Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH:11]=2)=[CH:4][C:3]=1[NH:23][C:24](=[O:36])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:26]=1.[CH2:37](I)[CH3:38]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[CH:11]=2)=[CH:4][C:3]=1[NH:23][C:24](=[O:36])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]([S:32]([CH3:35])(=[O:33])=[O:34])[CH2:37][CH3:38])[CH:26]=1
Reactant: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(NS(C)(=O)=O)c1
Reactant: CCI
Product: CCN(c1cccc(C(=O)Nc2cc(NC(=O)c3cccc(N4CCOCC4)c3)ccc2C)c1)S(C)(=O)=O
Yield: 64 %

Procedure:
Using an analogous procedure to that described in Example 61, N-[2-methyl-5-(3-morpholinobenzamido)phenyl]-3-methanesulphonylaminobenzamide was reacted with ethyl iodide to give the title compound in 64% yield; m.p. 192-193° C.; NMR Spectrum: (DMSOd6) 1.05 (t, 3H), 2.21 (s, 3H), 3.16 (t, 4H),3.73 (m, 6H), 7.13 (m, 1H) 7.23 (d, 1H), 7.36 (m, 2H), 7.43 (d, 1H), 7.58 (m, 3H), 7.81 (d, 1H), 7.95 (m, 2H), 7.99 (d, 1H), 10.0 (s, 1H), 10.12 (s, 1H); Mass Spectrum: M+H+537.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[CH3:11][C:12]1[N:13]=[CH:14][C:15]([C:18](O)=O)=[N:16][CH:17]=1.N>>[CH3:11][C:12]1[N:13]=[CH:14][C:15]([C:18]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)=[N:16][CH:17]=1
Reactant: NC(=NO)c1cccnc1
Reactant: Cc1cnc(C(=O)O)cn1
Agent: N
Product: Cc1cnc(-c2nc(-c3cccnc3)no2)cn1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 5-methylpyrazine-2-carboxylic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 2.71 (s, 3H), 7.66 (ddd, J=8.0, 5.1, 0.8 Hz, 1H), 8.59 (dt, J=7.9, 1.8 Hz, 1H), 8.74-8.78 (m, 2H), 9.33 (dd, J=2.0, 0.8 Hz, 1H), 9.40 (d, J=1.2 Hz, 1H) ppm; MS (DCl/NH3) m/z 240 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14]C)=[O:13])[CH:10]=2)[NH:5][N:4]=1)#[N:2].[OH-].[Li+]>C(O)C.O>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=2)[NH:5][N:4]=1)#[N:2]
Reactant: COC(=O)c1ccc2[nH]nc(C#N)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#Cc1n[nH]c2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.6 %

Procedure:
To a solution of methyl 3-cyano-1H-indazole-5-carboxylate (2.5 g, 12 mmol) in ethanol (40 mL), a solution of lithium hydroxide (1.04 g, 24.9 mmol) in water (15 mL) was added and stirred at ambient temperature for 16 h. The mixture was concentrated and the obtained residue was dissolved in water (25 mL) and washed with ethyl acetate (20 mL). The aqueous layer was acidified with 10% citric acid solution, the obtained precipitate was filtered, washed with 50% ethyl acetate in petroleum ether (2×10 mL) and dried to afford the title compound (1.9 g, 82%) as a brown solid. 1HNMR (DMSO-d6) δ ppm 13.8-12.4 (br, 2H), 8.44 (s, 1H), 8.1 (d, 1H), 7.82 (d, 1H).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:16]([F:19])([F:18])[F:17])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([OH:15])=O)[CH:7]=[CH:6]2)#[N:2].[Br:20][C:21]1[O:25][C:24]([C:26]([NH:28][NH2:29])=O)=[CH:23][CH:22]=1>>[Br:20][C:21]1[O:25][C:24]([C:26]2[O:15][C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)=[N:29][N:28]=2)=[CH:23][CH:22]=1
Reactant: N#Cc1ccc2c(ccn2CC(=O)O)c1C(F)(F)F
Reactant: NNC(=O)c1ccc(Br)o1
Product: N#Cc1ccc2c(ccn2Cc2nnc(-c3ccc(Br)o3)o2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 35C from [5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]acetic acid and 5-bromo-2-furancarbohydrazide: MS (ES) m/z 437 and 439 (M+1 Br isotopes).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3[C:14]4[C:18]([CH:19]=[CH:20][C:12]=3[O:11][CH2:10]2)=[N:17][O:16][N:15]=4)[C:2]1=[O:21].[H-].[Na+].[CH2:24]([O:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:38]Cl)=[N:36][CH:37]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Cl-].[NH4+]>CN(C)C=O.[I-].[K+].O>[CH2:24]([O:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:38][N:15]2[C:14]3[C:13]4[C:3]5([C:4]6[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=6)[NH:1][C:2]5=[O:21])[CH2:10][O:11][C:12]=4[CH:20]=[CH:19][C:18]=3[NH:17][O:16]2)=[N:36][CH:37]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: ClCc1ccc(OCc2ccccc2)cn1
Reactant: O=C1Nc2ccccc2C12COc1ccc3nonc3c12
Agent: [Cl-]
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Nc2ccccc2C12COc1ccc3c(c12)N(Cc1ccc(OCc2ccccc2)cn1)ON3
Reaction time: 0.33 h
Yield: 5.1 %

Procedure:
To a solution of 7H-spiro[benzofuro[4,5-c][1,2,5]oxadiazole-8,3′-indolin]-2′-one (0.400 g, 1.4 mmol) in anhydrous N,N-dimethylformamide (7 mL) was added sodium hydride (60% w/w dispersion in mineral oil, 0.086 g, 3.6 mmol) at 0° C. and the mixture was stirred for 20 minutes. 5-(Benzyloxy)-2-(chloromethyl)pyridine (0.44 g, 1.9 mmol) was added and the reaction mixture was stirred at ambient temperature for 19 h. Potassium iodide (−10 mg, catalytic amount) was added and the reaction mixture was stirred at 60° C. for 2 h, at ambient temperature for 43 h, at 60° C. for 7 h and at ambient temperature for 3 days. Saturated aqueous ammonium chloride (7 mL) and water (30 mL) were added and the mixture was extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with water (2×20 mL) and brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with hexanes/ethyl acetate (3/2), followed by trituration in hexanes to afford 1-{[5-(benzyloxy)pyridin-2-yl]methyl}spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one (0.034 g, 5%) as a pale yellow solid: mp 209-212° C.; 1H NMR (300 MHz, CDCl3) δ 8.36 (d, J=2.7 Hz, 1H), 7.83 (d, J=9.6 Hz, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.45-7.23 (m, 8H), 7.18 (d, J=7.5 Hz, 1H), 7.03 (t, J=7.5 Hz, 1H), 6.92 (J=7.8 Hz, 1H), 5.39 (d, J=15.9 Hz, 1H), 5.27 (d, J=9.6 Hz, 1H), 5.11 (s, 2H), 4.99 (d, J=9.3 Hz, 1H), 4.87 (d, J=15.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ176.0, 163.0, 154.4, 148.3, 147.1, 144.9, 142.2, 137.8, 136.0, 129.8, 129.7, 128.7, 128.3, 127.6, 123.7, 123.6, 122.4, 122.3, 121.9, 119.3, 110.2, 107.0, 82.0, 70.4, 57.4, 46.0; MS (ES+) m/z 477.2 (M+1).
Reaction SMILES: [C:1]1([C:7]2[C:12]([NH:13][C:14]([C:16]3[N:17](COCC[Si](C)(C)C)[CH:18]=[C:19]([C:21]#[N:22])[N:20]=3)=[O:15])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.CO.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[C:1]1([C:7]2[C:12]([NH:13][C:14]([C:16]3[NH:17][CH:18]=[C:19]([C:21]#[N:22])[N:20]=3)=[O:15])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1cccnc1C1=CCCCC1
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c[nH]c(C(=O)Nc2cccnc2C2=CCCCC2)n1
Yield: 30 %

Procedure:
A solution of 615 mg (1.45 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-pyridin-3-yl)-amide (as prepared in the previous step) in CH2Cl2 (12 mL) was treated with MeOH (100 μL) and TFA (3 mL) at RT for 3.5 h. MeOH (5 mL) was added to the mixture before concentrating in vacuo. RP-HPLC (C18) of the residue with 10-80% CH3CN in 0.1% TFA/H2O over 30 min afforded 177 mg (30%) of the title compound as a white solid: 1H-NMR (CD3OD; 400 MHz): δ 9.03 (dd, 1H, J=8.4, 1.6 Hz), 8.45 (dd, 1H, J=5.2, 1.6 Hz), 8.07 (s, 1H), 7.81-7.74 (m, 1H), 6.36-6.29 (m, 1H), 2.49-2.34 (m, 4H), 1.97-1.79 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C16H15N5O, 294.1 (M+H), found 294.1.
Reaction SMILES: [CH2:1]([N:8]([C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24])[CH2:9][CH2:10]OS(C)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:26].[Na+]>CC(C)=O>[CH2:1]([N:8]([C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24])[CH2:9][CH2:10][I:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCCN(Cc1ccccc1)c1ccc(Br)cc1[N+](=O)[O-]
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cc(Br)ccc1N(CCI)Cc1ccccc1
Reaction time: 16 h
Yield: 87.7 %

Procedure:
A mixture of methanesulphonic acid 2-[benzyl-(4-bromo-2-nitro-phenyl)-amino]-ethyl ester (25 g, Reference Example 8) and sodium iodide (16.23 g) in anhydrous acetone (100 ml) was heated at reflux for 4 hours when a further portion of sodium iodide (8.12 g) was added and refluxing was continued for a further 16 hours. The reaction mixture was evaporated under reduced pressure (2.7 kPa) at 40° C. and the residue was treated with distilled water (200 ml). The resulting mixture was extracted three times with dichloromethane (150 ml). The combined organic extracts were dried over magnesium sulphate and then evaporated under reduced pressure (2.7 kPa) at 40° C. The resulting brown oil (29,16 g) was subjected to flash chromatography on silica (0,040-0,063 mm) eluting with a mixture of cyclohexane and ethyl acetate (9:1, v/v) to give the title compound (23.55 g) as a yellow oil. 1H NMR, 300 HMz, (CD3)2SO: δ3.3 (m, 4H); 4.4 (s, 2H); 7.25(m, 5H); 7.4 (d, J=8 Hz, 1H); 7.6 (dd, J=8 Hz and J=1.5 Hz, 1H); 8 (d, J=1.5 Hz, 1H). MS (EI): M+ 462 and 460 (5%), 445 and 443 (20%), 321 and 319 (10%), 91 (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[Br:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1I>>[Br:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Fc1ccc(I)c(Br)c1
Reactant: Sc1ccccc1Cl
Product: Fc1ccc(Sc2ccccc2Cl)c(Br)c1

Procedure:
Prepared from 2-chloro-benzenethiol and 2-bromo-4-fluoro-1-iodo-benzene.
Reaction SMILES: CCC([O:5][CH2:6][C:7]([C@:9]1([O:32]C(CC)=O)[C@@:13]2([CH3:30])[CH2:14][C@H:15]([OH:29])[C@:16]3([Cl:28])[C@:26]4([CH3:27])[C:20](=[CH:21][C:22]([CH:24]=[CH:25]4)=[O:23])[CH2:19][CH2:18][C@H:17]3[C@@H:12]2[CH2:11][C@@H:10]1[CH3:31])=[O:8])=O>O.C(Cl)(Cl)Cl.CC(C)=O>[CH3:31][C@@H:10]1[C@:9]([OH:32])([C:7]([CH2:6][OH:5])=[O:8])[C@:13]2([CH3:30])[C@H:12]([C@H:17]3[C@:16]([Cl:28])([C@@H:15]([OH:29])[CH2:14]2)[C@:26]2([CH3:27])[C:20](=[CH:21][C:22]([CH:24]=[CH:25]2)=[O:23])[CH2:19][CH2:18]3)[CH2:11]1
Reactant: CCC(=O)OCC(=O)[C@@]1(OC(=O)CC)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(Cl)[C@@H](O)C[C@@]21C
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(C)=O
Product: C[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(Cl)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CO

Procedure:
Also preferably, the steroidal anti-inflammatory of the present formulations is beclomethasone dipropionate or its monohydrate. Beclomethasone dipropionate has the chemical name 9-chloro-11 b, 17,21-trih-ydroxy-16b-methylpregna-1,4-diene-3,20-doine 17,21-dipropionate. The compound may be a white powder with a molecular weight of 521.25; and is very slightly soluble in water (Physicians' Desk Reference.RTM), very soluble in chloroform, and freely soluble in acetone and in alcohol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9]C1C=CC(C(C2C=C(N3C=C(CCO)N=N3)C=CC=2C)=O)=C(C)C=1.Br[C:35]1[CH:40]=[CH:39][C:38]([C:41]([C:43]2[CH:48]=[C:47]([N:49]3[CH:53]=[C:52]([CH2:54][CH2:55][OH:56])[N:51]=[N:50]3)[CH:46]=[CH:45][C:44]=2[Cl:57])=[O:42])=[C:37]([Cl:58])[CH:36]=1.FC1C=C(F)C=CC=1N>>[Cl:58][C:37]1[CH:36]=[C:35]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH:40]=[CH:39][C:38]=1[C:41]([C:43]1[CH:48]=[C:47]([N:49]2[CH:53]=[C:52]([CH2:54][CH2:55][OH:56])[N:51]=[N:50]2)[CH:46]=[CH:45][C:44]=1[Cl:57])=[O:42]
Reactant: Cc1cc(Nc2ccc(F)cc2F)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C
Reactant: O=C(c1ccc(Br)cc1Cl)c1cc(-n2cc(CCO)nn2)ccc1Cl
Agent: Nc1ccc(F)cc1F
Product: O=C(c1ccc(Nc2ccc(F)cc2F)cc1Cl)c1cc(-n2cc(CCO)nn2)ccc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 148, using compound 456 (0.91 mmol) and 2,4-difluoro-phenylamine (0.91 mmol). The crude product was purified by continuous gradient flash chromatography using MeOH/DCM 0:100, 10:90 as the eluent to afford the title compound as yellow solid. 13C NMR (CDCl3) δ 191.1, 159.6 (dd), 155.9 (dd), 149.1, 146.7, 141.1, 136.1, 135.7, 134.5, 131.7, 131.6, 126.9, 125.1 (dd), 123.8 (dd), 122.8, 121.0, 119.9, 116.1, 112.8, 111.7 (dd), 105.1 (dd), 61.5, 28.7
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:8][CH2:7][NH:6][CH2:5]1.C(N(CC)CC)C.[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[N:24]1[C:33]2[C:28](=[CH:29][C:30]([F:51])=[C:31](OP(OC3C=CC=CC=3)(OC3C=CC=CC=3)=O)[N:32]=2)[C:27](=[O:52])[C:26]([C:53]([O:55][CH2:56][CH3:57])=[O:54])=[CH:25]1.O>C(O)C>[NH2:3][CH:4]1[CH2:8][CH2:7][N:6]([C:31]2[N:32]=[C:33]3[C:28]([C:27](=[O:52])[C:26]([C:53]([O:55][CH2:56][CH3:57])=[O:54])=[CH:25][N:24]3[C:18]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=3[F:16])=[CH:29][C:30]=2[F:51])[CH2:5]1
Reactant: NC1CCNC1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(OP(=O)(Oc3ccccc3)Oc3ccccc3)c(F)cc2c1=O
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(N3CCC(N)C3)c(F)cc2c1=O
Yield: 75.9 %

Procedure:
In 2 ml of ethanol was suspended 64 mg of 3-aminopyrrolidine dihydrochloride, and 130 mg of triethylamine was added to the resulting suspension to form a solution. Subsequently, 200 mg of ethyl 1-(2,4-difluorophenyl)-7-diphenoxyphosphinyloxy-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate was added to the solution, and the resulting mixture was subjected to reaction at room temperature of 1 hour. Subsequently, 3 ml of water was added to the reaction mixture, and the crystals thus deposited were collected and washed with 3 ml of water to obtain 110 mg (yield 75.9%) of ethyl 7-(3-amino-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate. The physical properties of this compound were identical with those of the compound obtained in Example 64.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:17])[CH2:9][CH:10]([CH2:15]O)[CH2:11][CH2:12][CH2:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:11]([CH:10]1[CH2:15][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8](=[O:17])[CH2:9]1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCC(CO)CC(=O)Nc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCC1CC(=O)N(c2ccccc2)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
To a solution of 3-hydroxymethylheptanoic acid phenylamide (0.61 g, 2.6 mmol) in THF (30 mL) under argon was added triphenylphosphine (1.36 g, 5.2 mmol). The solution was cooled to 0° C. and diethyl azodicarboxylate (0.61 mL, 3.9 mmol) was added dropwise. The reaction mixture was warmed up to rt and stirred overnight. The reaction was quenched with saturated aqueous NaHCO3 (50 mL) and extracted with dichloromethane (3×50 mL). The combined extractions were dried (Na2SO4), filtered and concentrated. The residue was purified by flash column chromatography (silica gel, ethyl acetate/hexanes 1:2) to afford 4-butyl-1-phenylpyrrolidin-2-one as a white solid (0.4 g, 72%). MS(ES) m/e 218 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C@:5]([OH:11])([CH3:10])[C:6]([F:9])([F:8])[F:7])[CH3:2].CC([O-])(C)C.[K+].[Br:19][C:20]1[N:25]=[C:24]([C:26]2([CH3:41])[CH2:28][N@@:27]2[S:29]([C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[C:23]([F:42])=[CH:22][CH:21]=1.Cl>CN(C=O)C.[Cl-].[Na+].O.CC(OC)(C)C>[CH2:1]([O:3][C:4](=[O:12])[C@:5]([O:11][CH2:41][C@@:26]([C:24]1[C:23]([F:42])=[CH:22][CH:21]=[C:20]([Br:19])[N:25]=1)([NH:27][S:29]([C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)(=[O:30])=[O:31])[CH3:28])([CH3:10])[C:6]([F:7])([F:8])[F:9])[CH3:2]
Reactant: CC1(c2nc(Br)ccc2F)C[N@@]1S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)[C@@](C)(O)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: CC1(c2nc(Br)ccc2F)C[N@]1S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: O
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@](C)(OC[C@](C)(NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1nc(Br)ccc1F)C(F)(F)F
Reaction time: 3 h
Yield: 65.8 %

Procedure:
A solution of (R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid ethyl ester (11.93 g, 64.1 mmol) in DMF (158 ml) was evacuated/flushed with nitrogen twice. A solution of KOtBu (6.21 g, 55.5 mmol) in DMF (17 ml) was added in a dropwise while maintaining a reaction temperature of ca 25° C. using cooling with a water bath. After 15 min solid 6-bromo-3-fluoro-2-[(S)-2-methyl-1-(4-nitro-benzenesulfonyl)-aziridin-2-yl]-pyridine (17.78 g, 42.7 mmol) was added and stirring was continued for 3 h. The reaction mixture was poured onto a mixture of 1M HCl (56 ml), brine and TBME. The layers were separated, washed with brine and TBME. The combined organic layers were dried over MgSO4.H2O, filtered and evaporated. The crude reaction product was purified via chromatography on silica gel (hexanes/25-33% TBME) to yield 16.93 g of the title compound as a yellow resin that was contaminated with an isomeric side-product (ratio 70:30 by 1H-NMR).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][NH2:15].Cl>O>[CH3:14][NH:15][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CN
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Solvent: O
Product: CNc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 87.5 °C
Reaction time: 5 h

Procedure:
A mixture of 4-chloro-3-nitrobenzoic acid compound of formula-8 (200 g) and 40% solution of methyl amine (660 ml) was taken into autoclave and heated to 85-90° C. and stirred for 5 hours. After completion of the reaction, the reaction mixture was cooled to 25-35° C. Water was added to the reaction mixture and acidified with hydrochloric acid. Filtered the precipitated solid, washed with water and then dried to get title compound.
Reaction SMILES: O1CC[CH2:3][CH2:2]1.[C:6]([O:10][C:11](=[O:47])[N:12]([CH2:36][C:37]1[CH:46]=[CH:45][C:40]2[O:41][CH2:42][CH2:43][O:44][C:39]=2[CH:38]=1)[CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][N:21]2[C:30]3[C:25](=[C:26]([CH:33]=[O:34])[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=3)[CH:24]=[CH:23][C:22]2=[O:35])[CH2:15][CH2:14]1)([CH3:9])([CH3:8])[CH3:7].C([Mg]Br)C.O1CCCC1.[Cl-].[NH4+]>C(Cl)(Cl)Cl.O>[C:6]([O:10][C:11](=[O:47])[N:12]([CH2:36][C:37]1[CH:46]=[CH:45][C:40]2[O:41][CH2:42][CH2:43][O:44][C:39]=2[CH:38]=1)[CH:13]1[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][N:21]2[C:30]3[C:25](=[C:26]([CH:33]([OH:34])[CH2:2][CH3:3])[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=3)[CH:24]=[CH:23][C:22]2=[O:35])[CH2:17][CH2:18]1)([CH3:9])([CH3:7])[CH3:8]
Reactant: COc1cc(C=O)c2ccc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Reactant: C1CCOC1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCC(O)c1cc(OC)cc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Reaction time: 1.5 h

Procedure:
To 20 mL of a tetrahydrofuran solution containing 0.65 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-formyl-7-methoxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 8.8 mL of 1 mol/L ethylmagnesium bromide/tetrahydrofuran was added at −78° C. and stirred for 1.5 hours. To the reaction mixture, aqueous saturated ammonium chloride solution, water and chloroform were added. The organic layer was separated, washed sequentially with aqueous saturated sodium hydrogen carbonate solution and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; chloroform:methanol=20:1], to give 200 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-(1-hydroxypropyl)-7-methoxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[OH:24][C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]1[NH:31][C:32]1[CH2:36][S:35][C:34](=[O:37])[N:33]=1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:1][C:2]([F:22])([F:23])[C:3]1[CH:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:7][CH2:8][CH:9](/[CH:12]=[C:36]2/[C:32]([NH:31][C@@H:26]3[CH2:27][CH2:28][CH2:29][CH2:30][C@H:25]3[OH:24])=[N:33][C:34](=[O:37])[S:35]/2)[CH2:10][CH2:11]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: O=C1N=C(N[C@@H]2CCCC[C@H]2O)CS1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=C1N=C(N[C@@H]2CCCC[C@H]2O)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 80 °C
Reaction time: 8 h
Yield: 44.7 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1.01 g) in 2-propanol (15 mL) were added 4-{[(1R,2R)-2-hydroxycyclohexyl]amino}thiazol-2(5H)-one (960 mg) and piperidinium acetate (443 mg). The reaction mixture was stirred at 80° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and silica gel column chromatography (NH, methanol/ethyl acetate), and recrystallized from ethyl acetate/heptane to give the title compound (712 mg).
Reaction SMILES: [CH3:1][O:2][Na].CO.Br[C:7]1[C:16]([OH:17])=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[N:14]2)=[CH:9][CH:8]=1.C(N(CC([O-])=O)CC(O)=O)CN(CC([O-])=O)CC(O)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>CN(C=O)C.CC(O)=O.O>[CH3:1][O:2][C:7]1[C:16]([OH:17])=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[N:14]2)=[CH:9][CH:8]=1
Reactant: CO[Na]
Reactant: Oc1c(Br)ccc2cccnc12
Agent: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)O)CC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2cccnc2c1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40 %

Procedure:
It was prepared using protocols by D. Planchenault et al. Tetrahedron 1995, 51, 5823-5830; D. Nobel, J. Chem. Soc., Chem. Commun. 1993, 419-420 and M. Numazawa et al. J. Chem. Soc., Chem. Commun. 1983, 533-534. A solution of CH3ONa (30% by weight) in CH3OH (17 ml, 89.30 mmol) is added to a solution of 7-bromo-8-hydroxyquinoline (2.00 g; 8.93 mmol), in 125 ml of DMF. The mixture is stirred for 10 minutes under argon. CuCl2.2H2O (0.46 g; 2.68 mmol) is added and the reaction mixture is heated under reflux for 20 hours. After cooling to ambient temperature, water (100 ml) and disodium EDTA dihydrate (7.83 g; 26.80 mmol) are added and the mixture is stirred for 1 hour. The solution is acidified to pH=4-5 with CH3COOH (3 ml) and it is subsequently basified gently with a saturated aqueous solution of NaHCO3. The aqueous phase is extracted with CH2Cl2 (3×100 ml). The combined organic phases are dried over anhydrous Na2SO4 and concentrated under reduced pressure. The solid obtained is purified by silica gel chromatography, eluted using a gradient of CH2Cl2/CH3OH/CH3COOH (94/4/2, v/v) to CH2Cl2/CH3OH (90/10, v/v). The fractions containing the product are combined and washed with a saturated aqueous solution of NaHCO3 (3×100 ml). The organic phase is dried over anhydrous Na2SO4 and concentrated under reduced pressure to yield 7-methyloxy-8-hydroxyquinoline in the form of a white powder (0.65 g; 3.68 mmol, yield=40%). NMR-1H (250 MHz, CDCl3) δ, ppm: 8.77 (dd, 3J (H, H)=4.0 Hz, 4J (H, H)=1.5 Hz, 1H); 8.11 (dd, 3J (H, H)=8.5 Hz, 4J (H, H)=1.5 Hz, 1H); 7.36 (m, 2H), 7.31 (dd, 3J (H, H)=8.5 Hz, 3J (H, H)=4.0 Hz, 1H), 4.06 (s, 3H). NMR-13C (63 MHz, CDCl3) δ, ppm: 148.6 (CH); 144.0 (Cq); 139.7 (Cq); 138.6 (CH); 136.0 (Cq); 123.5 (CH); 119.7 (CH); 117.7 (CH); 116.4 (CH); 57.3 (CH3). MS (CID, NH3): m/z=176 (MH+). Analysis (%) for C10H9NO2.0.1H2O: calculated C, 67.86. H, 5.24. N, 7.91. found C, 67.82. H, 5.11. N, 7.95.