Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](F)=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>CS(C)=O.C(OCC)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: Nc1ccc(CCC(=O)c2ccc(F)cc2)cc1
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Nc1ccc(CCC(=O)c2ccc(N3CCOCC3)cc2)cc1
Temperature: 105 °C

Procedure:
A mixture of 3-(4-aminophenyl)-1-(4-fluorophenyl)propan-1-one (0.56 g, 2.32 mmol) (prepared as described in Example 1b) and morpholine (1.01 g, 11.62 mmol) in dimethylsulfoxide (12 mL) was heated at 100-110° C. under nitrogen for about 12 hours. The reaction mixture was cooled, diluted with ethyl acetate (150 mL), washed with cold water and brine. The organic layer was separated, dried, and evaporated in vacuo to give the title compound as an oil which was used as such in the next step.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][C:4]([OH:8])=[CH:3][C:2]=1[OH:9].[CH2:10](O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:10]([O:7][C:6]1[CH:5]=[C:4]([OH:8])[CH:3]=[C:2]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:1]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: Oc1cc(O)cc(O)c1
Reactant: CCCCCCCCCCO
Product: CCCCCCCCCCOc1cc(O)cc(OCCCCCCCCCC)c1
Temperature: 70 °C
Yield: 37 %

Procedure:
Into a suspension of phloroglucin 8 (5.00 g, 39.7 mmol) in 1-decanol (80 ml) dry gaseous HCl is introduced for 40 min, and the orange/red mixture is subsequently heated to 70° C. for an additional 3.5 h. After finalization of the reaction, the excess 1-decanol is distilled off in vacuo, and the residue of the reaction is purified by means of column chromatography (silica gel, CH2Cl2). 5.92 g (37%) of compound 9 are obtained as a colorless solid. Melting point: 48-50° C.; IR (KBr) 3340, 2880, 2810 cm−1; 1H-NMR (CDCl3) δ 6.06 (t, 2.1 Hz, 1H), 5.99 (d, 2.1 Hz, 2H), 4.80 (s, 1H, OH), 3.89 (t, 6.7 Hz, 4H), 1.80-1.69 (m, 4H), 1.48-1.23 (m, 28H), 0.88 (t, 6.8 Hz, 6H); MS (FD) m/z 407 (M+). Anal. calc. for C26H46O3. C, 76.79; H, 11.40. Found C, 76.74; H, 11.44.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH2:16]OS(C)(=O)=O)[CH:13]([CH3:14])[CH:12]([CH3:15])[O:11]2)=[CH:6][CH:5]=1.[NH:22]1[CH:26]=[N:25][CH:24]=[N:23]1.[I-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CN1CCN(C)C1=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C@@:10]2([CH2:16][N:22]3[CH:26]=[N:25][CH:24]=[N:23]3)[C@@H:13]([CH3:14])[C@@H:12]([CH3:15])[O:11]2)=[CH:6][CH:5]=1
Reactant: CC1OC(COS(C)(=O)=O)(c2ccc(Cl)cc2)C1C
Reactant: c1nc[nH]n1
Agent: O=S([O-])([O-])=S
Agent: [H-]
Agent: [I-]
Solvent: CN1CCN(C)C1=O
Product: C[C@H]1O[C@@](Cn2cncn2)(c2ccc(Cl)cc2)[C@H]1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
38 mg (0.950 mmole) of sodium hydride (as a 60% w/w dispersion in mineral oil) were added at 0° C. to a suspension of 107 mg (0.351 mmole) of 2-(4-chlorophenyl)-3,4-dimethyl-2-methanesulfonyloxymethyloxetane, 51.5 mg (0.746 mmole) of 1H-1,2,4-triazole and 45.6 mg (0.304 mmole) of sodium iodide in 10 ml of dimethylimidazolidinone, and the mixture was stirred at room temperature for 30 minutes and then at 90° C. for a further 12 hours. At the end of this time, an aqueous solution of sodium thiosulfate was added to the resulting mixture, which was then extracted with a 1:1 by volume mixture of ethyl acetate and hexane. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography through silica gel, eluted with a 1:1 by volume mixture of hexane and ethyl acetate, to afford 76.3 mg (yield 78%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16](N(CC)CC)C.COC(ON=C(C#N)C(N)=O)=O>C(Cl)(Cl)Cl.C(#N)C>[CH3:16][O:14][C:13](=[O:15])[CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: CCN(CC)CC
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: COC(=O)ON=C(C#N)C(N)=O
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: COC(=O)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-benzyloxycarbonylglycine (1.05 g) and triethylamine (0.7 ml) in chloroform (10 ml) and acetonitrile (5 ml), 2-methoxycarbonyloxyimino-2-cyanoacetic acid amide (0.85 g) is added, and the resulting mixture is stirred at room temperature for 1 hour and allowed to stand over night. The reaction mixture is treated as in Example A to give N-benzyloxycarbonylglycine methyl ester (1.1 g) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:10]([CH2:20][C:21](O)=[O:22])[N:9]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl.[CH3:34][O:35][C:36]1[CH:37]=[N:38][C:39]([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[N:40][CH:41]=1.C(Cl)Cl>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:10]([CH2:20][C:21]([N:45]3[CH2:46][CH2:47][N:42]([C:39]4[N:38]=[CH:37][C:36]([O:35][CH3:34])=[CH:41][N:40]=4)[CH2:43][CH2:44]3)=[O:22])[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1
Reactant: COc1cnc(N2CCNCC2)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cnc(N2CCN(C(=O)Cn3nc(-c4ccc(F)cc4)nc3-c3ccc(F)cc3)CC2)nc1
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 20.5 %

Procedure:
100 mg (3,5-bis-(4-fluoro-phenyl)-(1,2,4)triazol-1-yl)-acetic acid was dissolved in 2 mL DMF. 163 mg PFTU and 0.5 mL DIPEA were added to this solution and the mixture was stirred for 7 min at RT. Then, 88 mg 5-Methoxy-2-piperazin-1-yl-pyrimidine hydrochloride and 0.11 mL DIPEA dissolved in 1.5 mL DMF were added and the reaction was stirred 3 h at RT. Then, a saturated sodiumhydrogencarbonate solution and CH2Cl2 were added, the organic phase was separated and the solvent was removed. The residue was purified by HPLC and crystallized with diethylether to give 32 mg of the desired compound. Rt: 0.82 min (method E), (M+H)+: 492
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][C@@H:15]1[CH2:19][NH:18][CH2:17][C@H:16]1[NH:20][C:21]([C:23]1[S:24][C:25]3[CH2:26][N:27]([CH3:32])[CH2:28][CH2:29][C:30]=3[N:31]=1)=[O:22])=[O:13])=[CH:6]2.C(N(CC)CC)C.[CH3:40][O:41][C:42]([CH2:44][S:45](Cl)(=[O:47])=[O:46])=[O:43]>C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][C@H:15]1[C@H:16]([NH:20][C:21]([C:23]3[S:24][C:25]4[CH2:26][N:27]([CH3:32])[CH2:28][CH2:29][C:30]=4[N:31]=3)=[O:22])[CH2:17][N:18]([S:45]([CH2:44][C:42]([O:41][CH3:40])=[O:43])(=[O:47])=[O:46])[CH2:19]1)=[O:13])=[CH:6]2
Reactant: CN1CCc2nc(C(=O)N[C@@H]3CNC[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Reactant: COC(=O)CS(=O)(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CS(=O)(=O)N1C[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1
Reaction time: 8 h
Yield: 54.3 %

Procedure:
The compound (230 mg) obtained in Example 95 and triethylamine (0.10 ml) were dissolved in methylene chloride (6.9 ml), and the mixture was cooled with ice. Methoxycarbonylmethanesulfonyl chloride (Synthesis, p. 321, 1975) (105 mg) was added, and the resultant mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with chloroform, washed with water and saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by preparative thin-layer chromatography on silica gel (chloroform:methanol=20:1) and powdered with methanol-water to obtain the title compound (150 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:23][CH:24]=2)[CH2:19]1)=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:36]([N:38](CC)CC)[CH3:37].Cl.C(OC(=N)C)C.C(OCC)(=O)C>O1CCCC1.C(O)C.C(OCC)C>[C:14]([O:13][C:11]([NH:10][C:9]([N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][N:33]([C:36](=[NH:38])[CH3:37])[CH2:32][CH2:31]3)=[CH:23][CH:24]=2)[CH2:19]1)=[N:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCc2ccc(OCC3CCNCC3)cc2C1
Reactant: CCN(CC)CC
Agent: CCOC(C)=N
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=N)N1CCC(COc2ccc3c(c2)CN(C(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)CC3)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N,N′-di-tert-butoxycarbonyl-7-(piperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine (100 mg) in a mixture of tetrahydrofuran (1.5 ml) and ethanol (1.5 ml) were added triethylamine (0.086 ml) and ethylacetoimidate hydrochloride (38 mg), and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, ethyl acetate and diethyl ether were added and insoluble material was removed. The solvent was evaporated and the residue was dried under reduced pressure to give the title compound (120 mg).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:20](O)=[O:21]>>[CH:20]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7])=[O:21]
Reactant: O=C(O)C(F)(F)F
Reactant: Oc1ccccc1
Agent: C1N2CN3CN1CN(C2)C3
Product: O=Cc1ccccc1O

Procedure:
A mixture of an appropriate phenol and hexamethylene-tetramine are treated with an appropriate acid, such as trifluoroacetic acid, to provide upon aqueous workup the corresponding o-formylphenol. This o-formylphenol is then treated with (bromomethyl)triphenylphosphonium bromide followed by an appropriate base such as potassium tert-butoxide to provide the desired benzofuran.
Reaction SMILES: [NH:1]([C:8]([C@H:10]1[N:14]2[C:15](=[O:41])[C:16]([N:19]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)=[CH:17][N:18]=[C:13]2[C@@:12]([CH2:43][C:44]([OH:46])=[O:45])([CH3:42])[CH2:11]1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH:53]1[CH:58]=[CH:57][C:56]([CH2:59]Br)=[CH:55][CH:54]=1>CN(C=O)C.CCOC(C)=O>[NH:1]([C:8]([C@H:10]1[N:14]2[C:15](=[O:41])[C:16]([N:19]([C:31]([O:33][CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[O:32])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)=[CH:17][N:18]=[C:13]2[C@@:12]([CH2:43][C:44]([O:46][CH2:59][C:56]2[CH:57]=[CH:58][CH:53]=[CH:54][CH:55]=2)=[O:45])([CH3:42])[CH2:11]1)=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: C[C@@]1(CC(=O)O)C[C@@H](C(=O)Nc2ccccc2)n2c1ncc(N(Cc1cccc(C(F)(F)F)c1)C(=O)OCc1ccccc1)c2=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@]1(CC(=O)OCc2ccccc2)C[C@@H](C(=O)Nc2ccccc2)n2c1ncc(N(Cc1cccc(C(F)(F)F)c1)C(=O)OCc1ccccc1)c2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 117b (1.740 mmol) in 7 mL DMF, were added Cs2CO3 (850 mg, 2.61 mmol) and BnBr (0.31 mL, 2.61 mmol). The mixture was stirred at rt for 1 h, then diluted with EtOAc. The organic phase was washed with 0.5 N HCl and brine, dried (Na2SO4), and concentrated. The crude product was purified by flash chromatography (35% EtOAc/hexanes) to afford 533 mg (42%, 2 steps) of 117c as a colorless glass. MS(ESI) 725.3 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl[CH2:11][CH2:12][NH:13][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:20]=1.OCCN.ClCC1C=NC=C(C2C=CC=CC=2)C=1.P(Cl)(Cl)Cl>C(#N)C>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[O:1][CH2:11][CH2:12][NH:13][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:20]=1)#[N:5]
Reactant: ClCCNCc1cncc(-c2ccccc2)c1
Reactant: N#Cc1ccccc1O
Agent: ClCc1cncc(-c2ccccc2)c1
Solvent: ClP(Cl)Cl
Solvent: CC#N
Solvent: NCCO
Product: N#Cc1ccccc1OCCNCc1cncc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 1.2 g 2-hydroxy-benzonitril and 2.5 g N-2-chloroethyl-N-(5-phenyl-3-pyridylmethyl)-amine [obtainable by reaction of 2-hydroxyethylamine with 3-chloromethyl-5-phenyl-pyridine and subsequent transformation of the product to the 2-chloroethyl-compound by reaction with PCl3 ] in 200 ml of acetonitrile is stirred for 5 hours at room temperature and worked up in a conventional manner to give N-[2-(2-cyanophenoxy)-ethyl]-N-(5-phenyl-3-pyridylmethyl)-amine. Stirring with 0.5 equivalenets of oxalic acid in 100 ml ethanol gives the oxalate, m.p. 208°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9]2)[N:5]=[C:4]([NH:17][CH3:18])[N:3]=1.C([O-])=O.[NH4+]>[Pd].CO>[N:8]1([C:6]2[N:5]=[C:4]([NH:17][CH3:18])[N:3]=[CH:2][N:7]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1
Reactant: CNc1nc(Cl)nc(N2CCc3ccccc32)n1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CNc1ncnc(N2CCc3ccccc32)n1
Temperature: 50 °C
Yield: 39.2 %

Procedure:
A mixture of 2-chloro-4-indolin-1-yl-6-methylamino-1,3,5-triazine (5.0 g, 19.1 mM), ammonium formate (6.02 g, 95.6 mM), 10% w/w palladium on charcoal (1.0 g) and methanol (100 ml) was heated at 50° C., under argon, for 6 hours The mixture was cooled, basified, and filtered. The solid collected by filtration was heated at reflux with ethanol, and the mixture refiltered. The filtrates were combined and the solvent evaporated. The residual solid was washed with water and then purified by flash column chromatography (silica, Merck 9385), eluting with ethyl acetate/hexane (1:3). This gave a solid which was recrystallised from ethyl acetate. There was thus obtained 2-(indolin-1-yl)-4-methylamino-1,3,5-triazine (1.7 g, 39% yield); m.p. 185°-187° C.: micro analysis, found: C, 62.8; H, 6.1; N, 30.3%; C12H13N5. 1/4 H2O requires: C, 62.2; H, 5.8; N, 30.2%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.C([Li])CCC.CON(C)[C:18]([CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)=[O:19]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:18]([CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)=[O:19])=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(Cl)cc1
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)C#Cc2ccc(Cl)cc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-chloro-4-ethynylbenzene (2.76 g, 20.20 mmol) in THF (50 mL) at −78° C. was added 2.5 M butyllitium (8.81 ml, 22.03 mmol in hexane) and stirred for 1 h at −78° C. tert-Butyl 4-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate (Compound 1.2, 5 g, 18.36 mmol) was added. The mixture was stirred at −78° C. for 30 min, then warmed up to 0° C., stirred for another hour at the same temperature, and diluted with water. The organic layer was separated and the aqueous was extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, and the drying agent was filtered off. The filtrate was concentrated. The residue was purified by silica gel column chromatography using gradient elution (5 to 30%, EtOAc/hexane). LC-MS m/z 292.06 [M−56+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][C:10]([CH3:13])=[N:9]2)[CH:5]=[CH:4][C:3]=1[C:14](N1C2C=CC=CC=2CN2C(C)=CC=C2C1)=[O:15].[Cl:31]C1C=C(N2C=CC(C)=N2)C=CC=1C(O)=O.C(Cl)(=O)C(Cl)=O>CN(C)C=O.ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][C:10]([CH3:13])=[N:9]2)[CH:5]=[CH:4][C:3]=1[C:14]([Cl:31])=[O:15]
Reactant: Cc1ccn(-c2ccc(C(=O)N3Cc4ccc(C)n4Cc4ccccc43)c(Cl)c2)n1
Reactant: Cc1ccn(-c2ccc(C(=O)O)c(Cl)c2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccn(-c2ccc(C(=O)Cl)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Step e) [2-Chloro-4-(3-methylpyrazol-1-yl)-phenyl]-(3-methyl-5H, 11H-pyrrolo[2,1-c][1,4]-benzodiazepin-10-yl)-methanone: A mixture of 2-chloro-4-(3-methylpyrazol-1-yl)-benzoic acid (0.18 g) from step d), oxalyl chloride (0.18 g) and one drop of dimethylformamide in dichloromethane (10 ml), was stirred at room temperature for 18 hours. The mixture was concentrated in vacuo, and the residue was redissolved in dichloromethane and reconcentrated in vacuo to yield 2-chloro-4-(3-methyl-pyrazol-1-yl)-benzoyl chloride. A slurry of the acid chloride in dichloromethane (25 ml) was added dropwise to a solution of 10,11-dihydro-3-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.12 g) and diisopropylethylamine (0.10 g) in dichloromethane (25 ml). The mixture was stirred at room temperature for 18 h, and washed with water and saturated aqueous sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium magnesium silicate. The solution was concentrated in vacuo and triturated with diethyl ether to yield 0.115 g of product as colorless crystals, m.p. 178-180° C., MS m/z: 417.3 (M+H)+, 833.3 (2M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[C:13]([OH:27])[C:14]([C:24]([OH:26])=O)=[N:15][C:16]=2[C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:11]=[C:10]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]1=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[CH2:50]([O:52][C:53](=[O:59])[C:54]([CH3:58])([CH3:57])[CH2:55][NH2:56])[CH3:51].CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O.[Cl-].[Na+].O.Cl>[CH2:50]([O:52][C:53](=[O:59])[C:54]([CH3:58])([CH3:57])[CH2:55][NH:56][C:24]([C:14]1[C:13]([OH:27])=[C:12]2[C:17](=[C:16]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:15]=1)[N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9](=[O:34])[C:10]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[CH:11]2)=[O:26])[CH3:51]
Reactant: CCOC(=O)C(C)(C)CN
Reactant: O=C(O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)CNC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reaction time: 0.17 h
Yield: 44.1 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid (53 mg, 0.118 mmol) and HOBt (26 mg, 0.189 mmol) was dissolved in CH2Cl2 (3 mL). EDC (41 mg, 0.212 mmol) was added, and the resulting mixture was stirred for 10 min. 3-Amino-2,2-dimethyl-propionic acid ethyl ester HCl salt (34 mg, 0.189 mmol) and Hunig's base (0.075 mL, 0.425 mmol) were added, and the mixture was stirred overnight. The mixture was diluted with EtOAc and brine, and 1 M HCl was added until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-60% EtOAc/hexanes+1% AcOH) to give 30 mg of the title compound. MS: (+) m/z 577.40 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][N:28]=1)[C:5]([NH:7][C:8]1[O:9][C:10]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[CH:15][CH:14]=[C:13]([O:24][CH3:25])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>CN1C(=O)CCC1>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]2[C:10]3[O:9][C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:26]=[CH:27][N:28]=[C:2]([N:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)[CH:3]=4)=[N:12][C:11]=3[C:13]([O:24][CH3:25])=[CH:14][CH:15]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(-c2ccc(F)cc2)c2oc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COc1ccc(-c2ccc(F)cc2)c2oc(NC(=O)c3ccnc(N4CCOCC4)c3)nc12

Procedure:
From 2-bromo-N-[7-(4-fluoro-phenyl)-4-methoxy-benzooxazol-2-yl]-isonicotinamide with cesium carbonate and morpholine in NMP. ES-MS m/e (%): 449 (M+H+, 100).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[CH:12][C:13]3[NH:17][CH:16]=[C:15]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:14]=3[CH3:23])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([O:34][CH3:35])[CH:33]=1)[CH2:29]Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:35][O:34][C:32]1[CH:31]=[C:28]([CH:27]=[C:26]([O:25][CH3:24])[CH:33]=1)[CH2:29][O:21][C:20](=[O:22])[CH2:19][CH2:18][C:15]1[C:14]([CH3:23])=[C:13]([CH:12]=[C:6]2[C:5]3[C:9](=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=3)[NH:8][C:7]2=[O:11])[NH:17][CH:16]=1
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=C1C(=O)Nc2cc(O)ccc21
Reactant: COc1cc(CCl)cc(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COC(=O)CCc2c[nH]c(C=C3C(=O)Nc4cc(O)ccc43)c2C)cc(OC)c1
Yield: 28.1 %

Procedure:
3-[5-(6-Hydroxy-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4-methyl-1H-pyrrol-3-yl]-propionic acid (100 mg), 56 mg 3,5-dimethoxy- benzylchloride and 207 mg potassium carbonate in 2 mL anhydrous dimethylformamide were heated at 90° C. overnight. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by chromatography on a silica gel column eluting with ethyl acetate-hexane-acetic acid to give 39 mg of the title compound as a brown solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[NH:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)[N:10]=1.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:5][C:6]1[NH:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([N+:1]([O-:4])=[O:2])=[C:13]([CH3:17])[CH:12]=2)[N:10]=1
Reactant: Cc1cccc(-c2c[nH]c(C)n2)c1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1nc(-c2ccc([N+](=O)[O-])c(C)c2)c[nH]1
Temperature: 90 °C
Yield: 36.1 %

Procedure:
2-Methyl-4-(3-methyl-phenyl)-1H-imidazole nitrate (15 g) was added portionwise to 96% sulfuric acid (40 ml) at room temperature. The resulting solution was heated at 90° C. for one hour, cooled, diluted with water (200 ml) and neutralized with aqueous sodium carbonate. The solid which separated out was filtered off, and the filtrate was made strongly alkaline with 10% sodium hydroxide. The base which precipitated was filtered off and dried to give 5 g of the title compound sufficiently pure to be used in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]=O)[CH:10](C([O-])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].S(Cl)(C1C=CC(C)=CC=1)(=O)=O.Cl[C:32](=[CH2:37])[C:33]([O:35][CH3:36])=[O:34].C(N(CC)CC)C>ClC(Cl)C.C(OCC)(=O)C>[CH2:9]1[N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][CH2:12][N:11]2[CH:14]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:10]12
Reactant: CC(C)(C)OC(=O)N1CCN(C=O)C(C(=O)[O-])C1
Reactant: C=C(Cl)C(=O)OC
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccn2c1CN(C(=O)OC(C)(C)C)CC2

Procedure:
To a suspension of 29 g of the compound obtained in Step B (103 mmoles) in 800 mL of dichloroethane there are added in succession 24 g of tosyl chloride (124 mmol), 12.6 mL of methyl 2-chloroacrylate (124 mmol) and then 35 mL of triethylamine (247 mmoles). The whole is stirred at reflux for 2 hours. After cooling, the reaction mixture is diluted with ethyl acetate, and the organic phase is washed with a saturated NaCl solution until neutral. After drying over MgSO4, filtration and concentration to dryness, the title product is isolated by chromatography over silica gel (petroleum ether/AcOEt gradient: 0-20%) in the form of a solid.