Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH2:21][CH2:20][NH:19][C:18]=3[CH:23]=2)=[O:13])=[CH:7][CH:6]=1)C.[F:25][C:26]1[CH:27]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>N1C=CC=CC=1>[F:25][C:26]1[CH:27]=[C:28]([S:32]([N:19]2[C:18]3[CH:23]=[C:14]([C:12]([NH:11][C:8]4[CH:9]=[CH:10][C:5]([C:4]([OH:3])=[O:24])=[CH:6][CH:7]=4)=[O:13])[CH:15]=[CH:16][C:17]=3[O:22][CH2:21][CH2:20]2)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)NCCO3)cc1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Solvent: c1ccncc1
Product: O=C(O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(F)c2)CCO3)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.1 %

Procedure:
Step 7 and 8. A solution of 4-[(3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl)-amino]-benzoic acid ethyl ester (27 mg, 0.085 mmol) in pyridine (0.4 mL) was treated with a solution of 3-fluoro-benzenesulfonyl chloride (25 mg, 0.13 mmol) in pyridine (0.2 mL). The resulting mixture was stirred at room temperature for 18 hours. The pyridine was evaporated, and the residual crude 4-{[4-(3-fluoro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid ethyl ester was dissolved in ethanol (0.6 mL) and treated with KOH 3N (0.15 mL). The resulting mixture was stirred at room temperature overnight. The mixture was acidified with HCl 3N and evaporated. The residue was purified by preparative HPLC (ZORBAX Eclipse XDB-C18, 21.2×50 mm, 5 μm, gradient acetonitrile/water +0.1% formic acid). 4-{[4-(3-Fluoro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid (17.1 mg, 44%) was obtained as an off-white solid, MS (ISP): m/e=455.0 (M−H).
Reaction SMILES: Cl.NC(C([O-])=O)C(OC)=O.[NH2:11][CH:12]([C:18]([O-:20])=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=N>>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]2[NH:21][C:18](=[O:20])[CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:11]=[C:29]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:23]=2[CH:24]=1
Reactant: CCOC(=O)C(N)C(=O)[O-]
Reactant: Cc1ccc(N)c(C(=N)c2ccccc2)c1
Agent: COC(=O)C(N)C(=O)[O-]
Agent: Cl
Product: CCOC(=O)C1N=C(c2ccccc2)c2cc(C)ccc2NC1=O

Procedure:
This compound is obtained by the procedure described in Example 22, the hydrochloride of methyl aminomalonate and compound 4356 CB being replaced by the equivalent quantities of, respectively, the hydrochloride of ethyl aminomalonate and (2-amino-5-methylphenyl)-phenyl-methane-imine prepared according to Example 12.
Reaction SMILES: [C:1](Cl)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=C.II>CO>[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)OC
Reactant: O=C(Cl)c1ccccc1
Agent: II
Solvent: CO
Product: COC(=O)C=Cc1ccccc1

Procedure:
On the other hand, it is known that the reaction of benzoyl chloride with methyl acrylate in the presence of stoichiometric amounts of a nickel(O) catalyst leads to the formation of methyl trans-3-benzoyl acrylate if the reaction mixture is subsequently treated with iodine in methanol. Methyl cinnamate is formed as a by-product in this reaction. Methyl cinnamate is obtained as the main product and methyl benzoyl acrylate as a by-product by reacting a complex formed from benzoyl-palladium chloride and triphenylphosphine with methyl acrylate at 70° to 85° C. in the presence of triethylamine. If only catalytic amounts of the palladium and the triphenylphosphine are employed, the equilibrium of the reaction is shifted in favour of the formation of methyl benzoyl acrylate (the ratio by weight of methyl benzoyl acrylate:methyl cinnamate is approx. 8.3:1) [cf. Transition Met. Chem. 2, 270 (1977) and 4, 298 (1979)]. Finally, it is known from Synthesis, 777 (1977), that the reaction of aromatic acid halides with 1-alkines, catalysed by Pd, leads to alkinyl ketones without decarbonylation.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:17][C:18]([CH3:20])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1CCCCC1>[CH2:23]([O:22][C:16](=[O:21])[CH:17]=[C:18]([NH:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)[CH3:20])[CH3:24]
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1cccc(OCc2ccccc2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCCCC1
Product: CCOC(=O)C=C(C)Nc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 9987.2 %

Procedure:
20 g (98.4 mmol)of 3-benyloxyaniline, 12.6 ml (0.984 mmol) of ethyl acetoacetate and 0.189 g (1 mmol) of p-toluenesulfonic acid monohydrate in 32 ml of cyclohexane were heated at reflux for 5.5 h in the presence of a water separator funnel. The reaction mixture was cooled to RT, some solid material was filtered off by suction and the filtrate was concentrated in vacuo to give 30.6 g (99%) of the desired 3-(3-benzyloxy-phenylamino)-but-2-enoic acid ethyl ester as a yellow oil. This was used without further purification in the next reaction step.
Reaction SMILES: [N:1]1([S:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:19]([O:21][C:22]([C:24]1[C:25](=[O:48])[C:26]2[CH:31]=[N:30][C:29](S(CC)(=O)=O)=[N:28][C:27]=2[N:37]([C:39]2[CH:40]=[C:41]3[C:45](=[CH:46][CH:47]=2)[CH2:44][CH2:43][CH2:42]3)[CH:38]=1)=[O:23])[CH3:20]>>[CH2:19]([O:21][C:22]([C:24]1[C:25](=[O:48])[C:26]2[CH:31]=[N:30][C:29]([NH:18][C:15]3[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][S:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)(=[O:9])=[O:8])=[CH:13][CH:14]=3)=[N:28][C:27]=2[N:37]([C:39]2[CH:40]=[C:41]3[C:45](=[CH:46][CH:47]=2)[CH2:44][CH2:43][CH2:42]3)[CH:38]=1)=[O:23])[CH3:20]
Reactant: Nc1ccc(CCS(=O)(=O)N2CCOCC2)cc1
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(=O)(=O)CC)ncc2c1=O
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(CCS(=O)(=O)N4CCOCC4)cc3)ncc2c1=O

Procedure:
Using the procedure outlined in Example 1(g) the title compound was prepared from 4-[2-(morpholine-4-sulfonyl)-ethyl]-phenylamine (65 mg, 0.24 mmol) and 8-indan-5-yl-2-ethanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(e) above, 100 mg, 0.24 mmol). The title compound was obtained as a white solid (42 mg, 29%). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.35 (s, 1H), 8.53 (s, 1H), 8.01 (br, 1H), 7.42 (d, J=7.8 Hz, 1H), 7.30 (m, 3H), 7.19 (d, J=7.8 Hz, 1H), 6.94 (br, 2H), 4.37 (q, J=7.1 Hz, 2H), 3.72 (t, J=4.5 Hz, 4H), 3.25 (t, J=4.7 Hz, 4H), 3.08 (m, 6H), 3.01 (t, J=7.4 Hz, 2H), 2.24 (m, 2H), 1.38 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[C:8](O)=O.[NH2:11][C:12]1[CH:13]=[C:14]([CH:23]=[CH:24][C:25]=1[NH2:26])[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>N1C=CC=CC=1>[C:15]([C:14]1[CH:23]=[CH:24][C:25]2[N:26]=[C:8]([C:3]3[NH:4][C:5]([CH3:7])=[CH:6][C:2]=3[CH3:1])[NH:11][C:12]=2[CH:13]=1)(=[O:16])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1N
Reactant: Cc1cc(C)c(C(=O)O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: c1ccncc1
Product: Cc1cc(C)c(-c2nc3ccc(C(=O)c4ccccc4)cc3[nH]2)[nH]1
Temperature: 70 °C
Reaction time: 8 h
Yield: 15.2 %

Procedure:
3,5-Dimethylpyrrole-2-carboxylic acid (99 mg, 0.71 mmol) was added to a pyridine (3 ml) solution of 3,4-diaminobenzophenone (150 mg, 0.71 mmol). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (149 mg, 0.78 mmol) and 1-hydroxybenzotriazole monohydrate (119 mg, 0.78 mmol) were further added, and the mixture was heated to 70° C. and stirred overnight. The reaction mixture was allowed to cool to room temperature with stirring, and then the solvent was evaporated. The residue was purified using medium pressure silica gel flash column chromatography (NH silica gel, chloroform:methanol=98:2). The residue was dissolved in acetic acid (3 ml), and stirred for 8 hours at 100° C. The reaction mixture was allowed to cool to room temperature with stirring, and then the solvent was evaporated. The residue was purified using medium pressure silica gel flash column chromatography (NH silica gel, chloroform:methanol=98:2), to afford 5-benzoyl-2-(3,5-dimethylpyrrol-2-yl)-benzimidazole (34 mg, 15% in two steps) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]2[CH2:12][NH:11][C:10](=[O:13])[CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.I[CH3:15].[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[C:7]([CH:8]2[CH2:12][N:11]([CH3:15])[C:10](=[O:13])[CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CI
Reactant: O=C1CC(c2cccnc2F)CN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1CC(c2cccnc2F)CC1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
To a solution of 4-(2-fluoropyridin-3-yl)pyrrolidin-2-one (0.254 g, 1.41 mmol) in DMF (5 mL) at 0° C. was added iodomethane (0.090 mL, 1.4 mmol) and sodium hydride (60% weight dispersion in mineral oil, 0.056 g, 1.4 mmol). The reaction mixture was stirred at 0° C. for 30 min, warmed to room temperature, and stirred for 30 min. The reaction mixture was diluted with EtOAc, quenched with water, and diluted with brine and water. The aqueous phase was extracted with EtOAc (6×) and the combined organic extracts were washed with brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (50% to 100% EtOAc (10% MeOH) in hexanes) gave 4-(2-fluoropyridin-3-yl)-1-methylpyrrolidin-2-one (0.226 g, 1.16 mmol, 83% yield) as a pale yellow oil. MS (ESI, pos. ion) m/z: 195.1 (M+1).
Reaction SMILES: P(Br)(Br)[Br:2].[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13]O)=[CH:8][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl>[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][Br:2])=[CH:8][CH:7]=1
Reactant: OCCc1ccc(F)cc1
Reactant: BrP(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(CCBr)cc1

Procedure:
Phosphorus tribromide (14 g) was added, over 2 minutes, to a solution of 2-(4-fluorophenyl)ethanol (14 g) in carbon tetrachloride (80 ml). The mixture was heated under reflux for 2 hours then cooled in an ice bath. 10% Aqueous sodium carbonate solution was added until all of the solid has dissolved. The mixture was transferred to a separating funnel and the layers were separated. The aqueous layer was extracted with dichloromethane (50 ml) and the organic solutions were combined, dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica eluting with 1:1 hexane/dichloromethane. The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless oil, 10 g.
Reaction SMILES: [C:1]1([CH:7]2[NH:10][C:9](=[O:11])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]([Si:16](Cl)([CH3:18])[CH3:17])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>CN(C=O)C>[C:1]1([CH:7]2[N:10]([Si:16]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:18])[CH3:17])[C:9](=[O:11])[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1CC(c2ccccc2)N1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)N1C(=O)CC1c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.1 %

Procedure:
4-Phenylazetidin-2-one (10.4 gm, 71.0 mmole) (Graf, Chem. Ber, 111 (1963); Durst et al. J. Org. Chem., 35, 2043 (1970)) was dissolved in DMF (200 ml) and was treated with tert.-butyldimethylsilyl chloride (12.8 gm, 85 mmol) and triethylamine (11.8 ml, 85 mmol). The mixture was stirred at room temperature for 16 hrs. and taken up in either (500 ml). The ethereal solution was washed with 1N hydrochloric acid (1×100 ml), water (2×50 ml) and brine (1×50 ml). After the solution was dried (anhyd. magnesium sulfate) and evaporated, the residue was flash chromatographed on SiO2 -gel column. Elution with 15% ethyl acetate in hexane afforded 4-phenyl-1-(tert.-butyldimethylsilyl)azetidin-2-one (18.4 gm, 99%) as an oil which solidified on standing.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[Cl:16].[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC([O-])=O.CC([O-])=O.[Cu+2].ClCCl>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[Cl:16]
Reactant: OB(O)c1ccccc1
Reactant: Oc1ccc(Br)c(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Clc1cc(Oc2ccccc2)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.3 %

Procedure:
Triethylamine (0.52 mL, 3.75 mmol) was added to a mixture of 4-bromo-3-chlorophenol (156 mg, 0.75 mmol), phenyl boronic acid (187 mg, 1.53 mmol), Cu(OAc)2 (208 mg, 1.15 mmol), molecular sieves (4 Å), and dichloromethane (7.5 mL). The mixture was stirred at room temperature overnight, and then additional phenyl boronic acid (186, 1.53 mmol) was added. The reaction was stirred at rt for an additional 7 h and filtered through Celite with dichloromethane. The filtrate was concentrated and purified by silica gel chromatography (100% hexanes) to give 1-bromo-2-chloro-4-phenoxybenzene (90 mg) as a clear liquid. 1H NMR (400 MHz, DMSO-d6): δ 7.75 (d, 1H), 7.42-7.47 (m, 2H), 7.27 (d, 1H), 7.23 (t, 1H), 7.11 (d, 2H), 6.92 (dd, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:2]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[C:34]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:2]1)(=[O:37])[CH2:35][CH3:36]
Reactant: CCC(=O)Cl
Reactant: O=C(NCC1CCCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Product: CCC(=O)N1CCCC(CNC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (piperidin-3-ylmethyl)-amide (example A145) and propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: CC(S([NH:7][CH:8]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH2:20][CH2:21][CH3:22])(=[O:19])=[O:18])=[CH:13][CH:12]=1)[CH:9]=[CH2:10])=O)(C)C.Cl.C(N(CC)CC)C.[Cl:31][C:32]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:33]=1[C:34](Cl)=[O:35]>CO>[Cl:31][C:32]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:33]=1[C:34]([NH:7][CH:8]([C:11]1[CH:12]=[CH:13][C:14]([S:17]([CH2:20][CH2:21][CH3:22])(=[O:18])=[O:19])=[CH:15][CH:16]=1)[CH:9]=[CH2:10])=[O:35]
Reactant: C=CC(NS(=O)C(C)(C)C)c1ccc(S(=O)(=O)CCC)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: C=CC(NC(=O)c1ccc(Cl)cc1Cl)c1ccc(S(=O)(=O)CCC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Methyl-N-{1-[4-(propylsulphonyl)phenyl]prop-2-en-1-yl}propane-2-sulphinamide (213 mg, 0.62 mmol) was dissolved in methanol. Methanolic hydrogen chloride was added and the reaction mixture was stirred at room temperature for 2 h. Following concentration in vacuo the residue was suspended in dichloromethane and stirred under nitrogen. Triethylamine (0.173 mL, 1.24 mmol) was added followed by 2,4-dichlorobenzoyl chloride (87 μL, 0.62 mmol) and the reaction mixture was stirred overnight. The reaction was quenched by addition of water and satd. NaHCO3(aq). The product was extracted into ethyl acetate (×2) and then the combined organic layers washed with brine, dried (MgSO4) and concentrated. 1H NMR 5 (400 MHz, CDCl3) δ 0.99 (3H, t, J=7.4 Hz), 1.66-1.76 (2H, m), 3.00-3.04 (2H, m), 5.30-5.37 (2H, m), 5.86 (1H, t, J=6.9 Hz), 6.02-6.10 (1H, m), 7.19 (1H, d, J=7.9 Hz), 7.29 (1H, dd, J=8.5, 2.1 Hz), 7.40 (1H, d, J=1.9 Hz), 7.56 (2H, dd, J=8.3, 2.5 Hz), 7.83 (2H, d, J=8.3 Hz).
Reaction SMILES: ClC(OC(C)C)=O.[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[CH:15][C:16]2[S:21][CH:20]([CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:19](=[O:33])[N:18]([CH2:34][C:35]([OH:37])=O)[C:17]=2[CH:38]=1)=[O:12])[CH3:9].CN1CCOCC1.C[Si](C)(C)[O:48][NH2:49].Cl>O1CCCC1>[OH:48][NH:49][C:35](=[O:37])[CH2:34][N:18]1[C:17]2[CH:38]=[C:13]([C:11]([O:10][CH2:8][CH3:9])=[O:12])[CH:14]=[CH:15][C:16]=2[S:21][CH:20]([CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[C:19]1=[O:33]
Reactant: CCOC(=O)c1ccc2c(c1)N(CC(=O)O)C(=O)C(CCCc1ccc(OC)cc1)S2
Reactant: C[Si](C)(C)ON
Agent: CC(C)OC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(c1)N(CC(=O)NO)C(=O)C(CCCc1ccc(OC)cc1)S2
Reaction time: 0.42 h

Procedure:
At −15° C., isopropyl chloroformate (2.84 ml) was added dropwise to a solution of {6-(ethoxycarbonyl)-2-[3-(4-methoxyphenyl)propyl]-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl}acetic acid (10.64 g) and N-methylmorpholine (3.2 ml) in tetrahydrofuran (200 ml). After the dropwise addition of the whole isopropyl chloroformate, the resulting mixture was stirred for 25 minutes and then O-(trimethylsilyl)hydroxylamine (3.52 ml) was added dropwise thereto. After 3 hours, the reaction mixture was poured into a 0.5N aqueous hydrochloric acid solution and extracted with ethyl acetate. The oil layer was washed with a saturated aqueous sodium chloride solution, dehydrated over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by a silica gel chromatography (hexane/ethyl acetate=2/3 to 1/3). To the resulting yellow oil were added toluene and hexane to effect crystallization. The solid obtained was collected by filtration and concentrated under reduced pressure. Ethyl 4-[2-(hydroxyamino)-2-oxoethyl]-2-[3-(4-methoxyphenyl)propyl]-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate (8.24 g) was obtained as a yellow solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:13][CH2:14][CH2:15][C:16](Cl)=[O:17]>C1C=CC=CC=1>[Cl:13][CH2:14][CH2:15][C:16]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:17]
Reactant: C1CCNC1
Reactant: O=C(Cl)CCCl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(CCCl)N1CCCC1
Reaction time: 0.25 h

Procedure:
A solution of pyrrolidine (35 grams; 0.5 mol) and triethylamine (50 grams; 0.5 mol) in benzene (500 ml) is placed in a glass reaction flask equipped with a mechanical stirrer and reflux condenser. β-Chloropropionyl chloride (64 grams; 0.5 mol) is then slowly added with stirring over a period of about 15 minutes. Stirring is continued for a period of about 30 minutes. After this time the reaction mixture is first filtered to remove triethylamine hydrochloride nd is the stripped of benzene to yield 1-(β-chloropropionyl) pyrrolidine.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]1.Br[C:15]1[S:16][CH:17]=[CH:18][N:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.CN(C=O)C>[S:16]1[CH:17]=[CH:18][N:19]=[C:15]1[N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]1
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: Brc1nccs1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(-c2nccs2)c2ccccc12
Temperature: 110 °C

Procedure:
To a solution of methyl 1H-indole-3-carboxylate (200 mg, 1.142 mmol) in NMP (Volume: 1142 μl) were added 2-bromothiazole (206 μl, 2.283 mmol) and cesium carbonate (1116 mg, 3.42 mmol) at RT. The mixture was heated at 110° C. for 2 h, then diluted with DMF, filtered and purified by HPLC to afford the title compound as a brown solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O)#[N:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH2:55][CH2:56][C:57]1[CH:62]=[CH:61][C:60]([S:63]([NH2:66])(=[O:65])=[O:64])=[CH:59][CH:58]=1>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([NH:55][CH2:56][C:57]1[CH:58]=[CH:59][C:60]([S:63](=[O:65])(=[O:64])[NH2:66])=[CH:61][CH:62]=1)=[O:11])#[N:2]
Reactant: N#Cc1cccc(Oc2ncccc2C(=O)O)c1
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cccc(Oc2ncccc2C(=O)NCc2ccc(S(N)(=O)=O)cc2)c1
Temperature: 25 °C
Yield: 40.8 %

Procedure:
To a solution of 2-(3-Cyano-phenoxy)-nicotinic acid (0.140 g 0.600 mmole), BOP (0.260 grams, 0.600 mmole) and DIEA (0.310 μl, 1.8 mmole) in dimethylformamide (5 ml) was added 4-Aminomethyl-benzenesulfonamide (0.135 grams, 0.600 mmole) and stirred at room temperature over night. The reaction was quenched with water and extracted with ethyl acetate. The combined organics were washed with alternating portions of 5% citric acid and sat'd bicarb, dried over Na2SO4, filtered and concentrated to a product which was recrystalized from ethyl acetate to give a white solid (0.100 g). M.P. 179-180° C.; Anal. calcd. for C20H16N4O4S; C, 58.81; H, 3.95; N, 13.72. Found: C, 57.47; H, 4.15; N. 13.45.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([NH2:17])[S:15][CH:16]=2)=[CH:8][CH:7]=1.[N:18]1([C:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[S:26][N:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(N(C(C)C)CC)(C)C.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CC(CC(C)C)=O>[S:26]1[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:24]([N:18]2[CH2:19][CH2:20][N:21]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]3[CH:11]=[CH:10][C:9]([C:12]4[N:13]=[C:14]([NH2:17])[S:15][CH:16]=4)=[CH:8][CH:7]=3)[CH2:22][CH2:23]2)=[N:25]1
Reactant: Nc1nc(-c2ccc(CCCCCl)cc2)cs1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)CC(C)C
Product: Nc1nc(-c2ccc(CCCCN3CCN(c4nsc5ccccc45)CC3)cc2)cs1

Procedure:
To a 100 ml round-bottomed flask equipped with condenser and N2 inlet were added 1.22 g (3.52 mmol) (4-(4-(4-chlorobutyl)phenyl)-2-aminothiazole, 0.90 g (3.52 mmol) 3-piperazinyl-benzisothiazole, 1.84 ml (10.57 mmol) diisopropylethylamine, 0.75 g (7.04 mmol) sodium carbonate, 2 mg sodium iodide, and 35 ml methylisobutylketone. The reaction mixture was refluxed 6 days, cooled, and evaporated. The residue was chromatographed on silica gel using methylene chloride/ethyl acetate as eluent, and the product fractions dissolved in methylene chloride/methanol and precipitated by addition of methylene chloride saturated with HCl. The precipitate was filtered and dried to give a solid, 242 mg (13%), m.p. 258-261° C. NMR (DMSO-d6): 1.6-1.8 (m, 4H), 2.7 (t, 2H), 3.2-3.6 (m, 8H), 4.1 (m, 2H), 7.20 (s, 1H), 7.3-8.2 (m, 8H).