Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([F:14])[CH:8]=1)([OH:6])[CH2:4]Cl.C(=O)(O)[O-].[Na+].[CH2:20]([NH2:22])[CH3:21].O>C(#N)C.COC(C)(C)C>[F:14][C:9]1[CH:8]=[C:7]([C:3]2([OH:6])[CH2:4][N:22]([CH2:20][CH3:21])[CH2:2]2)[CH:12]=[C:11]([F:13])[CH:10]=1
Reactant: CCN
Reactant: OC(CCl)(CCl)c1cc(F)cc(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: CC#N
Product: CCN1CC(O)(c2cc(F)cc(F)c2)C1
Yield: 23 %

Procedure:
1,3-dichloro-2-(3,5-difluorophenyl)propan-2-ol (1.0 g, 4.15 mmol) was dissolved in acetonitrile (10 ml) and sodium bicarbonate (1.39 g, 16.59 mmol and ethylamine in water (70%, 0.33 ml, 4.15 mmol) was added and the mixture was refluxed for 10 h. Water (50 ml) and tert-butyl methyl ether (50 ml) was added and the organic phase was collected. The aqueous phase was extracted with tert-butyl methyl ether (50 ml, the pooled organic phase was extracted with aqueous hydrochloric acid (10%, 50 ml). The aqueous phase was basified and extracted with tert-butyl methyl ether (2×50 ml), dried (Na2SO4) and evaporated to give 0.35 g crude product. Purification by flash column chromatography on silica gel (ethyl acetate/MeOH 1:0→1:1) gave the title compound (0.2 g, 23%). The amine was converted to the fumaric acid salt and recrystallized from ethanol/diethyl ether/diisopropyl ether: M.p. 140-141° C. MS m/z (relative intensity, 70 eV) 213 (M+, 1), 156 (36), 141 (37), 127 (64), 114(50), 58 (bp).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:14]([Li])CCC.[C:19]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH:29]=O)[CH2:24][CH2:23]1)(=[O:21])[CH3:20]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:19]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH:29]=[CH:14][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH2:24][CH2:23]1)(=[O:21])[CH3:20]
Reactant: [Li]CCCC
Reactant: CC(=O)N1CCC(CC=O)CC1
Reactant: COc1ccc2nccc(Cl)c2c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: COc1ccc2nccc(C=CCC3CCN(C(C)=O)CC3)c2c1

Procedure:
Following the procedure of Example 3, 4-chloro-6-methoxyquinoline was reacted with the reaction product of methyl triphenylphosphonium bromide and n-butyllithium. This reaction product was then reacted with N-acetyl-4-piperidine-acetaldehyde to produce 4-[3-(1-acetyl-4-piperidyl)-1-propenyl]-6-methoxyquinoline.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[N:15][CH:16]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27].C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>O.Cl[Pd-2](Cl)(P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[CH:12]=[CH:13][C:14]([OH:17])=[N:15][CH:16]=4)=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: Oc1ccc(-c2c[nH]c3ncc(Br)cc23)cn1
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(-c2cnc3[nH]cc(-c4ccc(O)nc4)c3c2)cc1OC
Reaction time: 0.33 h
Yield: 34 %

Procedure:
To 5-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-pyridin-2-ol, 3,4-dimethoxyphenyl boronic acid (1.3 equiv.) and dichlorobis(triphenylphosphino)palladium (ii) (6 mol %) in a Smith process vial was added a 3:2:1 mixture of acetonitrile, water, and a 2 M solution of sodium carbonate in water to achieve an overall concentration of the starting material of 0.10 M. The reaction was run in a Personal Chemistry® microwave reactor at 165° C. for 1200 s. Water was added and the mixture extracted three times with ethyl acetate. Purification on silica gel with a gradient of MeOH/CH2Cl2 afforded 5-[5-(3,4-dimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-pyridin-2-ol as an off-white solid (34% yield). 1H NMR (DMSO-d6): δ 11.86 (broad s, 1H), 11.67 (broad s, 1H), 8.52 (d, J=2.0 Hz, 1H), 8.22 (d, J=2.0 Hz, 1H), 7.89 (dd, J=2.5, 10 Hz, 1H), 7.75 (s, 1H), 7.73 (s, 1H), 7.29 (d, J=2.0 Hz, 1H), 7.23 (dd, J=2.0, 8.0 Hz, 1H), 7.04 (d, J=8.5 Hz, 1H), 6.44 (d, J=9.0 Hz, 1H), 3.85 (s, 3H), 3.79 (s, 3H); MS: m/z 348.1 [MH]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([C:25]4[CH:26]=[CH:27][C:28]([O:35][CH3:36])=[C:29]([CH:34]=4)[C:30]([O:32]C)=[O:31])=[CH:18][C:11]=3[C:12]=2[C:13]2[NH:14][CH:15]=[CH:16][N:17]=2)=[CH:4][CH:3]=1.O.[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([C:25]4[CH:26]=[CH:27][C:28]([O:35][CH3:36])=[C:29]([CH:34]=4)[C:30]([OH:32])=[O:31])=[CH:18][C:11]=3[C:12]=2[C:13]2[NH:17][CH:16]=[CH:15][N:14]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(-c2cc3c(-c4ncc[nH]4)c(-c4ccc(F)cc4)oc3cc2[N+](=O)[O-])ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2cc3c(-c4ncc[nH]4)c(-c4ccc(F)cc4)oc3cc2[N+](=O)[O-])cc1C(=O)O
Temperature: 50 °C

Procedure:
To a mixture of methyl 5-(2-(4-fluorophenyl)-3-(1H-imidazol-2-yl)-6-nitrobenzofuran-5-yl)-2-methoxybenzoate (370 mg, 0.759 mmol) in a mixture of THF (40 mL)/water (4 mL) at room temperature was added a 2.0 M aqueous sodium hydroxide solution (1.518 mL, 3.04 mmol). The reaction mixture was heated to 50° C. and maintained at the same temperature overnight. The reaction mixture was concentrated to remove the solvent. The residue was diluted with water, acidified by using 1.5 N HCl, filtered and dried under suction to give the title compound as a yellow solid. Yield: 320 mg (89%). 1H NMR (400 MHz, DMSO-d6) δ ppm: 13.11-13.73 (m, 1H) 12.66-12.97 (m, 1H) 8.53 (s, 1H) 7.94-8.09 (m, 2H) 7.63-7.82 (m, 1H) 7.34-7.51 (m, 5H) 7.23 (d, J=8.78 Hz, 2H) 3.88 (s, 3H). LCMS: (ES+) m/z=474.23 (M+H)+; Column—ACQUITY UPLC BEH C8 (50×2.1 mm; 1.7 nm); Mphase A: 5 mM Ammonium Acetate:MeCN (95:5); Mphase B: 5 mM Ammonium Acetate:MeCN (5:95)
Reaction SMILES: [O:1]=[C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:14]/[C:15](/[CH2:19][CH2:20][CH:21]=[C:22](C)[CH3:23])=[CH:16]\CO.O(C)[Na]>C1CCCCC1.CCOCC>[O:1]=[C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6]/[CH:7]=[C:22](\[CH3:23])/[CH2:21][CH2:20][CH:19]=[C:15]([CH3:16])[CH3:14])=[O:4]
Reactant: CCOC(=O)C(=O)c1ccccc1
Reactant: CC(C)=CCC/C(C)=C/CO
Agent: CO[Na]
Solvent: CCOCC
Solvent: C1CCCCC1
Product: CC(C)=CCC/C(C)=C/COC(=O)C(=O)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of ethyl 2-oxo-2-phenylacetate (17.6 g, 99 mmol), (E)-3,7-dimethyl-2,6-octadienol (18.5 g, 120 mmol) and NaOCH3 (30% in methanol, 1.5 ml) in cyclohexane (170 ml) was heated under reflux for 72 h. After cooling to room temperature the reaction mixture was taken up in ether, washed with water (pH≈7), dried (Na2SO4), filtered and concentrated. Column chromatography (SiO2, heptane/ether 8:2) afforded 14.5 g (52%) of a slightly yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:1][C:2]2[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=2)=[O:20])=[CH:22][CH:23]=1)([O-:14])=[O:13]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Product: O=C(Nc1ccc(O)c(C(=O)O)c1)c1ccc([N+](=O)[O-])cc1
Yield: 55.8 %

Procedure:
By following the similar procedure in Synthesis Example 1 by using 5-aminosalicylic acid (500 mg, 3.26 mmole) and 4-nitrobenzoyl chloride (700 mg, 3.77 mmole), 550 mg (56% yield) of 5-(4-nitrobenzoyl)aminosalicylic acid was obtained as a pale yellow solid.: mp 270-271 ° C.
Reaction SMILES: [OH:1][CH:2]([CH2:4][CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[CH:7]=1)[CH3:3].N1C=CC=CC=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[C:29](Cl)=[O:30].C(Cl)(=O)C(Cl)=O>C1(C)C=CC=CC=1.O>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[C:29]([O-:1])=[O:30].[OH:1][CH:2]([CH2:4][CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[CH:7]=1)[CH3:3]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: COc1ccc2cc(CCC(C)O)ccc2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COc1cc(C(=O)[O-])cc(OC)c1OC
Reaction time: 48 h

Procedure:
To a stirred mixture of 2-hydroxy-4-(6-methoxy-2-naphthyl)butane (1.15 g: 0.005 mole) in toluene (45 ml) containing dry pyridine (3 ml) was added 3,4,5-trimethoxy-benzoyl chloride, prepared from the corresponding acid (1.06 g: 0.005 mole) and oxalyl chloride (1 ml). After standing for 48 hours at room temperature, the resulting mixture was added to water and extracted with ether. The organic extract was washed twice with water, dried (Na2SO4) and concentrated. The crude oil was chromatographed on alumina (100 g) using 10% ethereal hexane as eluant to afford the 3,4,5-trimethoxybenzoate of 2-hydroxy-4-(6-methoxy-2-naphthyl)butane as a pale yellow oil
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH:11]2[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)([CH3:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:18]([NH:20][C:21]([NH2:23])=[NH:22])#[N:19]>C(OCCOCCO)C>[NH2:23][C:21]1[N:20]=[C:18]([NH2:19])[C:15]2[CH2:16][CH:11]([C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)([CH3:10])[CH3:9])[CH2:12][CH2:13][C:14]=2[N:22]=1
Reactant: CC(C)(c1cccc(Cl)c1)C1CCC(=O)CC1
Reactant: N#CNC(=N)N
Solvent: CCOCCOCCO
Product: CC(C)(c1cccc(Cl)c1)C1CCc2nc(N)nc(N)c2C1

Procedure:
This compound is prepared in a manner analogous to that of Example 1, using 3.2 grams (0.013 mole) of 4-[2-(3-chlorophenyl)propan-2-yl]cyclohexanone and 1.2 grams (0.014 mole) of cyanoguanidine in 2-(2-ethoxyethoxy)ethanol, yielding 2,4-diamino-6-[2-(3-chlorophenyl)propan-2-yl]-5,6,7,8-tetrahydroquinazoline.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[C:33]5[C:28](=[CH:29][C:30]([O:35][CH3:36])=[C:31]([OH:34])[CH:32]=5)[N:27]=[CH:26][CH:25]=4)=[C:19]([F:37])[CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.O[CH2:39][CH2:40][CH2:41][N:42]([CH2:45][CH3:46])[CH2:43][CH3:44].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[CH2:43]([N:42]([CH2:45][CH3:46])[CH2:41][CH2:40][CH2:39][O:34][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][C:30]=1[O:35][CH3:36])[N:27]=[CH:26][CH:25]=[C:24]2[O:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:14]([C:11]2([C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:10])[CH2:12][CH2:13]2)=[O:15])=[CH:18][C:19]=1[F:37])[CH3:44]
Reactant: CCN(CC)CCCO
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)c2cc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCN(CC)CCCOc1cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccnc2cc1OC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a slurry of cyclopropane-1,1-dicarboxylic acid [3-fluoro-4-(6-hydroxy-7-methoxy-quinolin-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide (0.12 g, 0.23 mmol), hydroxypropyldiethylamine (0.090 mL, 0.61 mmol), triphenylphosphine (0.20 g, 0.76 mmol) in DCM (10 mL) was added DIAD (0.17 mL, 0.86 mmol). The resulting mixture was stirred at room temperature for 12 hours, after which time, the solvent was removed under reduced pressure. The residue was extracted with EtOAc and 1N HCl (6×) and brine (1×) followed by drying with Na2SO4. Concentration of the organic fraction in vacuo afforded ′N-(4-{[6-{[3-(diethylamino)propyl]oxy}-7-(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide as a yellow oil (0.18 g, wet, ca 95% purity by analytical HPLC). Further purification by preparatory HPLC using ammonium acetate afforded the product in 99% purity by analytical HPLC. LCMS: m/z 619 (M+H)+. 1H NMR (DMSO-d6) δ 10.37 (br s, 1H), 10.00 (s, 1H), 8.44 (d, 1H), 7.87 (d, 1H), 7.62 (m, 2H), 7.49 (m, 2H), 7.41 (m, 2H), 7.13 (t, 2H), 6.40 (d, 1H), 4.17 (t, 2H), 3.93 (s, 3H), 2.59 (t, 2H), 2.49 (m, 6H), 1.91 (m, 4H), 0.94 (t, 6H).
Reaction SMILES: C([Mg]Cl)(C)C.[Li+].[Cl-].[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1Br.O1CCN([C:23](=[O:50])[CH2:24][O:25][CH:26]([CH:48]=[CH2:49])[CH2:27][O:28][C:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)CC1>C1COCC1>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C:23](=[O:50])[CH2:24][O:25][CH:26]([CH:48]=[CH2:49])[CH2:27][O:28][C:29]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: C=CC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OCC(=O)N1CCOCC1
Reactant: Fc1cccc(Br)c1F
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OCC(=O)c1cccc(F)c1F
Reaction time: 1 h

Procedure:
Isopropylmagnesiumchloride-LiCl complex (1.30 M in THF, 155.0 mL, 0.0715 mol) under nitrogen was cooled to 0-5° C., and 2,3-difluorobromobenzene (13.8 g, 0.0715 mol, 1.50 equiv.) was added while T<10° C. After 1 h at 0-5° C., a solution of 1-morpholino-2-(1-(trityloxy)but-3-en-2-yloxy)ethanone (21.8 g, 0.048 mol, 1.0 equiv.) in THF (2.0 vols) was added while T<10° C. The reaction mixture was stirred for 2.5 h and monitored for consumption of 1-morpholino-2-(1-(trityloxy)but-3-en-2-yloxy)ethanone (target>97%). The reaction mixture was quenched by charging into cold sat. aq. NH4Cl (110 mL) and water (33 mL) while T<20° C. 2-Methoxy-2-methylpropane (218 mL) was added and the layers were separated. The organics were washed with sat. aq. NH4Cl (65 mL) and 18% aq. NaCl (44 mL). The organics were concentrated under vacuum T<25° C. to a light yellow oil (21.6 g). 1H NMR (500 MHz, CDCl3) δ ppm 7.70-7.64 (m, 1H), 7.47-7.42 (m, 6H), 7.37-7.30 (m, 1H), 7.30-7.25 (m, 6H), 7.24-7.19 (m, 3H), 7.19-7.13 (m, 1H), 5.84-5.71 (m, 1H), 5.30 (d, J=17.3 Hz, 1H), 5.25 (d, J=10.4 Hz, 1H), 4.78 (dd, J=17.7, 3.1 Hz, 1H), 4.70 (dd, J=17.7, 3.1 Hz, 1H), 4.03 (dd, J=11.8, 6.5 Hz, 1H), 3.35 (dd, 1=9.8, 6.4 Hz, 1H), 3.18 (dd, J=9.8, 4.6 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ ppm 194.15 (dd, JCF=4.9, 2.4 Hz), 150.77 (dd, JCF=250.3, 14.1 Hz), 150.29 (dd, JCF=256.4, 13.9 Hz), 143.98, 135.34, 128.75, 127.76, 126.95, 125.70 (d, JCF=12.0 Hz), 125.16 (d, JCF=3.5 Hz), 124.55 (dd, JCF=6.4, 4.2 Hz), 121.62 (d, JCF=17.6 Hz), 118.83, 86.78, 81.35, 74.98 (d, JCF=9.5 Hz), 66.71.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10](=O)[CH3:11])=[CH:4][CH:3]=1>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[S:8][CH:9]=[C:10]([CH3:11])[C:4]=2[CH:3]=1
Reactant: CC(=O)CSc1ccc(Cl)cc1
Solvent: O
Product: Cc1csc2ccc(Cl)cc12
Temperature: 120 °C
Yield: 38.3 %

Procedure:
1-[(4-Chlorophenyl)thio)-2-propanone (50 g, 0.25 mol) was added to polyphosphoric acid (300 g) and the mixture was stirred as the temperature was gradually raised to 120° C. as an exotherm started. The mixture was stirred at 130° C. for 1 hour, diluted with water, extracted with ethyl ether and the organic phase was dried and concentrated. The residue was stirred in methanol (200 ml), filtered and the filtrate concentrated to give 17.5 g (40%) of 5-chloro-3-methylbenzo(b)thiophene: bp 120° C. (0.6 mm Hg).
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10](=O)[CH3:11])[CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH:13]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[NH2:23])([CH3:15])[CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)CC>[CH:13]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[N:23]=[C:10]([C:8]1[N:9]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=[CH:6][CH:7]=1)[CH3:11])([CH3:15])[CH3:14]
Reactant: CC(=O)c1cccc(C(C)=O)n1
Reactant: Cc1cccc(C(C)C)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCO
Product: CC(=O)c1cccc(C(C)=Nc2c(C)cccc2C(C)C)n1

Procedure:
1-(6-Acetyl-pyridin-2-yl)-ethanone 2 (35.54 g, 0.22 mol), 25.0 g (0.168 mol) of 2-Isopropyl-6-methyl-phenylamine 14, 350 ml of n-propanol, and a few crystals of p-toluenesulfonic acid were stirred at room temperature for 36 h in a 500 ml flask under a flow of the nitrogen. The resultant yellow precipitate was filtered and washed by 20 ml of methanol. It was then dried at 1-mm vacuum overnight. The yield of 1-{6-[1-(2-Isopropyl-6-methyl-phenylimino)-ethyl]-pyridin-2-yl}-ethanone 15 was 13.35 g (27%) as a yellow solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[S:21][CH:20]=[CH:19][C:18]=2[CH:22]=1.Cl[Si:24]([CH3:27])([CH3:26])[CH3:25]>C1COCC1>[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[S:21][C:20]([Si:24]([CH3:27])([CH3:26])[CH3:25])=[CH:19][C:18]=2[CH:22]=1
Reactant: C[Si](C)(C)Cl
Reactant: Brc1ccc2sccc2c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cc2cc(Br)ccc2s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
To a solution of diisopropylamine (15.5 mL, 110 mmol) in THF (100 mL) at 0° C. was added n-butyllithium (40 mL of 2.5M in hexanes, 100 mmol). The resultant reaction solution was stirred at 0° C. for 30 minutes and then cooled to −40° C., before it was cannulated to a solution of 5-bromobenzothiophene (10.5 g, 50.0 mmol) and chlorotrimethylsilane (12.7 mL, 100 mmol) in THF (150 mL) at −78° C. The reaction solution was stirred at −78° C. for 1 hour, and then it was quenched with aqueous ammonium chloride at −78° C. and warmed to room temperature. The resultant mixture was extracted with ethyl acetate and the organic extract obtained was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue obtained was purified by flash column chromatography (hexanes to 98:2 hexanes/ethyl acetate) to give the desired 5-bromo-2-trimethylsilylbenzothiophene (14.1 g, 98%) as a clear colorless oil: 1H NMR (500 MHz, CDCl3) δ 7.93 (d, J=2.0 Hz, 1H), 7.72 (d, J=8.5 Hz, 1H), 7.39 (dd, J=8.5, 2.0 Hz, 1H), 7.37 (s, 1H), 0.38 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([S:11](Cl)(=[O:13])=[O:12])[S:10][C:6]=2[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[CH3:21][C:22]1[CH:23]=[CH:24][C:25]([NH2:28])=[CH:26][CH:27]=1.C(OC([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CCOC(C)=O>[ClH:1].[C:22]1([CH3:21])[CH:27]=[CH:26][C:25]([NH:28][S:11]([C:9]2[S:10][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([N:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)[C:7]=3[CH:8]=2)(=[O:13])=[O:12])=[CH:24][CH:23]=1
Reactant: Cc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)c1cc2c(Cl)nccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(NS(=O)(=O)c2cc3c(N4CCNCC4)nccc3s2)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 13.1 %

Procedure:
To a solution of 4-chloro-thieno[3,2-c]pyridine-2-sulfonyl chloride (0.640 g, 2.39 mmol) in DCM (20 mL) was added pyridine (1.9 mL, 23.9 mmol) followed by p-tolylamine (0.307 g, 2.86 mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated and re-dissolved in DMSO (10 mL), piperazine-1-carboxylic acid tert-butyl ester (1.34 g, 7.17 mmol) and K2CO3 (0.989 g, 7.17 mmol) were added. The mixture was stirred at 100° C. for 16 hours and then concentrated. The crude reaction mixture was dissolved in EtOAc (100 mL) and washed with brine (2×50 mL). The organic phase was dried (Na2SO4) and concentrated. The crude intermediate was purified by column chromatography on silica using EtOAc/n-pentane (1:1) as eluent. The intermediate was dissolved in EtOAc/MeOH and diethyl ether saturated with HCl (g) was added. The mixture was stirred at room temperature for 16 hours. The precipitate was collected by filtration and washed with diethyl ether/n-pentane to give 0.475 g of the crude product. Purification by preparative reversed phase HPLC gave 0.133 g of the pure product: 1H NMR (DMSO-d6, 25° C., 270.17 MHz) δ 10.61 (br s, 1H), 9.23 (br s, 2H), 8.13 (d, J=5.80 Hz, 1H), 7.91 (s, 1H); 7.67 (d, J=5.80 Hz, 1H), 7.09-7.07 (m, 4H), 3.68-3.59 (m, 4H), 3.33-3.22 (m, 4H), 2.20 (s, 3H); m/z (posESI) 399 (M+H).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]([CH2:11][CH2:12][CH:13]([NH2:17])[C:14]([OH:16])=[O:15])=[O:10])=[CH:3][CH:2]=1.[CH2:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>ClCCCl>[CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]([CH2:11][CH2:12][C@H:13]([NH2:17])[C:14]([OH:16])=[O:15])=[O:10])=[CH:3][CH:2]=1.[NH2:17][C@H:13]([C:14]([O:16][CH:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:19][CH3:18])=[O:15])[CH2:12][CH2:11][C:9]([O-:10])=[O:8]
Reactant: CCCCCCCCCCCCO
Reactant: NC(CCC(=O)OCc1ccccc1)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: ClCCCl
Product: CCCCCCCCCC(CC)OC(=O)[C@@H](N)CCC(=O)[O-]
Product: N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Reaction time: 15 h

Procedure:
20 g of poly(γ-benzyl L-glutamate)(molecular weight: 15000; average degree of polymerization: 69) prepared by the NCA method was dissolved in 1,2-dichloroethane. To the resulting solution were added 150 ml of n-dodecyl alcohol and 5 g of p-toluenesulfonic acid. The reaction was allowed to proceed at 60° C. for 15 hours. The reaction mixture was poured into a large amount of methanol to precipitate the formed polymer. The polymer was filtered and dried. Subsequently, the polymer was dissolved in 1,2-dichloroethane again, reprecipitated with methanol, filtered and dried to obtain a purified γ-benzyl L-glutamate/γ-dodecyl L-glutamate copolymer. The ratio of the benzyl ester to the dodecyl ester in the copolymer was determined by NMR and was found to be 61:39.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH2:10][O:9][CH2:8][N:7]([S:11]([C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=3[O:21][CH3:22])(=[O:13])=[O:12])[C:6]=2[CH:23]=1.C(N(CC)CC)C.[C:31]([O:34][CH2:35]C)(=[O:33])C>CO>[CH3:35][O:34][C:31]([C:2]1[CH:3]=[CH:4][C:5]2[CH2:10][O:9][CH2:8][N:7]([S:11]([C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=3[O:21][CH3:22])(=[O:13])=[O:12])[C:6]=2[CH:23]=1)=[O:33]
Reactant: CCOC(C)=O
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1COCc2ccc(Br)cc21
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)COC2
Yield: 43 %

Procedure:
A solution of 7-bromo-1-(5-chloro-2-methoxy-benzenesulfonyl)-1,4-dihydro-2H-benzo[d][1,3]oxazine (2.00 g, 4.78 mmol), triethylamine (1.21 g, 11.9 mmol), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane complex (200 mg, 0.239 mmol) in methanol (30 mL) and ethyl acetate (30 mL) was heated at 130° C. under a carbon monoxide atmosphere (100 bar) for 3 h. The reaction mixture was evaporated and the residue chromatographed (SiO2, heptane-ethyl acetate gradient) to produce 1-(5-chloro-2-methoxy-benzenesulfonyl)-1,4-dihydro-2H-benzo[d][1,3]oxazine-7-carboxylic acid methyl ester (825 mg, 43%). Orange solid, MS (ISP)=398.1 (M+H)+.