Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][CH2:11][CH2:12][C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[CH3:9])=[CH:4][CH:3]=1.[C:18]([O-:21])([O-])=[O:19].[K+].[K+].Cl[C:25]([O-])=O>C(Cl)Cl>[CH3:25][O:21][C:18](=[O:19])[N:10]([CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH3:9])[CH2:11][CH2:12][C:13](=[O:17])[CH:14]([CH3:16])[CH3:15]
Reactant: O=C([O-])Cl
Reactant: O=C([O-])[O-]
Reactant: CC(C)C(=O)CCNC(C)c1ccc(Br)cc1
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)N(CCC(=O)C(C)C)C(C)c1ccc(Br)cc1
Yield: 78.6 %

Procedure:
To a solution of 1-[1-(4-bromo-phenyl)-ethylamino]-4-methyl-pentan-3-one (3.42 g, 0.01 mol) and K2CO3 (6.9 g, 0.05 mol) in dried CH2Cl2 (50 mL) was added chloroformate (1.41 g, 0.015 mol). The mixture was refluxed overnight. The solvent was removed to give the crude product, which was purified by column to give [1-(4-bromo-phenyl)-ethyl]-(4-methyl-3-oxo-pentyl)-carbamic acid methyl ester (2.8 g, 79%). 1H NMR (CDCl3): 1.01 (m, 6H), 1.48 (m, 3H), 2.25-2.47 (m, 2H), 2.62 (m, 1H), 3.24 (m, 2H), 5.46 (s, 1H), 7.17 (m, 2H), 7.45 (m, 2H).
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].[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[CH:19]=[C:20]3[CH:26]=[CH:25][NH:24][C:21]3=[N:22][CH:23]=2)[CH:13]=1.[OH-].[K+].O>CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]([C:26]2[C:20]3[C:21](=[N:22][CH:23]=[C:18]([C:14]4[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=4)[CH:19]=3)[NH:24][CH:25]=2)[OH:8])[CH:9]=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: c1cncc(-c2cnc3[nH]ccc3c2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1cccc(C(O)c2c[nH]c3ncc(-c4cccnc4)cc23)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 3-nitrobenzaldehyde (534, 1.08 g, 7.17 mmol) in methanol (34 mL) was added 5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine (89, 1.08 g, 5.52 mmol, prepared as described in Example 17) and potassium hydroxide (1.55 g, 27.6 mmol). The reaction was stirred at room temperature for four hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The mixture was purified by silica gel column chromatography eluting with 4% methanol in dichloromethane to provide two different compounds, a white solid (P-1399, R═H, 1.20 g, 63%) MS(ESI) [M+H+]+=347.2, and a light yellow solid (535, R=Me, 0.434 g, 22%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[CH:16]1[S:21][CH2:20][CH2:19][CH2:18][S:17]1)(=[O:10])=[O:9].C([Li])CCC.Cl[CH2:29][C:30]1[C:38]([CH3:39])=[CH:37][C:33]2[CH2:34][O:35][CH2:36][C:32]=2[CH:31]=1.C(O)(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.O1CCCC1>[Cl:1][C:2]1[C:3]([CH3:22])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]1([CH2:29][C:30]2[C:38]([CH3:39])=[CH:37][C:33]3[CH2:34][O:35][CH2:36][C:32]=3[CH:31]=2)[S:21][CH2:20][CH2:19][CH2:18][S:17]1)(=[O:10])=[O:9]
Reactant: Cc1cc2c(cc1CCl)COC2
Reactant: Cc1noc(NS(=O)(=O)c2ccsc2C2SCCCS2)c1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc2c(cc1CC1(c3sccc3S(=O)(=O)Nc3onc(C)c3Cl)SCCCS1)COC2
Temperature: -35 °C
Reaction time: 0.33 h
Yield: 54 %

Procedure:
To a mixture of N-(4-chloro-3-methyl-1,2-oxazol-5-yl)-2-formylthiophene-3-sulfonamide described in Production Example 1-3 (4.9 g, 16 mmol) and dichloromethane (100 mL) was successively added boron trifluoride diethyl etherate (8.1 mL, 64 mmol) and 1,3-propanedithiol (1.9 mL, 19 mmol) under ice cooling, followed by stirring at room temperature for 90 minutes. Water was added under ice cooling to the reaction mixture, which was then extracted with dichloromethane. The organic layer was washed with brine, and the solvent was distilled away under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give N-(4-chloro-3-methyl-1,2-oxazol-5-yl)-2-(1,3-dithian-2-yl)thiophene-3-sulfonamide as a crude product. To a mixture of crude N-(4-chloro-3-methyl-1,2-oxazol-5-yl)-2-(1,3-dithian-2-yl)thiophene-3-sulfonamide and tetrahydrofuran (50 mL) was added dropwise n-butyl lithium (9.7 mL, 16 mmol, 1.6 M n-hexane solution) at −78° C., followed by stirring for 20 minutes at an internal temperature of −35° C. The reaction mixture was cooled to −78° C., and 5-(chloromethyl)-6-methyl-1,3-dihydro-2-benzofuran described in Production Example 1-6 (960 mg, 5.3 mmol) was added at that temperature and stirred for 1 hour at 0° C. The reaction mixture was cooled to −78° C., and a mixture of acetic acid (0.90 mL, 16 mmol) and tetrahydrofuran (7 mL) was added at that temperature. The reaction mixture was gradually returned to room temperature, water and an aqueous citric acid solution were added at that temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and the solvent was distilled away under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=4:1) to give the title compound (1.6 g, 54% yield).
Reaction SMILES: C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[NH2:13][CH:14]1[C:35](=[O:36])[N:16]2[C:17]([C:32]([OH:34])=[O:33])=[C:18]([CH2:21][S:22][C:23]3[N:24]([CH3:31])[N:25]=[C:26]([OH:30])[C:27](=[O:29])[N:28]=3)[CH2:19][S:20][C@H:15]12.S1C2C=CC=CC=2N=C1S[C:47](=[O:56])[C:48]([C:50]1[N:51]=[C:52]([NH2:55])[S:53][CH:54]=1)=[O:49].C(O)C>ClCCl>[NH2:55][C:52]1[S:53][CH:54]=[C:50]([C:48](=[O:49])[C:47]([NH:13][CH:14]2[C:35](=[O:36])[N:16]3[C:17]([C:32]([OH:34])=[O:33])=[C:18]([CH2:21][S:22][C:23]4[N:24]([CH3:31])[N:25]=[C:26]([OH:30])[C:27](=[O:29])[N:28]=4)[CH2:19][S:20][C@H:15]23)=[O:56])[N:51]=1
Reactant: Cn1nc(O)c(=O)nc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: Nc1nc(C(=O)C(=O)Sc2nc3ccccc3s2)cs1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: ClCCl
Solvent: CCO
Product: Cn1nc(O)c(=O)nc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=O)c3csc(N)n3)[C@H]2SC1
Reaction time: 2 h

Procedure:
14.85 ml of N,O-bis(trimethylsilyl)acetamide are added at 30° to 7.4 g of 7-amino-3-[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazin-3-yl)thiomethyl]ceph-3-em-4-carboxylic acid (water content: 3.7%) in 50 ml of dichloromethane. After two hours at 30°, the mixture is cooled to -15°. 8.1 g of 2-(2-amino-4-thiazolyl)-2-oxothioacetic-acid-S-benzothiazol-2-ylester are added, and stirred for six hours at -15°. The preparation is added to 500 ml of ethanol which has been warmed to 50°, then cooled whilst stirring and stirred for one hour at 0°. The deposit is filtered off, washed and dried. 9.1 g of the title compound are obtained as a yellow powder. IR: 3320 NH, 1805 c=o, 1735 c=o, 1690 c=o, 1645 (amide I), 1555 (amide II).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:21]2[CH:20]=[C:19]([C:22](=[O:24])[CH3:23])[CH:18]=[CH:17][C:16]=2[S:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:26].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CN(C)C=O.CCOCC>[C:22]([C:19]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([OH:26])=[O:1])[C:21]=2[CH:20]=1)(=[O:24])[CH3:23]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: CC(=O)c1ccc2c(c1)N(CCCCCCO)c1ccccc1S2
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(=O)c1ccc2c(c1)N(CCCCCC(=O)O)c1ccccc1S2
Temperature: 25 °C
Reaction time: 12 h
Yield: 23.4 %

Procedure:
A solution of 41 mg (0.12 mmol) of 1-[10-(6-hydroxyhexyl)-10H-phenothiazin-2-yl]ethanone in 0.16 mL of N,N-dimethylformamide is treated with 158 mg (0.42 mmol) of pyridinium dichromate and stirred at room temperature for 12 hours. The mixture is diluted with ether and filtered through a pad of celite with the aid of 100 mL of ether. The filtrate is washed successively with 10% sodium bisulfate solution and saturated sodium chloride solution, then dried over magnesium sulfate and concentrated in vacuo to give 10 mg (23%) of 2-acetyl-10H-phenothiazine-10-hexanoic acid as a dark residue. The 1 H NMR (300 MHz, CDCl3) is consistent with the desired product. MS (CI) m/e 323 (M+ +H).
Reaction SMILES: [C:1]([CH2:3][S:4]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][C@H:22]([CH2:24][NH:25][C:26](=[O:28])[CH3:27])[O:21][C:20]3=[O:29])=[CH:15][C:14]=2[F:30])[CH2:9][CH2:8]1)(=[O:6])=[O:5])#[N:2].C1C=C([O:37]O)C(C(O)=O)=C(C(O)=O)C=1>CO>[C:1]([CH2:3][S:4]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][C@@H:22]([CH2:24][NH+:25]([O-:37])[C:26](=[O:28])[CH3:27])[O:21][C:20]3=[O:29])=[CH:15][C:14]=2[F:30])[CH2:9][CH2:8]1)(=[O:6])=[O:5])#[N:2]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCN(S(=O)(=O)CC#N)CC3)c(F)c2)C(=O)O1
Reactant: O=C(O)c1cccc(OO)c1C(=O)O
Solvent: CO
Product: CC(=O)[NH+]([O-])C[C@@H]1CN(c2ccc(N3CCN(S(=O)(=O)CC#N)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(S)-N-[[3-[4-[4-[(cyanomethyl)sulfonyl]-1-piperazinyl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (VII-G, R1═COCH3, R9═NCCH2, X1═F, X2═H) (0.550 g) is dissolved in 15 mL of methanol. Monoperoxyphthalic acid, magnesium salt hexahydrate (80% pure, 0.616 g) is added and the reaction is stirred at room temperature for 4 hours. The reaction is then filtered and the filtrate is concentrated to afford an oil. This oil is chromatographed on silica gel using 10% methanol (saturated with ammonia) in chloroform as eluent to afford 0.42 g of the N-oxide.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1.C(N(CC)CC)C.[NH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCCNC(=O)OC(C)(C)C)c1C
Temperature: 60 °C
Yield: 77.4 %

Procedure:
A solution of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (60 g, 271 mmol) in anhydrous N,N-dimethylformamide (600 mL) was cooled to 0° C. Triethylamine (44.8 mL, 326 mmol) was added drop wise followed by tert-butyl 2-aminoethylcarbamate (52.2 g, 326 mmol). After 30 minutes the ice bath was removed and the reaction mixture was heated to 60° C. The reaction was heated at 60° C. overnight and then it was concentrated under reduced pressure to provide an orange oil. The oil was dissolved in ethyl acetate (1 L), washed with water (3×500 mL), dried over magnesium sulfate and then concentrated under reduced pressure to provide a yellow oil. The oil was triturated with methanol (˜100 mL). The resulting solid was isolated by filtration and washed with cold methanol to provide 72.3 g of tert-butyl 2-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]ethylcarbamate as a solid.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[NH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:27]3[CH2:28][CH2:29][CH:24]([CH2:23][NH2:22])[CH2:25][CH2:26]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: NCC1CCNCC1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Product: NCC1CCN(C(=O)Oc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)CC1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 4-aminomethylpiperidine. The crude product was purified by preparative HPLC (Method C) (32%, off-white crystals). HPLC-MS m/z=396.1 (M+1), Rt: 2.65 min. purity: 86%.
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]=[C:20]([NH2:22])[S:21][C:17]=2[C:16]=1Br)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C([O-])([O-])=O.[K+].[K+].[Cl:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.O1CCOCC1>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.O>[C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]=[C:20]([NH2:22])[S:21][C:17]=2[C:16]=1[C:37]1[CH:38]=[CH:39][C:34]([Cl:33])=[CH:35][CH:36]=1)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Cc1cc2nc(N)sc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc2nc(N)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 110 °C
Yield: 187.5 %

Procedure:
2 separate microwave tubes were each charged with (S)-2-(2-Amino-7-bromo-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (768 mg, 1.74 mmol), K2CO3 (960 mg, 6.96 mmol), 4-chlorophenylboronic acid (325 mg, 2.09 mmol), Pd(PPh3)4 (200 mg, 0.174 mmol), dioxane (8.0 mL), and H2O (2.0 mL). The two sealed vessels were separately heated at 110° C. for 3 h. The reactions were cooled to 23° C. and combined. H2O (50 mL) was added, and the system was extracted with EtOAc (3×50 mL). The combined extracts were dried (Na2SO4), filtered, and concentrated. The residue was treated with benzene and purified via chromatography on silica gel (80 g “gold” ISCO column; Hex/EtOAc) giving (S)-2-(2-Amino-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (1.55 g, 90% yield). LCMS-ESI+: calc'd for C25H31ClN2O3S: 475.2 and 477.2 (M+H+); found: 475.3 and 477.3 (M+H+). 1H-NMR: 400 MHz, (CDCl3) δ: 7.49-7.41 (m, 2H), 7.36-7.32 (m, 2H), 7.22 (d, J=7.3 Hz, 1H), 5.19 (s, broad, 2H), 4.67 (dd, J=9.0, 2.7 Hz, 1H), 4.36 (dd, J=11.7, 9.0 Hz, 1H), 4.23 (dd, J=11.7, 2.7 Hz, 1H), 2.68 (s, 3H), 1.14 (s, 9H), 0.94 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([C:9]2[CH:10]=[CH:11][C:12]3[NH:18][C:17]4[N:19]=[C:20]([C:23]([F:26])([F:25])[F:24])[CH:21]=[CH:22][C:16]=4[CH2:15][N:14]([S:27]([C:30]4[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[C:13]=3[CH:41]=2)=[O:8])[CH:3]=1.I[C:43]1C=CC2NC3N=C(C(F)(F)F)C=CC=3CN(S(C3C=CC(OC(F)(F)F)=CC=3)(=O)=O)C=2C=1.C([Mg]Cl)(C)C.CON(C)C(C1C=C(C)NN=1)=O>C1COCC1.C1(C)C=CC=CC=1>[CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([C:9]2[CH:10]=[CH:11][C:12]3[NH:18][C:17]4[N:19]=[C:20]([C:23]([F:24])([F:25])[F:26])[CH:21]=[CH:22][C:16]=4[CH2:15][N:14]([S:27]([C:30]4[CH:35]=[CH:34][C:33]([O:36][C:37]([F:39])([F:40])[F:38])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[C:13]=3[CH:41]=2)([OH:8])[CH3:43])[CH:3]=1
Reactant: O=S(=O)(c1ccc(OC(F)(F)F)cc1)N1Cc2ccc(C(F)(F)F)nc2Nc2ccc(I)cc21
Reactant: Cc1cc(C(=O)c2ccc3c(c2)N(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)Cc2ccc(C(F)(F)F)nc2N3)n[nH]1
Agent: CC(C)[Mg]Cl
Agent: CON(C)C(=O)c1cc(C)[nH]n1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cc(C(C)(O)c2ccc3c(c2)N(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)Cc2ccc(C(F)(F)F)nc2N3)n[nH]1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(5-Methyl-1H-pyrazol-3-yl)[6-{[4-(trifluoromethoxy)phenyl]sulfonyl}-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-8-yl]methanone To a solution of 8-iodo-6-{[4-(trifluoromethoxy)phenyl]sulfonyl}-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (950 mg, 1.544 mmol, intermediate 61) in 5 ml of THF was added a solution of isopropyl magnesium chloride (3.47 ml, 6.95 mmol) in THF (2M) at 0° C. The solution was stirred at 0° C. for 30 min, then a mixture of N-methoxy-N,5-dimethyl-1H-pyrazole-3-carboxamide (261 mg, 1.544 mmol) in 3 mL of toluene was added. The reaction mixture was stirred for 2 hr at 0° C. and then allowed to warm to rt overnight. The reaction was quenched by the addition of 4 mL of 0.5 N HCl. The resulting viscous residue was washed with ethyl acetate (30 mL×2) and acetone (20 mL×2). The combined washes were evaporated under reduced pressure and the residue was crystallized from CH2Cl2 to give the title compound as a light yellow solid; Mass Spectrum: m/e=598 (M+1).
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[N:8]=[C:9]([N:12]2[CH2:15][CH:14](OS(C)(=O)=O)[CH2:13]2)[S:10][CH:11]=1)=[O:6])[CH:2]=[CH2:3].[C:21]([O-:24])(=[S:23])[CH3:22].[K+]>CN(C)C=O>[C:21]([S:23][CH:14]1[CH2:13][N:12]([C:9]2[S:10][CH:11]=[C:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[N:8]=2)[CH2:15]1)(=[O:24])[CH3:22]
Reactant: CC([O-])=S
Reactant: C=CCOC(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1csc(N2CC(SC(C)=O)C2)n1
Temperature: 80 °C
Reaction time: 10 h
Yield: 63.4 %

Procedure:
To a solution of 1-(4-allyloxycarbonyl-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (2.70 g, 8.51 mmol) (obtained as described in Reference Example 41(3)) in dimethylformamide (135 ml) was added potassium thioacetate (5.83 g, 51.1 mmol) at room temperature. The mixture was stirred in an oil bath (80° C.) for 10 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (2:1) as the eluant to afford 3-acetylthio-1-(4-allyloxycarbonyl-1,3-thiazol-2-yl)azetidine (1.61 g, yield 63%) as a pale brown solid.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([Cl:18])[N:17]=2)[C:12]([NH2:14])=[O:13])[CH2:5][CH2:4]1.[Cl:19][C:20]1[C:21]([CH3:29])=[C:22]([C:26](O)=[O:27])[NH:23][C:24]=1[CH3:25]>>[Cl:18][C:16]1[CH:15]=[C:11]([CH:10]=[C:9]([N:6]2[CH2:5][CH2:4][CH:3]([NH:2][C:26]([C:22]3[NH:23][C:24]([CH3:25])=[C:20]([Cl:19])[C:21]=3[CH3:29])=[O:27])[CH2:8][CH2:7]2)[N:17]=1)[C:12]([NH2:14])=[O:13]
Reactant: Cc1[nH]c(C(=O)O)c(C)c1Cl
Reactant: NC(=O)c1cc(Cl)nc(N2CCC(N)CC2)c1
Agent: Cl
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(N)=O)cc(Cl)n3)CC2)c(C)c1Cl

Procedure:
Title compound was synthesized by an analogous method to Example 18 by coupling 2-(4-aminopiperidin-1-yl)-6-chloroisonicotinamide hydrochloride (Intermediate 70) with 4-chloro-3,5-dimethyl-1H-pyrrole-2-carboxylic acid (Intermediate 75).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[C:20]([N:27](C(OCC(Cl)(Cl)Cl)=O)[C:28](OCC(Cl)(Cl)Cl)=[O:29])=[N:19]1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[O:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[C:20]([NH:27][C:28]([N:15]2[CH2:16][CH2:17][N:12]([C:9]3[S:10][CH:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=3)[CH2:13][CH2:14]2)=[O:29])=[N:19]1
Reactant: O=C(OCC(Cl)(Cl)Cl)N(C(=O)OCC(Cl)(Cl)Cl)c1noc2ccccc12
Reactant: c1ccc(-c2csc(N3CCNCC3)c2)cc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1noc2ccccc12)N1CCN(c2cc(-c3ccccc3)cs2)CC1

Procedure:
A solution of 1-(4-phenyl-2-thienyl)piperazine (240 mg, 0.984 mmol), bis(2,2,2-trichloroethyl) 1,2-benzisoxazol-3-ylimidodicarbonate (239 mg, 0.492 mmol), diisopropylethylamine (0.0857 ml, 0.492 mmol) and dimethylsulfoxide (3 ml) was stirred at 70° C. for 2 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the desired product as a solid. This was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain the desired product (42.5 mg, 21.4%) as a solid.
Reaction SMILES: CN([CH2:4][CH2:5]C=C1C2C=CC=CC=2OCC2C=CC=CC1=2)C.CN(CCC=C1C2C=CC=CC=2[O:36]CC2C=CC=CC1=2)C.[ClH:43].CN1[C@@H]2[C@@H]3O[C@H]3[C@H]1C[C@@H](OC([C@@H](C1C=CC=CC=1)CO)=O)C2.C[C:67]1[CH:68]=[C:69]([C:81](C)(C)C)[C:70](O)=[C:71]([CH3:79])[C:72]=1CC1NCCN=1.Cl.CC1C=C(C(C)(C)C)C(O)=C(C)C=1[CH2:93][C:94]1[NH:98][CH2:97][CH2:96][N:95]=1.Cl>>[CH3:4][CH2:5][N:98]([CH2:97][C:96]([NH:95][C:70]1[C:69]([CH3:81])=[CH:68][CH:67]=[CH:72][C:71]=1[CH3:79])=[O:36])[CH2:94][CH3:93].[ClH:43]
Reactant: CN(C)CCC=C1c2ccccc2COc2ccccc21
Reactant: Cc1cc(C(C)(C)C)c(O)c(C)c1CC1=NCCN1
Agent: CN1[C@@H]2C[C@@H](OC(=O)[C@H](CO)c3ccccc3)C[C@H]1[C@@H]1O[C@H]12
Agent: Cl
Product: CCN(CC)CC(=O)Nc1c(C)cccc1C

Procedure:
A 2% composition of doxepin in the nanolipid-vesicle composition of Preparation 2 above was prepared by mixing doxepin hydrochloride with the nanolipid vesicle formulation as described in Preparation 2 which had been modified by the addition of Keltrol to render a thick creamy consistency, in a mass/mass ratio of 2:98 with the aid of a high speed stirrer. The composition is designated DOXIPEX CREAM. (b) In similar manner a 1.7307% composition of Lidocaine Hydrochloride was prepared and designated LIDAREX LOTION. (c) A 0.3% composition of Scopolamine HBR was also prepared in the same manner and designated MZL Scopolamine. (d) A 0.5% nasal spray composition of Oxymetazoline HCl was also prepared in the same manner with some modification and designated Oxymetazoline MZL. (e) A 0.5% injection formulation of Bupivicaine HCl was further prepared in the same manner but with some modification and designated Bupivicaine MZL.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][N:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])=[CH:17][CH:16]=2)[N:3]=1.[H-].[Na+].I[CH2:38][CH3:39].O>CN(C)C=O>[CH2:38]([O:1][C:2]1[C:6]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][N:4]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[O:26][C:27]=3[CH3:28])=[CH:19][CH:20]=2)[N:3]=1)[CH3:39]
Reactant: CCI
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a solution of ethyl 3-[3-hydroxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (462 mg) in N,N-dimethylformamide (10 ml), sodium hydride (60%, oily, 40.0 mg) was added at 0° C., and the solution was stirred at room temperature for 30 minutes. Iodoethane (0.240 ml) was added to the reaction mixture, which was stirred at room temperature for one hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-ethoxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate was obtained (452 mg, yield: 92%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).