Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:20])[CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:20])[CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(CC(=O)c2ccccc2Cl)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(CC(=O)c2ccccc2Cl)cc1
Yield: 96.7 %

Procedure:
A mixture of 18.78 g of methyl 4-[2-(2-chlorophenyl)-2-oxoethyl]benzoate in 288.8 ml of CH3OH, 72.2 ml of water and 5.2 g of NaOH is refluxed for 3 hours then acidified with 2N citric acid. The reaction mixture is evaporated in vacuo to remove the CH3OH. The aqueous phase is extracted with CH2Cl2 and acidified with 1N HCl. The resulting solid is collected and dried under vacuum to give 17.27 g of the desired product, m.p. 168-172° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](O)=[O:24].[CH3:37][C:38]([CH3:43])([CH3:42])[CH2:39][CH2:40][NH2:41]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([NH:41][CH2:40][CH2:39][C:38]([CH3:43])([CH3:42])[CH3:37])=[O:24]
Reactant: CC(C)(C)CCN
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NCCC(C)(C)C)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with 3,3-dimethylbutylamine.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:13]([C:17]1[CH2:24][S:23][CH:22]2[N:19]([C:20](=[O:33])[CH:21]2[NH:25]C(OC(C)(C)C)=O)[C:18]=1[C:34]([O:36][CH:37]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[C:14]([CH3:16])=[O:15]>C(#N)C>[CH2:13]([C:17]1[CH2:24][S:23][CH:22]2[N:19]([C:20](=[O:33])[CH:21]2[NH2:25])[C:18]=1[C:34]([O:36][CH:37]([C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:35])[C:14]([CH3:16])=[O:15]
Reactant: CC(=O)CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)OC(C)(C)C)C2SC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: CC(=O)CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)C2SC1
Reaction time: 0.5 h

Procedure:
A solution of p-toluenesulphonic acid monohydrate (3.8 g) in acetonitrile (50 cc) is added, in the course of 30 minutes, to a solution of 3-acetonyl-2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (5.23 g) in acetonitrile (50 cc) at 40° C. The mixture is kept at 40° C. for 30 minutes and then concentrated under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. to a volume of about 30 cc. It is diluted with methylene chloride (150 cc) and the solution is washed with a saturated aqueous solution of sodium bicarbonate (50 cc) and dried over magnesium sulphate. This yields a solution of 3-acetonyl-7-amino-2-benzhydryloxycarbonyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene, which is identical to the product described in Reference Example 2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:4]=1[CH2:5][N:6]1[C@H:9]([CH:10]=O)[C@H:8]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:7]1=[O:20].[C:27]([CH:30]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:29])[NH2:28]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:4]=1[CH2:5][N:6]1[C@@H:9](/[CH:10]=[CH:30]/[C:27](=[O:29])[NH2:28])[C@@H:8]([NH:12][C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[C:7]1=[O:20]
Reactant: NC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H]2C=O)c(OC)c1
Solvent: ClCCl
Product: COc1ccc(CN2C(=O)[C@H](NC(=O)OC(C)(C)C)[C@@H]2/C=C/C(N)=O)c(OC)c1
Reaction time: 1 h
Yield: 80.7 %

Procedure:
4.0 g (11 mmol) of t-butyl (3S,4S)-1-(2,4-dimethoxybenzyl)-4-formyl-2-oxo-3-azetidinecarbamate are dissolved in 300 ml of methylene chloride and the solution obtained is treated dropwise with a solution of 3.9 g (12 mmol) of carbamoylmethylene-triphenylphosphorane in 100 ml of methylene chloride. After 1 hour, the mixture is filtered and the crystals obtained are washed with methylene chloride. There are obtained 3.6 g (81%) of t-butyl (3R,4S)-1-(2,4-dimethoxybenzyl)-4-[(E)-2-carbamoylvinyl]-2-oxo-3-azetidinecarbamate of melting point 270° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:27]=[CH:26][C:13]2[N:14]([CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[C:15]([CH3:17])=[N:16][C:12]=2[CH:11]=1.[OH-].[Na+].CO>C(Cl)(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:27]=[CH:26][C:13]2[N:14]([CH2:18][C:19]([OH:21])=[O:20])[C:15]([CH3:17])=[N:16][C:12]=2[CH:11]=1
Reactant: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1CC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a solution of 5-(benzoxazol-2-yl)-2-methyl-1-tert-butoxycarbonylmethylbenzimidazole (see Working Example 91-2) (100 mg, 0.275 mmol) in chloroform (3 mL) was added aqueous sodium hydroxide solution (1 M, 0.55 mL, 0.55 mmol). This two-layer solution was homogenized by the addition of methanol, and this was stirred at room temperature for 2 hours. After the reaction was complete, the solution was concentrated, aqueous acetic acid solution was added, and this was stirred at room temperature. The precipitated crystals were filtered, and after washing with water were dried to yield the title compound (76.9 mg, 91% yield) as light yellow crystals.
Reaction SMILES: C([O:3][C:4](=[O:32])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:22][C:21]3[C:20]([CH3:24])([CH3:23])[CH2:19][CH2:18][C:17]([CH3:26])([CH3:25])[C:16]=3[CH2:15]2)=[O:13])=[N:7][CH:6]=1)C.[OH-].[K+].Cl>C(O)C.O>[CH3:25][C:17]1([CH3:26])[CH2:18][CH2:19][C:20]([CH3:23])([CH3:24])[C:21]2[CH2:22][C:14]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])([C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:32])=[O:3])=[CH:6][N:7]=3)=[O:13])[CH2:15][C:16]1=2
Reactant: CCCCCC1(C(=O)Nc2ccc(C(=O)OCC)cn2)CC2=C(C1)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCC1(C(=O)Nc2ccc(C(=O)O)cn2)CC2=C(C1)C(C)(C)CCC2(C)C

Procedure:
The ester was dissolved in 20 ml of ethanol and treated with a solution of 1 g of KOH (potassium hydroxyde) in 2 ml of water. After 2 hours at 40° C. the reaction mixture was poured on ice/water, acidified with 2 N HCl and extracted with ethyl acetate. The organic phase was dried (Na2SO4) and the solvent evaporated. The residue was crystallized from ethyl acetate/pentane and gave 0.6 g of 6-[(4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-indene-2-carbonyl)-amino]-nicotinic acid as colorless crystals, m. p. 172-174° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:11][CH3:12])[C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.[CH2:13](N)[CH2:14][NH2:15]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:9]2[NH:15][CH2:14][CH2:13][N:10]=2)[CH2:11][CH3:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CCC(C#N)c1cccc(Br)c1
Reactant: NCCN
Product: CCC(C1=NCCN1)c1cccc(Br)c1
Temperature: 130 °C

Procedure:
rac-2-[1-(3-Bromo-phenyl)-propyl]-4,5-dihydro-1H-imidazole was prepared from 2-(3-bromo-phenyl)-butyronitrile and ethylene diamine in analogy to Example 19 b) but the reaction mixture was heated under microwave irradiation to 130° C. for 1 hour: colourless powder; MS (ISP): 269.0 and 267.0 ((M+H)+.).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[O:9][CH:8]([C:14]([F:17])([F:16])[F:15])[C:7]([C:18]([OH:20])=[O:19])=[CH:6]2)[CH3:2].S(Cl)([Cl:24])(=O)=O>ClCCl.C(O)(=O)C.[Zn]>[Cl:24][C:11]1[C:12]([OH:13])=[C:3]([CH2:1][CH3:2])[CH:4]=[C:5]2[C:10]=1[O:9][CH:8]([C:14]([F:15])([F:16])[F:17])[C:7]([C:18]([OH:20])=[O:19])=[CH:6]2
Reactant: O=S(=O)(Cl)Cl
Reactant: CCc1cc2c(cc1O)OC(C(F)(F)F)C(C(=O)O)=C2
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1cc2c(c(Cl)c1O)OC(C(F)(F)F)C(C(=O)O)=C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 18.2 %

Procedure:
To a mixture of 1.0 g (3.4 mmol) of 6-ethyl-7-hydroxy-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid in anhydrous dichloromethane (30 mL) was added 4.2 mL (1.0 M in DCM, 22 mmol) sulfuryl chloride dropwise. The resulting mixture was stirred at room temperature for 24 h. The sample was concd and the residue dissolved in 30 mL of acetic acid, followed by addition of 0.5 g granular Zn. The mixture was stirred at room temperature for 3 h, filtered and the filtrate evaporated. The residue was purified by chromatography to afford 0.20 g (18%) of a white solid: 1H NMR(CDCl3/400 MHz) 7.79 (s, 1H), 7.26 (s, 1H), 5.77 (q, J=6.8 Hz, 1H), 2.63(q, J=7.6 Hz, 2H), 1.21(t, J=7.6 Hz, 3H). MS (ESI+) 323.0 (M+1, 100).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH3:36][C:37]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:40])[CH:38]=O.N1CCCCC1>O1CCOCC1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[C:32]([C:33]#[N:34])=[CH:40][C:37]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:36])[CH3:38])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Reactant: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Solvent: C1COCCO1
Solvent: C1CCNCC1
Product: CC(C)(C=C(C#N)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)NC(=O)OC(C)(C)C
Yield: 46.8 %

Procedure:
A solution of 3-((R)-2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-3-oxopropanenitrile (141 mg, 0.30 mmol, 1.0 equiv), tert-butyl 2-methyl-1-oxopropan-2-ylcarbamate (1.12 g, 6.00 mmol, 20.0 equiv), piperidine (255 mg, 3.0 mmol, 10.0 equiv) in 1,4-dioxane (15 mL) was refluxed for 2 h. The resulting mixture was concentrated under vacuum. The residue was submitted to flash chromatography eluting with ethyl acetate to give (R)-tert-butyl (5-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-4-cyano-2-methyl-5-oxopent-3-en-2-yl)carbamate 90 mg as a pale yellow solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]#[N:11])[CH:8]=2)[CH:3]=[CH:2]1.[Cl:12]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>CO>[Cl:12][C:3]1[C:4]2[C:9](=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: N#Cc1ccc2cc[nH]c2c1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc2c(Cl)c[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 104.6 %

Procedure:
To a solution of 6-indole carbonitrile (1.0 g) in methanol (10 mL) was added N-chlorosuccinimide (1.2 g) at room temperature, and then the reaction mixture was stirred at room temperature for 16 hours. To the reaction mixture was added a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled compound (1.3 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](O)([CH3:13])[O:11][C:10](=O)[C:9]=2[C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[CH:4][CH:3]=1.O.[NH2:22][NH2:23]>C(O)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH3:13])=[N:23][NH:22][C:10](=[O:11])[C:9]=2[C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CC1(O)OC(=O)C(c2cccs2)=C1c1ccc(Cl)cc1
Solvent: O
Solvent: CCCCO
Product: Cc1n[nH]c(=O)c(-c2cccs2)c1-c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 44.2 %

Procedure:
A mixture of 3.35 g of 4-(4-chlorophenyl)-5-hydroxy-5-methyl-3-(2-thienyl)-2(5H)-furanone, 0.70 g of hydrazine monohydrate and 30 ml of 1-butanol was heated under reflux for 7 hours. The reaction mixture was cooled to 0° C. The deposited solid was collected by filtration. The solid was washed with a mixed solvent of hexane and t-butyl methyl ether, and dried under reduced pressure to obtain 1.46 g of 5-(4-chloro-phenyl)-6-methyl-4-(2-thienyl)-2H-pyridazin-3-one.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][N:6]([C:8]2[CH:9]=[C:10]([NH2:20])[C:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:12][CH:13]=2)[CH2:5][CH2:4][O:3]1.Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=2)[N:25]=[C:24]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[C:23]=1[CH3:39].Cl.O1CCOCC1.CN1C(=O)CCC1>>[F:32][C:28]1[CH:27]=[C:26]2[C:31]([C:22]([NH:20][C:10]3[C:11]([N:14]4[CH2:15][CH2:16][O:17][CH2:18][CH2:19]4)=[N:12][CH:13]=[C:8]([N:6]4[CH2:5][CH2:4][O:3][C@H:2]([CH3:1])[CH2:7]4)[CH:9]=3)=[C:23]([CH3:39])[C:24]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)=[N:25]2)=[CH:30][CH:29]=1
Reactant: C[C@@H]1CN(c2cnc(N3CCOCC3)c(N)c2)CCO1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Nc1cc(N2CCO[C@H](C)C2)cnc1N1CCOCC1
Temperature: 165 °C

Procedure:
Prepared according to Procedure K, method 2 using (R)-5-(2-methylmorpholino)-2-morpholinopyridin-3-amine (68 mg, 0.25 mmol; described herein), 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (67 mg, 0.25 mmol; described herein), 4.0M hydrochloric acid in 1,4-dioxane (60 μL, 0.25 mmol), and NMP (280 μL, 3.0 mmol), and heating in a microwave at 165° C. for 3 h. Purification afforded 7-fluoro-3-methyl-N-(5-((2R)-2-methyl-4-morpholinyl)-2-(4-morpholinyl)-3-pyridinyl)-2-(2-pyridinyl)-4-quinolinamine as a yellow solid (absolute configuration of stereocenter not determined) 1H NMR (500 MHz, chloroform-d) δ ppm 8.68-8.76 (1H, m), 7.84-7.94 (2H, m), 7.75-7.84 (2H, m), 7.58 (1H, d, J=2.7 Hz), 7.39 (1H, ddd, J=7.3, 4.8, 1.6 Hz), 7.28 (1H, ddd, J=9.2, 8.0, 2.6 Hz), 6.76 (1H, s), 6.22 (1H, d, J=2.7 Hz), 3.82-3.97 (5H, m), 3.56-3.72 (2H, m), 3.22 (4H, m), 3.14 (1H, m), 2.97-3.10 (1H, m), 2.60-2.72 (1H, m), 2.29-2.42 (4H, m), 1.15 (3H, d, J=6.4 Hz). Mass Spectrum (ESI) m/e=515.2 (M+1).
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](Br)[S:21][C:17]=2[C:16]=1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl:33][C:34]1[CH:39]=[C:38](B(O)O)[CH:37]=[CH:36][N:35]=1.C(=O)([O-])[O-].[K+].[K+]>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>[C:1]([O:7][CH2:8][C@@H:9]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]=[C:20]([C:38]3[CH:37]=[CH:36][N:35]=[C:34]([Cl:33])[CH:39]=3)[S:21][C:17]=2[C:16]=1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: Cc1cc2nc(Br)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: OB(O)c1ccnc(Cl)c1
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+]
Product: Cc1cc2nc(-c3ccnc(Cl)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 90 °C

Procedure:
(S)-2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (400.0 mg, 0.742 mmol), 2-chloro-4-pyridinylboronic acid (140.2 mg, 0.891 mmol), potassium carbonate (307.7 mg, 2.227 mmol), and Pd(PPh3)4 (128.7 mg, 0.111 mmol) were placed in a microwave vial and the vial was vacuum pumped and flushed with argon three times. To this mixture was added degassed 1,4-dioxane (3.5 mL) and water (0.7 mL). The reaction mixture was heated at 90° C. for 4.5 h then cooled to rt. The aqueous layer was separated and extracted three times with ethyl acetate. All organic layers were combined, dried over Na2SO4, and concentrated. Purification by flash column chromatography on silica gel (hexanes/ethyl acetate eluent) provided the final compound. LCMS-ESI+: calc'd for C30H33Cl2N2O3S: 571.2 (M+H+); Found: 571.1 (M+H+); 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J=4.9 Hz, 1H), 7.93 (s, 2H), 7.77 (d, J=5.0 Hz, 1H), 7.55 (d, J=9.2 Hz, 1H), 7.50 (d, J=7.4 Hz, 1H), 7.40 (d, J=7.4 Hz, 1H), 7.29 (d, J=8.9 Hz, 1H), 4.82 (dd, J=8.9, 2.7 Hz, 1H), 4.42 (dd, J=11.2, 9.3 Hz, 1H), 4.29 (dd, J=11.5, 3.2 Hz, 1H), 2.80 (s, 3H), 1.14 (s, 9H), 0.97 (s, 9H).
Reaction SMILES: C1C2C(COC(=O)[NH:17][C@H:18]([C:39]([OH:41])=[O:40])[CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[CH2:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C=O)C>[NH2:17][C@@H:18]([CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:24][C:25]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:31])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1)[C:39]([OH:41])=[O:40]
Reactant: CC(C)(C)OC(=O)CN(CCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)Cc1ccccn1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN(CCCC[C@H](N)C(=O)O)Cc1ccccn1
Yield: 69.6 %

Procedure:
A solution of PAMA-K (0.600 g, 1.047 mmol) and piperidine (1.0 mL) in DMF (5.0 mL) was stirred at room temperature for 3 hrs. Solvent was evaporated under reduced pressure to give a residue, which was purified by Amberchrom (CG-161C) eluting with MeOH/H2O to give (S)-2-amino-6-((2-tert-butoxy-2-oxoethyl)(pyridin-2-ylmethyl)amino)hexanoic acid (0.256 g, 70%). MS (ESI), 352 (M+H)+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[CH3:11][C:12]1[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=1>>[CH3:11][C:12]1[CH:13]=[CH:14][C:15](=[O:18])[N:16]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=2)[CH:17]=1
Reactant: O=[N+]([O-])c1cccc(I)c1
Reactant: Cc1ccc(=O)[nH]c1
Product: Cc1ccc(=O)n(-c2cccc([N+](=O)[O-])c2)c1
Yield: 75 %

Procedure:
The reaction of 24.9 g of 1iodo-3-nitrobenzene (Aldrich Chemical Co.) with 10.9 of 5-methyl-2-(1H)-pyridone by the procedure described in Example 1 affords 16.2g (75%) of 5-methyl-1-(3-nitrophenyl) pyridone.
Reaction SMILES: Cl[S:2]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[CH2:10]/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][C:16]2[O:19][CH2:20][O:21][C:15]=2[CH:14]=1)(=[O:4])=[O:3].[NH2:22][C:23]1[O:27][N:26]=[C:25]([CH3:28])[C:24]=1[Br:29]>>[Br:29][C:24]1[C:25]([CH3:28])=[N:26][O:27][C:23]=1[NH:22][S:2]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[CH2:10]/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][C:16]2[O:19][CH2:20][O:21][C:15]=2[CH:14]=1)(=[O:4])=[O:3]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccsc1C/C=C/c1ccc2c(c1)OCO2
Product: Cc1noc(NS(=O)(=O)c2ccsc2C/C=C/c2ccc3c(c2)OCO3)c1Br
Yield: 33 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-[trans-3,4-(methylenedioxy)cinnamyl]thiophene-3-sulfonamide was prepared in the same manner as described in Example 1 by reaction of 3-chlorosulfonyl-2-[trans-3,4-(methylenedioxy)cinnamyl]thiophene with 5-amino-4-bromo-3-methylisoxazole. The crude product was purified by HPLC resulting in a 33% yield, m.p. 147-149° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:8]([NH2:12])=[C:7]([Cl:13])[CH:6]=[CH:5][C:4]=2[N:3]=1.[NH:14]1[CH2:19][CH2:18][CH:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]1>>[NH2:12][C:8]1[C:7]([Cl:13])=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]1)=[N:3]2
Reactant: CCOC(=O)C1CCNCC1
Reactant: Nc1c(Cl)ccc2nc(Cl)ccc12
Product: CCOC(=O)C1CCN(c2ccc3c(N)c(Cl)ccc3n2)CC1
Yield: 71.8 %

Procedure:
Prepared according to the method of example 30, using 2,6-dichloroquinolin-5-amine (Example 1(d)) (800 mg) and 4-piperidinecarboxylic acid, ethyl ester (1.8 g). Purification (SiO2, miethanol:dichloromethane 1:99 as eluant) gave the sub-title compound as a solid (900 mg).
Reaction SMILES: [NH:1]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@@H:2]([C:17]([O:19]C1C(F)=C(F)C(F)=C(F)C=1F)=O)[CH2:3][CH2:4][CH2:5][NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[NH2:38][C@H:39]([C:47]([NH:49][C@@H:50]([C:52]([OH:54])=[O:53])[CH3:51])=[O:48])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>O1CCOCC1.O>[NH:1]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])[C@@H:2]([C:17]([NH:38][C@H:39]([C:47]([NH:49][C@@H:50]([C:52]([OH:54])=[O:53])[CH3:51])=[O:48])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:19])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Reactant: C[C@@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)O
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C

Procedure:
8.0 g (15.0 mmol) of pentafluorophenyl ester of Boc-D-Orn(Z)-OPfp was dissolved in 15 ml dioxane. To this was added with mixing 4.3 g (17.7 mmol) H-Phe-D-Ala-OH dissolved in water with pH 8.5. The reaction mixture was stirred for a day and a night at room temperature. The solvents were evaporated under vacuum, 70 ml ethyl acetate was added, and the mixture was acidified to pH 2-3 by the addition of 2% sulfuric acid solution. The peptide was extracted twice with 70 ml ethyl acetate, washed with saturated sodium chloride solution to neutral pH and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under vacuum leaving a thick oil. The product was crystallized from ethyl acetate with ether and hexane. The yield was 6.92 g (74.4%), and the melting point was 145° C. Rf=0.44 in acetic acid:chloroform;methanol=0.5:16:1. Rf=0.32 in chloroform:ethyl acetate:methanol=6:3:1.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:22])[N:5]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=1)[C:6]2=[O:11].[N:23]1[CH:28]=[CH:27][C:26]([CH:29]=O)=[CH:25][CH:24]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([N:5]2[C:4](=[O:22])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][CH2:29][C:26]3[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=3)[C:6]2=[O:11])=[CH:13][CH:14]=1)([CH3:19])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1ccc(N2C(=O)c3cccc(N)c3C2=O)cc1
Reactant: O=Cc1ccncc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)c1ccc(N2C(=O)c3cccc(NCc4ccncc4)c3C2=O)cc1
Reaction time: 1 h

Procedure:
In a 25 mL round bottomed flask, 4-amino-2-(4-tert-butyl-phenyl)-isoindole-1,3-dione (30 mg, 0.101 mmol, Step B) was dissolved in 1,2-dichloroethane (10 mL). To this was added 4-pyridinecarboxaldehyde (0.05 mL, 0.524 mmol). The reaction was stirred for 1 h under N2. NaBH(OAc)3 (40 mg, 0.188 mmol) was added and the suspension was stirred for 6 h. The reaction was quenched with saturated NaHCO3 solution (50 mL). The reaction was rotary evaporated to remove the 1,2-dichloroethane. The product was extracted with EtOAc (3×50 mL). The combined organics were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to afford an oil. The oil was purified by flash chromatography on silica gel eluting with 30% EtOAc in hexanes. MS (ES+): 386.1 (M+H)+. Calc'd for C24H23N3O2-385.46.