Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[F:15][C:16]([F:30])([F:29])[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].CO>C(OCC)(=O)C>[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:26]3[CH2:25][CH2:24][N:23]([C:20]4[CH:19]=[CH:18][C:17]([C:16]([F:29])([F:30])[F:15])=[CH:22][CH:21]=4)[CH2:28][CH2:27]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCN(c2ccc(C(F)(F)F)cc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1-(4-trifluoromethylphenyl)piperazine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 89% overall yield. FDMS m/e=419 (M+ of free base). α[D]589=−7.78 (c=0.72, methanol).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([CH3:22])[CH:16]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[F:21][C:18]1[CH:19]=[CH:20][C:15]([N:10]2[CH2:11][CH2:12][N:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9]2=[O:13])=[CH:16][C:17]=1[CH3:22]
Reactant: Cc1cc(Br)ccc1F
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc(N2CCN(c3cnccc3C)C2=O)ccc1F
Yield: 12.8 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 160 mg, 0.9039 mmol) was reacted with 4-bromo-1-fluoro-2-methyl-benzene (0.135 mL, 0.7142 mmol), 1,4-dioxane (15 mL), copper iodide (0.005 g, 0.0263 mmol), trans-1,2-diamino cyclohexane (0.015 g, 0.1315 mmol) and potassium phosphate (0.575 g, 2.7094 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% MeOH in chloroform) afforded 26 mg of the product (30% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[NH2:41][C:42]1[CH:51]=[CH:50][C:45]([C:46]([NH:48][NH2:49])=[O:47])=[CH:44][CH:43]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[NH:48]([C:46]([C:45]1[CH:50]=[CH:51][C:42]([NH:41][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])=[CH:43][CH:44]=1)=[O:47])[NH2:49]
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: NNC(=O)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)NN)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Yield: 67.3 %

Procedure:
To a solution of chiral-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (52.7 mg, 0.113 mmol) in dichloromethane (3 mL) were added DIPEA (71.2 mg, 0.55 mmol), 4-aminobenzhydrazide (33.1 mg, 0.22 mmol, Aldrich) and HATU (72.3 mg, 0.19 mmol). (The acid, DIPEA, and HATU were added in thirds at 20 min intervals). After 90 minutes the reaction was diluted with dichloromethane, washed with water and saturated sodium chloride and purified by HPLC with acetonitrile and water (with TFA 0.1% VAT) to give chiral (2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-hydrazinocarbonyl-phenyl)-amide (45.7 mg., 67.5%) as a white solid. HRMS (ES+) m/z Calcd C30H29Cl2F2N5O2+H [(M+H): 600.1739. Found: 600.1737.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:19][CH2:20][O:21][CH3:22])[CH:11]=1.[NH2:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[CH:27][NH:28]2.CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.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]>[NH:28]1[C:29]2[C:25](=[C:24]([NH:23][C:2]3[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][C:3]=3[C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:19][CH2:20][O:21][CH3:22])[CH:11]=3)[CH:32]=[CH:31][CH:30]=2)[CH:26]=[CH:27]1
Reactant: Nc1cccc2[nH]ccc12
Reactant: COCCOc1cc(-c2cncc(C#N)c2Cl)ccc1OC
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Product: COCCOc1cc(-c2cncc(C#N)c2Nc2cccc3[nH]ccc23)ccc1OC
Temperature: 90 °C
Yield: 32.8 %

Procedure:
To a stirred solution of 4-chloro-5-[4-methoxy-3-(2-methoxyethoxy)phenyl]-nicotinonitrile (100 mg, 0.313 mmol), 4-aminoindole (62 mg, 0.47 mmol), DavePhos (37 mg, 0.094 mmol), and K3PO4 (99.8 mg, 0.47 mmol) in 4 mL of anhydrous ethylene glycol dimethyl ether was added Pd2(dba)3 (28.7 mg, 0.031 mmol). The mixture was heated to 90° C. for 2 h, then cooled, filtered through celite, concentrated in vacuo, and crystallized by tritration with ether/hexane to yield 42.5 mg (33% yield) of the title compound 153 as a tan solid. MS: 415.1 (M+H), HPLC retention time: 7.70 min(b).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10](=[O:15])[O:11][C:12]([CH3:14])=[CH2:13])[CH:4]=1.C1C=C(Cl)C=C(C(OO)=[O:26])C=1>C(Cl)(Cl)Cl>[O-:26][N+:6]1[CH:7]=[CH:8][C:3]([C:2]([F:16])([F:1])[F:17])=[CH:4][C:5]=1[NH:9][C:10](=[O:15])[O:11][C:12]([CH3:14])=[CH2:13]
Reactant: C=C(C)OC(=O)Nc1cc(C(F)(F)F)ccn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: C=C(C)OC(=O)Nc1cc(C(F)(F)F)cc[n+]1[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Isopropenyl [4-(trifluoromethyl)pyridin-2-yl]carbamate (1.2 g, 5.0 mmol) was suspended in CHCl3 (20 mL) and treated with m-CPBA (841 mg, 5.0 mmol). The reaction was stirred at rt overnight. The reaction was quenched with satd. NaHCO3 and extracted with CHCl3. The organic layer was dried (MgSO4) and concentrated. The crude residue was purified over silica using CH2Cl2 as the eluting solvent. An amber oil was collected (620 mg, 47%); 1H-NMR (DMSO-d6) δ 10.2 (s, 1 H), 8.56 (d, J=6.9 Hz, 1 H), 8.25 (d, J=2.6 Hz, 1 H), 7.52 (ddd, dd, J1=6.8 Hz, J2=2.5 Hz, J3=0.6 Hz, 1 H), 4.85 (q, J=1.2 Hz, 1 H), 4.80 (d, J=1.2 Hz, 1 H), 1.94 (d, J=0.4 Hz, 3 H).
Reaction SMILES: C([C:4]1[C:5](=[O:20])[N:6]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[C:7]([CH3:11])=[CH:8][C:9]=1[OH:10])(=O)C.S(=O)(=O)(O)O>C(O)CCC>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[N:6]1[C:7]([CH3:11])=[CH:8][C:9]([OH:10])=[CH:4][C:5]1=[O:20]
Reactant: CC(=O)c1c(O)cc(C)n(-c2c(Cl)cccc2Cl)c1=O
Agent: O=S(=O)(O)O
Solvent: CCCCO
Product: Cc1cc(O)cc(=O)n1-c1c(Cl)cccc1Cl
Temperature: 120 °C
Yield: 25.9 %

Procedure:
A mixture of 3-acetyl-1-(2,6-dichlorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one 0.7 g (0.002 mol) in n-butanol (3.0 mL) containing sulfuric acid (1.5 mL) was heated at 120° C. for 4 h. The dark reaction mixture was cooled, added ice/water (25 mL), and extracted with EtOAc (2×25 ml). The combined organic extracts were washed with water, dried (Na2SO4), filtered, concentrated under reduced pressure and the resulting material was purified by silica gel flash chromatography using 25% EtOAc in hexanes as the eluent to afford the title compound (0.14 g) as a pale yellow powder: 1H-NMR (CD3OD) δ: 7.6 (m, 2H), 7.48 (m, 1H), 6.10 (dd, 1H), 5.78 (d, 1H, J=2.4 Hz), 1.91 (s, 3H); ES-MS m/z=270 (MH+); HR-MS, m/z calc C12H10NO2Cl2 270.0083, found 270.0103.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N:6]1[S:10][N:9]=[C:8]2[CH:11]=[C:12]([CH2:15][CH2:16][OH:17])[CH:13]=[CH:14][C:7]=12.C(N(CC)CC)C>ClCCl>[N:6]1[S:10][N:9]=[C:8]2[CH:11]=[C:12]([CH2:15][CH2:16][O:17][S:2]([CH3:1])(=[O:4])=[O:3])[CH:13]=[CH:14][C:7]=12
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1ccc2nsnc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1ccc2nsnc2c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 84.5 %

Procedure:
Methanesulfonyl chloride (0.45 ml, 5.8 mmol) was added dropwise to an ice-cooled solution of 2-benzo[1,2,5]thiadiazol-5-yl-ethanol (c) (1.0 g, 5.5 mmol) and triethylamine (0.85 ml, 6 mmol) in dichloromethane (20 ml) The reaction mixture was allowed to warn to room temperature and stirred for 16 hours. The organic solution was washed with water, dried over magnesium sulfate and evaporated to dryness. The oily residue was triturated with diisopropyl ether. The solid was collected by filtration and dried to give methanesulfonic acid 2-benzo[1,2,5]thiadiazol-5-yl-ethyl ester (1.2 g, 78%) which was used without further purification in the next step.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH2:18]([N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34]2[O:35][C:36]([C:39](Cl)=[O:40])=[CH:37][CH:38]=2)=[N:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[CH2:18]([N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34]2[O:35][C:36]([C:39](=[O:40])[NH:7][C:6]3[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=3)=[CH:37][CH:38]=2)=[N:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
0.29 g (1.8 mmol) of 4-trifluoromethylaniline were initially charged in 20 ml of THF, 0.14 g (1.8 mmol) of pyridine were added and a solution of 0.5 g (1.5 mmol) of 1-benzyl-3-(5-chlorocarbonyl-2-furyl)indazole in 10 ml of THF was added dropwise at RT. After 0.5 h, the mixture was poured into ice-water and the precipitate was filtered off with suction and recrystallized from isopropanol. This gave 0.47 g (69%) of the title compound. m.p.: 205-206° C.
Reaction SMILES: CS(O[CH2:6][C:7]1([F:20])[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)(=O)=O.[C:21]1(=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:30])[NH:22]1.CC([O-])(C)C.[K+]>CN(C=O)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[I-]>[CH2:13]([N:10]1[CH2:11][CH2:12][C:7]([CH2:6][N:22]2[C:23](=[O:30])[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21]2=[O:31])([F:20])[CH2:8][CH2:9]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CS(=O)(=O)OCC1(F)CCN(Cc2ccccc2)CC1
Agent: CC(C)(C)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC1(F)CCN(Cc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 12 h
Yield: 37.6 %

Procedure:
The (1-benzyl-4-fluoropiperidin-4-yl)methyl methanesulfonate (1.82 g, 6.04 mmol, Preparation #V.1) was dissolved in DMF (18 mL) and isoindoline-1,3-dione (1.07 g, 7.25 mmol), Bu4NI (1.12 g, 3.02 mmol) and KOtBu (1.36 g, 12.1 mmol) were added. The resulting mixture was stirred at about 100° C. for about 12 h. The mixture was cooled to rt and concentrated under reduced pressure. The residue was diluted with water (10 mL) and extracted with Et2O (3×10 mL). The combined organic layers were washed with brine (2×20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0 to 10% MeOH/DCM to afford 2-((1-benzyl-4-fluoropiperidin-4-yl)methyl)isoindoline-1,3-dione (0.8 g, 38%): LC/MS (Table 2, Method f) Rt=2.21 min; MS m/z 353 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH:15](O)[C@H:14]2[N:10]([C@H:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:12][CH2:13]2)[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(F)(F)F.CCO[CH2:31][CH3:32]>ClCCl.CCOCC>[CH2:1]([N:8]1[C@@H:15]([C:1]#[C:2][CH2:3][CH2:4][CH2:31][CH3:32])[C@H:14]2[N:10]([C@H:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:12][CH2:13]2)[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1N(Cc2ccccc2)C(O)[C@@H]2CS[C@@H](c3ccccc3)N12
Reactant: CCOCC
Agent: FB(F)F
Solvent: ClCCl
Product: CCCCC#C[C@H]1[C@@H]2CS[C@@H](c3ccccc3)N2C(=O)N1Cc1ccccc1
Temperature: 0 °C
Yield: 98 %

Procedure:
To a solution of compound 6-benzyl-7-hydroxy-3-phenyl-(3S, 7aR)-perhydroimidazo[1,5-C][1,3]thiazol-5-one of formula (6) (0.326 parts, 1 mmol) in dichloromethane (10 parts) was added 1-(tri n-butyltin)hexyne(0.742 parts, 2 mmol). Then the solution was cooled to 0° C., and Lewis acid for example BF3.Et2O (0.142 parts, 1 mmol) was added drop wise. The reaction mixture was stirred at 0° C. for 10 mints, and the reaction mixture was quenched with saturated ammonium chloride (10 parts). Then the organic layer was separated, concentrated and column purification with ethylacetate:pet.ether (15:85) as eluent provided compound 6-benzyl-7-(1-hexynyl)-3-phenyl-(3S, 7S, 7aR)-perhydroimidazo[1,5-c][1.3]thiazol-5-one of formula (7g) (viscous liquid, 0.382 parts, 0.98 mmol) in 98% yield.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:22]=[C:23]([CH2:26][N:27]5[CH2:30][CH:29]([C:31]([O:33]CC)=[O:32])[CH2:28]5)[O:24][CH:25]=4)[N:17]=3)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+].C(O)(=O)C.C(O)(=O)C(O)=O>CO.O.O1CCCC1>[C:1]1([C:7]2[CH:8]=[C:9]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:22]=[C:23]([CH2:26][N:27]5[CH2:30][CH:29]([C:31]([OH:33])=[O:32])[CH2:28]5)[O:24][CH:25]=4)[N:17]=3)[S:10][C:11]=2[C:12]([F:14])([F:13])[F:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1CN(Cc2cc(-c3noc(-c4cc(-c5ccccc5)c(C(F)(F)F)s4)n3)co2)C1
Agent: O=C(O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(O)C1CN(Cc2cc(-c3noc(-c4cc(-c5ccccc5)c(C(F)(F)F)s4)n3)co2)C1
Yield: 43.1 %

Procedure:
To a solution of ethyl 1-[(4-{5-[4-phenyl-5-(trifluoromethyl)-2-thienyl]-1,2,4-oxadiazol-3-yl}-2-furyl)methyl]azetidine-3-carboxylate (0.20 g, 0.40 mmol) that was obtained in Example 1 (1f) in a mixed solvent of tetrahydrofuran (0.50 ml), methanol (0.50 ml) and water (0.50 ml) was added lithium hydroxide monohydrate (37 mg, 0.88 mmol) with stirring, and the resulting mixture was stirred at room temperature for 1 hour. After stirring, acetic acid (48 μl, 0.88 mmol) was added to the reaction mixture to quench the reaction. Subsequently, to the resulting mixture was added a solution of oxalic acid (18 mg, 0.20 mmol) in methanol (0.5 ml) with stirring, and the resulting mixture was stirred for 30 minutes. The white solid precipitated was collected by filtration using a Kiriyama funnel, washed with a mixed solvent of water and methanol (3:7), and dried in vacuo to afford the title compound (82 mg) in a yield of 39% as a white crystalline solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([NH2:14])=[O:13])[CH:4]=[CH:3]1.C[O:16][C:17](=O)[C:18]([C:20]1[C:28]2[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=2)[NH:22][CH:21]=1)=O.CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[F:29][C:25]1[CH:24]=[C:23]2[C:28]([C:20]([C:18]3[C:17](=[O:16])[NH:14][C:12](=[O:13])[C:11]=3[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:10]=3[N:2]([CH3:1])[CH:3]=[CH:4]4)=[CH:21][NH:22]2)=[CH:27][CH:26]=1
Reactant: COC(=O)C(=O)c1c[nH]c2cc(F)ccc12
Reactant: Cn1ccc2cccc(CC(N)=O)c21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1ccc2cccc(C3=C(c4c[nH]c5cc(F)ccc45)C(=O)NC3=O)c21
Temperature: 25 °C

Procedure:
To a solution of 2-(1-methyl-1H-indol-7-yl)-acetamide (0.466 g, 2.48 mmol) and (6-fluoro-1H-indol-3-yl)-oxo-acetic acid methyl ester (0.543 g, 2.45 mmol) in DMF (40 mL) under N2 was added a 1.0 M solution of potassium-tert-butoxide in THF (8.6 mL, 8.6 mmol) dropwise over 5 minutes. The mixture was heated at 65–70° C. for 15 h. The mixture was cooled to room temperature, quenched with 1N HCl (excess) and poured into EtOAc. The organic layer was separated, washed with water (3×), saturated aq NaHCO3, and brine, dried (MgSO4), filtered and concentrated onto flash SiO2. Flash chromatography (40% EtOAc/hex) gave the title compound as a bright orange solid which was dried under vacuum at 80–100° C. overnight (0.342 g, 39%). 1H NMR (400 MHz, DMSO-d6) 11.49 (br s, 1H), 11.08 (s, 1H), 7.49 (dd, J=6, 3 Hz, 1H), 7.30 (d, J=2.3 Hz, 1H), 7.24 (d, J=3 Hz, 1H), 6.86–7.05 (m, 4H), 6.43 (d, J=3 Hz, 1H), 6.40 (d, J=7 Hz, 1H), 3.76 (s, 3H). MS (electrospray, m/z) 360.0 (M++1), 358.0 (M−−1). HRMS 360.1161 (M++1, calcd for C21H15FN3O2 360.1148). Anal. Calcd for C21H14FN3O2: C, 70.19; H, 3.93; N, 11.69. Found: C, 69.94; H, 3.92; N, 11.59.
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[C:13](=O)[NH:12][C:11]4[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=4[S:9][C:8]=3[S:19][C:5]=2[CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([C:13]2[C:7]3[C:6]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[S:19][C:8]=3[S:9][C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[N:12]=2)[CH2:37][CH2:36]1
Reactant: O=C1Nc2ccccc2Sc2sc3ccccc3c21
Reactant: CN1CCNCC1
Solvent: CN(C)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCN(C2=Nc3ccccc3Sc3sc4ccccc4c32)CC1

Procedure:
In the same manner as in Example 80 and using [1]benzothieno[2,3-b][1,5]benzothiazepin-12(11H)-one (500 mg), phosphorus oxychloride (6.3 g), N,N-dimethylaniline (109 mg) and 1-methylpiperazine (5 ml), 12-(4-methylpiperazin-1-yl)-[1]benzothieno[2,3-b][1,5]benzothiazepine (278 mg) was obtained.
Reaction SMILES: C1(C)C=CC=CC=1.[Br:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[F:18])[C:12](Cl)=[O:13].[H][H]>[Pd].O>[Br:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[F:18])[CH:12]=[O:13]
Reactant: [H][H]
Reactant: O=C(Cl)c1ccc(F)c(Br)c1
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1ccc(F)c(Br)c1
Temperature: 85 °C
Yield: 88.6 %

Procedure:
2 g of palladium/activated carbon (5% by weight of Pd) and 350 g of toluene are heated for 1 hour at 75° C. in a three-necked flask equipped with a gas inlet tube, a reflux condenser and a stirrer while water gas (CO:H2 =1) is being passed through. 70.0 g of 3-bromo-4-fluorobenzoyl chloride prepared as in Example 3 were then added and hydrogen was passed in instead of water gas. The temperature was increased to 85° C. After 4 hours 95% of the amount of hydrogen chloride expected had been split off. After cooling down, the reaction mixture was filtered and the filtrate was distilled off. 53 g of 3-bromo-4-fluorobenzaldehyde, boiling point 112° C./20 mbars, nD30 1.5685 and melting point: 30° C., were obtained.
Reaction SMILES: O[N:2]=[C:3]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)[C:4](=O)[CH3:5].[CH3:13][CH:14]1[CH2:19][C:18](=[O:20])[CH2:17][C:16](=O)[CH2:15]1.C(O)(=O)C.[OH-].[Na+]>[Zn].CCOC(C)=O.O>[CH3:5][C:4]1[C:17]2[C:18](=[O:20])[CH2:19][CH:14]([CH3:13])[CH2:15][C:16]=2[NH:2][C:3]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1
Reactant: CC(=O)C(=NO)c1ccncc1
Reactant: CC1CC(=O)CC(=O)C1
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(-c2ccncc2)[nH]c2c1C(=O)CC(C)C2
Temperature: 25 °C
Yield: 17 %

Procedure:
According to the literature procedure (Chiswell, B. Inorganica Chimica Acta. 1972, 629), a mixture of 1-hydroxyimino-1-(4-pyridyl)-2-propanone (Tanaka, A et. al., Chem. Pharm. Bull., 1992, 40, 3206) (0.49 g, 3.0 mmol), 5-methyl-1,3-cyclohexanedione (0.38 g, 3.0 mmol), glacial acetic acid (2.4 mL) and H2O (0.6 mL) was stirred vigorously at room temperature. To this flask, zinc dust (0.6 g) was added slowly keeping the temperature below 60° C. Afer addition, the resulting brown solution was heated under reflux condition for 2 hours. After cooling down to room temperature, the reaction mixture was basified by an addition of 2 M aqueous NaOH, then filtered. The filtrate was extracted with CH2Cl2 (20 mL×3), the combined organic layer was dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography (1-5:1 EtOAc-Hexane then EtOAc only) to give the desired product (0.12 g, 17% yield).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:13]=[C:12]([C:14]2[CH:27]=[CH:26][C:25]3[C:16](=[CH:17][C:18]4[C:19]([CH3:31])([CH3:30])[CH2:20][CH2:21][C:22]([CH3:29])([CH3:28])[C:23]=4[CH:24]=3)[CH:15]=2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].I[CH3:33].O>CN(C=O)C>[CH3:33][O:3][C:4]1[CH:13]=[C:12]([C:14]2[CH:27]=[CH:26][C:25]3[C:16](=[CH:17][C:18]4[C:19]([CH3:31])([CH3:30])[CH2:20][CH2:21][C:22]([CH3:29])([CH3:28])[C:23]=4[CH:24]=3)[CH:15]=2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: CI
Reactant: COC(=O)c1ccc(-c2ccc3cc4c(cc3c2)C(C)(C)CCC4(C)C)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc3cc4c(cc3c2)C(C)(C)CCC4(C)C)cc1OC

Procedure:
130 mg (4.2 mmol) of sodium hydride (80% in oil) and 20 ml of DMF were introduced into a three-necked flask, a solution of 1.6 g (4.2 mmol) of methyl 2-hydroxy-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthryl)benzoate in 50 ml of DMF was added dropwise and the mixture was stirred until gaseous emission ceased. 340 μl (5.5 mmol) of iodomethane were then added and the mixture was stirred at room temperature for two hours. The reaction medium was poured into water, extracted with ethyl ether, the organic phase decanted, dried over magnesium sulfate and evaporated. 1.6 g (96%) of the expected compound was recovered in the form of a colorless oil.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][N:20]=2)[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=2)=[C:14]([NH:30][C:31]([NH:33][C:34]2[C:39]([CH:40]([CH3:42])[CH3:41])=[CH:38][CH:37]=[CH:36][C:35]=2[CH:43]([CH3:45])[CH3:44])=[O:32])[C:13]1=[O:46])C1C=CC=CC=1.Cl>C(O)C.[C].[Pd]>[OH:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][N:20]=2)[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=2)=[C:14]([NH:30][C:31]([NH:33][C:34]2[C:39]([CH:40]([CH3:42])[CH3:41])=[CH:38][CH:37]=[CH:36][C:35]=2[CH:43]([CH3:45])[CH3:44])=[O:32])[C:13]1=[O:46]
Reactant: COc1cccc(-c2c(NC(=O)Nc3c(C(C)C)cccc3C(C)C)c(=O)n(CCCOCc3ccccc3)c3ncccc23)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1cccc(-c2c(NC(=O)Nc3c(C(C)C)cccc3C(C)C)c(=O)n(CCCO)c3ncccc23)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of N-[1-(3-benzyloxypropyl)-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (1.31 g, 2.12 mmol) in ethanol (80 ml) was added 10% palladium-carbon (150 mg), and the mixture was stirred at room temperature under hydrogen atmosphere for three hours. To the mixture was added 12N hydrochloric acid (1 ml), and the mixture was further stirred at room temperature under hydrogen atmosphere for two hours. The mixture was filtered through a cerite pad, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1-3% methanol in chloroform) to give the title compound (1.12 g, 2.12 mmol).