Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[Br:7]Br.[CH3:9][C:10]1[CH2:19][S:18][C@@H:13]2[C@H:14]([NH2:17])[C:15](=[O:16])[N:12]2[C:11]=1[C:20]([OH:22])=[O:21].CCCCNCCCC>C(Cl)Cl>[Br:7][CH2:6][C:2](=[O:1])[CH2:3][C:4]([NH:17][CH:14]1[C:15](=[O:16])[N:12]2[C:11]([C:20]([OH:22])=[O:21])=[C:10]([CH3:9])[CH2:19][S:18][C@H:13]12)=[O:5]
Reactant: BrBr
Reactant: C=C1CC(=O)O1
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Solvent: ClCCl
Solvent: CCCCNCCCC
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)CC(=O)CBr)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.1 %

Procedure:
A solution of 2.2 g of diketene in 5 ml of methylene chloride was cooled to -40° C. and 4.4 g of bromine were added dropwise. Separately, 4.28 g of 7-aminodesacetoxycephalosporanic acid and 8.0 g of n-dibutylamine were dissolved in 120 ml of methylene chloride and cooled. The above reaction mixture was added dropwise to this mixed solution. The temperature of the mixture was increased to room temperature over 30 minutes, after which the mixture was stirred for an additional 30 minutes. The solvent was distilled off under reduced pressure and the resulting residue was shaken vigorously with 200 ml of ethyl acetate and 40 ml of 40% phosphoric acid. The organic layer was taken, washed with water, dried and concentrated to dryness under reduced pressure. To the residue was added ethyl ether, followed by stirring. The resultant powder was collected by filtration and dried. By the above procedure there were obtained 3.7 g of the captioned compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:21]=[CH:22][C:23]=1[N+:24]([O-])=O)[CH2:12][CH:13]1[NH:19][C:18](=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl.O>CCOC(C)=O>[NH2:24][C:23]1[CH:22]=[CH:21][C:11]([CH2:12][CH:13]2[NH:19][C:18](=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:10][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCCC(Cc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)N1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccc(CC2CCCCC(=O)N2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 7-(3-benzyloxy-4-nitrobenzyl)-azepan-2-one (600 mg, 1.7 mmol) in EtOAc (20 mL) is added tin (II) chloride dihydrate. The mixture is stirred at RT for 18 h then water is added. The mixture is extracted with EtOAc and the organic phase is washed with water and brine. The solution is dried over sodium sulfate and the solvent removed under reduced pressure to give the title compound: (M+1)+=325.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[C:15]([O:22][CH3:23])[C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:24][C:25]2[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=2)[N:11]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[C:19]3[C:14](=[C:15]([O:22][CH3:23])[C:16]([O:20][CH3:21])=[CH:17][CH:18]=3)[CH:13]=[C:12]([NH:24][C:25]3[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1OC
Reactant: Oc1ccc(Cl)cc1
Product: COc1ccc2c(Oc3ccc(Cl)cc3)nc(Nc3cc(C)[nH]n3)cc2c1OC

Procedure:
Similar procedure as described in example 10 was used, starting from 4-chloro-phenol and (1-Chloro-5,6-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(4-chloro-phenoxy)-5,6-dimethoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 411 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[CH:25]=[CH:24][C:23]([N:26]2[CH:32]3[CH2:33][CH2:34][N:29]([CH2:30][CH2:31]3)[CH2:28][CH2:27]2)=[CH:22][C:10]=1[C:11]([NH:13][CH2:14][C:15]([O:17][C:18](C)(C)C)=[O:16])=[O:12]>ClCCl.CO>[NH2:8][C:9]1[CH:25]=[CH:24][C:23]([N:26]2[CH:32]3[CH2:33][CH2:34][N:29]([CH2:30][CH2:31]3)[CH2:28][CH2:27]2)=[CH:22][C:10]=1[C:11]([NH:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:12]
Reactant: CC(C)(C)OC(=O)CNC(=O)c1cc(N2CCN3CCC2CC3)ccc1N
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CNC(=O)c1cc(N2CCN3CCC2CC3)ccc1N
Reaction time: 7 h

Procedure:
2,2,2-Trifluoroacetic acid (3.26 g, 28.0 mmol) was added to a solution of tert-butyl 2-(2-amino-5-(1,4-diazabicyclo[3.2.2]nonan-4-yl)benzamido)acetate (Intermediate 7B) (1.0 g, 2.67 mmol) in dichloromethane (20 mL) and methanol (2 mL). The resulting solution was stirred for 7 hours before leaving to stand over the weekend. The resultant crude material purified using a 5 g SCX cartridge to afford methyl 2-(2-amino-5-(1,4-diazabicyclo[3.2.2]nonan-4-yl)benzamido)acetate. This was dissolved in tetrahydrofuran (20 mL) and 1M lithium hydroxide solution (5.34 mL, 5.34 mmol) and water (2 mL) was added and the solution stirred overnight. The reaction mixture was then acidified and purified using a 5 g SCX cartridge to afford 2-(2-amino-5-(1,4-diazabicyclo[3.2.2]nonan-4-yl)benzamido)acetic acid (849 mg, 2.67 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[N+:11]([O-:13])=[O:12].[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(C(C)C)CC)(C)C>C(#N)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([N:17]2[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]2)[CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cc(F)cc(F)c1[N+](=O)[O-]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)cc(F)c1[N+](=O)[O-]
Temperature: 90 °C
Yield: 21.2 %

Procedure:
To a solution of 2.48 g (13.1 mmol) of the product prepared in step 10.1 in 26 mL of acetonitrile are added 2.43 g (13.1 mmol) of tert-butyl piperazinecarboxylate and 3.36 mL (19.65 mmol) of diisopropylethylamine. The reaction mixture is heated at 90°C. for 20 hours. It is diluted with ethyl acetate and washed with water and then with saturated aqueous NaCl solution. The crude solid is purified by chromatography on a column of silica, eluting with a cyclohexane/ethyl acetate gradient (85/15 to 50/50). A 3.25 g fraction predominantly containing the regioisomer tert-butyl 4-(5-fluoro-3-methoxy-2-nitrophenyl)piperazine-1-carboxylicate is isolated. An impure secondary fraction is purified again on a column of silica, eluting with a dichloromethane/ethyl acetate gradient (96/4 to 94/6). 0.985 g of expected product is finally obtained in the form of a yellow solid. Yield=21%.
Reaction SMILES: [SH:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:15]([C:17]1[N:22]=[C:21]([CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:20]=[CH:19][CH:18]=1)#[N:16]>N1C=CC=CC=1>[O:6]=[C:4]1[C:3]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:2]=2[S:1][C:15]([C:17]2[N:22]=[C:21]([CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:20]=[CH:19][CH:18]=2)=[N:16]1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1S
Reactant: CC(C)(C)OC(=O)CCc1cccc(C#N)n1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CCc1cccc(-c2nc(=O)c3ccc(C(F)(F)F)cc3s2)n1
Yield: 34.2 %

Procedure:
2-Mercapto-4-trifluoromethylbenzoic acid (1.59 g, 7.2 mmol) and tert-butyl 3-(6-cyano-2-pyridyl)propanoate (1.32 g, 5.7 mmol) were dissolved in pyridine (15 ml), and the mixture was refluxed for 15 hrs. The reaction mixture was concentrated under reduced pressure, subjected to a silica gel column chromatography, eluted with hexane-ethyl acetate (3:1, v/v) and recrystallized from ethyl acetate-hexane to give the titled compound (0.85 g, 34%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=O)=[O:7])(C)(C)C.[C:27](Cl)(=O)C.[O:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH2:36][NH2:37]>>[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:10][C@H:9]1[C:24]([NH:37][CH2:36][C:32]1[O:31][CH:35]=[CH:34][CH:33]=1)=[O:26])(=[O:7])[CH3:27]
Reactant: CC(=O)Cl
Reactant: NCc1ccco1
Reactant: CC(C)(C)OC(=O)N1CC(=NOCc2ccc(Cl)c(Cl)c2)C[C@H]1C(=O)O
Product: CC(=O)N1CC(=NOCc2ccc(Cl)c(Cl)c2)C[C@H]1C(=O)NCc1ccco1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, acetyl chloride, and 2-furylmethylamine the title compound was obtained in 199% purity by LC/MS. MS(ESI+): m/z=424.6.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]([C@H:17]1[CH2:22][CH2:21][C@H:20]([C:23]([OH:25])=O)[CH2:19][CH2:18]1)([O:15][CH3:16])=[O:14].[Cl:26][C:27]1[C:28]([CH:33]([NH2:50])[C:34]2[CH:43]=[C:42]3[C:37]([CH:38]=[CH:39][C:40]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[N:41]3)=[CH:36][CH:35]=2)=[N:29][CH:30]=[CH:31][N:32]=1>C1COCC1>[CH3:16][O:15][C:13]([C@H:17]1[CH2:18][CH2:19][C@H:20]([C:23](=[O:25])[NH:50][CH:33]([C:28]2[C:27]([Cl:26])=[N:32][CH:31]=[CH:30][N:29]=2)[C:34]2[CH:43]=[C:42]3[C:37]([CH:38]=[CH:39][C:40]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)=[N:41]3)=[CH:36][CH:35]=2)[CH2:21][CH2:22]1)=[O:14]
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Reactant: NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](C(=O)NC(c2ccc3ccc(-c4ccccc4)nc3c2)c2nccnc2Cl)CC1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
A THF solution (15 mL) of CDI (1.2 g, 7.3 mmol) and trans-4-carbomethoxycyclohexane-1-carboxylic acid (1.2 g, 6.6 mmol) was stirred at 60° C. for 16 h. The reaction mixture was charged with C-(3-chloropyrazin-2-yl)-C-(2-phenylquinolin-7-yl)-methylamine (compound of Formula IV where Q1=2-phenylquinolin-7-yl) (2.3 g, 6.6 mmol) and stirred at 60° C. for 20 h. The reaction mixture was concentrated in vacuo, taken up in EtOAc, and washed with water (2×) and brine (1×). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (20% EtOAc/Hexanes to 100% EtOAc) the desired product as an orange foam; 1H NMR (CDCl3, 400 MHz) δ 1.48-1.55 (m, 4H), 1.95-2.06 (m, 4H), 2.17-2.24 (m, 1H), 2.26-2.33 (m, 1H), 3.66 (s, 3H), 6.77 (d, 1H, J=7.6 Hz), 7.36-7.41 (m, 1H), 7.45-7.55 (m, 3H), 7.72-7.77 (m, 1H), 7.81-7.89 (m, 2H), 8.11 (d, 2H, J=7.2 Hz), 8.20-8.25 (m, 1H), 8.39 (d, 1H, J=2.4 Hz), 8.60 (d, 1H, J=2.8 Hz); MS (ES+): m/z 515.0 [MH+]; HPLC: tR=3.1 mM (Micromass Platform II, nonpolar—5 min).
Reaction SMILES: [CH2:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)C(=O)[C:4](=[O:13])[N:3]1[S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-:33].[K+].[K+]>C(C(C)=O)C(C)C>[CH2:24]([N:9]1[CH2:10][CH2:11][C:6]2([O:13][C:4](=[O:33])[N:3]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:15])=[O:16])[C:2]2=[CH2:1])[CH2:7][CH2:8]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C([O-])[O-]
Reactant: C=C1N(S(=O)(=O)c2ccc(C)cc2)C(=O)C(=O)C12CCNCC2
Reactant: BrCc1ccccc1
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: C=C1N(S(=O)(=O)c2ccc(C)cc2)C(=O)OC12CCN(Cc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
A mixture containing 3.2 g of 4-methylene-2-oxo-3-(4-toluenesulfonyl)-1-oxo-3,8-diazaspiro[4,5]decane, 2.1 g of benzyl bromide and 1.7 g of anhydrous potassium carbonate in 32 ml of methyl isobutyl ketone is refluxed under nitrogen while stirring for 8 hours. After cooling down the reaction mixture to room temperature the inorganic salts are filtered off and the filtrate is evaporated under reduced pressure. The residue is dissolved in 50 ml of benzene, washed to bromide-free and neutral with water, dried over anhydrous sodium sulfate fate and evaporated under reduced pressure. After recrystallizing the crude product obtained from ethanol the title substance is obtained in 84% yield, m.p.: 157°-158° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:4][CH:3]=1.[CH3:17][C:18]([OH:22])([C:20]#[CH:21])[CH3:19].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>N1C=CC=CC=1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:16][O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:21]#[C:20][C:18]([CH3:19])([OH:22])[CH3:17])=[CH:3][CH:4]=1
Reactant: C#CC(C)(C)O
Reactant: COCCCCCCOc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COCCCCCCOc1ccc(C#CC(C)(C)O)cc1

Procedure:
Under a nitrogen atmosphere, to a mixture of 1-bromo-4-(6-methoxyhexyloxy)benzene (3.68 g), 2-methyl-3-butyn-2-ol (1.86 ml) and triethylamine (18 ml) in pyridine (7.4 ml) was added triphenylphosphine (67.2 mg), copper(I) iodide (24.4 mg) and dichlorobis(triphenylphosphine)palladium(II) (18.0 mg), and refluxed overnight. After cooling, insoluble material was filtered off and washed with isopropyl ether. The filtrate was evaporated under reduced pressure. To the residue was added isopropyl ether and the mixture was washed with 0.1N-hydrochloric acid, water and brine. The organic layer was dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give a crude yellow oil. The crude yellow oil was purified by silica gel chromatography (10:1-2:1 hexane-ethyl acetate) to give 4-[4-(6-methoxyhexyloxy)phenyl]-2-methyl-3-butyn-2-ol (3.17 g) as a yellow powder.
Reaction SMILES: C([Si](C)(C)[N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[Cl:15])[CH:8]=[CH:7]1)(C)(C)C.Cl[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH:25][CH:26]2[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]2)[N:20]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[Cl:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[NH:6][CH:7]=[C:8]2[C:23]1[CH:24]=[CH:19][N:20]=[C:21]([NH:25][CH:26]2[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]2)[N:22]=1
Reactant: CC(C)(C)[Si](C)(C)n1ccc2cccc(Cl)c21
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC1(C)CC(Nc2nccc(-c3c[nH]c4c(Cl)cccc34)n2)CC(C)(C)N1

Procedure:
The title compound was prepared as described in Example 215, starting from 1-(tert-butyl-dimethyl-silanyl)-7-chloro-1H-indole (prepared by TBDMS protection of 7-chloro-1H-indole using standard procedures) and (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine, followed by in situ cleavage of the TBDMS protecting group with catalytic amounts of TBAF. Yield: 280 mg (34%).
Reaction SMILES: F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[OH:23][C:24]([CH3:29])([CH3:28])[C:25](O)=[O:26].C(N(CC)C(C)C)(C)C.[Br:39][C:40]1[C:49]([CH3:50])=[CH:48][C:43]([C:44]([NH:46]O)=[NH:45])=[CH:42][C:41]=1[CH3:51]>CN(C)C=O.O>[Br:39][C:40]1[C:49]([CH3:50])=[CH:48][C:43]([C:44]2[N:45]=[C:25]([C:24]([OH:23])([CH3:29])[CH3:28])[O:26][N:46]=2)=[CH:42][C:41]=1[CH3:51]
Reactant: CC(C)(O)C(=O)O
Reactant: Cc1cc(C(=N)NO)cc(C)c1Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-c2noc(C(C)(C)O)n2)cc(C)c1Br
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-(Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU; 0.55 g) is added to a solution of 2-hydroxy-isobutyric acid (0.18 g) and N,N-diisopropyl-ethylamine (1.4 mL) in N,N-dimethylformamide (5 mL) at room temperature. The solution is stirred at room temperature for 10 min prior to the addition of 4-bromo-N-hydroxy-3,5-dimethyl-benzamidine (0.40 g). The solution is stirred at room temperature for another 10 min and then at 110° C. overnight. After cooling to room temperature, water is added and the resulting mixture is extracted with ethyl acetate. The combined extract is washed with brine, dried (MgSO4), and concentrated. The residue is chromatographed on reversed phase (HPLC; acetonitrile/water/trifluoroacetic acid) to give the title compound. LC (method 11): tR=1.16 min; Mass spectrum (ESI+): m/z=313/315 (Br) [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:14]([C:16]1[CH:31]=[CH:30][C:19]([O:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][N:22]=2)=[CH:18][CH:17]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[Cl:50]CCCl>CO.C(Cl)Cl>[ClH:50].[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][C:16]3[CH:31]=[CH:30][C:19]([O:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][N:22]=4)=[CH:18][CH:17]=3)[CH2:9]2)=[CH:6][CH:7]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Reactant: ClCCCl
Reactant: Fc1ccc(C2CCCNC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: Cl
Product: NC(=O)c1ccc(Oc2ccc(CN3CCCC(c4ccc(F)cc4)C3)cc2)nc1
Yield: 51 %

Procedure:
Using a method similar to Example 345, using 3-(4-fluoro-phenyl)-piperidine (0.117 g, 0.542 mmol), 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1) (0.111 g, 0.458 mmol), sodium triacetoxyborohydride (0.135 g, 0.637 mmol), and acetic acid (0.034 mL, 0.594 mmol) in 1,2-dichloroethane (8.0 mL) provides, after silica gel chromatography (12:1 methylene chloride:methanol) and reverse-phase HPLC, 0.0938 g (51%) of the title compound as a white solid: high resolution mass spectrum (electrospray): m/z calc for C24H25FN3O2 406.1931, found 406.1926; 1H NMR (DMSO-d6): 8.64 (d, 1H, J=2.2 Hz), 8.31 (dd, 1H, J=2.6, 8.8 Hz), 8.08 (s br, 1H), 7.68 (d, 2H, J=8.4 Hz), 7.52 (s br, 1H), 7.42-7.08 (m, 5H), 4.33 (s, 2H), 3.50-3.30 (m, 2H), 3.30-2.84 (m, 3H), 2.05-1.79 (m, 3H), 1.75-1.57 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][NH:6][C:7](=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:20][C:21]2[CH:22]=[N:23][C:24](Cl)=[C:25]([CH3:27])[CH:26]=2)[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:10][CH:9]=1.[F-].[K+].[F:33][C:34]([F:46])([F:45])[O:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1>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>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][NH:6][C:7](=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:20][C:21]2[CH:22]=[N:23][C:24]([C:39]3[CH:38]=[CH:37][C:36]([O:35][C:34]([F:33])([F:45])[F:46])=[CH:41][CH:40]=3)=[C:25]([CH3:27])[CH:26]=2)[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:10][CH:9]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CC(C)(C)C)Oc2cnc(Cl)c(C)c2)cc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Product: COC(=O)CCNC(=O)c1ccc(C(CC(C)(C)C)Oc2cnc(-c3ccc(OC(F)(F)F)cc3)c(C)c2)cc1
Yield: 85.6 %

Procedure:
3-{4-[1-(6-Chloro-5-methyl-pyridin-3-yloxy)-3,3-dimethyl-butyl]-benzoylamino}-propionic acid methyl ester (200 mg, 0.46 mmol), potassium fluoride (80 mg, 1.38 mmol), 4-trifluoromethoxyphenyl boronic acid (190 mg, 0.92 mmol) and tetrakis(triphenylphosphine)palladium (53 mg, 0.046 mmol) are placed in a flask. After the reaction is purged with N2 for several times, THF/H2O (20 ml/5 ml) is added. The resulting solution is refluxed overnight, loaded on silica gel, eluted with hexane and ethyl acetate to give the titled compound (220 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:10][CH:9]([NH:24][C:25]([C:27]2[NH:28][C:29]3[C:34]([CH:35]=2)=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[C:8]1=[O:36].[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>C(OC(C)C)(C)C>[CH3:37][N:38]1[CH2:43][CH2:42][N:41]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:10][CH:9]([NH:24][C:25]([C:27]3[NH:28][C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])[C:8]2=[O:36])[CH2:40][CH2:39]1
Reactant: CN1CCNCC1
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2N(CCOCCCl)C1=O)c1cc2ccccc2[nH]1
Solvent: CC(C)OC(C)C
Product: CN1CCN(CCOCCN2C(=O)C(NC(=O)c3cc4ccccc4[nH]3)N=C(c3ccccc3)c3ccccc32)CC1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
A mixture of (3RS)-1-[2-(2-chloroethoxy)ethyl]-1,3-dihydro-3-(2-indolylcarbonylamino)-5-phenyl-2H-1,4-benzodiazepine-2-one (500 mg) and 1-methylpiperazine (5.0 ml) was stirred at 70° C. for 5.0 hours. Then diisopropyl ether (30 ml) was added to the reaction mixture. After the resultant precipitate was filtered off, the filtrate was evaporated. The residue was washed with water and dried to give (3RS)-1-[2-[2-(4-methyl-1-piperazinyl)-ethoxy]ethyl]-1,3-dihydro-3-(2-indolylcarbonylamino)-5-phenyl-2H-1,4-benzodiazepine-2-one (0.43 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[C:12]([NH:21][CH2:22]CC)=[N:11][N:10]=1.[C:26]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[C:12]([N:21]([CH3:26])[CH3:22])=[N:11][N:10]=1
Reactant: O=C([O-])[O-]
Reactant: CCCNc1nnc(Cc2c(Cl)cncc2Cl)c2ccc(OC)cc12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(N(C)C)c2c1
Temperature: 50 °C
Yield: 48.8 %

Procedure:
At room temperature a solution of [4-(3,5-dichloro-pyridin-4-ylmethyl)-7-methoxy-phthalazin-1-yl]-propyl-amine (3.5 g, 5.64 mmoles), prepared as described in example 78, in DMF (35 ml) was stirred under N2, then added with K2CO3 (0.78 g, 5.64 mmoles) and methyl iodide (0.35 ml, 5.64 mmoles). The mixture was heated at 50° C. and after 20 hours was dried and partitioned between water and CH2Cl2. The organic phase was washed with water, anhydrified and concentrated to give an oil which was flash chromatographed (eluent: hexane/ethyl acetate 4:6) to give 1 g of the title compound (yield: 50%). m.p.: 170-173° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:14][C:15]2[CH:19]=[C:18]([C:20]3[S:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[O:17][N:16]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].O.[OH-].[Li+].Cl>C1COCC1.O>[Cl:25][C:22]1[S:21][C:20]([C:18]2[O:17][N:16]=[C:15]([CH2:14][N:6]3[C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH:13]=[C:5]3[C:3]([OH:4])=[O:2])[CH:19]=2)=[CH:24][CH:23]=1
Reactant: COC(=O)c1cc2ccccc2n1Cc1cc(-c2ccc(Cl)s2)on1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2ccccc2n1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 288 mg 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid methyl ester in 10 ml THF, 3 ml water and 57.0 mg lithium hydroxide monohydrate were added. After stirring for 2 h at 60° C. the reaction was cooled to RT. The mixture was acidified with half concentrated hydrochloric acid. The resulting precipitate was collected by filtration and washed with 3 ml water. The product was obtained as a white solid which was dried under reduced pressure.