Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]1[C:17]([C:18]([O:20]CC)=[O:19])=[C:16]2[CH2:23][CH2:24][CH2:25][C:15]2=[CH:14][N:13]=1.[ClH:26]>>[ClH:26].[ClH:26].[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]1[C:17]([C:18]([OH:20])=[O:19])=[C:16]2[CH2:23][CH2:24][CH2:25][C:15]2=[CH:14][N:13]=1
Reactant: CCOC(=O)c1c(NCCSCc2nc[nH]c2C)ncc2c1CCC2
Agent: Cl
Product: Cc1[nH]cnc1CSCCNc1ncc2c(c1C(=O)O)CCC2
Yield: 38 %

Procedure:
2-[2-(5-Methyl-4-imidazolylmethylthio)ethylamino]-3-carbethoxy-4,5-propanopyridine (15.0 g, 41.7 m.mole) and concentrated hydrochloric acid (36% w/v, 250 ml) were refluxed for 21 hours. The solution was evaporated to dryness in vacuo, ethanol being added to assist in removal of the water. The residue was rinsed with methanol and isopropanol and dried to give 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]4,5-propanopyridine 3-carboxylic acid dihydrochloride (6.47 g, 38% yield; m.p. 208.5°-209°).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Br[C:40]1[C:45]([O:46][CH3:47])=[CH:44][CH:43]=[CH:42][N:41]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(COC)OC.O.Cl.CO.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>[CH3:47][O:46][C:45]1[C:40]([C:26]2[CH:25]=[CH:24][C:23]([C:20]3([C:17]4[N:13]5[CH2:14][CH2:15][S:16][C:10]([CH2:9][OH:8])([CH3:38])[CH2:11][C:12]5=[N:19][N:18]=4)[CH2:22][CH2:21]3)=[CH:28][CH:27]=2)=[N:41][CH:42]=[CH:43][CH:44]=1
Reactant: COc1cccnc1Br
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: COCCOC
Solvent: CO
Product: COc1cccnc1-c1ccc(C2(c3nnc4n3CCSC(C)(CO)C4)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 66.3 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 2-bromo-3-methoxypyridine (290 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 130° C. for 1.5 h under microwave irradiation. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain a partially purified product (589 mg, quant.) as a brown oily substance. This partially purified product was dissolved in a solution of 4 M hydrochloric acid (1,4-dioxane solution, 1 mL) in methanol (4 mL), and the mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (280 mg, 65%) as a colorless solid.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([N+:29]([O-])=O)[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].CC(O)=O>CCOC(C)=O.[Fe]>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:29])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCc2c1ncc([N+](=O)[O-])c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.1 %

Procedure:
A mixture of 4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (11.2 mg, 0.026 mmol), AcOH (73.3 μL) and iron powder (14.4 mg, 0.26 mmol) was stirred at room temperature for 3 h. The reaction mixture was diluted with EtOAc, filtered and washed with more EtOAc. The filtrate was concentrated under vacuum, and the residue was diluted with EtOAc and neutralized with Na2CO3 solution. The mixture was stirred at room temperature for 30 min. The organic layer was separated, dried over Na2SO4, filtered and concentrated under vacuum to give the sub-title compound as a yellowish solid (10.0 mg, 96%). LCMS calc. for C21H33N4O4 (M+H)+: m/z=405.2. Found: 405.1.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:17]([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH3:18])[CH:7]=[C:8]2[C:12]=1[C:11]([CH3:14])([CH3:13])[CH2:10][C:9]2([CH3:16])[CH3:15].[CH2:38]([O:40][C:41]([C:43]1[CH:50]=[CH:49][C:46]([CH:47]=O)=[CH:45][CH:44]=1)=[O:42])[CH3:39]>>[CH2:38]([O:40][C:41](=[O:42])[C:43]1[CH:50]=[CH:49][C:46](/[CH:47]=[C:17](/[C:6]2[CH:7]=[C:8]3[C:12](=[C:4]([O:3][CH3:2])[CH:5]=2)[C:11]([CH3:14])([CH3:13])[CH2:10][C:9]3([CH3:15])[CH3:16])\[CH3:18])=[CH:45][CH:44]=1)[CH3:39]
Reactant: COc1cc(C(C)[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc2c1C(C)(C)CC2(C)C
Reactant: CCOC(=O)c1ccc(C=O)cc1
Agent: [Br-]
Product: CCOC(=O)c1ccc(/C=C(\C)c2cc(OC)c3c(c2)C(C)(C)CC3(C)C)cc1

Procedure:
In a manner analogous to that described in Example 1, from [1-(7-methoxy-1,1,3,3-tetramethyl-5-indanyl)ethyl]-triphenylphosphonium bromide and 4-ethoxycarbonyl-benzaldehyde there can be obtained p-[(E)-2-(7-methoxy-1,1,3,3-tetramethyl-5-indanyl)-propenyl]-benzoic acid ethyl ester of melting point 72°-73° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C:21]3[CH:22]=[CH:23][S:24][C:20]=3[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH:13]2[CH2:25][CH3:26])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[Br:27]C1SC2C3C=CC=CC=3C(C)N(S(C3C=CC(O)=CC=3)(=O)=O)C=2C=1>>[Br:27][C:23]1[S:24][C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH:13]([CH2:25][CH3:26])[N:12]([S:9]([C:6]3[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=3)(=[O:11])=[O:10])[C:21]=2[CH:22]=1
Reactant: CC1c2ccccc2-c2sc(Br)cc2N1S(=O)(=O)c1ccc(O)cc1
Reactant: CCC1c2ccccc2-c2sccc2N1S(=O)(=O)c1ccc(OC)cc1
Product: CCC1c2ccccc2-c2sc(Br)cc2N1S(=O)(=O)c1ccc(O)cc1
Yield: 20 %

Procedure:
Starting from 4-[(4-Methoxyphenyl)sulfonyl]-5-ethyl-4,5-dihydrothieno[3,2-c]isoquinoline in place of 4-[(4-Methoxyphenyl)sulfonyl]-5-methyl-4,5-dihydrothieno[3,2-c]isoquinoline (Step 1), the title compound (0.19 g tan solid, 20%, m.p. 183-85° C.) was synthesized in essentially the same manner as described in Example 6, Method B, Steps 1-2, for 4-[(2-Bromo-5-methylthieno[3,2-c]isoquinolin-4(5H)-yl)sulfonyl]phenol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH:14]1([C:20]#[N:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[Cl-].[Al+3].[Cl-].[Cl-]>>[C:3]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:20]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[NH:21]
Reactant: Nc1ccccc1-c1ccccc1
Reactant: N#CC1CCCCC1
Agent: [Al+3]
Agent: [Cl-]
Product: N=C(Nc1ccccc1-c1ccccc1)C1CCCCC1
Temperature: 100 °C

Procedure:
A mixture of 2-aminobiphenyl (3.4 g), cyclohexane carbonitrile (6.5 g) and anhydrous aluminium chloride (8 g) was heated at 100° C. for 8 hours then at 120° C. for 8 hours to yield a product which was purified by chromatography on a neutral alumina column which was eluted with dichloromethane to give N-(2-biphenylyl)-cyclohexane-1-carboxamidine (m.p. 148°-150° C.).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@@H:8]([CH2:9][OH:10])[CH2:7][CH:6]=[CH:5][CH2:4]1.[H-].[Na+].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O>[OH:1][CH2:2][C@H:3]1[C@@H:8]([CH2:9][O:10][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7][CH:6]=[CH:5][CH2:4]1
Reactant: ClCc1ccccc1
Reactant: OC[C@@H]1CC=CC[C@@H]1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC[C@@H]1CC=CC[C@@H]1COCc1ccccc1
Reaction time: 0.33 h
Yield: 62.3 %

Procedure:
The diol (1) (16.2 g) in dimethylformamide (50 ml) is added dropwise to sodium hydride (3.1 g) in dimethylformamide (DMF) (50 ml). The mixture is stirred for 20 minutes and then benzyl chloride (16 g) is added and stirring is continued for a further 18 hours at 70° C. After removing the DMF in vacuo, water is added and the mixture is extracted with ether. The combined extracts are dried (MgSO4) and the solvent is evaporated to give a residue which is distilled under reduced pressure to give the title compound as an oil (16.5 g, ca. 60%), b.p. 140°-145° C./0.03 mm, νmax (film) 3440 and 1600 cm-1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH2:14][CH2:15][NH2:16])(=[O:12])=[O:11])([O-:3])=[O:2].[Cl:17][CH2:18][CH2:19][S:20](Cl)(=[O:22])=[O:21].C(N(CC)CC)C>C(Cl)Cl>[Cl:17][CH2:18][CH2:19][S:20]([NH:16][CH2:15][CH2:14][NH:13][S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)CCCl
Reactant: NCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCNS(=O)(=O)CCCl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A mixture of N-(2-nitrobenzenesulfonyl)ethylenediamine, 2-chloroethanesulfonyl chloride, triethylamine, and methylene chloride was stirred at 0° C. for 3 hours to yield N-(2-{[(2-chloroethyl)sulfonyl]amino}ethyl)-2-nitrobenzenesulfonamide. This compound was dissolved in acetonitrile, here were added cesium carbonate and tetrabutylammonium iodide, and the mixture was stirred at 80° C. for 21 hours to yield 5-[(2-nitrophenyl)sulfonyl]-1,2,5-thiadiazepane 1,1-dioxide. This compound was dissolved in acetonitrile, here were added 4-methylbenzenethiol and potassium carbonate, and the mixture was stirred at 50° C. for 21 hours to yield 1,2,5-thiadiazepane 1,1-dioxide.
Reaction SMILES: ClN[NH:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:7]([O:9][CH3:10])=[O:8].[C:16]([N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(OCC)(=O)C>C(O)C>[CH3:15][O:14][C:13]1[C:4]2[NH:3][C:26]3[CH2:27][CH2:28][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:24][C:25]=3[C:5]=2[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(OC)c(NNCl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC)c2[nH]c3c(c12)CN(C(=O)OC(C)(C)C)CC3
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of Methyl 3-(2-chlorohydrazino)-4-methoxybenzoate (from step 1) (0.0042 mol) and N-Boc-4-piperidone (0.0063 mol) in ethanol (20 ml) was stirred for 18 h at room temperature. Reaction was concentrated under vacuum and product was isolated with silica gel column chromatography using 20% ethyl acetate in petroleum ether.
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:12]([I:13])=[CH:11][C:10]([NH2:14])=[CH:9][C:7]=3[CH:8]=2)[CH2:3][CH2:2]1.N1C=CC=CC=1.[CH2:21]([S:23](Cl)(=[O:25])=[O:24])[CH3:22]>C(Cl)Cl>[CH:1]1([C:4]2[O:5][C:6]3[C:12]([I:13])=[CH:11][C:10]([NH:14][S:23]([CH2:21][CH3:22])(=[O:25])=[O:24])=[CH:9][C:7]=3[CH:8]=2)[CH2:3][CH2:2]1
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1cc(I)c2oc(C3CC3)cc2c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1cc(I)c2oc(C3CC3)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
To a solution of the title compound from Step 2 (1.0 g, 3.3 mmol) in 20 mL of dry DCM was added a solution of pyridine (793 mg, 10 mmol) in DCM (10 mL), followed by addition of EtSO2Cl (473 mg, 3.7 mmol). The reaction mixture was stirred at room temperature for 1 h. It was diluted with DCM (20 mL) and washed with water (20 mL×2) and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude title compound (1.3 g, 100% yield) that was used directly in the next step. 1H NMR (CDCl3, 400 MHz): δ 7.42 (d, J=2.0 Hz, 1H), 7.38 (d, J=2.0 Hz, 1H), 6.88 (br, 1H), 6.40 (s, 1H), 3.09 (q, J=7.2 Hz, 2H), 1.37 (t, J=7.2 Hz, 3H), 2.04-2.08 (m, 1H), 1.06-0.97 (m, 4H). LCMS: 409 (M+18)+.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:27]2[O:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33](O)=[O:34])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:33]([C:28]3[N:29]=[C:30]([CH3:32])[O:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH3:19])[CH:22]=3)=[O:34])=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: COc1cccc(-c2oc(C)nc2C(=O)O)c1
Reactant: CC1(c2csc(Cn3ccc(N)n3)n2)OCCO1
Product: COc1cccc(-c2oc(C)nc2C(=O)Nc2ccn(Cc3nc(C(C)=O)cs3)n2)c1

Procedure:
Following general procedure B followed by C, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(3-methoxy-phenyl)-2-methyl-oxazole-4-carboxylic acid. LC-MS-conditions 05: tR=0.87 min; [M+H]+=438.02.
Reaction SMILES: C([O:9][C@@H:10]1[CH2:18][C@@H:13]2[O:14][C:15](=[O:17])[CH2:16][C@@H:12]2[C@H:11]1/[CH:19]=[CH:20]/[C@H:21]([C:40]1[S:44][C:43]2[CH:45]=[CH:46][CH:47]=[CH:48][C:42]=2[CH:41]=1)[O:22][Si:23]([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=O)C1C=CC=CC=1>CO.C(=O)([O-])[O-].[K+].[K+]>[S:44]1[C:40]([C@H:21]([O:22][Si:23]([C:36]([CH3:39])([CH3:38])[CH3:37])([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)/[CH:20]=[CH:19]/[C@@H:11]2[C@@H:12]3[C@@H:13]([O:14][C:15](=[O:17])[CH2:16]3)[CH2:18][C@H:10]2[OH:9])=[CH:41][C:42]2[CH:48]=[CH:47][CH:46]=[CH:45][C:43]1=2
Reactant: CC(C)(C)[Si](O[C@H](/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1)c1cc2ccccc2s1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)[Si](O[C@H](/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1O)c1cc2ccccc2s1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture consisting of (3aR,4R,5R,6aS)-4-((R,E)-3-(benzo[b]thiophen-2-yl)-3-(tert-butyldiphenylsilyloxy)prop-1-enyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate (6a, limiting reagent) in methanol (0.2 M) and potassium carbonate (0.6 molar equivalent) is stirred at room temperature and the reaction progress is monitored by TLC every 30 minutes. After complete consumption of starting material, the reaction mixture is acidified with 5% aqueous KHSO4 and diluted with brine. The product is extracted with ethyl acetate twice. The combined organic layers are dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude product is purified by flash chromatography on regular silica gel eluted with hexanes-ethyl acetate (1:1) to afford the title intermediate 7a.
Reaction SMILES: [C:1]([OH:11])(=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl-].[NH4+:13].[OH-].[NH4+]>O>[NH2:13][C@H:2]([C:1]([OH:11])=[O:10])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: [NH4+]
Reactant: O=C(O)/C=C/c1ccccc1
Agent: [Cl-]
Agent: [OH-]
Solvent: O
Product: N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 37 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
A suspension of 14.74 g of wet immobilized cells of Example 14 in 30 ml of water containing 2.25 g of trans-cinnamic acid, 652 mg of ammonium chloride and 3.3 ml of concentrated ammonium hydroxide was adjusted to pH 9.5. The mixture was shaken at 37°C for 18 hours giving about 90% yield of L-phenylalanine, based on recovered cinnamic acid. The reaction solids were filtered and washed with water to give 14 g of wet immobilized cells containing 77% of their original phenylalanine ammonia-lyase activity. The L-phenylalanine was isolated from the filtrate using standard procedures.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[C:27]([O:31][C:32]([NH:34][CH2:35][CH2:36][C:37](O)=O)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([NH:34][CH2:35][CH2:36][C:37]1[O:20][N:19]=[C:17]([C@@H:10]2[CH2:11][C:12](=[N:14][O:15][CH3:16])[CH2:13][N:9]2[C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[N:18]=1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Product: CON=C1C[C@@H](c2noc(CCNC(=O)OC(C)(C)C)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 75 %

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and N-(tert-butoxycarbonyl)-β-alanine, this compound was obtained in 75% yield (91.9% purity by HPLC).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1B(O)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[N:25]=[CH:24][C:23](Br)=[CH:22][N:21]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:23]1[CH:22]=[N:21][C:20]([Cl:19])=[N:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cc(Cl)ccc1OCc1ccccc1
Reactant: Clc1ncc(Br)cn1
Product: Clc1ccc(OCc2ccccc2)c(-c2cnc(Cl)nc2)c1

Procedure:
The subtitle compound was prepared by the method of example 1 step (ii) using the product from example 16 step (ii) (3.2 g) and 2-chloro-5-bromopyrimidine (2.59 g). Yield 2.43 g
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:12][C:13]([F:30])([F:29])[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([C:26](O)=[O:27])=[CH:16][CH:15]=1>>[N:1]1([CH:6]2[CH2:10][CH2:9][CH2:8][CH:7]2[NH:11][C:26]([C:17]2[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:19][C:14]([C:13]([F:29])([F:30])[F:12])=[CH:15][CH:16]=2)=[O:27])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1-c1ccccc1
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Product: O=C(NC1CCCC1N1CCCC1)c1ccc(C(F)(F)F)cc1-c1ccccc1

Procedure:
The title compound, off-white oil, MS: m/e=403.3 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 5-trifluoromethyl-biphenyl-2-carboxylic acid (intermediate AI).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1B(O)O.Br[C:14]1[N:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+].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.CO>[F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:14]1[N:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=1
Reactant: CSc1ccc(B(O)O)c(F)c1
Reactant: Nc1cnc(Br)cn1
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: [Na+]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: CSc1ccc(-c2cnc(N)cn2)c(F)c1
Temperature: 100 °C
Yield: 54.2 %

Procedure:
A mixture of [2-fluoro-4-(methylthio)phenyl]boronic acid (5 g, 26.9 mmol), 5-bromo-2-pyrazinamine (4.7 g, 26.9 mmol), Pd(PPh3)4 (0.62 g, 0.54 mmol), 2M Na2CO3 (25 mL), 1,4-dioxane (50 mL), and methanol (25 mL) was stirred and heated at 100° C. for 5 h, then at 25° C. overnight. The reaction was charged with water (300 mL) and extracted with EtOAc (100 mL). The organic extracts were dried over MgSO4, filtered, and concentrated to dryness to give a tan solid. The solid was triturated with CH2Cl2, filtered, and the solid air-dried to afford 5-[2-fluoro-4-(methylthio)phenyl]-2-pyrazinamine (3.43 g, 54% yield) as a tan solid. The filtrate was concentrated to dryness to give additional solid (2.5 g) that was purified by SiO2 chromatography (0-25% EtOAc/hexanes, 20 min. gradient; then 25% EtOAc/hexanes, 60 min.; 100 g column) to afford additional product (940 mg, 15% yield) as a tan solid. 1H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 8.10 (d, 1H, J=1.4 Hz), 7.83 (t, 1H, J=8.3 Hz), 7.10 (dd, 1H, Ja=8.3 Hz, Jb=1.9 Hz), 7.00 (dd, 1H, Ja=12.1 Hz, Jb=1.9 Hz), 4.80 (bs, 2H), 2.50 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[N+:10]([C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=O)([O-:12])=[O:11]>C(O)C>[N+:10]([C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=[N:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)([O-:12])=[O:11]
Reactant: N#Cc1ccc(N)cc1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Solvent: CCO
Product: N#Cc1ccc(N=Cc2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 78.9 %

Procedure:
The mixture of 4-aminobenzonitrile (20 g, 0.17 mol) and 2-nitrobenzaldehyde (28.2 g, 0.17 mol) in anhydrous ethanol was heated to reflux for 3 h. The reaction mixture was cooled to room temperature. The solvent was removed under reduced pressure. The residue was washed with diethyl ether to give 4-(2-nitrobenzylideneamino)benzonitrile as yellow solid (33.7 g, yield 79.3%) LC/MS m/e obsd. (ESI+) [(M+H)+] 252.10.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([NH:16][NH2:17])=[O:15])(=[O:10])=[O:9])[CH2:4][CH2:3]1.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([OH:31])=[C:26]([C:28](=O)[CH3:29])[CH:27]=1>CO.C(O)(=O)C>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([OH:31])=[C:26](/[C:28](=[N:17]/[NH:16][C:14](=[O:15])[C:13]2[CH:18]=[CH:19][CH:20]=[C:11]([S:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)(=[O:10])=[O:9])[CH:12]=2)/[CH3:29])[CH:27]=1
Reactant: CC(=O)c1cc(Cl)ccc1O
Reactant: CN1CCN(S(=O)(=O)c2cccc(C(=O)NN)c2)CC1
Solvent: CO
Solvent: CC(=O)O
Product: C/C(=N\NC(=O)c1cccc(S(=O)(=O)N2CCN(C)CC2)c1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 53.3 %

Procedure:
3-((4-methylpiperazin-1-yl)sulfonyl)benzohydrazide (85 mg, 0.285 mmol) and 1-(5-chloro-2-hydroxyphenyl)ethanone (48.6 mg, 0.285 mmol) was dissolved in methanol (Volume: 4 ml) in the presence of acetic acid as a catalyst and then the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Reaction was monitored by TLC. After completion of the reaction, following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) afforded the product (E)-N′-(1-(5-chloro-2-hydroxyphenyl)ethylidene)-3-((4-methylpiperazin-1-yl)sulfonyl)benzohydrazide (70 mg, 0.152 mmol, 53.4% yield) as a solid. 1H NMR (CD3OD, 400 MHz): δ 8.29 (s, 1H), 8.21 (d, 1H, J=7.2 Hz), 7.99 (d, 1H, J=8.0 Hz), 7.78 (t, 1H, J=7.6 Hz), 7.59 (d, 1H, J=2.4 Hz), 7.27 (dd, 1H, J=2.4 & 9.2 Hz), 6.92 (d, 1H, J=8.8 Hz), 3.09 (m, 4H), 2.54 (m, 4H), 2.48 (s, 3H), 2.28 (s, 3H). Mass [M+H]+:450.9