Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[S:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.[CH:15](=[O:20])[CH2:16][CH:17]([CH3:19])[CH3:18]>C1COCC1>[S:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[CH:15]([OH:20])[CH2:16][CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)CC=O
Reactant: c1ccc2scnc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)CC(O)c1nc2ccccc2s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 17.7 %

Procedure:
A solution of n-butyllithium (2.5M in hexanes; 65.1 ml, 0.163 mol) was added to a stirred solution of benzothiazole (20.0 g, 0.148 mol) in dry THF (250 ml) under argon at -78° C. After 10 min a solution of isovaleraldehyde (17.4 ml, 0.163 mol) in dry THF (50 ml) was added slowly and the mixture stirred for 1 h at -78° C. The reaction mixture was removed from the cooling bath and after 10 min was quenched by the addition of excess water and the mixture extracted with ethyl acetate. The combined organic layers were washed with water, dried, filtered and evaporated. Chromatography (20-30% diethyl ether in hexane) gave 1-(2-benzothiazolyl)-3-methylbutanol (5.8 g, 18%) as an amorphous yellow solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[H-].[Na+].Cl[C:10]1[C:15]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=2[O:13][C:12]([CH2:25][F:26])([CH2:23][F:24])[N:11]=1>CN(C)C=O>[F:26][CH2:25][C:12]1([CH2:23][F:24])[N:11]=[C:10]([N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])[C:15]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=2[O:13]1
Reactant: O=C1CCCN1
Reactant: O=[N+]([O-])c1ccc2c(c1)C(Cl)=NC(CF)(CF)O2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCCN1C1=NC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47.2 %

Procedure:
In 1 ml of N,N-dimethylformamide was dissolved 62 mg of 2-pyrrolidinone and 35 mg of sodium hydride (60%) was added thereto under nitrogen stream. The mixture was stirred at room temperature for 20 minutes and 90 mg of 4-chloro-2,2-bisfluoromethyl-6-nitro-2H-1,3-benzoxazine dissolved in 2 ml of N,N-dimethylformamide was added thereto. The mixture was stirred at 45°-55° C. for 5 hours. After addition of saturated saline solution, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried. The solvent was distilled off and the resultant residue was purified using silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain 50 mg of 2,2-bisfluoromethyl-6-nitro-4-(2-oxo-1-pyrrolidinyl)-2H-1,3-benzoxazine represented by the following formula having a melting point of 195°-198° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8])([O-:3])=[O:2].S([CH2:22][N+:23]#[C-:24])(C1C=CC(C)=CC=1)(=O)=O.CO>COCCOC>[N+:1]([C:4]1[CH:5]=[C:6]([C:7]2[O:8][CH:24]=[N:23][CH:22]=2)[CH:9]=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: COCCOC
Solvent: CO
Product: O=[N+]([O-])c1cccc(-c2cnco2)c1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
2.04 g (13.5 mmol, 1 eq.) of 3-nitrobenzaldehyde, 2.90 g (14.85 mmol, 1.1 eq.) of tosylmethyl isocyanide, 200 mL of MeOH and 200 mL of DME are introduced into a 1 L flask. 25 g of Amberlyst A26 OH— resin are added and the mixture is heated under reflux for 1 hour. The reaction medium is cooled to room temperature, then the resin is filtered over a frit and rinsed with methanol. After concentration to dryness, 2.56 g (yield=100%) of 5-(3-nitrophenyl)oxazole are obtained. The product is used without subsequent purification.
Reaction SMILES: [CH3:1][N:2]([CH3:48])[C:3]([C:5]1[S:6][C:7]([C:10]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]4[N:19]([C:21]([C:24]5[S:25][CH:26]=[CH:27][N:28]=5)=[CH:22][N:23]=4)[CH:20]=3)=[CH:13][N:12](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:11]=2)=[CH:8][CH:9]=1)=[O:4].[ClH:49]>O1CCCC1.CO>[ClH:49].[ClH:49].[CH3:1][N:2]([CH3:48])[C:3]([C:5]1[S:6][C:7]([C:10]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]4[N:19]([C:21]([C:24]5[S:25][CH:26]=[CH:27][N:28]=5)=[CH:22][N:23]=4)[CH:20]=3)=[CH:13][NH:12][N:11]=2)=[CH:8][CH:9]=1)=[O:4]
Reactant: CN(C)C(=O)c1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4nccs4)n3c2)s1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccc(-c2n[nH]cc2-c2ccc3ncc(-c4nccs4)n3c2)s1
Reaction time: 3 h

Procedure:
29 mg 5-[4-(3-thiazol-2-yl-imidazo[1,2-a]pyridin-6-yl)-1-trityl-1H-pyrazol-3-yl]-thiophen-2-carboxylic acid dimethylamide obtained in Example 444 was dissolved in 8.0 mL solvent mixture of tetrahydrofuran and methanol (1:1), then 3.0 mL of 5 N hydrochloric acid was added thereto, and the mixture was left at room temperature for 3 hours. The reaction solution was neutralized, then extracted with ethyl acetate and purified by NH silica gel column chromatography (ethyl acetate/hexane) The product was converted into the corresponding hydrochloride by 4 N hydrogen chloride in ethyl acetate and recrystallized from methanol/ethyl acetate to give 20 mg of the title compound as colorless crystals.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=O.[Br-].[CH:18]1([CH2:24][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1>>[C:18]1([CH:24]=[CH:1][C:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc([P+](CC2CCCCC2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)c1[nH]c2ccccc2c1C=O
Agent: [Br-]
Agent: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)c1[nH]c2ccccc2c1C=Cc1ccccc1
Yield: 73 %

Procedure:
Using the procedure of Example 121 but replacing the resultant compound of Example 98 with the resultant compound of Example 97 and replacing the resultant compound of Example 120 with benzyltriphenylphosphonium bromide gave the desired compound in 73% yield after silica gel chromatography using 4:1 hexane/ethyl acetate. 1H NMR (CDCl3) δ 1.49 (t,J=7 Hz,3H), 4.48 (q,J=7 Hz,2H), 7.2-7.3 (m,2H), 7.35-7.45 (m,5H), 7.60 (br d,J=8 Hz,1H), 8.07 (d,J=16 Hz,1H), 8.16 (d,J=8 Hz,1H), 8.88 (br,1H). Mass spectrum: (M+H)+ =292.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][OH:17])=[CH:10][CH:9]=1.Cl[C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[O:24])=[CH:21][N:20]=1.CC(N(C)C)=O>[OH-].[Na+].C(CC(C)(C)C)(C)C>[OH:17][CH2:16][CH2:15][CH2:14][C:11]1[CH:10]=[CH:9][C:8]([O:7][C:19]2[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[O:24])=[CH:21][N:20]=2)=[CH:13][CH:12]=1
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: OCCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)CC(C)(C)C
Solvent: CC(=O)N(C)C
Product: NC(=O)c1ccc(Oc2ccc(CCCO)cc2)nc1
Yield: 87 %

Procedure:
Add potassium carbonate (2.2821 g, 16.51 mmol) to a stirred solution of 3-(4-hydroxyphenyl)-1-propanol (1.0041 g, 6.598 mmol), 6-chloronicotinamide (1.0038 g, 6.411 mmol), dimethylacetamide (21 mL) and isooctane (3 mL). Equip the reaction setup with a Dean-Stark trap and heat the reaction to reflux under nitrogen for 6 h. Cool the reaction to room temperature and filter off the solids. Concentrate on a rotary evaporator to give the crude product. Take the crude product up in 1 N sodium hydroxide (250 mL), extract with ethyl acetate (4×100 mL), dry the extracts over magnesium sulfate, filter, and concentrate on a rotary evaporator to give the crude product. The crude product is purified by flash chromatography on silica gel eluting with 1.5% concentrated ammonium hydroxide/15% ethanol/chloroform to yield 1.5188 g (87%) of 6-[4-(3-hydroxy-propyl)-phenoxy]-nicotinamide: mass spectrum (ion spray): m/z=273.2 (M+1); 1H NMR (DMSO-d6): 8.61 (d, 1H), 8.24 (dd, 1H), 8.03 (s, 1H), 7.48 (s, 1H), 7.25 (d, 2H), 7.07-7.03 (m, 3H), 4.50 (t, 1H), 3.46-3.41 (m, 2H), 2.63 (t, 2H), 1.77-1.70 (m, 2H).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[F:9][C:10]1[C:18]2[O:17][C:16](=[O:19])[N:15]([CH2:20][C:21]([NH2:23])=[O:22])[C:14]=2[CH:13]=[CH:12][CH:11]=1>S(=O)(=O)(O)O>[Cl:1][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH2:20][C:21]([NH2:23])=[O:22])[C:16](=[O:19])[O:17][C:18]=2[C:10]=1[F:9]
Reactant: NC(=O)Cn1c(=O)oc2c(F)cccc21
Reactant: O=C1CCC(=O)N1Cl
Agent: O=S(=O)(O)O
Product: NC(=O)Cn1c(=O)oc2c(F)c(Cl)ccc21
Reaction time: 120 h
Yield: 46.5 %

Procedure:
In a three neck flask, fitted with a magnetic stirrer, under inert atmosphere, N-chlorosuccinimide (0.635 g, 4.75 mmol) is added to a suspension of 2-(7-fluoro-2-oxo-1,3-benzoxazol-3(2H)-yl)acetamide 12 (1 g, 4.75 mmol) and sulfuric acid (90% w/w; 20 ml) at 0° C. The reaction is stirred 5 days then poured carefully into ice. The precipitate is collected by filtration and washed with water. The residue is recrystallized in EtOH/water (20/80 (v/v)) to afford 0.54 g of 2-(6-chloro-7-fluoro-2-oxo-1,3-benzoxazol-3(2H)-yl)acetamide 19.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:9][N:10]=[C:4]2[C:3]=1I.[C:17]([Zn]C#N)#[N:18]>CN(C=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>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:9][N:10]=[C:4]2[C:3]=1[C:17]#[N:18]
Reactant: N#C[Zn]C#N
Reactant: FC(F)(F)Cc1cnc2c(I)c(Cl)ccn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: N#Cc1c(Cl)ccn2c(CC(F)(F)F)cnc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 142.5 %

Procedure:
A 2.0-5.0 mL microwave vial was charged with 7-chloro-8-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (30 mg, 0.083 mmol) dissolved in DMF (832 μl). To that stirring solution was added dicyanozinc (5.86 mg, 0.050 mmol) followed by tetrakis(triphenylphosphine)palladium(0) (28.8 mg, 0.025 mmol). The vial was sealed and degassed using sonication and ultra pure argon for 1 min. After which the vial was placed into a reaction block preheated to 120° C. After 5 hours, LCMS showed a good proportion of desired product by mass (m/z=260 [M+H]+Methanol/Water/Ammonium Acetate Phenomenex Luna C18, 30×2 mm, 3u ES+/−). The mixture was cooled to rt and diluted with sat'd sodium bicarbonate and EtOAc. The organic was washed with brine, dried with magnesium sulfate, concentrated under reduced pressure, and purified by flash chromatography: (4 g, equilibrated with none, loaded with DCM, initial waste: 0 mL, fraction size: 12 mL 16×100 mm, and eluted with EtOAc in hexanes 0% [20 mL], 0-100% [120 mL]). Collected fractions to give 7-chloro-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-8-carbonitrile (18.5 mg, 86% yield) as a plaque white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.16 (d, J=7.3 Hz, 1H), 7.78 (s, 1H), 7.06 (d, J=7.3 Hz, 1H), 3.78 (q, J=9.8 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1.F[B-](F)(F)F.[O:18]=[N+:19]=[O:20].O>C(#N)C>[CH3:1][O:2][C:3]1[C:4]([N+:19]([O-:20])=[O:18])=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(NC(C)=O)c1
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CC#N
Product: COc1cccc(NC(C)=O)c1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
N-(3-methoxyphenyl)acetamide (14.23 g, 0.086 mol) was dissolved in acetonitrile (200 mL) and cooled to 0° C. Solid nitronium tetrafluoroborate (14.79 g, 0.106 mol) was added in four portions. The temperature rose to about 5° C. during each addition and was allowed to cool down to 0°0 C. between additions. After the last addition of nitronium tetrafluoroborate, water (200 mL) was added to the reaction mixture and the mixture was concentrated under reduced pressure to give approximately 200 mL of a dark oil. The dark oil was dissolved in dichloromethane (200 mL) and washed with water (6×150 mL). The organic layer was concentrated under reduced pressure and dried to obtain 16.1 g of a dark red oil. The red oil was purified by flash chromatography (silica gel, 25% ethyl acetate/hexane) to give 4.53 g (27%) of the crude product. The crude product was triturated with 25% ethyl acetate/hexane to give 3.0 g (17%) of the title compound.
Reaction SMILES: O.C([O-])=O.[Na+].C(O)(=O)C.[F:10][CH:11]([F:35])[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[C:21]([N+:32]([O-])=O)[CH:20]=1>[C].[Pd].CC(O)C>[NH2:32][C:21]1[CH:20]=[C:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[O:12][CH:11]([F:10])[F:35])[CH:31]=[CH:30][C:22]=1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2OC(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2OC(F)F)cc1N
Temperature: 25 °C
Yield: 90.8 %

Procedure:
Water (0.53 mL), sodium formate (0.13 g), acetic acid (0.13 mL), and 10% palladium-carbon (35 mg) were added to a 2-propanol (2.1 mL) solution of tert-butyl 4-(2-(difluoromethoxy)phenyl)-2-nitrobenzoate (0.18 g), followed by heating to reflux for 2 hours. The reaction mixture was cooled to room temperature, and then the insoluble substance was removed by filtration. The solvent was evaporated under reduced pressure, and ethyl acetate and a saturated aqueous solution of sodium bicarbonate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 99-91% hexane/ethyl acetate] to obtain 0.15 g of tert-butyl 2-amino-4-(2-(difluoromethoxy)phenyl)benzoate as a yellow oily substance.
Reaction SMILES: [CH3:1][C@@:2]12[CH:9]=[CH:8][C:7](=[O:10])[N:6]1[C@@H:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4][O:3]2.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([NH:24][C@H:9]1[C@@:2]2([CH3:1])[O:3][CH2:4][C@H:5]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:6]2[C:7](=[O:10])[CH2:8]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCc1ccccc1
Reactant: C[C@@]12C=CC(=O)N1[C@@H](c1ccccc1)CO2
Product: C[C@]12OC[C@H](c3ccccc3)N1C(=O)C[C@H]2NCc1ccccc1

Procedure:
(3S,7R,7aR)-7-(Benzylamino)-7a-methyl-3-phenyltetrahydropyrrolo[2,1-b]oxazol-5(6H)-one was synthesized from (3S,7aR)-7a-methyl-3-phenyl-2,3-dihydropyrrolo[2,1-b]oxazol-5(7aH)-one and benzyl amine using general procedure Y. RP-HPLC (Table 1, Method a) Rt 1.73; m/z: (M+H)+ 323.
Reaction SMILES: COCCOC[N:7]1[C:11]2=[N:12][CH:13]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH:15]=[C:10]2[C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])=[CH:8]1.C(O)=O.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(O)C.O.[Cl-].[Na+].O>[CH3:29][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:9]1[C:10]2[C:11](=[N:12][CH:13]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH:15]=2)[NH:7][CH:8]=1
Reactant: COCCOCn1cc(-c2ccccc2OC)c2cc(N3CCOCC3)cnc21
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=CO
Solvent: O
Product: COc1ccccc1-c1c[nH]c2ncc(N3CCOCC3)cc12
Temperature: 65 °C
Yield: 88.2 %

Procedure:
65 mg (0.17 mmol) of 1-(2-methoxy-ethoxymethyl)-3-(2-methoxy-phenyl)-5-morpholin-4-yl-1H-pyrrolo[2,3-b]pyridine was dissolved in a mixture of 3 ml of ethanol and 2 ml of water. 500 μl of formic acid was added and the mixture heated to 65° C. for 16 h and then irradiated in the microwave to 150° C. for 40 min. The resulting mixture was neutralized by addition of sodium bicarbonate and water and the crude distributed between ethyl acetate and brine. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated to afford 47 mg (0.15 mmol, 94% yield) of 3-(2-methoxy-phenyl)-5-morpholin-4-yl-1H-pyrrolo[2,3-b]pyridine. 1H-NMR (d6-DMSO): δ11.58 (s, 1H), 8.11 (d, J=2.5 Hz, 1H), 7.59 (d, J=2.4 Hz, 1H), 7.51 (dd, J=1.4 Hz, 7.3 Hz, 1H), 7.46 (s, 1H), 7.27 (ddd, J=1.5 Hz, 8.8 Hz, 1H), 7.11 (d, J=8.3 Hz, 1H), 7.02 (dd(d), J=1.5 Hz, 7.3 Hz, 1H), 3.82 (s, 3H), 3.77 (m, 4H), 3.07 (m, 4H); MS: m/z 310 [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[S:20](Cl)(=[O:22])=[O:21].C(N(CC)CC)C>CC(C)=O>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[S:20]([O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: Nc1ccc(OS(=O)(=O)c2c(Cl)cccc2Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 44.3 %

Procedure:
To a solution of 3.14 g of 4-amino-3-nitrophenol in 50 cm3 of acetone are added 5 g of 2,6-dichlorobenzenesulfonyl chloride. The reaction medium is stirred for five minutes and then placed in a bath of ice-water so as not to exceed 30° C. during the addition of 2.9 cm3 of triethylamine. The formation of a precipitate is observed, and the mixture is stirred for twenty-four hours at a temperature in the region of 20° C. 500 mg of 2,6-dichlorobenzenesulfonyl chloride are added and, after stirring for two hours, the insoluble material is filtered off, washed with three times 30 cm3 of acetone and set aside*. The filtrate is evaporated to dryness under reduced pressure (2 kPa) and the residue is taken up in 1 L of dichloromethane and then washed with three times 40 cm3 of water. The organic phase is dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2 kPa). 3.28 g of 4-amino-3-nitrophenyl 2,6-dichlorobenzenesulfonate are obtained in the form of orange crystals, the characteristics of which are as follows:
Reaction SMILES: N1CCC[C@H]1C(O)=O.[H-].[Na+].C[O:12][C:13](=[O:27])[C@@H:14]1[CH2:18][C@@H:17]([OH:19])[CH2:16][N:15]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].[Br:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1>C1COCC1.O>[C:20]([N:15]1[CH2:16][C@H:17]([O:19][CH2:33][C:32]2[CH:35]=[CH:36][C:29]([Br:28])=[CH:30][CH:31]=2)[CH2:18][C@H:14]1[C:13]([OH:12])=[O:27])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: BrCc1ccc(Br)cc1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: O=C(O)[C@@H]1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](OCc2ccc(Br)cc2)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 30.6 %

Procedure:
The compound of formula (P5), wherein R′ is 4-Bromo and the bonds linking the benzyloxy and methyl ester groups (depicted in P5 as wavy bonds) define the trans, L-proline configuration (2S,4R) was prepared as follows. To a suspension of sodium hydride (60% in oil) (0.12 g) (1.5 eq.) in 5 mL of dry THF was added trans-N-Boc-4-hydroxy-L-proline methyl ester (0.5 g) in 5 mL of dry THF. The reaction mixture was stirred for 45 minutes and a solution of 4-bromobenzyl bromide (0.75 g) (1.5 eq.) in 5 mL of dry THF was added. The reaction mixture was refluxed for 3 hours. After cooling to RT, the reaction mixture was diluted with water and extracted with EtOAc. The aqueous layer was acidified and extracted with DCM. The combined organic extracts were washed with water, dried over MgSO4, and evaporated under reduced pressure to afford trans-N-Boc-4-(4-bromo-benzyloxy)-L-proline (0.25 g). NMR (CDCl3, 200 MHz): 7.47 (2H, d), 7.2 (2H, d), 4.50-4.30 (3H, m), 4.25-4.1 (1H, m), 3.75 (3H, s), 3.8-3.5 (2H, m), 2.5-2.3 (1H, m), 2.15-1.95 (1H, m), 1.5-1.35 (9H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[S:19](=[O:21])(=[O:20])[CH2:18][CH2:17][C:16]([C:22]([O:24]C)=[O:23])=[CH:15][C:14]=3[CH:26]=2)=[CH:6][CH:5]=1)[CH3:2].Cl>COCCOC>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[S:19](=[O:21])(=[O:20])[CH2:18][CH2:17][C:16]([C:22]([OH:24])=[O:23])=[CH:15][C:14]=3[CH:26]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Agent: Cl
Solvent: COCCOC
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1
Yield: 87.9 %

Procedure:
To a solution of methyl 7-(4-ethoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (600 mg) in 1,2-dimethoxyethane (40 ml) was added 6N hydrochloric acid (30 ml), and the mixture was refluxed for 7 hours and concentrated under reduced pressure. To the residue was added 2-propanol, and precipitated crystals were collected by filtration. The crystals were dissolved in THF, and the solution was concentrated to give crystals, which were collected by filtration to give pale yellow crystals of 7-(4-ethoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (507.5 mg).
Reaction SMILES: [C:1]12[CH2:7][C:4](=[CH:5][CH:6]=1)[C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][C:2]2=1.[OH-:12].[Na+].[BH4-].[Na+]>O.O1CCCC1>[C:4]12[C:5](=[O:12])[CH:6]=[C:1]([CH:7]=1)[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]2=1
Reactant: C1=C2CC(=C1)c1ccccc12
Reactant: [OH-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1C=C2C=C1c1ccccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of mercuric acetate (4 g) in water (10 ml) was treated with a solution of benzobicyclo[2.2.1]heptadiene (2 g) in tetrahydrofuran (25 ml) and the resulting mixture was stirred at room temperature for 24 hours. The solution was treated with a solution of 10% sodium hydroxide in water (5 ml), followed by sodium borohydride (0.5 g). The resulting mixture was stirred for 30 minutes and the resulting layers were separated. The aqueous layer was extracted with ether (2×30 ml) and the combined organic layers were dried over magnesium sulfate and concentrated on a rotary evaporator. The residue was combined with methylene chloride (25 ml) and pyridinium chlorochromate (3 g) and the solution was stirred at room temperature for 12 hours. The solution was washed with water (30 ml) and the organic layer was dried over magnesium sulfate. The solvent was removed on a rotary evaporator and the product was purified by preparative centrifugally accelerated radial thin layer chromatography using 25% ethyl acetate in hexane as the eluant. After removal of the eluant on a rotary evaporator, the product was obtained as a yellow oil.
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)=[C:18]([CH:21]=1)[C:19]#[N:20]>>[C:19]([C:18]1[CH:21]=[C:14]([NH:13][C:6]([C:5]2[S:1][C:2]3[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=3[CH:4]=2)=[O:8])[CH:15]=[CH:16][C:17]=1[N:22]1[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]1)#[N:20]
Reactant: CN1CCN(c2ccc(N)cc2C#N)CC1
Reactant: O=C(O)c1cc2ccccc2s1
Product: CN1CCN(c2ccc(NC(=O)c3cc4ccccc4s3)cc2C#N)CC1
Yield: 36.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 6 using benzo[b]thiophene-2-carboxylic acid (1.3 g) and 5-amino-2-(4-methylpiperazin-1-yl)benzonitrile (1.6 g), the title compound (1.0 g) was obtained. melting point: 263-264° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19]Cl.C(OC(C)C)(C)C>CN(C)C=O.O>[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CN(C)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)OC(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCOc1ccc(C=O)cc1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 71.5 %

Procedure:
To a solution of 61.1 g of p-hydroxybenzaldehyde in 240 ml of N,N-dimethylformamide was added 138 g of potassium carbonate, 80.7 g of 2-dimethylaminoethyl chloride and 30 ml of isopropyl ether. The mixture was stirred at 60° C. for 1.5 hours. After cooling, the reaction mixture was poured into 720 ml of water, and the whole was extracted with chloroform. The chloroform layer was extracted with aqueous hydrochloric acid. The aqueous layer was made alkaline with aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The residue was distilled to give 69.1 g of colorless oil, b.p. 142°-144° C. (4 mmHg).