Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[F:10].[C:11]([O-])([O-])=O.[K+].[K+].CB1OB(C)OB(C)O1>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>[F:10][C:3]1[CH:4]=[C:5]([CH2:8][OH:9])[CH:6]=[N:7][C:2]=1[CH3:11]
Reactant: O=C([O-])[O-]
Reactant: OCc1cnc(Cl)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ncc(CO)cc1F
Temperature: 110 °C
Yield: 49.3 %

Procedure:
To a solution of (6-chloro-5-fluoro-3-pyridinyl)methanol (1.3 g, 8.05 mmol) in 1,4-dioxane (10 ml) was added K2CO3 (3.34 g, 24.14 mmol), trimethylboroxin (1.125 ml, 8.05 mmol) and Pd(PPh3)4 (0.465 g, 0.402 mmol). The mixture was then heated at 110° C. for 20 h in a pressure tube. The resulting mixture was quenched with H2O, extracted with EtOAc, dried over MgSO4 and concentrated under vacuum. The residue was purified by flash chromatography using Flashmaster II, a 25 g spherical silica gel cartridge and DCM/MeOH 98:2 as eluent to give 560 mg of the title compound along with Ph3PO. This was washed again with water and extracted with EtOAc to remove Ph3PO. The organic layer was dried over MgSO4, filtered and concentrated under vacuum to give 468 mg (39%) of the title compound pure enough to be used in the next step.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])[CH:6]=1.C([Mg]Cl)(C)C.[F:20][C:21]([F:31])([F:30])[C:22](N1CCCCC1)=[O:23]>O1CCCC1>[F:20][C:21]([F:31])([F:30])[C:22]([C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])[CH:6]=1)=[O:23]
Reactant: FC(F)(F)CCCCn1cc(I)cn1
Reactant: O=C(N1CCCCC1)C(F)(F)F
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C(c1cnn(CCCCC(F)(F)F)c1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
To a stirred solution of Intermediate 12A (460 mg, 1.446 mmol) in tetrahydrofuran (5 mL) at 0° C. was added isopropylmagnesium chloride (0.795 mL, 1.591 mmol) quickly. After 30 min, additional 0.25 eq of iPrMgCl was added and after 30 min, the mixture was cooled to −78° C. 2,2,2-Trifluoro-1-(piperidin-1-yl)ethanone (288 mg, 1.591 mmol) was added quickly and the reaction was warmed to rt and stirred for 3 h. The reaction was quenched with sat'd aq NH4Cl and diluted with EtOAc. The organic layer was washed with sat'd aq NH4Cl, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (40 g silica gel, eluted with 0-100% EtOAc in hexanes) to give the desired product (265 mg, 64%) as clear oil. 1H NMR (500 MHz, CDCl3) δ 8.08 (s, 2H), 4.22 (t, J=7.0 Hz, 2H), 2.07-2.20 (m, 2H), 1.98-2.05 (m, 2H), 1.55-1.65 (m, 2H).
Reaction SMILES: NO.Cl.[OH-].[Na+].CC1[N:8]([C@H:13]2[CH2:20][C@@:19]3([C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])[C@H:15]([CH2:16][CH2:17][CH2:18]3)[CH2:14]2)C(C)=CC=1>O.CO>[NH2:8][C@H:13]1[CH2:20][C@@:19]2([C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:22])[C@H:15]([CH2:16][CH2:17][CH2:18]2)[CH2:14]1
Reactant: Cc1ccc(C)n1[C@@H]1C[C@H]2CCC[C@@]2(C(=O)OCc2ccccc2)C1
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N[C@@H]1C[C@H]2CCC[C@@]2(C(=O)OCc2ccccc2)C1
Temperature: 65 °C

Procedure:
To a aqueous solution of NH2OH.HCl (8.4 g, 121.2 mmol) and NaOH (2.2 g, 19.54 mmol) in H2O (20 mL) was added a solution of Example 48C (2.81 g, 8.36 mmol) in MeOH (70 mL) and the mixture was heated at 65° C. for 8 hours. The mixture was cooled to room temperature, sufficient water was added and MeOH was removed under reduced pressure. The resulting slurry was adjusted to pH=10 with NaOH solution (2.5 N) and extracted with dichloromethane. The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to give a crude product, which was purified by column chromatography (SiO2, dichloromethane:MeOH from 100:1 to 10:1) to get the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:44])([CH3:43])[C@H:3]([NH:8][C:9](=[O:42])[C@@H:10]([CH2:18][C@@H:19]([OH:41])[CH2:20][S:21][C:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:4](=[O:7])[NH:5][CH3:6].N1C=CC=CC=1.FC(F)(F)C(O)=O.Cl.CN(C)CCCN=C=NCC>CS(C)=O.CCOC(C)=O>[CH3:43][C:2]([CH3:1])([CH3:44])[C@H:3]([NH:8][C:9](=[O:42])[C@@H:10]([CH2:18][C:19](=[O:41])[CH2:20][S:21][C:22]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:4](=[O:7])[NH:5][CH3:6]
Reactant: CCCCCCC[C@H](C[C@@H](O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N[C@H](C(=O)NC)C(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCCCCCC[C@H](CC(=O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N[C@H](C(=O)NC)C(C)(C)C
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a solution of 0.962 g (1.562 mmol) of the product of Example 33 in 3 mL of DMSO was added 0.505 mL (6.246 mmol) of pyridine followed by 0.120 mL (1.562 mmol) of trifluoroacetic acid and 0.898 (4.685 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The reaction mixture was stirred at room temperature for 36 h and then diluted with 200 mL of EtOAc. The resulting solution was washed with 0.1 N HCl solution, water, saturated NaHCO3 solution and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue, 0.948 g (99%) was used in the next step without purification. Electrospray Mass Spec: 615.4 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].C([O-])([O-])=O.[K+].[K+].[CH3:18][C:19]([NH2:22])([CH3:21])[CH3:20]>C(#N)C>[C:19]([NH:22][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])([CH3:21])([CH3:20])[CH3:18]
Reactant: O=C(CCCl)c1ccccc1
Reactant: CC(C)(C)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)NCCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
To a solution of 3-chloro-1-phenylpropan-1-one (5.0 g, 0.03 mol) and K2CO3 (12.4 g, 0.09 mol) in acetonitrile (100 mL) was added 2-methylpropan-2-amine (4.38 g, 0.06 mol), and the reaction mixture was stirred at rt overnight. The solution was filtered, and the filtrate was concentrated to give 3-(tert-butylamino)-1-phenylpropan-1-one (5.89 g, 96%). 1H NMR (CDCl3): 1.01-1.10 (s, 9H), 1.42-1.56 (s, 1H), 2.86-2.92 (m, 2H), 3.09-3.14 (m, 2H), 7.34-7.43 (m, 2H), 7.44-7.51 (m, 1H), 7.85-7.91 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-])=O.I[CH2:14][CH3:15]>>[CH2:14]([N:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:4]([NH2:1])[C:5]=2[CH:6]=[N:7]1)[CH3:15]
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Reactant: CCI
Product: CCn1ncc2c(N)cccc21

Procedure:
In accordance with Example 68 (Step 2), 4-nitro-1H-indazole was used instead of 4-nitro-1H-indole, and iodoethane was used instead of (S)-tetrahydrofuran-3-yl methanesulfonate to obtain 1-ethyl-1H-indazol-4-amine.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][SH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS[C:14](SC)=[CH:15][N+:16]([O-:18])=[O:17]>C(O)C>[CH2:1]([N:8]1[CH2:9][CH2:10][S:11][C:14]1=[CH:15][N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCCNCc1ccccc1
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CCO
Product: O=[N+]([O-])C=C1SCCN1Cc1ccccc1
Reaction time: 0.33 h
Yield: 95.8 %

Procedure:
3.34 g (20 moles) of N-benzyl-cysteamine and 3.3 g of 1,1-bis-methylthio-2-nitro-ethylene are refluxed in 50 ml of ethanol for one hour. The gas evolution terminates after boiling for 20 minutes. The mixture is cooled and the precipitated product is isolated by filtration. 4.52 g of 3-benzyl-2-nitromethylene-thiazolidine are obtained, melting at 136° to 138° C. Crystallization of the product from 140 ml of ethanol yields 4.08 g of a purified product, melting at 139° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@@H:9]1[C:14]([NH:16][CH:17]([CH:25]([OH:36])[C:26](=[O:35])[NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=[N-]>>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@@H:9]1[C:14]([NH:16][CH:17]([C:25](=[O:36])[C:26](=[O:35])[NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCc1ccccn1)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1
Agent: [N-]=O
Product: O=C(NCc1ccccn1)C(=O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1

Procedure:
(2R)-1-Benzyl-N-(3-hydroxy-4-oxo-1-phenyl-4-(pyridin-2-ylmethylamino)butan-2-yl)-5-oxopyrrolidine-2-carboxamide was converted into the corresponding ketoamide as described in step 1.2 of Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-])=O.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O.C(OCC)C>[CH2:18]([O:8][C:5]1[CH:4]=[C:3]([C:2]([Cl:1])=[CH:7][CH:6]=1)[NH2:9])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Nc1cc(OCc2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Chloro-3-nitrophenol (0.13 g) was dissolved in N,N-dimethylformamide (3 mL). To the solution were added potassium carbonate (0.31 g) and benzyl bromide (0.14 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with diethyl ether, and the resulting mixture was washed with water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in tetrahydrofuran (3 mL). To the solution were added methanol (3 mL), nickel(II) bromide (8 mg) and sodium borohydride (85 mg) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. Then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (0.15 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([CH2:15][NH:16][CH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:26])[CH:18]1[CH3:27])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1>[CH2:7]([CH2:15][NH:16][CH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]([OH:26])[CH:18]1[CH3:27])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC1C(=O)c2ccccc2C1NCCCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1C(O)c2ccccc2C1NCCCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
An ice-cold suspension of 1.5 grams (0.040 mole) of lithium aluminum hydride in 35 ml. of dry tetrahydrofuran is treated dropwise over a period of about 30 minutes with a solution of 10.9 grams (0.039 mole) of 3-phenethylmethylamino-2-methylindan-1-one in 80 ml of tetrahydrofuran. The mixture is stirred at 0° for 4 hours and then quenched by the addition of ethylacetate, 2N sodium hydroxide and water. The solids are filtered, an the filtrate is dried over magnesium sulfate, filtered and evaporated to yield 3-phenethylmethylamino-2-methylindan-1-ol as an oil.
Reaction SMILES: IC.[F:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([OH:14])=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1.[C:15](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:14])[CH:9]=[CH:10][N:11]2[CH3:15])=[CH:6][CH:5]=1
Reactant: Oc1ccnc2cc(F)ccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccc(=O)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Iodomethane (11.6 ml) was added to a stirred suspension of 7-fluoro-4-hydroxyquinoline (25 g) and anhydrous potassium carbonate (21.7 g) in dimethylformamide (120 ml) and stirring was continued for 15 hours at room temperature. Further quantities of iodomethane (5.8 ml) and anhydrous potassium carbonate (10.85 g) were added and the mixture stirred for a further 2.5 hours at 40°. The mixture was then cooled to room temperature and poured into water (750 ml). The solid product was collected and crystallised from water to give 7-fluoro-1-methyl-4-quinolone, m.p. 146°-149°.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:13][CH2:14][NH:15][CH2:16][CH2:17][OH:18])[N:8]=[C:7]3[C:19]4[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=4[S:21][C:5]=1[C:6]=23)([O-:3])=[O:2].[C:26](=O)(OC1C=CC=CC=1)[O:27]C1C=CC=CC=1.CC([O-])=O.[Na+].C1(O)C=CC=CC=1>>[N+:1]([C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:13][CH2:14][N:15]3[CH2:16][CH2:17][O:18][C:26]3=[O:27])[N:8]=[C:7]3[C:19]4[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=4[S:21][C:5]=1[C:6]=23)([O-:3])=[O:2]
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Reactant: O=[N+]([O-])c1ccc2c3c(nn2CCNCCO)-c2ccccc2Sc13
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Oc1ccccc1
Product: O=C1OCCN1CCn1nc2c3c(c([N+](=O)[O-])ccc31)Sc1ccccc1-2
Temperature: 25 °C

Procedure:
A mixture of 1.0 g (0.0025 mol) of 2-[[2-(5-nitro-2H[1]benzothiopyrano[4,3,2-cd]indazol-2-yl)-ethyl]amino]ethanol, 10.0 g (0.045 mol) of diphenyl carbonate, 0.3 g (0.0036 mol) of NaOAc and 10.0 g of phenol was treated at 110° C. for 16 hours, allowed to cool to room temperature, and triturated twice in a small amount of acetone. The insoluble material was recrystallized to give the product.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:75])[CH2:6][NH:7][C:8](=[O:74])[C@H:9]([NH:13][C:14](=[O:73])[C@H:15]([NH:37][C:38](=[O:72])[C:39]([NH:42][C:43](=[O:71])[CH2:44][C@H:45](O)/[CH:46]=[CH:47]/[CH2:48][CH2:49][S:50][C:51]([C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)([CH3:41])[CH3:40])[CH2:16][S:17][C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:10]([CH3:12])[CH3:11].Cl.CC1C=CC=C([N+]([O-])=O)C=1C(OC(=O)C1C([N+]([O-])=O)=CC=CC=1C)=O>O.C1COCC1.[Cl-].[Na+].O.C(Cl)Cl.C1COCC1.CN(C)C1C=CN=CC=1.C(Cl)Cl.CCOC(C)=O>[CH:10]([C@H:9]1[NH:13][C:14](=[O:73])[C@@H:15]([CH2:16][S:17][C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[NH:37][C:38](=[O:72])[C:39]([CH3:40])([CH3:41])[NH:42][C:43](=[O:71])[CH2:44][C@H:45](/[CH:46]=[CH:47]/[CH2:48][CH2:49][S:50][C:51]([C:64]2[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=2)([C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=2)[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[O:75][C:5](=[O:4])[CH2:6][NH:7][C:8]1=[O:74])([CH3:12])[CH3:11]
Reactant: COC(=O)CNC(=O)[C@H](NC(=O)[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)C(C)(C)NC(=O)C[C@H](O)/C=C/CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)C
Agent: CN(C)c1ccncc1
Agent: Cc1cccc([N+](=O)[O-])c1C(=O)OC(=O)c1c(C)cccc1[N+](=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@H]1NC(=O)[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)C(C)(C)NC(=O)C[C@H](/C=C/CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)OC(=O)CNC1=O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 47.4 %

Procedure:
LiOH (9 mg, 0.37 mmol) in water (2 mL) was added to 4 (255 mg, 0.25 mmol) in THF (8 mL) at 0° C. After 45 minutes of stirring at 0° C. the reaction mixture was neutralized with aqueous 0.5M HCl, then brine (40 mL) and EtOAc (40 mL) were added. The phases were separated and the aqueous phase was extracted with EtOAc (20 mL). The organic extracts were combined, dried over MgSO4, filtered then concentrated under reduced pressure. The crude product was dried under high vacuum before being used in the next step. The crude carboxylic acid in CH2Cl2/THF (200 mL, 12:1 v/v) was added dropwise over a period of 3 h to 2-methyl-6-nitrobenzoic anhydride (103 mg, 0.30 mmol) and 4-(dimethylamino)pyridine (73 mg, 0.60 mmol) in CH2Cl2 (50 mL) at rt under Ar(g). After 15 h, the reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluting with CH2Cl2/isopropanol (100:2.5 then 100:5) to yield 5 as a white solid (117 mg, 47%).
Reaction SMILES: [OH-].[Ba+2].[OH-].B(O)O.[O:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]1[CH:13]=[C:14]([CH:38]=[CH:39][CH:40]=1)/[CH:15]=[C:16]1\[CH2:17][CH2:18][C:19]2[N:20](S(C3C=CC(C)=CC=3)(=O)=O)[C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:23]\1=2>CN(C=O)C.O.C(OCC)(=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>[O:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]1[CH:13]=[C:14]([CH:38]=[CH:39][CH:40]=1)/[CH:15]=[C:16]1\[CH2:17][CH2:18][C:19]2[NH:20][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:23]\1=2
Reactant: COC(=O)c1cc2c(n1S(=O)(=O)c1ccc(C)cc1)CC/C2=C\c1cccc(-c2ccco2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: OBO
Agent: [Ba+2]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2c([nH]1)CC/C2=C\c1cccc(-c2ccco2)c1
Reaction time: 1 h

Procedure:
The starting aryl halide (i.e., (E)-methyl 4-(3-bromobenzylidene)-1-tosyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate) (0.824 mmol) was dissolved in DMF (8 mL) and H2O (2 mL) was added, forming a suspension. Barium hydroxide (0.213 g, 1.24 mmol) was then added, and the suspension was isolated and back-flushed four times with N2. The boronic acid (i.e. furan-2-boronic acid) (1.23 mmol) was added, and the suspension was isolated and back-flushed with N2 an additional four times and finally sparged with N2 for about 5-10 min. Then tetrakis(triphenylphosphine)palladium(0) (0.143 g, 0.21 mmol) was added, and the reaction was placed in a preheated (80° C.) heating block and stirred for 1 hour. The reaction was diluted with H2O (20 mL) and ethyl acetate (20 mL) and filtered through Celite. The organic layer was collected, washed once with H2O, once with brine, and dried over Na2SO4. Purification by column chromatography afforded the desired coupled product (i.e., (E)-methyl 4-(3-(furan-2-yl)benzylidene)-1-tosyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate). De-protected product (i.e., (E)-methyl 4-(3-(furan-2-yl)benzylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate) may also be formed.
Reaction SMILES: C(OCC)(=O)C#C.[C:8]([CH:10]1[CH2:12][N:11]1[CH:13]=[CH:14][C:15](OCC)=[O:16])#[N:9]>>[C:8]([CH:10]1[CH2:12][N:11]1[CH:13]=[CH:14][CH:15]=[O:16])#[N:9]
Reactant: CCOC(=O)C=CN1CC1C#N
Agent: C#CC(=O)OCC
Product: N#CC1CN1C=CC=O
Yield: 24 %

Procedure:
ethyl propiolate: ethyl 3-(2-cyanoaziridin-1-yl)-acrylate; oily substance, purified with a silica gel column; yield 24% of theory.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([C:14](=[O:19])[CH:15]=[C:16]([CH3:18])[CH3:17])[CH2:4][CH:3]1[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].Br[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH3:38])=[O:31].[OH-].[Na+].Cl>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:33]1([CH3:38])[C:32]([C:30]([CH2:29][N:8]2[C:7]3[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=3[N:5]([C:14](=[O:19])[CH:15]=[C:16]([CH3:18])[CH3:17])[CH2:4][CH:3]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:2]2=[O:1])=[O:31])=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)=CC(=O)N1CC(NC(=O)OC(C)(C)C)C(=O)Nc2cc(C)ccc21
Reactant: Cc1ccccc1C(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CC(C)=CC(=O)N1CC(NC(=O)OC(C)(C)C)C(=O)N(CC(=O)c2ccccc2C)c2cc(C)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 108.4 %

Procedure:
2-Oxo-3-tert-butoxycarbonylamino-5-(3-methyl-2-butenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (1.54 g) was suspended in toluene (22 ml), 2-bromo-2′-methylacetophenone (1.05 g), 1N aqueous sodium hydroxide (11 ml) and tetra n-butylammonium bromide (25 mg) were added, and the mixture was stirred for 4 hours at room temperature. The reaction mixture was acidified with 1N hydrochloric acid, extracted with methylene chloride. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography(chloroform:ethyl acetate=10:1), to thereby obtain 2.26 g of the titled compound (Yield: 100%).
Reaction SMILES: Cl[C:2]1[CH:12]=[C:11]([N+:13]([O-])=O)[C:5]2[O:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1>CCO.[Pd]>[NH2:13][C:11]1[C:5]2[O:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=[CH:2][CH:12]=1
Reactant: O=C1COc2c(cc(Cl)cc2[N+](=O)[O-])N1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc2c1OCC(=O)N2
Reaction time: 4 h
Yield: 83 %

Procedure:
Intermediate 57 (326 mg, 1.4 mmol) was dissolved in EtOH, then Pd/C (0.03 g) was added. The mixture was hydrogenated under H2 for 4 h at 50° C. The reaction mixture was filtered over Hyflo and the filtrate was concentrated in vacuo to give 8-amino-2H-benzo[b][1,4]oxazin-3(4H)-one (intermediate 58) (83%) as a brown solid, which was used in the next step without any further purification.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:12]=1[NH2:13]>>[Br:10][C:11]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:12]=1[N:13]([C:7]([C:5]1[S:6][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:9])[C:7]([C:5]1[S:6][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:9]
Reactant: Cc1ccc(C(=O)O)s1
Reactant: COc1ccc(N)c(Br)c1
Product: COc1ccc(N(C(=O)c2ccc(C)s2)C(=O)c2ccc(C)s2)c(Br)c1
Yield: 37 %

Procedure:
Following Step 1 from General Procedure A, 5-methylthiophene-2-carboxylic acid (8.5 g, 60 mmol) was reacted with 2-bromo-4-methoxyaniline (6.7 g, 30 mmol) to afford the desired product (5.0 g, 57%) as a solid: ESI MS m/z 327 [C13H12BrNO2S+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N+:15]([O-])=O)=[C:11]([CH:14]=2)[NH:12][CH3:13])=[C:4]([CH2:20][N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)[CH:3]=1.C(OCC)(=O)C>C(O)(=O)C.[Zn]>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([NH2:15])=[C:11]([NH:12][CH3:13])[CH:14]=2)=[C:4]([CH2:20][N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)[CH:3]=1
Reactant: CNc1cc(Oc2ccc(Cl)cc2Cn2ccnc2)ccc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CNc1cc(Oc2ccc(Cl)cc2Cn2ccnc2)ccc1N
Yield: 69.8 %

Procedure:
5-[4-Chloro-2-(1H-imidazol-1-ylmethyl)phenoxy]-N-methyl-2-nitroaniline (250 mg) from Example 28 was dissolved in acetic acid (3 ml), followed by gradual addition of zinc powder (250 mg) at room temperature. After the addition, ethyl acetate was added to filter off insoluble materials. To the filtrate was added saturated sodium hydrogencarbonate solution carefully for separation. The organic layer was washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the residue was purified by chromatography on a silica gel column (methylene chloride:methanol=97:3) to give 4-[4-chloro-2-(1H-imidazol-1-ylmethyl)phenoxy]-2-methylaminoaniline (160 mg; 70%).