Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:22]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:35][C:36]1[CH:50]=[CH:49][C:39]([C:40]([NH:42][CH:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)=[O:41])=[CH:38][CH:37]=1>C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:35][C:36]4[CH:37]=[CH:38][C:39]([C:40]([NH:42][CH:43]5[CH2:48][CH2:47][O:46][CH2:45][CH2:44]5)=[O:41])=[CH:49][CH:50]=4)=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Nc1ccc(C(=O)NC2CCOCC2)cc1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Cl)ncc21
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CC(C)O
Solvent: O
Product: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Nc3ccc(C(=O)NC4CCOCC4)cc3)ncc21
Yield: 54.1 %

Procedure:
A mixture of 0.0562 g (0.18 mmole) 2-chloro-9-cyclohexyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-246), 0.0514 g (0.27 mmole) of toluenesulfonic acid monohydrate, 0.0396 g (0.18 mmole) of 4-amino-N-(tetrahydro-pyran-4-yl)-benzamide and 1 mL of isopropanol was heated in a sealed vessel at 140 degrees for 16.5 hours, cooled and concentrated under reduced pressure. The residue taken up in ethyl acetate and washed successively with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of water, 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from acetonitrile to give 0.0501 g of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(tetrahydro-pyran-4-yl)-benzamide (I-263) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.[C:9](O)(=[O:18])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16].[OH-].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:18])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:5]=[N:6][CH:7]=1
Reactant: Nc1cncc(Br)c1
Reactant: O=C(O)CCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCC(=O)Nc1cncc(Br)c1
Temperature: 130 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
The mixture of 5-bromopyridin-3-amine (2.0 g, 11.6 mmol) and heptanedioic acid (2.22 g, 13.9 mmol) was heated and stirred at 130° C. for 8 h. After the reaction was completed, the solution was cooled to 50° C. and added to NaOH solution. The mixture was filtered. The filtration was extracted with EtOAc (50 mL×3) and concentrated HCl was added until pH=1. The solid was collected to give the product as a yellow solid 2.42 g (yield 66.2%).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N+:10]([O-])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-:15].[K+].[K+]>C(OC(=O)C)(=O)C.C(OCC)(=O)C.C(Cl)(Cl)Cl>[C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([OH:15])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])[O-]
Reactant: [O-][n+]1ccc(-c2ccccc2)cc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: Oc1cc(-c2ccccc2)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-phenylpyridine-1-oxide (2.00 g, 0.012 mol) in acetic anhydride (6 mL) was heated at reflux for 48 hours. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate (80 mL) and washed with saturated aqueous sodium bicarbonate (2×15 mL) and brine (15 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in methanol (20 mL) and potassium carbonate (0.32 g, 0.002 mol) was added to the solution. The reaction mixture was stirred at ambient temperature for 1 hour, then diluted with chloroform (100 mL) and filtered through Celite. The filtrate was concentrated in vacuo. The residue was dissolved in a mixture of methanol/chloroform 1/10 (30 mL). The title compound was precipitated with the addition of hexanes (30 mL) as a white solid which was collected by filtration (1.20 g, 60%): 1H NMR (300 MHz, DMSO-d6) δ 7.66-7.62 (m, 2H), 7.48-7.37 (m, 4H), 6.51 (d, J=1.2 Hz, 1H), 6.44 (dd, J=6.7, 1.8 Hz, 1H); MS (ES+) m/z 172.5 (M+1).
Reaction SMILES: C([O:3][C:4]([CH:6]1[C:15]([CH2:16][NH:17][C@H:18]([C:23]([O:25][CH3:26])=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:14][C:13]2[C:8](=[C:9]([O:29][CH3:30])[CH:10]=[CH:11][C:12]=2[O:27][CH3:28])[O:7]1)=O)C>C(#N)C>[CH3:26][O:25][C:23](=[O:24])[C@@H:18]([N:17]1[CH2:16][C:15]2[CH2:14][C:13]3[C:12]([O:27][CH3:28])=[CH:11][CH:10]=[C:9]([O:29][CH3:30])[C:8]=3[O:7][C:6]=2[C:4]1=[O:3])[CH2:19][CH:20]([CH3:22])[CH3:21]
Reactant: CCOC(=O)C1Oc2c(OC)ccc(OC)c2C=C1CN[C@@H](CC(C)C)C(=O)OC
Solvent: CC#N
Product: COC(=O)[C@H](CC(C)C)N1CC2=C(Oc3c(OC)ccc(OC)c3C2)C1=O
Yield: 52.4 %

Procedure:
A solution of 5,8-dimethoxy-3-[((S)-1-methoxycarbonyl-3-methyl-butylamino)-methyl]-2H-chromene-2-carboxylic acid ethyl ester (3.0 g, 7.12 mmol) and N,N′-diisopropylethyl amine (5.1 mL, 28.5 mmol) in acetonitrile (4 mL) was heated in a sealed tube at 140° C. for 48 h. The reaction mixture, after aqueous work-up, was extracted with ethyl acetate (3×). The combined ethyl acetate layer was washed with brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated in vacuo and the residue was purified over neutral alumina using hexanes-ethyl acetate (1:1.2) as eluents to afford (S)-2-(5,8-dimethoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid methyl ester (1.4 g, 53.8%) as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Br:38])[C:33]=2[F:39])=[O:11])=[C:5]([O:40][CH3:41])[CH:4]=1)#[N:2].[OH:42]O.[OH-].[Na+]>CS(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Br:38])[C:33]=2[F:39])=[O:11])=[C:5]([O:40][CH3:41])[CH:4]=1)(=[O:42])[NH2:2]
Reactant: COc1cc(C#N)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Br)c1F
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cc(C(N)=O)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Br)c1F
Temperature: 10 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
To the solution of rac-(2′S,3′R,4′S,5′R)-4′-(3-bromo-2-fluoro-phenyl)-6-chloro-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-2-methoxy-phenyl)-amide (0.16 g, 0.26 mmol) prepared in Example 116 in DMSO (1 mL) at 0° C. was added an aqueous solution (30% Aldrich) of H2O2 (0.43 g, 3.8 mmol), then aqueous solution (1N) of NaOH (1.3 mL, 1.3 mmol) was added dropwise. The reaction mixture was stirred at 10° C. for 1 h. The mixture was partitioned between ethyl acetate and saturated aqueous Na2SO3 solution. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was triturated with dichlormethane and hexanes to give rac-(2′S,3′R,4′S,5′R)-4′-(3-bromo-2-fluoro-phenyl)-6-chloro-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoyl-2-methoxy-phenyl)-amide as a white solid (Yield 0.11 g, 67%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:11])[C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:19][CH2:20]Br>CN(C=O)C.ClCCl>[F:1][C:2]1[C:9]2[O:10][CH2:19][CH2:20][O:11][C:8]=2[CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1
Reactant: O=Cc1cc(O)c(O)c(F)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=Cc1cc(F)c2c(c1)OCCO2
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 86.7 %

Procedure:
3-fluoro-4,5-dihydroxybenzaldehyde (0.9 g; 5.7 mmol) and cesium carbonate (4.6 g; 14.2 mmol) were stirred in DMF (15 ml) at room temperature for 15 min. 1,2 Dibromoethane (638 μl; 7.4 mmol) was added and reaction mixture was stirred at 80° C. for 2.5 h and then diluted with dichloromethane (100 ml). The mixture was washed with water (2×50 ml), 10% aqueous citric acid (50 ml), brine (50 ml), dried over sodium sulfate and evaporated to dryness to yield 8-fluoro-2,3-dihydro-1,4-benzodioxine-6-carbaldehyde (0.9 g; 87% yield). 1H NMR (400 MHz, CD3OD) δ 9.74 (d, 1H), 7.25 (m, 2H), 4.37 (m, 4H).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([C:7]1[N:12]=[CH:11][C:10]([O:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][C:22]=2[CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][C:25]2=[O:29])[NH:19][C:18]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[CH:17]3)=[CH:9][CH:8]=1)(=[O:6])=[O:5].[CH3:36][Si:37]([CH3:44])([CH3:43])[CH2:38][CH2:39][O:40][CH2:41]Cl.[Cl-].[NH4+]>CN(C)C=O>[CH3:3][S:4]([C:7]1[N:12]=[CH:11][C:10]([O:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][C:22]=2[CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][C:25]2=[O:29])[N:19]([CH2:41][O:40][CH2:39][CH2:38][Si:37]([CH3:44])([CH3:43])[CH3:36])[C:18]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[CH:17]3)=[CH:9][CH:8]=1)(=[O:6])=[O:5]
Reactant: CS(=O)(=O)c1ccc(Oc2cc3cc(-c4ccccn4)[nH]c3cc2CN2CCCC2=O)cn1
Reactant: C[Si](C)(C)CCOCCl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(-c2ccccn2)cc2cc(Oc3ccc(S(C)(=O)=O)nc3)c(CN3CCCC3=O)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
With cooling with ice, sodium hydride (30% liquid paraffin added) (6 mg) was added to an N,N-dimethylformamide (2 ml) solution of the indole compound (50 mg) obtained in Example 3, then 2-(trimethylsilyl)ethoxy methyl chloride (24 mg) was added, and stirred at room temperature for 1 hour. With cooling with ice, aqueous saturated ammonium chloride solution was added, then extracted with ethyl acetate, and the organic layer was washed with water and saturated saline water. After dried, the solvent was evaporated away under reduced pressure, and the residue was purified by partitioning reversed-phase liquid chromatography to obtain the entitled compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][C@@H:24]2[OH:27])[C@:20]2([CH3:21])[C@H:15]([CH2:16][C@@H:17]([O:28]S(C)(=O)=O)[CH2:18][CH2:19]2)[CH2:14][C@H:13]3[OH:33])[CH2:10][CH2:9]1)[CH3:7].[CH2:35](O)[CH2:36][OH:37].N1C=CC=CC=1>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][C@@H:24]2[OH:27])[C@:20]2([CH3:21])[C@@H:15]([CH2:16][C@@H:17]([O:28][CH2:35][CH2:36][OH:37])[CH2:18][CH2:19]2)[CH2:14][C@H:13]3[OH:33])[CH2:10][CH2:9]1)[CH3:7]
Reactant: OCCO
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@H]4C[C@@H](OS(C)(=O)=O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@@H](OCCO)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Temperature: 120 °C
Yield: 37 %

Procedure:
A pressure vessel (250 mL flask) containing the compound of Example 1A (10.0 g, 20 mmol) was charged with ethylene glycol (20 mL) and pyridine (4 mL) at ambient temperature, sealed and then heated at 120° C. for 4 hours. The reaction was cooled to ambient temperature, diluted with EtOAc (50 mL), and quenched with 1N HCl (30 mL). The layers were separated and the organic layer was washed with 1N HCl (2×30 mL), dried (Na2SO4), and concentrated. Purification by silica gel chromatography (10%—>40% acetone/hexanes) provided the title compound (3.5 g, 37%). MS (ESI) m/e 484 (M+NH4)+
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:11]([C:12]2[S:13][C:14]3[CH2:15][NH:16][CH2:17][CH2:18][C:19]=3[N:20]=2)[N:10]=[C:9]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[S:8]1)=[N+]=[N-].Cl.CO>CO.[Pd]>[F:28][C:22]1[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=1[C:9]1[S:8][C:7]([CH2:6][CH2:5][CH2:4][NH2:1])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:11]([C:12]2[S:13][C:14]3[CH2:15][NH:16][CH2:17][CH2:18][C:19]=3[N:20]=2)[N:10]=1
Reactant: [N-]=[N+]=NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1c1nc2c(s1)CNCC2
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1c1nc2c(s1)CNCC2
Reaction time: 1 h

Procedure:
To a solution of 2-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (prepared as in Example 16, Steps A-D) (0.050 g, 0.100 mmol) in 2 mL of methanol was added 1N HCl/MeOH (0.30 mL, 0.30 mmol) followed by 10% Pd/C (10 mg). The mixture was hydrogenated under a balloon atmosphere for 1 hour then filtered through GF paper and the filtrate concentrated in vacuo. The residue was triturated with diethyl ether, filtered, washed with ether and dried in vacuo to afford the desired product as a bright yellow solid, 0.018 g, 31%. MS ESI (+) m/z 472 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 7.59 (m, 1H), 7.46 (m, 2H), 7.33 (m, 3H), 7.05 (m, 2H), 3.88 (m, 2H), 3.46 (m, 1H), 3.06 (m, 2H), 2.79 (m, 2H), 2.44 (m, 3H), 2.01 (m, 1H), 1.57 (m, 1H) ppm.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]([CH2:4][C:5](O)=[O:6])=[CH2:3].[C:10]1([C@@H:16]([NH2:18])[CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>CN1CCN(C)C1=O>[C:10]1([C@@H:16]([N:18]2[C:5](=[O:6])[CH2:4][CH:2]([C:1]([OH:9])=[O:8])[CH2:3]2)[CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: C=C(CC(=O)O)C(=O)O
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: C[C@@H](c1ccccc1)N1CC(C(=O)O)CC1=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 81.6 %

Procedure:
Itaconic acid (650 g) and (S)-1-phenylethylamine (605 g) were suspended in 1,3-dimethylimidazolidinone (650 ml), and the suspension was stirred at 80° C. for 1 hr with heating, and further at 120° C. for 3 hr with heating. The mixture was cooled to room temperature, and water (4 l) was added. The precipitated crystals were collected by filtration and dried to give 950 g of 1-((S)-1-phenylethyl)-5-oxo-3-pyrrolidinecarboxylic acid. The crystals were recrystallized 3 times with isopropyl alcohol to give 156 g of (3S)-1-((S)-1-phenylethyl)-5-oxo-3-pyrrolidinecarboxylic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:24]2[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=2)=[CH:9][CH2:10][S:11][C:12]2[CH:22]=[CH:21][C:15]([O:16][CH2:17][C:18]([OH:20])=[O:19])=[C:14]([CH3:23])[CH:13]=2)=[CH:4][CH:3]=1.[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[F-].[K+].[Cl-].[NH4+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C1COCC1>[C:2]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:7]=[CH:6][C:5]([C:8]([C:24]2[CH:29]=[CH:28][C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)=[CH:9][CH2:10][S:11][C:12]2[CH:22]=[CH:21][C:15]([O:16][CH2:17][C:18]([OH:20])=[O:19])=[C:14]([CH3:23])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc(SCC=C(c2ccc(Br)cc2)c2ccc(Br)cc2)ccc1OCC(=O)O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(SCC=C(c2ccc(-c3ccccc3)cc2)c2ccc(-c3ccccc3)cc2)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an evaporated schlenk flask kept under nitrogen atmosphere were added {4-[3,3-bis-(4-bromo-phenyl)-allylsulfanyl]-2-methyl-phenoxy}-acetic acid (297 mg, 0.54 mmol), phenylboronic acid (152 mg, 1.2 mmol), KF (104 mg, 1.79 mmol), Pd2(dba)3 (30 mg, 33 mmol) and Pd(P(t-Bu)3)2 (33 mg, 65 mmol). THF (6 ml) was added to the solid mixture keeping the mixture under nitrogen. The reaction mixture was stirred at room temperature for 1 h, followed by 4 h at 50° C. A saturated solution of ammonium chloride (5 ml) was added, and the mixture was extracted with dichloromethane (2×20 ml). The organic phases were dried and evaporated. The residue was purified by column chromatography (eluent: dichloromethane:THF (8:3)) to give the title compound in 155 mg (53%) yield.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:12])([CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:13]([O-:16])(=[O:15])=[O:14])[CH:8]=2)[N+:3]=1[CH2:17][CH2:18][CH2:19][S:20]([O-:23])(=[O:22])=[O:21].[Na+:24].[CH2:25]1COS(=O)(=O)CC1>>[CH3:1][C:2]1[C:10]([CH3:11])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:13]([O-:16])(=[O:15])=[O:14])[CH:8]=2)[N+:3]=1[CH2:17][CH2:18][CH:19]([S:20]([O-:23])(=[O:22])=[O:21])[CH3:25].[Na+:24]
Reactant: CC1=[N+](CCCS(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc2C1(C)C
Reactant: O=S1(=O)CCCCO1
Agent: [Na+]
Product: CC1=[N+](CCC(C)S(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc2C1(C)C

Procedure:
Compound 38 is prepared analogously to compound 4 (Example 4), except that 1,4-butanesultone is used as a starting material.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[C:25]([F:32])[CH:24]=1>>[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:1][CH2:2][C:3]2[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:20])[CH3:21])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:7][C:8]=2[O:9][CH3:10])=[O:28])=[C:25]([F:32])[CH:24]=1
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CN)c1)OC(C)C
Reactant: O=C(O)c1ccc(Cl)cc1F
Product: CCOC(=O)C(Cc1ccc(OC)c(CNC(=O)c2ccc(Cl)cc2F)c1)OC(C)C

Procedure:
Ethyl 3-[3-(aminomethyl)-4-methoxyphenyl]-2-isopropoxypropanoate and 4-chloro-2-fluorobenzoic acid were treated in the same manner as in Example 19d), to give ethyl 3-(3-{[(4-chloro-2-fluorobenzoyl)amino]methyl}-4-methoxyphenyl)-2-isopropoxypropanoate.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH3:15][NH:16][CH3:17].[H-].[Na+].O>O1CCCC1>[CH3:15][N:16]([CH3:17])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12]
Reactant: CNC
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)c1ccc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 50 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
To a solution of 1-floro-4-nitro-2-trifluoromethylbenzene (2.0 g) in tetrahydrofuran (20 mL) were added dimethyamine (0.64 g) and sodium hydride (0.34 g) at room temperature, and this mixture was stirred at 50° C. for 16 hours. This reaction mixture was poured into water, and this mixture was extracted with ethyl acetate. This organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (0.94 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:18]=[C:17]([C:19]([O:21]C)=O)[C:16](=[O:23])[N:15]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=4)[C:14]=3[CH3:34])=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.CO.[NH3:37]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:18]=[C:17]([C:19]([NH2:37])=[O:21])[C:16](=[O:23])[N:15]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:31])[F:33])[CH:25]=4)[C:14]=3[CH3:34])=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc(-c2ccnn2-c2ccc(Cl)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: N
Solvent: CO
Product: Cc1c(-c2ccnn2-c2ccc(Cl)cc2)nc(C(N)=O)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 60 °C
Yield: 72 %

Procedure:
Methyl 6-[1-(4-chlorophenyl)-pyrazol-5-yl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylate (0.0915 g, 0.187 mmol) was dissolved in 7M ammonia in methanol (4.0 mL, 28 mmol) and heated in a microwave reactor (Biotage) at 60° C. for 7 minutes. The violet coloured solution was concentrated by rotary evaporation. The crude product was purified by semi-preparative reversed phase-HPLC (Kromasil C18 column) with acetonitrile-water (60 to 97% MeCN) as eluent to give 6-[1-(4-chlorophenyl)-1H-pyrazol-5-yl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide (0.0636 g, 72%) as a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[C:5]([O:13]C(OC)=O)=[CH:4][C:3]=1[NH:18][C:19]([CH:21]1[O:26][C:25]2[CH:27]=[CH:28][C:29]([C:31]#[N:32])=[CH:30][C:24]=2[N:23]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:22]1)=[O:20].CC1(C)C(C)(C)OB([C:46]2[CH2:47][CH2:48][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:50][CH:51]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.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:55]([O:54][C:52]([N:49]1[CH2:48][CH:47]=[C:46]([C:2]2[CH:7]=[C:6]([CH:8]3[CH2:12][CH2:11][CH2:10][CH2:9]3)[C:5]([OH:13])=[CH:4][C:3]=2[NH:18][C:19]([CH:21]2[O:26][C:25]3[CH:27]=[CH:28][C:29]([C:31]#[N:32])=[CH:30][C:24]=3[N:23]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:22]2)=[O:20])[CH2:51][CH2:50]1)=[O:53])([CH3:58])([CH3:56])[CH3:57]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CCOC(=O)N1CC(C(=O)Nc2cc(OC(=O)OC)c(C3CCCC3)cc2Br)Oc2ccc(C#N)cc21
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: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1CC(C(=O)Nc2cc(O)c(C3CCCC3)cc2C2=CCN(C(=O)OC(C)(C)C)CC2)Oc2ccc(C#N)cc21
Temperature: 90 °C
Yield: 55.9 %

Procedure:
Ethyl 2-(2-bromo-4-cyclopentyl-5-(methoxycarbonyloxy)phenylcarbamoyl)-6-cyano-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (166 mg, 0.29 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (90 mg, 0.29 mmol), Pd(PPh3)4 (34 mg, 0.03 mmol), and Cs2CO3 (189 mg, 0.58 mmol) were combined in DMF (4 mL) and heated at 90° C. for 4 h. The reaction was quenched with water (50 mL) and extracted with dichloromethane (3×10 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (0-100% ethyl acetate/hexanes) yielded ethyl 2-(2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-4-cyclopentyl-5-hydroxyphenylcarbamoyl)-6-cyano-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (100 mg, 56% yield). LC/MS m/z 617.4 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@H:9]([OH:10])[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].N1C=CN=C1.[Si:23](Cl)([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>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]([C@@H:5]1[C@H:9]([O:10][Si:23]([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@@H]1[C@H](O)CCN1C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
To a solution of (2S,3R)-N-tert-butyloxycarbonyl-3-hydroxy-2 pyrrolidinecarboxylic acid methyl ester (1D) (736 mg, 3.00 mmol) in DMF (10 mL) at rt was added imidazole (1.02 g, 15.0 mmol), DMAP (12.0 mg), and tert-butydiphenylsilyl chloride (988 mg, 3.60 mmol). After stirring overnight, the reaction mixture was partitioned between H2O and CH2Cl2. The organic layer was washed with 1 M H3PO4, saturated aqueous NaHCO3 and brine, then dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography (eluting with 30% EtOAc/hexane) to yield compound 1E (1.36 g).