Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH:7]([C:9]([OH:11])=[O:10])[O:8][C:4]=2[C:3]=1[Cl:14].[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20](Cl)=[O:21].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:1][C:2]1[C:13]([C:20]([C:16]2[O:15][CH:19]=[CH:18][CH:17]=2)=[O:21])=[CH:12][C:5]2[CH2:6][CH:7]([C:9]([OH:11])=[O:10])[O:8][C:4]=2[C:3]=1[Cl:14]
Reactant: O=C(Cl)c1ccco1
Reactant: O=C(O)C1Cc2ccc(Cl)c(Cl)c2O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccco1)c1cc2c(c(Cl)c1Cl)OC(C(=O)O)C2

Procedure:
To a well stirred mixture of 6,7-dichloro-2,3-dihydro-benzofuran-2-carboxylic acid (3.3 g.), furan-2-carbonyl-chloride (3.6 g.) and 200 ml. methylene chloride, protected from the atmosphere with a calcium chloride tube is added anhydrous aluminum chloride (3.7 g.) over a one-half hour period. The reaction solution is stirred 18 hours at 25° C. and then refluxed for 1 hour. The solvent is removed and the residue added to ice water (200 ml.) and hydrochloric acid (20 ml.). The product is extracted into ether, washed with water, then extracted into aqueous sodium bicarbonate (200 ml.) from which the sodium salt of the product precipitates. The sodium salt of the product is placed in a separatary funnel with dilute hydrochloric acid (100 ml.) and ether (100 ml.) and shaken until the solid dissolves. The ether solution is washed with water, brine, dried over magnesium sulfate and the ether distilled at reduced pressure. The 6,7-dichloro-2,3-dihydro-5-(2-furoyl)benzofuran-2-carboxylic acid melts at 166° C after crystallization from acetonitrile/n-butyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[C:24]([O:29][CH2:30][CH3:31])=[N:25][CH:26]=[CH:27][CH:28]=3)=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:34][S:35]([CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)(=[O:37])=[O:36]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:43]3[CH2:42][CH2:41][N:40]([CH2:39][CH2:38][S:35]([CH3:34])(=[O:36])=[O:37])[CH2:45][CH2:44]3)=[O:21])[C:10]([C:23]3[C:24]([O:29][CH2:30][CH3:31])=[N:25][CH:26]=[CH:27][CH:28]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1ncccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCN1CCNCC1
Agent: Cl
Product: CCOc1ncccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1

Procedure:
4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-pyridin-3-yl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 1) was reacted with 1-(2-methanesulfonylethyl)piperazine dihydrochloride to give cis-[4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-pyridin-3-yl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C30H34N5O4SCl2 [(M+H)+] 630.1703, observed 603.1705.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9]2[CH:28]=[CH:27][CH:26]=[CH:25][C:10]=2[C:11]([NH:13][O:14][CH2:15][C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=2)[C:19](O)=[O:20])=[O:12])=[CH:3][CH:2]=1.Cl.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[N:30]1([C:19]([C:18]2[CH:17]=[C:16]([CH:24]=[CH:23][CH:22]=2)[CH2:15][O:14][NH:13][C:11](=[O:12])[C:10]2[CH:25]=[CH:26][CH:27]=[CH:28][C:9]=2[NH:8][CH2:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[O:20])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: C1COCCN1
Reactant: O=C(O)c1cccc(CONC(=O)c2ccccc2NCc2ccncc2)c1
Agent: Cl
Product: O=C(NOCc1cccc(C(=O)N2CCOCC2)c1)c1ccccc1NCc1ccncc1

Procedure:
Prepared by a similar procedure as described for preparation of example 405. Starting materials: 3-{2-[(Pyridin-4-ylmethyl)-amino]-benzoylaminooxymethyl}-benzoic acid (see example 403) and morpholine hydrochloride. 1H-NMR (DMSO-d6) δ 11.6 (bs, 1H), 8.49 (m, 2H), 7.89 (bt, 1H), 7.56 (m, 1H), 7.52-7.44 (m, 2H), 7.42-7.34 (m, 2H), 7.31 (m, 2H), 7.19 (m, 1H), 6.58-6.49 (m, 2H), 4.98 (s, 2H), 4.47 (d, 2H), 3.80-3.10 (m, 8H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1.[CH2:12]([O:26][C:27]1[O:31][C:30]([C:32]([OH:34])=[O:33])=[CH:29][CH:28]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[CH2:12]([O:26][C:27]1[O:31][C:30]([C:32]([O:34][CH2:2][CH2:3][CH2:4][O:5][CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][O:7]2)=[O:33])=[CH:29][CH:28]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)o1
Reactant: BrCCCOC1CCCCO1
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OCCCOC2CCCCO2)o1

Procedure:
The title compound was prepared as in Example 30 starting with 0.335 g (1.5 mmol) of 2-(3-bromopropoxy)tetrahydro-2H-pyran and 0.162 g (0.5 mmol) of 5-(tetradecyloxy)furan-2-carboxylic acid. 1H NMR (300 MHz, CDCl3) δ: 7.15 (d, 1H), 5.30 (d, 1H), 4.59-4.62 (m, 1H), 4.40 (app t, 2H), 4.10 (t, 2H), 3.80-3.90 (m, 2H), 3.40-3.60 (m, 2H), 2.05 (p, 2H), 1.20-1.85 (m, 30H), 0.89 (t, 3H).
Reaction SMILES: [CH2:1]([CH:3]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH2:18][C:19](=[O:31])[NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:11]=1)[C:4]([O:6]CC)=[O:5])[CH3:2].[OH-].[Na+].Cl>C(O)C>[CH2:1]([CH:3]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH2:18][C:19](=[O:31])[NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:29])([F:28])[F:30])=[CH:25][CH:26]=2)[CH:11]=1)[C:4]([OH:6])=[O:5])[CH3:2]
Reactant: CCOC(=O)C(CC)Cc1ccc(OC)c(CC(=O)Nc2ccc(C(F)(F)F)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC(Cc1ccc(OC)c(CC(=O)Nc2ccc(C(F)(F)F)cc2)c1)C(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 73.6 %

Procedure:
Ethyl 2-ethyl-3-[4-methoxy-3-[[N-[4-(trifluoromethyl)phenyl]carbamoyl]methyl]phenyl]propanoate (206 mg, 0.471 mmol), ethanol (5 mL) and 10% aqueous solution of sodium hydroxide (3 mL) were mixed and the mixture was stirred for 6 hours at room temperature. The reaction mixture was poured into ice water and made acidic with 1 mol/L hydrochloric acid, which was then extracted with ethyl acetate. The extracte was washed with water and brine, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (eluent n-hexane:ethyl acetate=4:1→1:1 v/v) and recrystallized from a mixed solvent of n-hexane with ethyl acetate to afford 142 mg (73%) of the title compound as colorless powder.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][C:15]([CH3:19])=[C:16]([CH3:18])[N:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[S:14][C:15]([CH3:19])=[C:16]([CH3:18])[N:17]=1)=[O:9]
Reactant: Cc1nc(N)sc1C
Reactant: O=C(O)c1cc(Br)ccc1O
Product: Cc1nc(NC(=O)c2cc(Br)ccc2O)sc1C
Yield: 14.4 %

Procedure:
Using 5-bromosalicylic acid and 2-amino-4,5-dimethylthiazole as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: Br[C:2]1[S:10][C:5]2[S:6][C:7](Br)=[CH:8][C:4]=2[C:3]=1[CH2:11][N:12]1[CH2:15][CH:14]([CH2:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:13]1.[H][H]>[Pd].CO>[F:26][C:23]1[CH:24]=[CH:25][C:20]([S:17]([CH2:16][CH:14]2[CH2:15][N:12]([CH2:11][C:3]3[C:4]4[CH:8]=[CH:7][S:6][C:5]=4[S:10][CH:2]=3)[CH2:13]2)(=[O:19])=[O:18])=[CH:21][CH:22]=1
Reactant: O=S(=O)(CC1CN(Cc2c(Br)sc3sc(Br)cc23)C1)c1ccc(F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=S(=O)(CC1CN(Cc2csc3sccc23)C1)c1ccc(F)cc1
Yield: 9.4 %

Procedure:
A mixture of 1-[(2,5-dibromothieno[2.3-b]thien-3-yl)methyl]-3-{[(4-fluorophenyl)sulfonyl]methyl}azetidine (Step 4, 39 mg, 0.07 mmol) and 10% palladium on carbon (50 mg) in methanol (7 mL) was stirred under a balloon of hydrogen for 3.5 hours. The catalyst was removed by filtration through Celite®, washing with methanol after the addition of triethylamine (30 μL) to quench any HBr formed. The filtrate was concentrated in vacuo. The residue was purified by preparative TLC (50% ethyl acetate/isohexane) to give the title compound (2.5 mg). 1H NMR (500 MHz, CDCl3) δ 7.91–7.89 (2H, m), 7.34 (1H, dd, J=1.0, 5.2 Hz), 7.23 (3H, t, J=7.3 Hz), 7.10 (1H, s), 3.70 (2H, s), 3.47 (2H, t, J=7.3 Hz), 3.38 (2H, d, J=7.3 Hz), 2.96 (2H, br s), 2.88–2.82 (1H, m).
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(O)[CH2:8][CH2:9][CH2:10][CH2:11]OC)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.[BrH:25]>O>[C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH2:9][CH2:10][CH2:11][Br:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COCCCCC(O)(c1ccccc1)c1ccccc1
Reactant: Br
Solvent: CC(=O)O
Solvent: O
Product: BrCCCC=C(c1ccccc1)c1ccccc1

Procedure:
A mixture of the pentanol prepared as above (8.88 g., 0.0328 mole) in 132 ml. of glacial acetic acid and 66 ml. of distilled hydrobromic acid was stirred at ambient temperature for two hours and then refluxed for 90 minutes. The reaction mixture was cooled, diluted with water and extracted with ether. The ether extract was washed with 5% sodium carbonate solution, water, dried and concentrated to obtain an oil which is chromatographed on silica to yield 5,5-diphenyl-4-pentenyl bromide.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH:11]([CH3:22])[C:12]([O:14][C:15]3([CH3:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.N[C:24]1[CH:29]=CC(C(C)C(OC23CC4CC(CC(C4)C2)C3)=O)=C[CH:25]=1>>[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH:11]([CH3:22])[C:12]([O:14][C:15]34[CH2:21][CH:24]5[CH2:29][CH:19]([CH2:18][CH:17]([CH2:25]5)[CH2:16]3)[CH2:20]4)=[O:13])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CC(C(=O)OC12CC3CC(CC(C3)C1)C2)c1ccc(N)cc1
Reactant: CC(C(=O)OC1(C)CCCCC1)c1ccc2nc(N)sc2c1
Product: CC(C(=O)OC12CC3CC(CC(C3)C1)C2)c1ccc2nc(N)sc2c1
Yield: 83 %

Procedure:
Using the methpod similar to that used in the preparation of 1-methylcyclohexyl 2-amino-α-methylbenzothiazole-6-acetate, 19.1 g of 1-adamantyl 2-(p-aminophenyl)propionate were reacted to obtain 18.97 g (83% yield) of 1-adamantyl 2-amino-α-methylbenzothiazole-6-acetate as a creamy white solid melting at 151°-153° C.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([CH3:3])[CH3:2].[N:11]([O-])=O.[Na+]>O.Cl>[CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][NH2:11])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(C)c1ccccc1NN
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of the substituted aniline, 2-isopropylaniline (27g, 0.2 mole), concentrated hydrochloric acid (150 ml) and water (160 ml) is stirred mechanically for 30 minutes at room temperature. After cooling to 0° C., the mixture is diazotized by adding dropwise a solution of sodium nitrite (14 g, 0.203 mole) in water (140 ml) over a period of 20 minutes. Stirring is continued for an additional one hour at 0° C. The diazo solution is reduced by adding dropwise a solution of stannous chloride dihydrate (112 g, 0.497 mole) in concentrated hydrochloric acid (90 ml) over a period of 30 minutes at -10° C. to -15° C. The reaction mixture is stirred for an additional 1.5 hour at -10° C. to -15° C. The precipitate is collected by filtration to give the hydrochloric acid addition salt of the title compound. The salt is purified further by dissolving it in ethanol, concentrating the solution and adding a saturated solution of hydrochloric acid in ether to give the hydrochloride salt with mp 206°-210° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C@:10]3([C@@H:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=4[F:22])[C@H:13]([C:23]([NH:25][C:26]4[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=4)=[O:24])[NH:12][C@H:11]3[CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C:5]2=[CH:4][CH:3]=1.C[CH2:42][N:43]=[C:44]=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CNC>>[CH3:42][N:43]([CH3:44])[C:30]([C:29]1[CH:28]=[CH:27][C:26]([NH:25][C:23]([CH:13]2[NH:12][CH:11]([CH2:35][C:36]([CH3:37])([CH3:38])[CH3:39])[C:10]3([C:5]4[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:9]3=[O:40])[CH:14]2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[F:22])=[O:24])=[CH:34][CH:33]=1)=[O:31]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Agent: CNC
Agent: On1nnc2ccccc21
Product: CN(C)C(=O)c1ccc(NC(=O)C2NC(CC(C)(C)C)C3(C(=O)Nc4cc(Cl)ccc43)C2c2cccc(Cl)c2F)cc1

Procedure:
In a manner similar to the method described in Example 22, rac-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-benzoic acid (30 mg, 0.051 mmol) was reacted with EDCI (19 mg, 0.1 mmol), HOBt (14 mg, 0.1 mmol), and dimethylamine (0.1 mL, O2 mmol) at 60° C. to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-dimethylcarbamoyl-phenyl)-amide as a light yellow solid (Yield, 10 mg, 32%).
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:31][C@H:32]([CH2:37][CH3:38])[CH:33]([OH:36])[CH2:34][CH3:35]>CCCCO.CS(C)=O>[CH:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH:31][C@H:32]([CH2:37][CH3:38])[CH:33]([OH:36])[CH2:34][CH3:35])=[N:3][C:4]=2[NH:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)([CH3:13])[CH3:12]
Reactant: CCC(O)[C@H](N)CC
Reactant: CC(C)n1cnc2c(NCc3cccnc3)nc(F)nc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Solvent: CS(C)=O
Product: CCC(O)[C@@H](CC)Nc1nc(NCc2cccnc2)c2ncn(C(C)C)c2n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of (2-fluoro-9-isopropyl-9H-purin-6-yl)-pyridin-3-ylmethyl-amine (20 mg, 1 eq, 0.07 mmol) in n-BuOH/DMSO (3.75 mL, 4:1) at room temperature under an argon atmosphere was added DIEA (0.18 mL, 15 eq, 1.03 mmol) followed by (3RS,4R)-4-amino-hexan-3-ol (110 mg, 13 eq, 0.94 mmol). The reaction mixture was placed in a preheated oil bath at 140° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and brine/water (1:1, 100 mL), the aqueous phase was extracted with more EtOAc (2×25 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient column chromatography on silica gel eluted with CHCl3:MeOH (100:0→98:2), to afford the title compound as a white solid. Yield: 23 mg (75%). (57% de 4R,3S: 43% de 4R,3R). 1H-NMR (d-CDCl3, 250 MHz): δ 0.87-1.07 (m, 6H, —NHCH(CH2CH3) CH(CH2CH3)OH), 1.56 (d, 6H, J=6.63 Hz, & —CH(CH3)2), 1.43-1.63 (m, 4H, —NHCH(CH2CH3)CH(CH2CH3)OH), 3.44 (d, 1H, J=6.31 Hz, OH), 3.58-3.71 (m, 1H, —NHCH(CH2CH3)CH(CH2CH3)OH), 3.89-4.01 (m, 1H, —NHCH(CH2CH3)CH(CH2CH3)OH), 4.56-4.70 (m, 1H, —CH(CH3)2), 4.76-4.95 (m, 2H, —HNCH2-Pyr), 5.20-5.29 & 6.17-6.34 (m, 1H, —NHCH(CH2CH3)CH(CH2CH3)OH), 7.19-7.38 (m, 3H, 2×Pyr-H & —N═CH—N—), 7.48-7.60 (m, 1H, Pyr-H), 7.72 (d, 1H, J=7.74 Hz, Pyr-H), 8.67 (m, 1H, HNCH2-Pyr). FABMS m/z (relative intensity): 384 ([M+H]+, 100), 324 (50), 297 (30). Accurate Mass (M+H): Actual: 384.2512, Measured: 384.2500.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=1>C(Cl)(Cl)Cl>[Cl:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N+:14]=1[O-:9]
Reactant: Cc1ccnc(Cl)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1cc[n+]([O-])c(Cl)c1
Yield: 464.3 %

Procedure:
40% meta-chloroperbenzoic acid (13.5 g, 31.4 mmol) was added at ambient temperature to a solution of 2-chloro-4-methyl-pyridine (2.0 g, 1.5 mmol) in chloroform (20 mL) and heated at reflux for 24 h. After allowing to cool, the mixture was washed with water followed by sodium bicarbonate solution. The separated organic phase was further washed with water and brine, dried over anhydrous sodium sulfate and concentrated to give a residue which was purified by column chromatography over silica gel (60-120 mesh) using 10% methanol in ethyl acetate as eluent to afford 2-chloro-4-methyl-pyridine 1-oxide (1.0 g, 45%) as a deep brown oily liquid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[N:6][C:7]([NH2:10])=[N:8][CH:9]=1.[CH:11]1([N:17]=[C:18]=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>CN(C=O)C>[Br:3][C:4]1[CH:5]=[N:6][C:7]([NH:10][C:18]([NH:17][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:19])=[N:8][CH:9]=1
Reactant: Nc1ncc(Br)cn1
Reactant: O=C=NC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ncc(Br)cn1)NC1CCCCC1
Reaction time: 0.5 h

Procedure:
NaH (230 mg) was suspended in DMF (10 ml), and a solution of 5-bromopyrimidine-2-amine in DMF (5 ml) and a solution of cyclohexyl isocyanate (791 mg) in DMF (5 ml) were added dropwise thereto in this order under ice-cooling, followed by stirring at the same temperature for 30 minutes. The obtained solid was collected by filtration and washed with diethyl ether to obtain 1-(5-bromopyrimidin-2-yl)-3-cyclohexylurea (1.47 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[C:19](=O)(O)[O-].[Na+]>CO>[Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:19])=[O:5]
Reactant: O=C([O-])O
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc([N+](=O)[O-])cc1Cl
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 2-chloro-4-nitrobenzoic acid (10 g, 0.06 mol) in MeOH (120 mL) was added H2SO4 (5 mL). The resulting mixture was stirred at 60° C. overnight. After cooling to room temperature, the mixture was brought to pH=8 using sodium bicarbonate solution. After removal of MeOH, the resulting crude mixture was purified by column chromatography (20% CH2Cl2/PE) to afford 4 g of the title compound. LC-MS: m/z 216.6 (M+H)+
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH:12]([Sn](CCCC)(CCCC)CCCC)=[CH2:13].[F-].[K+]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.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>[CH2:12]([C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:13]
Reactant: COC(=O)c1cccc(I)c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCc1cccc(C(=O)OC)c1
Reaction time: 24 h

Procedure:
Methyl 3-iodobenzoate (13 g) and vinyl tributyltin (20 g) were dissolved in toluene (100 ml) and tetrakis(triphenylphosphine)palladium (0) (500 mg) added. The solution was heated at reflux with stirring under N2 for 1 day. Potassium fluoride (3 g) in water (50 ml) was added and the reaction mixture was allowed to stir under N2 for 15 minutes. The product was taken up in ethyl acetate and washed with water and then brine (×2). The organic extract was dried (MgSO4) and evaporated in vacuo.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:24])(=[O:5])[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].Cl.Cl[CH2:33][CH2:34][CH2:35][N:36]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:37].O>CN(C=O)C>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:33][CH2:34][CH2:35][N:36]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:37])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(O)cccc2c1Nc1ccccc1C
Reactant: CN(CCCCl)Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(=O)c1cnc2c(OCCCN(C)Cc3ccccc3)cccc2c1Nc1ccccc1C
Reaction time: 2 h
Yield: 14.5 %

Procedure:
3-Butyryl-4-(2-methylphenylamino)-8-hydroxyquinoline (3.2 g, 10 mmol) and potassium t-butoxide (5.0 g, 40 mmol) were dissolved in dry DMF (100 ml) and N-(3-chloropropyl)-N-methylbenzylamine hydrochloride (4.1 g, 16 mmol) added. The temperature was raised to 90° and the mixture stirred for 2 hours, then poured into water and extracted with ethyl acetate. Drying, evaporation of the solvent, chromatography (silica gel, 0-3% methanolic ammonia in chloroform) and crystallisation from ether gave 3-butyryl-4-(2-methylphenylamino)-8-(3-(N-benzyl-N-methylamino)propoxy)quinoline (0.7 g, 15%), m.p. 100°-102°.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][CH3:10])[C:3]=1[F:11].B1([O-])OO1.[OH2:16].[OH2:17].O.O.[Na+].O>C(O)(C(F)(F)F)=O.C(O)(=O)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N+:6]([O-:17])=[O:16])=[C:4]([O:9][CH3:10])[C:3]=1[F:11]
Reactant: O
Reactant: COc1c(N)ccc(Br)c1F
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1c([N+](=O)[O-])ccc(Br)c1F
Temperature: 60 °C
Yield: 40 %

Procedure:
To 4-bromo-3-fluoro-2-methoxyaniline (1 g, 4.5 mmol) in a mixture of TFA and acetic acid (10 mL/10 mL) was added sodium perborate tetrahydrate (3.2 g, 21 mmol). The reaction mixture was warmed up to 60° C. and heated for 24 h. It was then diluted to water, extracted with ethyl acetate. The product was obtained by flash column as a yellow solid (450 mg, 40%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.11 (s, 3 H) 7.40 (dd, J=9.0, 6.2 Hz, 1 H) 7.54 (dd, J=9.0, 1.9 Hz, 1 H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)=[C:20]([C:35]([F:38])([F:37])[F:36])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:40]>C(O)C>[ClH:40].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=2)=[C:20]([C:35]([F:38])([F:36])[F:37])[CH:19]=1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(OCCCc3cccc(F)c3)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: Cl
Solvent: CCO
Product: NC(CO)(CO)CCc1ccc(OCCCc2cccc(F)c2)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
Compound 23-3 (700 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (525 mg) as a white powder.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:17]3[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[CH:13]2[CH2:14][C:15](=[O:24])[CH2:16]3)(=[O:11])=[O:10])=[CH:5][CH:4]=1.CC(O[CH:32](N(C)C)[N:33]([CH3:35])[CH3:34])(C)C>>[CH3:32][N:33]([CH:35]=[C:14]1[C:15](=[O:24])[CH2:16][CH:17]2[N:12]([S:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:25])[F:26])=[CH:4][CH:5]=3)(=[O:10])=[O:11])[CH:13]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=12)[CH3:34]
Reactant: O=C1CC2c3ccccc3C(C1)N2S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CN(C)C=C1C(=O)CC2c3ccccc3C1N2S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Compound 16 (15 mg, 0.04 mmol) was mixed with 0.3 mL of Bredereck's reagent and the mixture was stirred at room temperature for 30 min. The reaction was quenched with water (1 mL) and extracted with EtOAc. After evaporation of the solvent, the crude product was obtained as a yellow oil and used without further purification.