Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:17](=[O:19])(=[O:18])[NH:16][C:15](=[O:20])[CH:14]=2)=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[C:21](OC(=O)C)(=[O:23])[CH3:22].C(N(CC)C(C)C)(C)C>CN1CCCC1=O.CS(C)=O>[C:21]([NH:1][C@@H:2]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:17](=[O:19])(=[O:18])[NH:16][C:15](=[O:20])[CH:14]=2)=[CH:11][CH:12]=1)[C:3]([OH:5])=[O:4])(=[O:23])[CH3:22]
Reactant: N[C@@H](Cc1ccc(C2=CC(=O)NS2(=O)=O)cc1)C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: CS(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@@H](Cc1ccc(C2=CC(=O)NS2(=O)=O)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 120.2 %

Procedure:
(2S)-2-amino-3-[4-(1,1-dioxido-3-oxo-2,3-dihydroisothiazol-5-yl)phenyl]propanoic acid (45 mg, 0.15 mmol) was dissolved in N-methylpyrrolidinone (1.0 mL) with 20 drops of DMSO added to fully dissolve. To the solution was added acetic anhydride (14 μL, 0.15 mmol) and N,N-diisopropylethylamine (79 μL, 0.46 mmol). The solution was stirred at room temperature for 2 h. The product was purified by preparative LCMS to afford the desired product (61 mg, 96%). LCMS found for C14H15N2O6S (M+H)+: m/z=339.1
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:9][CH3:10].[Br:11][CH:12]([CH2:16][CH2:17]Br)[C:13](Cl)=[O:14].C(N(CC)CC)C.O>C(Cl)Cl>[Br:11][CH:12]1[CH2:16][CH2:17][N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:9][CH3:10])[CH:4]=2)[C:13]1=[O:14]
Reactant: O=C(Cl)C(Br)CCBr
Reactant: COc1cc(N)ccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1cc(N2CCC(Br)C2=O)ccc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 43.3 %

Procedure:
To a stirred solution of 4-chloro-3-methoxybenzeneamine (4.7 g, 29.6 mmol) in methylene chloride (100 mL) at ˜0° C. was slowly added 2,4dibromobutyryl chloride (5.1 mL, 39 mmol). After the addition, the reaction mixture was stirred for ˜5 minutes and triethylamine (24.7 mL, 178 mmol) was then added. The resulting reaction mixture was allowed to warm up to room temperature and stirred at room temperature for 5 days. Water (˜100 mL) was then added to the reaction mixture. The organic layer was separated, dried over MgSO4 and concentrated. The residue was purified by column chromatography (silica gel, ˜33% ethyl acetate/˜67% hexanes) to give the title compound as a yellow solid (3.9 g) melting at 113–115° C.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[CH2:5]([O:9][CH2:10][CH:11]([OH:28])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:6]1[O:8][CH2:7]1>C(O)C>[OH:2][CH2:1][CH2:3][NH:4][CH2:7][CH:6]([OH:8])[CH2:5][O:9][CH2:10][CH:11]([OH:28])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: NCCO
Reactant: CCCCCCCCCCCCCCCCC(O)COCC1CO1
Solvent: CCO
Product: CCCCCCCCCCCCCCCCC(O)COCC(O)CNCCO
Temperature: 80 °C
Yield: 75.2 %

Procedure:
A 300-ml flask equipped with a stirrer, reflux tube and dropping funnel was charged with 40.5 g (0.66 mol) of ethanolamine and 8.6 g of ethanol. While heating and stirring the mixture at 80° C., an ethanol solution of 4.08 g (11.8 mmol) of 2-hydroxyoctadecyl glycidyl ether was added dropwise over 3 hours. After the resultant mixture was heated and stirred further for 3 hours, it was poured into 500 ml of ice water to collect crystals formed by filtration. The thus-obtained crystals were recrystallized again from n-hexane, thereby obtaining 3.58 g (yield: 75%) of the title compound (Ia-12).
Reaction SMILES: C[O:2][C:3](=O)/[CH:4]=[CH:5]/[C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][C:7]=1[N+:17]([O-])=O.C(O)C>[Pd].O1CCCC1>[O:2]=[C:3]1[CH2:4][CH2:5][C:6]2[C:7](=[CH:8][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:15][CH:16]=2)[NH:17]1
Reactant: CCOC(=O)c1ccc(/C=C/C(=O)OC)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1ccc2c(c1)NC(=O)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
To a mixture of 1.8 g of ethyl 4-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]-3-nitrobenzoate, 32 ml of ethanol and 32 ml of tetrahydrofuran was added 640 mg of 10% palladium/carbon under an argon atmosphere, followed by 2 hours of stirring at room temperature under a hydrogen atmosphere. The reaction solution was filtrated through celite and the organic solvent in the filtrate was removed under reduced pressure. To the residue were added 50 ml of methanol and 2 drops of concentrated hydrochloric acid, followed by 30 minutes of stirring at 60° C. After cooling to room temperature, the reaction solution was concentrated under reduced pressure and water and chloroform were added to the residue, followed by an operation for separation. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by evaporation. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to obtain 1.16 g of ethyl 2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylate as a white solid.
Reaction SMILES: O=[C:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:9]([O:11]C)=O.[NH2:13][C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([F:24])[CH:23]=1)[C:17]([O:19][CH3:20])=[O:18].O1CCOCC1>O>[F:24][C:22]1[CH:21]=[C:16]([C:17]([O:19][CH3:20])=[O:18])[C:15]2[C:9](=[O:11])[C:3]3[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:2]=3[NH:13][C:14]=2[CH:23]=1
Reactant: COC(=O)c1cc(N)cc(F)c1
Reactant: COC(=O)C1CCCCCC1=O
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(F)cc2[nH]c3c(c(=O)c12)CCCCC3
Temperature: 130 °C
Yield: 107.2 %

Procedure:
A mixture of methyl 2-oxocycloheptanecarboxylate (0.34 g, 2 mmol), methyl 3-amino-5-fluorobenzoate (0.33 g, 2 mmol), polyphosphoric acid (4.0 g) and dioxane (5 mL) was heated at 130° C. for 5 hours. After cooling to room temperature, the solution was diluted with water (100 mL), and NaOAc.3H2O (7.3 g) was added. Then the resulting precipitate was collected by filtration and dried. The solid was suspended in methanol (20 mL) and SOCl2 (10 mL) was added, the mixture was stirred at reflux for 5 hours, concentrated and treated with water (50 mL), extracted with ethyl acetate (3×50 mL). The organic layer was separated, concentrated and the residue was chromatographed to give the crude product (0.62 g). MS (ESI) m/e [M+1]+290.0.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)([C:21]3[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=3)[OH:20])[CH:8]=2)[N:3]=1.[N-:34]=[N+:35]=[N-:36].[Na+]>CN(C=O)C>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=4)([C:21]4[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=4)[OH:20])[CH:8]=3)[N:3]3[N:34]=[N:35][N:36]=[C:2]3[N:11]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cn1cncc1C(O)(c1ccc(F)cc1)c1ccc2nc(Cl)nc(-c3cccc(Cl)c3)c2c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cncc1C(O)(c1ccc(F)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)nc1nnnn12
Temperature: 90 °C
Reaction time: 2 h
Yield: 57.6 %

Procedure:
A mixture of intermediate 7 (0.0125 mol) and sodium azide (0.038 mol) in DMF (60 ml) was stirred at 90° C. for 2 hours, then brought to room temperature, poured out into ice water and stirred. The precipitate was filtered, washed with water, taken up in DCM, filtered, washed with diethyl ether and dried under a vacuo, yielding 3.5 g (58%) of intermediate 8. The filtrate was extracted with DCM. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (15-40 μm) (eluent: DCM/MeOH/NH4OH 95/5/0.1). The pure fractions were collected and the solvent was evaporated. The residue (0.9 g, 15%) was crystallized from 2-propanone. The precipitate was filtered off and dried, yielding 0.7 g (12%) of 5-(3-chlorophenyl)-α-(4-fluorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-α]quinazoline-7-methanol (intermediate 8), mp. 200° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CC(C)=O.O>[CH2:22]([O:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)Cc1cc(O)cc(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)Cc1cc(O)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.9 %

Procedure:
A solution of methyl [3,5-dihydroxyphenyl]acetate (2.1 g, 11.5 mmol) in acetone (100 mL) was treated with potassium carbonate (2.4 g, 17.4 mmol), potassium iodide (0.38 g, 2.31 mmol) and benzyl bromide (1.5 mL, 12.7 mmol), and the mixture was stirred at room temperature overnight. The reaction was diluted with water, and was extracted with dichloromethane (×3). Combined organic extracts were dried over sodium sulfate and evaporated in vacuo. The crude material was purified on a Biotage™ 40 M column (silica), eluting with 40% ethyl acetate/hexane, to give methyl [3-benzyloxy-5-hydroxyphenyl]acetate (1.0 g, 33%). 1H NMR (400 MHz, CDCl3): δ 7.32-7.42 (m, 5H), 6.48 (d, J=1.4 Hz, 1H), 6.38-6.39 (m, 2H), 4.99 (s, 2H), 3.69 (s, 3H), 3.53 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[O:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.C([O-])(=[O:17])C.[Na+]>O>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH:4][C:11](=[O:10])[CH2:12][C:13](=[O:17])[CH3:14]
Reactant: Nc1c(F)cccc1F
Reactant: C1CCOC1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)CC(=O)Nc1c(F)cccc1F
Temperature: 25 °C

Procedure:
To a mixture of 2,6-difluoroaniline (5.00 g), 2,2,6-trimethyl-4H-1,3-didioxin-4-one (7.16 g) and tetrahydrofuran (13 mL) was added sodium acetate (3.18 g) at room temperature. The reaction mixture was refluxed overnight, and cooled to room temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (5.04 g).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][Mg]Cl.Cl[CH2:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[C:19](=[O:27])[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:14]#[N:15].O.[NH4+].[Cl-]>C1(C)C=CC=CC=1.C1COCC1>[CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][C:19]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:18]2[C:11](=[CH:12][C:13]([C:14]#[N:15])=[CH:16][CH:17]=2)[CH2:10][O:27]1
Reactant: N#Cc1ccc(C(=O)c2ccc(F)cc2)c(CCl)c1
Reactant: CN(C)CCC[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Yield: 95 %

Procedure:
A solution of 3-dimethylaminopropylmagnesium chloride (1.2M in THF, 84 ml) was added to a cooled solution of 3-chloromethyl-4-(4-fluoro-benzoyl)-benzonitrile (25.0 g) in a mixture of toluene (175 ml) and THF (50 ml) so that the temperature did not raise above −5° C. The mixture was stirred for 2 hours at 0° C. before water (100 ml) and saturated NH4Cl solution were added to adjust the pH to 9. The phases were separated and the aqueous phase was extracted twice with toluene (200 ml). The combined organic phases were washed with water (200 ml) and concentrated in vacuo to give a viscous oil (28.0 g, 95%). Spectral and analytical data were in accordance with the literature.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(N(CC)CC)C.[CH3:18][C:19]([O:22][C:23]([NH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:24])([CH3:21])[CH3:20]>C(O)C>[C:19]([O:22][C:23](=[O:24])[NH:25][CH:26]1[CH2:31][CH2:30][N:29]([C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:28][CH2:27]1)([CH3:21])([CH3:18])[CH3:20]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Clc1ncnc2[nH]ccc12
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 80 °C
Yield: 37.4 %

Procedure:
To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (74 mg, 0.48 mmol) in ethanol (1 ml) was added triethylamine (200 μl, 1.43 mmol) and 4-N-Boc-aminopiperidine (106 mg, 0.53 mmol). The solution was heated at 80° C. for 4 hours, and then cooled to room temperature. The precipitate was collected by filtration and washed with ethanol (2 ml), then dried under vacuum to yield the product (57 mg, 36%). LC/MS (LCT) Rt 4.57 [M+H]+ 318
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CC(C)=O.C(=O)=O.[C:13]([C:15]1(O)[CH2:21][CH:20]2[N:22]([CH2:23][CH:24]([F:26])[F:25])[CH:17]([CH2:18][CH2:19]2)[CH2:16]1)#[N:14].C(=O)([O-])[O-].[Na+].[Na+]>N1C=CC=CC=1>[C:13]([C:15]1[CH2:16][CH:17]2[N:22]([CH2:23][CH:24]([F:26])[F:25])[CH:20]([CH2:19][CH2:18]2)[CH:21]=1)#[N:14]
Reactant: N#CC1(O)CC2CCC(C1)N2CC(F)F
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: N#CC1=CC2CCC(C1)N2CC(F)F
Temperature: 55 °C
Reaction time: 24 h
Yield: 23 %

Procedure:
An oven-dried 50 ml 3-necked round bottom flask was fitted with a reflux condenser, thermometer and magnetic stirrer and an atmosphere of nitrogen was introduced. Phosphorous oxychloride (1.9 ml, 3.16 g, 24 mmol) and pyridine (14.7 ml) were charged and the mixture then cooled to −10° C. in an acetone/Drikold™ bath. 3-Cyano-3-hydroxy-8-(2,2-difluoroethyl)-8-azabicyclo[3.2.1]octane (2 g, assumed 9 mmol, from Step 2) was added in one portion and the resulting exotherm raised the reaction mass temperature to 55° C. The mixture was then heated to 80° C. and held at this temperature for 24 hours. The reaction mass was cooled to ambient, then added to a stirred mixture of ice/water (100 ml). The drowned out mass was made basic by addition of solid sodium carbonate (6 g) and the resulting aquesous solution was then extracted with ethyl acetate (3×100 ml). The combined organics were washed with brine (100 ml), dried (Na2SO4) and concentrated in vacuo to give 3-cyano-8-(2,2-difluoroethyl)-8-azabicyclo[3.2.1]oct-2-ene as a brown oil (0.41 g, 13% yield).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH:5]=[C:4]([CH3:16])[N:3]=1.[N-:17]=[N+:18]=[N-:19].[Na+].CN(C)C=O>O>[CH3:14][CH:13]([CH3:15])[CH2:12][NH:11][C:6]1[CH:5]=[C:4]([CH3:16])[N:3]2[N:17]=[N:18][N:19]=[C:2]2[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(NCC(C)C)c([N+](=O)[O-])c(Cl)n1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(NCC(C)C)c([N+](=O)[O-])c2nnnn12
Temperature: 60 °C
Reaction time: 5 h
Yield: 91.3 %

Procedure:
Under a nitrogen atmosphere, a mixture of 2-chloro-N-(2-methylpropyl)-6-methyl-3-nitropyridin-4-amine (10.0 g, 41.0 mmol), sodium azide (2.67 g, 41.0 mmol), and anhydrous N,N-dimethylformamide (200 mL) was heated at 60° C. After 5 hours, the dark green solution was allowed to cool to room temperature, poured slowly into water (2 L), and stirred for fifteen minutes. A green precipitate formed, which was filtered and washed with water to yield 9.37 g of N-(2-methylpropyl)-5-methyl-8-nitrotetraazolo[1,5-a]pyridin-7-amine as a light green solid, m.p. 185–187° C.
Reaction SMILES: C[CH:2]1[CH:7](C)[CH2:6][CH2:5][CH:4]([NH:9][C:10](=[O:35])[C@H:11]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28]C3C=CC=CC=3)=[CH:23][CH:22]=2)[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:3]1.[H-].[Na+].C([C:40]1[CH:41]=[C:42]([CH:45]=[CH:46][CH:47]=1)[CH2:43]Br)#N.CN(C)C=[O:51]>>[CH:4]1([NH:9][C:10](=[O:35])[C@H:11]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:28][C:43]([C:42]3[CH:41]=[CH:40][CH:47]=[CH:46][CH:45]=3)=[O:51])=[CH:25][CH:26]=2)[NH:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:5][CH2:6][CH2:7][CH2:2][CH2:3]1
Reactant: CN(C)C=O
Reactant: N#Cc1cccc(CBr)c1
Reactant: CC1CCC(NC(=O)[C@H](Cc2ccc(OCc3ccccc3)cc2)NC(=O)OC(C)(C)C)CC1C
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCC(=O)c2ccccc2)cc1)C(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-(t-butyloxycarbonyl)-4-benzyloxy-L-phenylalanine 4-acetylanilide (1.2 g), palladium black (0.15 g) and cyclohexene (8 ml) were added into ethanol (40 ml) and the reaction was carried out under reflux of ethanol for 1 hour. After cooling, the mixture was filtered and a filtrate was concentrated under a reduced pressure to obtain N-(t-butyloxycarbonyl)-4-hydroxy-L-phenylalanine 4-acetylanilide (I) (0.99 g). The above compound (I) (0.99 g) was dissolved in dimethylformamide (30 ml), added with oily sodium hydride (0.1 g) and the mixture was stirred at room temperature for 30 minutes. A solution of 3-cyanobenzylbromide (0.4 g) in dimethylformamide (5 ml) was added and allowed to react at room temperature for 6 hours, and the reaction mixture was poured into ice-water (100 ml) and extracted with ethyl acetate. A conventional post-treatment was carried out to obtain N-(t-butyloxycarbonyl)-4-(3-cyanobenzyloxy)-L-phenylalanine 4-acetylanilide (II) (1.25 g). The above compound (II) (1.25 g) was allowed to react with 4N-hydrogen chloride/dioxane (12 ml) to obtain 4-(3-cyanobenzyloxy)-L-phenylalanine 4-acetylanilide (III).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C[Al](C)C.[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[C@@:22]([OH:48])([CH2:42][N:43]1[CH:47]=[N:46][CH:45]=[N:44]1)[C@H:23]([S:25][C@@H:26]1[CH2:31][O:30][C@@H:29]([C:32]2[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=2)[C:35](OC)=[O:36])[O:28][CH2:27]1)[CH3:24]>>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:35](=[O:36])[C:34]2[CH:39]=[CH:40][CH:41]=[C:32]([C@H:29]3[O:28][CH2:27][C@H:26]([S:25][C@H:23]([CH3:24])[C@:22]([C:16]4[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=4[F:14])([OH:48])[CH2:42][N:43]4[CH:47]=[N:46][CH:45]=[N:44]4)[CH2:31][O:30]3)[CH:33]=2)=[CH:3][CH:4]=1)#[N:7]
Reactant: COC(=O)c1cccc([C@H]2OC[C@H](S[C@H](C)[C@](O)(Cn3cncn3)c3ccc(F)cc3F)CO2)c1
Reactant: N#Cc1ccc(N)cc1
Agent: C[Al](C)C
Product: C[C@@H](S[C@H]1CO[C@H](c2cccc(C(=O)Nc3ccc(C#N)cc3)c2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
In the same manner as that described in Example 3(4) a reaction was carried out using commercially available 4-aminobenzonitrile (138 mg, 1.2 mmol), trimethylaluminium (1.08 ml, 1.07M n-hexane solution, 1.2 mmol) and methyl 3-[trans-5-[[(1R, 2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]benzoate (147 mg, 0.29 mmol), obtained in Example 6(1), and the reaction mixture was treated using a similar procedure to that described in Example 3(4) to afford the title compound (162 mg, yield 94%) as a pale yellow oil which was recrystallized from ethyl acetate-hexane to give pale yellow powdery crystals.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9]/[CH:10]=[CH:11]/[C:12]1[C:21]2[C:20]([NH2:22])=[N:19][S:18](=[O:24])(=[O:23])[NH:17][C:16]=2[CH:15]=[CH:14][CH:13]=1.CC(O)=O.O>C1COCC1>[NH2:22][C:20]1[C:21]2[C:12](/[CH:11]=[CH:10]/[CH2:9][CH2:8][OH:7])=[CH:13][CH:14]=[CH:15][C:16]=2[NH:17][S:18](=[O:24])(=[O:23])[N:19]=1
Reactant: NC1=NS(=O)(=O)Nc2cccc(/C=C/CCOC3CCCCO3)c21
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: NC1=NS(=O)(=O)Nc2cccc(/C=C/CCO)c21
Temperature: 45 °C
Yield: 0.1 %

Procedure:
To a solution of (E)-5-(4-(tetrahydro-2H-pyran-2-yloxy)but-1-enyl)-1H-benzo[c][1,2,6]thiadiazin-4-amine-2,2-dioxide (322 mmol, 43 mg) (Example 273) in THF (860 μL) was added AcOH (1.7 mL) and water (430 μL) and the solution heated overnight at 45° C. The solution was cooled to room temperature and the solvent evaporated. The residue was triturated with boiling water then cooled to room temperature. The resulting solid was collected and washed with water to give the desired product (69 mg, 80%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 2.365 (q, J=6 Hz, 2H), 3.568 (q, J=6 Hz, 2H), 4.681 (t, J=6 Hz, 1H), 6.186 (d of t, J=7 Hz, 16 Hz, 1H), 6.786 (d, J=16 Hz, 1H), 6.922 (d, J=8 Hz, 1H), 7.022 (br. s, 1H), 7.088 (d, J=8 Hz, 1H), 7.468 (t, J=8 Hz, 1H), 8.388 (br. s, 1H), 10.935 (s, 1H). MS 268 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:20]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:18]=[C:17]([O:27][CH2:28][CH2:29][C:30]([OH:32])=O)[C:16]=2[O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[O:40][CH3:41])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:42]([C:45]1[CH:46]=[C:47]([CH:49]=[CH:50][CH:51]=1)[NH2:48])([CH3:44])[CH3:43]>>[CH:42]([C:45]1[CH:46]=[C:47]([NH:48][C:30](=[O:32])[CH2:29][CH2:28][O:27][C:17]2[C:16]([O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[O:40][CH3:41])=[C:15]([NH:14][S:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:10][CH:9]=3)(=[O:13])=[O:12])[N:20]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:18]=2)[CH:49]=[CH:50][CH:51]=1)([CH3:44])[CH3:43]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCCC(=O)O
Reactant: CC(C)c1cccc(N)c1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCCC(=O)Nc1cccc(C(C)C)c1

Procedure:
The procedure described in Example 2 was repeated by use of 3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-morpholino-4-pyrimidinyloxy]propionic acid and 3-isopropylaniline, to thereby obtain the title compound as a colorless oil.
Reaction SMILES: C(N(CC)CC)C.I[C:9]1[CH:21]=[CH:20][C:12]2[S:13][C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:15][C:11]=2[CH:10]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]=[CH:31][C:32]([C:35]#[CH:36])=[N:33][CH:34]=2)=[CH:25][CH:24]=1.CCOC(C)=O>C1COCC1.[Cu]I>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:30]=[CH:31][C:32]([C:35]#[C:36][C:9]3[CH:21]=[CH:20][C:12]4[S:13][C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:15][C:11]=4[CH:10]=3)=[N:33][CH:34]=2)=[CH:27][CH:28]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: COC(=O)c1cc2cc(I)ccc2s1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc2cc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)ccc2s1
Temperature: 25 °C
Reaction time: 70 h

Procedure:
Under an argon atmosphere 3.7 mL (26.72 mmol) of triethylamine was added to a solution of 3.4 g (10.69 mmol) of methyl 5-iodobenzo[b]thiophen-2-carboxylate and 2.48 g (10.69 mmol) of 5-(4-chlorophenyl)-2-ethynylpyridine in 20 mL of THF and the reaction mixture was evacuated three times and in each case gassed with argon. Then 195 mg (0.267 mmol) of PdCl2(dppf)*DCM complex and 51 mg (0.267 mmol) of CuI were added and the reaction mixture was stirred for 70 hours at RT. EtOAc was added, and the precipitated product was filtered off, washed with a little EtOAc, and dried in the air. Yield: 3.0 g (70% of theoretical); C23H14ClNO2S (M=403.881); calc.: molpeak (M+H)+: 404/406 (Cl); found: molpeak (M+H)+: 404/406 (Cl); HPLC-MS: 7.3 minutes (method B).
Reaction SMILES: [CH2:1]([N:3]([CH:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[F:11])[CH3:2].[Cl:19][C:20]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>O1CCOCC1.CO>[Cl:19][C:20]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:21]=1[C:22]([NH:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N:3]([CH2:1][CH3:2])[CH:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[C:5]=1[F:11])=[O:23]
Reactant: CCN(c1cccc(N)c1F)C1CCN(C)CC1
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCN(c1cccc(NC(=O)c2ccc(F)cc2Cl)c1F)C1CCN(C)CC1

Procedure:
Heat a mixture of N-ethyl-2-fluoro-N-(1-methyl-piperidin-4-yl)-benzene-1,3-diamine (Preparation 27) and 2-chloro-4-fluorobenzoyl chloride (23 mg) in 1,4-dioxane (5 mL) at reflux for 1 hour. Dilute with methanol (5 mL), load on a SCX column (10 g), wash with methanol, elute the product with 2M NH3 in methanol, evaporate to give the title compound: mass spectrum (electric spray) m/z=408 (M+1). Purify further by HPLC to give the di-trifluoroacetic acid salt.