Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C([Li])CCC.[C:17](OCC)(=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19].[NH4+].[Cl-]>C1COCC1>[CH:7]1[C:8]2[C:3](=[C:2]([C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Brc1cccc2cnccc12
Reactant: CCOC(=O)C(=O)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1cccc2cnccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.2 %

Procedure:
The product from Example 57A (11.80 g, 56.6 mmol) in THF (200 mL) at −78° C. was treated with n-butyllithium (30 mL, 75.0 mmol, 2.5M in hexanes) dropwise. After 30 minutes, the mixture was treated with diethyl oxalate (25.0 mL, 184 mmol). After 20 minutes, the solution was allowed to warm to room temperature and was treated with saturated NH4Cl (150 mL). The mixture was concentrated under reduced pressure. The residue was treated with dichloromethane (100 mL) filtered, and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography (20% ethyl acetate/hexanes) to provide the title compound as light brown oil (4.57 g, 35%). MS (ESI+) m/z 248 (100), 230 (M+H)+, (ESI−) m/z 200 (M−Et−; 1H NMR (DMSO-d6, 300 MHz) rotomers δ 1.26 (t, J 7.1, 0.6H), 1.37 (t, J 7.1, 2.4H), 4.21 (q, J 7.1, 0.4H), 4.47 (q, J 7.1, 1.6H), 7.89 (t, J 7.5, 1H), 8.41 (dd, J 1.0, 7.5, 1H), 8.57 (d, J 8.1, 1H), 8.64 (d, J 5.7, 1H), 8.73 (d, J 6.3, 1H), 9.50 (s, 1H).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([CH3:4])=O.Cl.[NH2:10][OH:11].C([O-])(=O)C.[Na+]>C(O)C>[OH:11]/[N:10]=[C:2](\[CH3:4])/[C:1]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(C)=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)/C(C)=N/O
Yield: 59 %

Procedure:
A mixture of ethyl pyruvate (9.50 g), hydroxylamine hydrochloride (6.82 g), sodium acetate (10.1 g) and ethanol (150 ml) was heated under reflux for 17 hours. The reaction mixture was concentrated, and the residue was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and then concentrated. The residual crystals were recrystallized from ethyl acetate-hexane to obtain ethyl E-2-hydroxyiminopropionate (6.33 g, yield 59%) as colorless crystals. m.p. 98-99° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:13][C:14]1[C:19]2[CH:20]=[CH:21][O:22][C:18]=2[CH:17]=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:23]([O-])(=[O:25])C.[Na+]>CN(C)C=O>[CH2:6]([O:13][C:14]1[C:19]2[CH:20]=[CH:21][O:22][C:18]=2[C:17]([CH:23]=[O:25])=[CH:16][CH:15]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(=O)[O-]
Reactant: c1ccc(COc2cccc3occc23)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc(OCc2ccccc2)c2ccoc12
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 17 %

Procedure:
Dry N,N-dimethylformamide (12.1 g, 166 mmol) was added dropwise with stirring and cooling under an argon atmosphere to phosphorous oxychloride (11.4 g, 75 mmol) at such a rate that the temperature did not exceed 10° C. After 30 min at 10° C., a solution of 4-benzyloxy-benzofuran (9.3 g, 41 mmol) in N,N-dimethylformamide (9 ml) was added dropwise within 30 min. The reaction mixture was stirred 30 min at ambient temperature and then continuously heated to 100° C. After 10 min at 100° C. the mixture was heated at 85° C. for 3 h, cooled to 10° C., neutralized with 25% aqueous sodium acetate, with cooling, and extracted with diethyl ether. The extract was washed with saturated aqueous sodium bicarbonate and water and dried over sodium sulfate. Removal of the solvent under reduced pressure gave a brown oil which was purified by column chromatography (silica gel, hexane/AcOEt=19/1) to give 1.8 g (7 mmol, 17%) of the title compound as yellow oil.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.Br[CH2:13][CH2:14][CH2:15][O:16][C:17]1[C:22]([Cl:23])=[CH:21][C:20]([O:24][CH2:25][CH:26]=[C:27]([Cl:29])[Cl:28])=[CH:19][C:18]=1[Cl:30]>>[Cl:23][C:22]1[CH:21]=[C:20]([O:24][CH2:25][CH:26]=[C:27]([Cl:29])[Cl:28])[CH:19]=[C:18]([Cl:30])[C:17]=1[O:16][CH2:15][CH2:14][CH2:13][NH:7][C:6]1[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=1
Reactant: ClC(Cl)=CCOc1cc(Cl)c(OCCCBr)c(Cl)c1
Reactant: Nc1ccc(C(F)(F)F)cc1
Product: FC(F)(F)c1ccc(NCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.9 %

Procedure:
A mixture of 3.9 g of 4-(trifluoromethyl)aniline and 0.50 g of 1-(3-bromopropyloxy)-2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)benzene was stirred at 90° C. to 100° C. for 3 hours. After cooling to room temperature, the reaction mixture was subjected to silica gel chromatography, which afforded 0.37 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(3-(4-(trifluoromethyl)phenylamino)propyloxy)benzene (62% yield), nD23.5 1.5617.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[C:16]2[CH2:17][NH:18][CH2:19][CH2:20][S:21][C:15]=2[CH:14]=[CH:13][CH:12]=1.Cl.C(N(CC)CC)C>ClCCl>[C:1]([N:18]1[CH2:17][C:16]2[C:11]([Cl:10])=[CH:12][CH:13]=[CH:14][C:15]=2[S:21][CH2:20][CH2:19]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cccc2c1CNCCS2
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)N1CCSc2cccc(Cl)c2C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of benzoyl chloride (3.93 g) in dichloromethane (50 ml) was added dropwise at room temperature to a stirred solution of 6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (4.5 g, prepared in a similar manner to its hydrochloride, Example 1 above) and triethylamine (2.82 g) in dichloromethane (100 ml). The reaction mixture was stirred at room temperature for 15 minutes, washed with water, dried and the solvent was removed by evaporation. Purification of the residue by flash chromatography using dichloromethane as eluent gave 4-benzoyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine, which was recrystallised from ethanol/water. Yield 5.93 g (m.p. 64°-72° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[CH:12]([Sn](CCCC)(CCCC)CCCC)=[CH2:13]>O1CCOCC1>[CH:12]([C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1)=[CH2:13]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1ccc(Br)cn1
Solvent: C1COCCO1
Product: C=Cc1ccc(C(=O)OC)nc1
Temperature: 100 °C
Yield: 66.3 %

Procedure:
The title compound was prepared by following general procedure 2. Methyl 5-bromopyridine-2-carboxylate (4.0 g, 18.5 mmol) was dissolved in 160 mL dioxane. Vinyltributyltin (11.7 g, 37 mmol) was added to this solution at 25° C., followed by addition of dichlorobis(triphenylphosphine) palladium (1.5 g, mmol). The reaction mixture was degassed and purged with nitrogen for 5 min. and then heated at 100° C. for 2 h. The reaction mixture was evaporated under reduced pressure and the residue was purified by SiO2 chromatography (100-200 mesh, eluent: hexane-50% ethyl acetate-hexane gradient). The requisite fractions were concentrated below 40° C. under reduced pressure to obtain 2 g of methyl 5-vinylpyridine-2-carboxylate as a pale yellow oil (solid at −20° C.). TLC Rf 0.3 in 40% Ethyl acetate:Hexane.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:35])[C@H:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23](OC2C=CC([N+]([O-])=O)=CC=2)=[O:24])=[CH:18][CH:17]=1)[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:2]=[CH2:3].[NH2:36][CH2:37][CH2:38][CH:39]([N:43]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH3:44])[C:40]([OH:42])=[O:41]>ClCCl>[CH2:1]([O:4][C:5](=[O:35])[C@@H:6]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([NH:36][CH2:37][CH2:38][CH:39]([N:43]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH3:44])[C:40]([OH:42])=[O:41])=[O:24])=[CH:18][CH:17]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1)NC(=O)OC(C)(C)C
Reactant: CN(C(=O)OC(C)(C)C)C(CCN)C(=O)O
Solvent: ClCCl
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCCC(C(=O)O)N(C)C(=O)OC(C)(C)C)cc1)NC(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
0.931 g (1.92 mmol) of the compound from example 1A was dissolved in 30 ml dichloromethane. 0.455 g (1.92 mmol) of the compound from example 6A was added. The reaction mixture was split into 2 portions. The portions were heated for 30 min in a sealed tube at 80° C. in a microwave synthesizer. From the combined reaction mixture the solvent was removed under reduced pressure. The raw product was purified by preparative RP-HPLC on a C18 column with a water methanol gradient from 9/1 to 1/9. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 0.523 g (0.85 mmol, 44% of theory) of the desired product as a mixture of 2 diastereomers.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[C:18]1([C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:14]2)=[O:17])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)C1(NC(=O)c2cccc3ccccc23)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
The mixture of 2-[(naphthalene-1-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (41) (220 mg, 0.61 mmol) and KOH (600 mg, 10.7 mmol) is dissolved in EtOH (10 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more white precipitate formed. The precipitate is filtered to give a pure product (42) as white solid (196 mg, 97%).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH3:6][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=C(C)C=[CH:13]2.IC>O1CCCC1>[CH2:3]([C:2]1[CH:1]=[CH:13][C:12]2[C:17](=[C:8]([O:7][CH3:6])[CH:9]=[CH:10][CH:11]=2)[N:16]=1)[CH3:4]
Reactant: COc1cccc2ccc(C)nc12
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CCc1ccc2cccc(OC)c2n1
Temperature: -60 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (1 ml, 1.6M in hexanes) was added dropwise to a stirred solution of 8-methoxy-2-methylquinoline (0.25 g) in tetrahydrofuran (4 ml) at -60° C. under an inert atmosphere. The resulting red solution was stirred at -60° C. for 15 minutes, and then warmed to -40° C. Iodomethane (0.27 ml) was then added dropwise and the reaction warmed slowly to room temperature with continued stirring for 12 hours. The reaction was quenched with brine (50 ml) and extracted with dichloromethane (2×5ml). The organic phases were combined, dried over magnesium sulphate and preadsorbed onto silica. Purification was achieved by column chromatography eluting with ethyl acetate to afford the title compound as a pale yellow solid (0.16 g).
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[CH:15]=[CH:14][C:10]2[CH:11]=[CH:12][S:13][C:9]=2[CH:8]=1.CS(O[CH2:21][CH:22]1[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>O>[CH3:27][C:24]1([CH3:28])[O:23][CH:22]([CH2:21][O:6][C:7]2[CH:15]=[CH:14][C:10]3[CH:11]=[CH:12][S:13][C:9]=3[CH:8]=2)[CH2:26][O:25]1
Reactant: CC1(C)OCC(COS(C)(=O)=O)O1
Reactant: Oc1ccc2ccsc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OCC(COc2ccc3ccsc3c2)O1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
Dimethylformamide (10 mL) was added to a reactor containing 6-hydroxybenzothiophene (22, 619 mg, 4.12 mmol), (R/S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl methanesulfonate ((R/S)-18a, 1.04 g, 4.95 mmol) and Cs2CO3(1.61 g, 4.95 mmol). The reaction mixture was agitated at 100° C. for 6 hours and then cooled to room temperature. After adding water, extracting with ethyl acetate, washing with saturated ammonium chloride aqueous solution, and removing water using sodium sulfate, column chromatography yielded 6-[(R/S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyloxy]benzothiophene ((R/S)-25, 1.08 g, 99%) as a liquid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:25])=[N:8][C:9]2[C:14]([C:15]=1[NH2:16])=[C:13]([O:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][NH:20]1)[CH:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2].[OH:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:25])=[N:8][C:9]2[C:14]([C:15]=1[NH2:16])=[C:13]([O:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]1[C:30](=[O:31])[C:29]1[CH:33]=[CH:34][CH:35]=[C:27]([OH:26])[CH:28]=1)[CH:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC3CCCCN3)c2c1N
Reactant: O=C(O)c1cccc(O)c1
Product: CCOC(=O)c1c(C)nc2cccc(OCC3CCCCN3C(=O)c3cccc(O)c3)c2c1N

Procedure:
Prepared as in Example 24a from ethyl-4-amino-2-methyl-5-(piperidin-2-ylmethoxy)-quinoline-3-carboxylate (Example 111b) and 3-hydroxybenzoic acid as a white solid (28%). MS 464 (MH+).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[C:13]([O:25][CH3:26])[C:14]([O:23][CH3:24])=[C:15]([O:21][CH3:22])[C:16]=2[O:19][CH3:20])[CH2:11]1.[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.[K]>CN(C=O)C.C(OCC)(=O)C>[CH3:26][O:25][C:13]1[C:14]([O:23][CH3:24])=[C:15]([O:21][CH3:22])[C:16]([O:19][CH3:20])=[C:17]2[C:12]=1[CH2:11][CH:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:31]1[C:30](=[O:32])[C:29]3=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]3[C:27]1=[O:37])[CH2:18]2
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCI)C2
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCN1C(=O)c3ccccc3C1=O)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.5 %

Procedure:
To a solution of 2-(8-iodooctyl)-4,5,6,7-tetramethoxyindan (1.98 g) in DMF (10 ml) was dropwise added potassium phthalimide (924 mg). After being stirred at room temperature for 12 hr, the reaction mixture was diluted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo and the residue was purified by alumina column chromatography (hexane to hexane:ethyl acetate=10:1) and then recrystallized from hexane gave the entitled compound (1.74 g) as crystals.
Reaction SMILES: [CH2:1]([C:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)([CH2:7][CH2:8][OH:9])[CH2:4][CH2:5][OH:6])[CH3:2].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C1(C)C=CC=CC=1>[CH3:26][S:27]([O:6][CH2:5][CH2:4][C:3]([CH2:1][CH3:2])([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)[CH2:7][CH2:8][O:9][S:27]([CH3:26])(=[O:29])=[O:28])(=[O:29])=[O:28]
Reactant: CCC(CCO)(CCO)c1cccc([N+](=O)[O-])c1
Reactant: CS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCC(CCOS(C)(=O)=O)(CCOS(C)(=O)=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-ethyl-3-(3-nitrophenyl)-1,5-pentanediol (Preparation 61, 661 mg, 2.27 mmol) in toluene (24 ml) was added triethylamine (0.76 ml, 5.43 mmol) followed by methanesulfonyl chloride (0.42 ml, 5.4 mmol). The reaction mixture was stirred at room temperature under nitrogen for 18 h. The reaction mixture was poured onto water (10 ml), the phases were separated and the aqueous layer was extracted with dichloromethane (10 ml). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo to give the title compound as an oil which was used without further purification (850 mg, 81% crude yield).
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[NH2:2].[CH2:12]([CH2:14][CH2:15][CH2:16][C:17](CC([O-])=O)=[O:18])[CH3:13]>>[O:18]=[C:17]1[N:1]([C:3]2[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=2)[N:2]=[C:15]([CH2:14][CH2:12][CH3:13])[CH2:16]1
Reactant: CCCCCC(=O)CC(=O)[O-]
Reactant: NNc1ccc(C(=O)O)cc1
Product: CCCC1=NN(c2ccc(C(=O)O)cc2)C(=O)C1

Procedure:
From the reaction of 4-hydrazinobenzoic acid and ethylbutyrylacetate, 4-(4,5-dihydro-5-oxo-3-propyl-1H-pyrazol-1-yl)-benzoic acid is obtained. Subsequent reaction with 2-ethylaniline yields 4-(4-(2-ethylanilinomethylene)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazol-1-yl)-benzoic acid, Mp 254.5° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][N:8]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:9][CH2:10][OH:11])([CH3:4])([CH3:3])[CH3:2].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:22])[CH2:7][N:8]([C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[CH2:9][CH2:10][O:11][S:24]([CH3:23])(=[O:26])=[O:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CN(CCO)C(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CN(CCOS(C)(=O)=O)C(=O)OCc1ccccc1

Procedure:
The product from Example 5 (14.4 g; 47 mmol) is reacted in anhydrous pyridine (270 ml) with methanesulphonyl chloride (4.47 ml; 58 mmol) and then worked up as described in Example 2. Yield: 14.7 g (82%), brown oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][CH2:6][C:7]1[S:8][C:9]([N+:12]([O-])=O)=[CH:10][CH:11]=1>C(OCC)(=O)C.CO.[OH-].[Pd+2].[OH-]>[CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][CH2:6][C:7]1[S:8][C:9]([NH2:12])=[CH:10][CH:11]=1
Reactant: COC(=O)CCCc1ccc([N+](=O)[O-])s1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)CCCc1ccc(N)s1
Reaction time: 48 h
Yield: 66.2 %

Procedure:
A mixture of 4-(5-nitro-thiophen-2-yl)-butyric acid methyl ester (2.29 g, 10.0 mmol) and palladium hydroxide (500 mg, 20% on carbon) in 30 mL of ethyl acetate and 30 mL of methanol is hydrogenated at 50 psi for 48 hours. The reaction mixture is filtered and concentrated. The residue is purified by flash column chromatography eluting with 1:3 ethyl acetate:hexane to provide 1.32 g of 4-(5-amino-thiophen-2-yl)-butyric acid methyl ester as a dark oil; 1H NMR (DMSO-d6) δ 1.74 (m, 2H), 2.38 (m, 2H), 2.54 (m, 2H), 3.59 (s, 3H), 5.66 (d, J=3 Hz, 1H), 6.24 (d, J=3 Hz, 1H); MS 200.2 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:9][N:8]([C:10](=[O:22])[CH:11]([NH:14]C(OC(C)(C)C)=O)[CH2:12][CH3:13])[CH:7]([CH2:23][C:24]2[C:32]3[C:27](=[CH:28][C:29]([F:33])=[CH:30][CH:31]=3)[NH:26][C:25]=2[C:34]2[NH:35][C:36]3[C:41]([C:42]=2[CH2:43][CH:44]2[N:48]([C:49](=[O:61])[CH:50]([NH:53]C(OC(C)(C)C)=O)[CH2:51][CH3:52])[CH2:47][CH:46]([O:62][C:63](=[O:65])[CH3:64])[CH2:45]2)=[CH:40][CH:39]=[C:38]([F:66])[CH:37]=3)[CH2:6]1)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([O:4][CH:5]1[CH2:9][N:8]([C:10](=[O:22])[CH:11]([NH2:14])[CH2:12][CH3:13])[CH:7]([CH2:23][C:24]2[C:32]3[C:27](=[CH:28][C:29]([F:33])=[CH:30][CH:31]=3)[NH:26][C:25]=2[C:34]2[NH:35][C:36]3[C:41]([C:42]=2[CH2:43][CH:44]2[N:48]([C:49](=[O:61])[CH:50]([NH2:53])[CH2:51][CH3:52])[CH2:47][CH:46]([O:62][C:63](=[O:65])[CH3:64])[CH2:45]2)=[CH:40][CH:39]=[C:38]([F:66])[CH:37]=3)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCC(NC(=O)OC(C)(C)C)C(=O)N1CC(OC(C)=O)CC1Cc1c(-c2[nH]c3cc(F)ccc3c2CC2CC(OC(C)=O)CN2C(=O)C(CC)NC(=O)OC(C)(C)C)[nH]c2cc(F)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(N)C(=O)N1CC(OC(C)=O)CC1Cc1c(-c2[nH]c3cc(F)ccc3c2CC2CC(OC(C)=O)CN2C(=O)C(N)CC)[nH]c2cc(F)ccc12
Temperature: 0 °C

Procedure:
A solution containing 11 (27.5 g, 30 mmol) in DCM (200 mL) was cooled to 0° C. TFA (50 mL) was added and the reaction was monitored by LC/MS analysis until complete conversion of 11 to 12 (ca. 3 h). The solvent was removed in vacuo and the dark, green-colored residue was dissolved in EtOAc (ca. 1 L). The EtOAc solution was carefully poured into a saturated aqueous NaHCO3/ice/water mixture to neutralize the residual TFA. The organic phase was separated and washed twice with saturated aqueous NaHCO3 then once with brine. The combined aqueous washes were back-extracted with EtOAc (2×100 mL) and the combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to afford 22 g of crude 12 as an off-white solid. 1H NMR (300 MHz, CDCl3+d4-MeOH), mixture of rotomers: δ11.62 (br s, 2H), 7.48-7.62 (m, 4H), 6.89 (ddd, J=2.4, 9.3, 9.3 Hz, 2H), 5.48 (dd, J=4.5, 4.8 Hz, 2H), 4.52 (dd, J=9.3, 9.3 Hz, 2H), 4.06 (dd, J=4.8, 12.3 Hz, 2H), 3.78 (d, J=12.3 Hz, 2H), 3.54-3.70 (m, 4H), 3.30-3.40 (m, 2H), 2.33 (s, 6H), 2.02-2.16 (m, 2H), 1.70-1.96 (m, 4H), 1.09 (t, J=7.2 Hz, 6H) ppm; 13C NMR (75 MHz, CDCl3+d4-MeOH): 6173.5, 170.9, 161.8, 158.6, 137.2, 137.1, 128.2, 128.1, 125.6, 118.7, 118.6, 108.6, 108.3, 108.0, 98.6, 98.1, 74.6, 60.1, 53.5, 33.5, 28.0, 21.4, 9.7 ppm. Mass spectrum (ESI), m/z 721.4 [(M)+; calcd for C38H46F2N6O6: 720.8].
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH2:16][CH2:15]1)=[O:13].[CH3:24][C:25](OC(C)=O)=[O:26].CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:25]([N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:14]([C:12](=[O:13])[CH2:11][S:10][C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH2:15][CH2:16]1)(=[O:26])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(CSc1nc2ccccc2s1)N1CCNc2ccccc21
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN(C(=O)CSc2nc3ccccc3s2)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.2 %

Procedure:
To a 0° C. solution of compound 41 (0.41 g, 1.20 mmol) in dry CH2Cl2 (20 mL) were added Ac2O (1.12 mL, 12.0 mmol) followed by dropwise addition of Et3N (1.12 mL, 8.00 mmol), and DMAP (10 mg) The reaction was stirred for 18 h under N2 at room temperature. The reaction mixture was diluted with CH2Cl2 (20 mL), washed with saturated NaHCO3 (10 mL), water (2×10 mL), and saturated NaCl (2×10 mL). Dried over MgSO4 and filtered. The solvent was removed under reduced pressure and the product was purified by column chromatography (CH2Cl2/EtOAc 1:1), and triturated from CH2Cl2/hexanes to afford 48 as a yellow solid (0.24 g, 52%); MS m/z: 384 (M+H)+. Anal. Calcd. For, C19H17N3O2S2.0.1H2O: C, 59.23; H, 4.92; N, 10.91; S, 16.64. Found: C, 58.84; H, 4.55; N, 10.55; S, 16.32.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][CH:9]([CH3:13])[C:10](Cl)=[O:11].Cl>>[Cl:8][CH:9]([CH3:13])[C:10]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:11]
Reactant: CC(Cl)C(=O)Cl
Reactant: Nc1ccccc1
Agent: Cl
Product: CC(Cl)C(=O)Nc1ccccc1
Yield: 94.8 %

Procedure:
18 g of aniline are introduced dropwise into 22.6 g of 2-chloropropionyl chloride at a temperature of about 10° C., with stirring until the evolution of HCl has ended. After filtration, 31 g (yield: 84.5%) of α-chloro-α-methylacetanilide are obtained in the form of a pink powder. M.p. (inst.)=80° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]([OH:14])=O)([O-:3])=[O:2].S(Cl)([Cl:17])=O>ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]([Cl:17])=[O:14])([O-:3])=[O:2]
Reactant: O=C(O)CCc1ccccc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)CCc1ccccc1[N+](=O)[O-]

Procedure:
A solution of 3-(2-nitrophenyl)propanoic acid (1.20 g, 6.15 mmol) and thionyl chloride (0 878 g, 7.38 mmol) in dichloromethane (5 ml) was stirred and heated to reflux for 2 hours. The mixture was concentrated under reduced pressure to obtain 3-(2-nitrophenyl)propanoyl chloride. To the obtained crude 3-(2-nitrophenyl)propanoyl chloride (1.31 g, 6.15 mmol) was added CS2, and aluminum trichloride (1.07 g, 8.0 mmol) was added portionwise at 0° C. The mixture was stirred at 70° C. for 3 hours, and after cooled to ambient temperature, water was added and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethylacetate 10:1) to afford 4-nitroindan-1-one (0.44 g).