:23])[N:6]=1)=[O:4].[Br:24]Br.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:10](/[CH:11]=[CH:12]/[Br:24])=[C:9]([NH2:13])[N:8]=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([O:21][CH3:22])[C:15]=2[F:23])[N:6]=1)=[O:4]
Reactant: BrBr
Reactant: C=Cc1c(N)nc(-c2ccc(Cl)c(OC)c2F)nc1C(=O)OC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1/C=C/Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.3 %

Procedure:
6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-vinylpyrimidine-4-carboxylic acid methyl ester (0.720 g, 2.13 mmol) was dissolved in chloroform (20 mL) and bromine (0.511 g, 3.2 mmol) was added. The reaction mixture was stirred at ambient temperature for 2 h then concentrated under vacuum. The product was dissolved in dichloromethane (20 mL), treated with triethylamine (0.430 g, 4.26 mmol), stirred at ambient temperature for 2 h, and then concentrated under vacuum. The product was purified by flash chromatography on silica gel (dichloromethane/ethyl acetate gradient) to provide the title compound (0.5 g, 56% yield over two steps) as a white solid, mp 171-173° C.: 1H NMR (CDCl3) δ 7.66 (dd, 1H), 7.22 (dd, 1H), 7.22 (d, 1H), 6.72 (d, 1H), 5.37 (br s, 2H), 4.0 (s, 3H), 3.97 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.Br[CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].O>C(#N)C>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][N:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3][CH2:2]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)C1CCN(CC(=O)OCc2ccccc2)CC1
Reaction time: 4 h

Procedure:
To a suspension (39 mL) of tert-butyl piperidine-4-carboxylate (2.6 g) in acetonitrile was added diisopropylethylamine (4.4 mL), subsequently, benzyl bromoacetate (2.0 mL) was added at room temperature in portions, and the mixture was stirred for 4 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. This was washed with an aqueous saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:3→0:1) to obtain the title compound (3.4 g) having the following physical property values.