Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:7]([C:14]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:15]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O)[C:8](=[O:13])C(Cl)(Cl)Cl)[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1.C([O-])(=O)C.[NH4+].C([N:38](CC)CC)C>C(O)(C)(C)C>[CH2:1]([N:7]1[C:14]2[C:15](=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=2)[C:16]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:38][C:8]1=[O:13])[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1N(CC1CCCO1)C(=O)C(Cl)(Cl)Cl
Reactant: CCN(CC)CC
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(C)(C)O
Product: O=c1nc(-c2ccccc2)c2cc([N+](=O)[O-])ccc2n1CC1CCCO1

Procedure:
A mixture of 2.36 g of 2-(N-tetrahydrofurfuryltrichloroacetamido)-5-nitrobenzophenone, 2.4 g of ammonium acetate, 0.5 g of triethylamine and 30 ml of tertiary butanol was stirred under reflux for 10 hours. Then the solvent was removed and water was added to the residue. The resulting mixture was extracted with chloroform and the extract was washed successively with dilute ammonia water and water, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was washed with ether and the insoluble product was collected by filtration and dried to give 1-tetrahydrofurfuryl-4-phenyl-6-nitro-2(1H)-quinazolinone, m.p. 150°-152° C.
Reaction SMILES: C(O[C:4](=[O:23])[CH:5]([O:20][CH2:21][CH3:22])[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]1=[O:19])C.[NH2:24][CH2:25][C:26]1[CH:34]=[C:33]2[C:29]([C:30]([NH2:35])=[N:31][NH:32]2)=[CH:28][CH:27]=1>>[NH2:35][C:30]1[C:29]2[C:33](=[CH:34][C:26]([CH2:25][NH:24][C:4](=[O:23])[CH:5]([O:20][CH2:21][CH3:22])[N:6]3[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:7]3=[O:19])=[CH:27][CH:28]=2)[NH:32][N:31]=1
Reactant: NCc1ccc2c(N)n[nH]c2c1
Reactant: CCOC(=O)C(OCC)n1cccc(Nc2ccccc2)c1=O
Product: CCOC(C(=O)NCc1ccc2c(N)n[nH]c2c1)n1cccc(Nc2ccccc2)c1=O

Procedure:
Using similar procedures as described in example 25, (RS)-ethoxy-(2-oxo-3-phenylamino-2H-pyridin-1-yl)-acetic acid ethyl ester (example 21.1) was hydrolyzed according to general procedure B. The corresponding acid was reacted according to general procedure C with 6-aminomethyl-1H-indazol-3-ylamine (CAS 368426-75-9) to give (RS)-N-(3-amino-1H-indazol-6-ylmethyl)-2-ethoxy-2-(2-oxo-3-phenylamino-2H-pyridin-1-yl)-acetamide. Off-white solid. MS 433.3 ([M+H]+)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH:16]([O:18][Si](C(C)(C)C)(C)C)[CH3:17])[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([CH:16]([OH:18])[CH3:17])[CH2:14][CH2:15]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(O[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H](CNC(=O)OC(C)(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(O)[C@H]1CC[C@H](CNC(=O)OC(C)(C)C)CC1

Procedure:
In 20 ml of dry tetrahydrofuran was dissolved 1.3 g of trans-N-t-butoxycarbonyl-4-(1-t-butyldimethylsilyloxyethyl)cyclohexylmethylamine, and 5.25 ml of tetrabutylammonium fluoride (1.0M tetrahydrofuran solution) were added dropwise thereto with stirring under ice-cooling, and the mixture was stirred at room temperature for 55 minutes. Then, 5.0 ml of tetrabutylammonium fluoride (1.0M tetrahydrofuran solution) were added dropwise thereto and the mixture was stirred at room temperature overnight and further at 50° C. for 9 hours. To the reaction mixture were added 200 ml of ethyl acetate, and the mixture was washed successively with an aqueous citric acid solution, an aqueous sodium chloride solution, an aqueous sodium bicarbonate solution and an aqueous sodium chloride solution. The mixture was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: cyclohexane/ethyl acetate=2/1) to obtain 701 mg of the desired compound as a colorless crystalline solid. Further, 38 mg of the desired compound was obtained from the mother liquid.
Reaction SMILES: BrCC[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1F.[C:15]([Cu])#[N:16]>CN(C=O)C.O>[CH3:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[C:15]#[N:16]
Reactant: N#C[Cu]
Reactant: N#Cc1ccc(OCCCBr)c(F)c1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C#N)cc1C#N
Temperature: 120 °C
Reaction time: 15 h
Yield: 47.8 %

Procedure:
2,4-Dibromo-1-methoxybenzene (25 g, 0.094 mol; see step (i) above) was dissolved in dry DMF (50 mL). CuCN (25.3 g, 0.283 mol) was then added and the resulting mixture was stirred at 120° C. for 15 h, before being cooled to RT. The crude mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel, using 25% ethyl acetate in petroleum ether as eluent, to yield the sub-title compound (7.1 g, 24%) as pale yellow solid.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([N:23]5[CH2:28][CH:27]([CH3:29])[O:26][CH:25]([CH3:30])[CH2:24]5)=[CH:19][N:18]=4)[N:14]=[CH:15][C:10]=3[C:9]([CH3:31])=[C:8]([C:32]([O:34]CC)=[CH2:33])[C:7]2=[O:37])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>C(OCC)(=O)C.ClCCl.C([O-])(O)=O.[Na+]>[C:32]([C:8]1[C:7](=[O:37])[N:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:11]2[N:12]=[C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:24][CH:25]([CH3:30])[O:26][CH:27]([CH3:29])[CH2:28]4)=[CH:19][N:18]=3)[N:14]=[CH:15][C:10]=2[C:9]=1[CH3:31])(=[O:34])[CH3:33]
Reactant: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CC(C)OC(C)C4)cn3)nc2n(C2CCCC2)c1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)c1c(C)c2cnc(Nc3ccc(N4CC(C)OC(C)C4)cn3)nc2n(C2CCCC2)c1=O
Yield: 38.5 %

Procedure:
8-Cyclopentyl-2-[5-(2,6-dimethyl-morpholin-4-yl)-pyridin-2-ylamino]-6-(1-ethoxy-vinyl)-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.055 g, 0.109 mmol) was dissolved in ethyl acetate (3 mL) and 1 N aqueous HCl (2 mL) and stirred at room temperature for 48 hours. The reaction mixture was diluted with dichloromethane and aqueous NaHCO3. The layers were separated and the organic layer was dried over MgSO4, filtered, and the solvent evaporated to give 6-acetyl-8-cyclopentyl-2-[5-(2,6-dimethyl-morpholin-4-yl)-pyridin-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.020 g, 38.4%). MS (APCl) Calc'd for M+1: 477.3. Found: 477.2. 1H NMR δ(400 MHz, CDCl3) 8.79 (s, 1H), 8.1 (d, J=9.0 Hz, 1H), 8.00 (d, J=2.7 Hz, 1H), 7.90 (s, 1H), 7.30 (dd, J=3.1, 9.3 Hz, 1H), 5.87 (m, 1H), 3.83 (m, 2H), 3.37 (d, J=10.0 Hz, 2H), 2.54 (s, 3H), 2.46 (dd, J=11.7, 11.7, 2H), 2.37 (s, 3H), 2.32 (m, 2H), 2.05 (m, 2H), 1.87 (m, 2H), 1.68 (m, 2H), 1.27 (d, J=6.4 Hz, 6H).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH2:19]([O:21][C:22](=[O:32])[CH2:23][NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:20].C(OCC)(=O)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:19]([O:21][C:22](=[O:32])[CH2:23][N:24]([C:16](=[O:18])[C@H:12]([CH:13]([CH3:14])[CH3:15])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:20]
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(Cc1ccccc1)C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C

Procedure:
CBZ-L-Valine (12.6g, 0.05mol) was dissolved in CH2Cl2 (250mL) and the following reagents were added in equal molar amounts in the stated order; 4-Dimethylaminopyridine (DMAP), ethyl-N-(benzyl)glycinate and WSCDI. The reaction mixture was allowed to stir at room temperature over night. Evaporation of the solvent yielded a viscous semisolid which was treated with ethyl acetate and then IN HCl and separated. The organic extract was washed with 1N HCl followed by 5% aqueous Na2CO3 and saturated aqueous NaCl-solution. After drying over MgSO4, filtration and evaporation under reduced pressure afforded an oil (17.6 g) which ws used as is for saponification.
Reaction SMILES: [O:1]=[C:2]([CH3:5])[CH:3]=[CH2:4].[CH3:6][NH:7][CH2:8][CH2:9][CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(OCC)C>[CH3:6][N:7]([CH2:8][CH2:9][CH:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:4][CH2:3][C:2](=[O:1])[CH3:5]
Reactant: C=CC(C)=O
Reactant: CNCCC(c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: CC(=O)CCN(C)CCC(c1ccccc1)c1ccccc1
Yield: 100 %

Procedure:
A solution of 3.72 ml of 3-oxo-but-1-ene was added dropwise, over a period of 20 minutes and such that the temperature did not exceed 2°-3° C., to a cooled solution of 7.87 g of N-methyl-3,3-diphenylpropylamine in 7 ml of diethyl ether. The solution thus obtained was evaporated in vacuo at room temperature to give 10.3 g of N-methyl-N-(3,3-diphenylpropyl)-4-aminobutan-2-one (100%) as free base, shown to be practically pure by TLC (chloroform: methanol 9:1 by volume) which could be used as such for further reactions. This compound could be transformed into the corresponding hydrochloride (m.p. 133°-135° C.) by treating the free base with hydrogen chloride in diethyl ether, and crystallizing the product thus obtained first from acetone: ethyl acetate: isopropanol then from acetone.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[NH:11][CH:12]=[C:13]([C:15]2[C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:17][O:18][C:19]=2[CH3:20])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:28][C:29]1[CH:33]=[C:32]([CH3:34])[O:31][N:30]=1>>[CH2:1]([O:8][CH2:9][C:10]1[N:11]([CH2:28][C:29]2[CH:33]=[C:32]([CH3:34])[O:31][N:30]=2)[CH:12]=[C:13]([C:15]2[C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:17][O:18][C:19]=2[CH3:20])[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(CCl)no1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]c(COCc2ccccc2)n1
Product: Cc1cc(Cn2cc(-c3c(-c4ccccc4)noc3C)nc2COCc2ccccc2)no1
Yield: 63 %

Procedure:
As described for Example 67, 4-(2-benzyloxymethyl-1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (100 mg, 0.29 mmol) using 3-(chloromethyl)-5-methylisoxazole instead of benzyl bromide was converted to the title compound (80 mg, 63%) which was obtained as a light yellow gum. MS: m/e=441.4 [M+H]+.
Reaction SMILES: O.[CH3:2][N:3]1[C@H:13]2[CH2:14][C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[C:17]4[O:22][C@H:7]5[C:8]([CH:10]=[CH:11][C@:12]2([OH:23])[C@:6]5([C:16]=34)[CH2:5][CH2:4]1)=[O:9].[H][H]>[Pd].C(O)(=O)C>[CH3:2][N:3]1[C@@H:13]2[CH2:14][C:15]3=[CH:20][CH:19]=[C:18]([OH:21])[C:17]4[O:22][C@H:7]5[C:8]([CH2:10][CH2:11][C@:12]2([OH:23])[C@:6]5([C:16]=43)[CH2:5][CH2:4]1)=[O:9]
Reactant: [H][H]
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)C=C[C@@]3(O)[C@@H]1C5
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Temperature: 30 °C

Procedure:
A hydrogenation vessel is charged with kg litre water and 0.73 kg acetic acid before adding 1 kg of 14-hydroxymorphinone prepared as in Example 1.1A and the mixture stirred until clear. 40 g of wet 10% Pd on carbon catalyst is added under a stream of nitrogen, and hydrogen supplied at 35-40 psi (2.41-2.76 bar). The temperature is maintained at 30±5° C. until hydrogen uptake stops, then the vessel is maintained at 35-40 psi (2.41-2.76 bar) and 30±5° C. for 3-4 hours. The reaction vessel is cooled to less than 25° C. and a sample subjected to HPLC to check for 14-hydroxymorphinone. If the 14-hydroxymorphinone area detected by HPLC is >0.1%, the hydrogenation is repeated.
Reaction SMILES: Cl.Cl.Cl.[S:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH:6]=[CH:5]1.C[O:29][C:30](=O)[CH2:31][C@H:32]1[CH2:36][CH2:35][C@H:34]([O:37][CH3:38])[CH2:33]1>>[CH3:38][O:37][C@H:34]1[CH2:35][CH2:36][C@H:32]([CH2:31][C:30]([NH:27][C@H:24]2[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]3[CH2:17][CH2:18][N:13]([C:8]4[C:7]5[CH:6]=[CH:5][S:4][C:12]=5[CH:11]=[CH:10][N:9]=4)[CH2:14][CH2:15]3)[CH2:22][CH2:23]2)=[O:29])[CH2:33]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4sccc34)CC2)CC1
Reactant: COC(=O)C[C@H]1CC[C@H](OC)C1
Agent: Cl
Product: CO[C@H]1CC[C@H](CC(=O)N[C@H]2CC[C@H](CCN3CCN(c4nccc5sccc45)CC3)CC2)C1

Procedure:
The title compound was prepared in analogy to example 2 starting from trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (intermediate B) (100 mg, 0.22 mmol) and racemic trans-(3-methoxy-cyclopentyl)-acetic acid methyl ester [WO 2009/019174] (46 mg, 0.27 mmol). Purification by flash chromatography on silica gel (CH2Cl2/MeOH 95:5). White crystals (61 mg, 57%), MS (ISP) m/z=485.4 [(M+H)+].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13].C(N(CC)C(C)C)(C)C>CN1CCCC1=O.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.[Cu]I>[N+:8]([C:5]1[CH:4]=[CH:3][C:2]([C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])=[CH:7][N:6]=1)([O-:10])=[O:9]
Reactant: C#C[Si](C)(C)C
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: C[Si](C)(C)C#Cc1ccc([N+](=O)[O-])nc1
Temperature: 65 °C
Reaction time: 4 h
Yield: 45.1 %

Procedure:
To a solution of 5-bromo-2-nitropyridine (1.00 g, 4.93 mmol) in N-methylpyrrolidinone (20 mL) were added trimethylsilyl acetylene (1.39 mL, 9.85 mmol), tetrakis(triphenylphosphine)palladium (0) (114 mg, 985 μmol), copper (I) iodide (37.5 mg, 197 μmol) and N,N-diisopropylethylamine (1.72 mL, 9.85 mmol) at room temperature, which was stirred under nitrogen atmosphere for 4 hours at 65° C. The reaction solution was partitioned into water and ethyl acetate at 0° C. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=6:1) to obtain the title compound (490 mg, 45%).
Reaction SMILES: C(CC1C=CC(C[CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[C@@H:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([O:31]C(=O)C(C)(C)C)[CH:25]=[CH:24][C:23]=3[CH2:22]2)=CC=1)(O)=O.[CH3:40][CH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>>[CH2:11]([N:12]([CH2:27][C:28]1[CH:29]=[CH:30][C:21]([CH2:14][CH2:13][N:44]2[CH2:45][CH2:46][CH:41]([CH3:40])[CH2:42][CH2:43]2)=[CH:22][CH:23]=1)[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[C@@H:21]1[CH2:30][CH2:29][C:28]2[CH:27]=[C:26]([OH:31])[CH:25]=[CH:24][C:23]=2[CH2:22]1)[CH3:10]
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(CC(=O)O)cc2)c1
Reactant: CC1CCNCC1
Product: CCN(Cc1ccc(CCN2CCC(C)CC2)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 33.7 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(4-carboxymethylbenzyl)ethylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 4-methylpiperidine (17 mg) according to an analogous synthetic method to Example 715 and purified by LC-MS, the title compound (3.1 mg) was obtained.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[O:25][N:24]=[C:23]([CH:26]([CH3:28])[CH3:27])[N:22]=3)[CH2:17][CH2:16]2)=[CH:9][CH:8]=1.C([O:32][B:33](OC(C)C)[O:34]C(C)C)(C)C.Cl>C1COCC1>[CH3:27][CH:26]([C:23]1[N:22]=[C:21]([N:18]2[CH2:19][CH2:20][CH:15]([CH2:14][O:13][C:10]3[CH:11]=[CH:12][C:7]([B:33]([OH:34])[OH:32])=[CH:8][CH:9]=3)[CH2:16][CH2:17]2)[O:25][N:24]=1)[CH3:28]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)c1noc(N2CCC(COc3ccc(Br)cc3)CC2)n1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)c1noc(N2CCC(COc3ccc(B(O)O)cc3)CC2)n1
Temperature: -78 °C
Reaction time: 2 h
Yield: 34.8 %

Procedure:
n-Butyllithium (2.5M in hexanes, 0.56 mL, 1.4 mmol) was added dropwise to a solution of 4-{[(4-bromophenyl)oxy]methyl}-1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]piperidine (prepared as in Example 24, Step 1, 380 mg, 1 mmol) in THF (5 mL) at −78° C. The mixture was stirred at −78° C. for 2 h, and was then charged with a cooled solution (−78° C.) of triisopropylborate (0.46 mL, 2 mmol) in THF (3 mL) at −78° C. The reaction mixture was allowed to warm up to ambient temperature and stirred at ambient temperature overnight. The reaction mixture was charged with 1N HCl (20 mL) and stirred at ambient temperature for 1 h. The mixture was then extracted with Et2O, and the organic extracts were dried over MgSO4, filtered, and the filtrate was concentrated. The crude product was purified by chromatography on a silica gel column using 0 to 7% MeOH/CH2Cl2 to give 120 mg (35%) of the {4-[({1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]phenyl}boronic acid as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.82 (s, 2H), 7.69 (d, 2H, J=8.8 Hz), 6.86 (d, 2H, J=8.8 Hz), 4.04-3.92 (m, 2H), 3.85 (d, 2H, J=6.4 Hz), 3.15-3.05 (m, 2H), 2.84-2.73 (m, 1H), 2.04-1.94 (m, 1H), 1.88-1.78 (m, 2H), 1.37-1.22 (m, 2H), 1.16 (d, 6H, J=6.9 Hz); LRMS (ESI), m/z 346 (M+H).
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][OH:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].[CH2:9]([O:16][C:17](Cl)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:9]([O:16][C:17](=[O:18])[NH:1][C@H:2]([CH2:7][OH:8])[C@@H:3]([CH3:4])[CH2:5][CH3:6])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC[C@H](C)[C@H](N)CO
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](C)[C@@H](CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.3 %

Procedure:
To a solution of L-isoleucinol (2.20 g, 18.8 mmol) in methylene chloride (66 ml) were added chloroformic acid benzyl ester (3.22 ml, 22.5 mmol) and triethylamine (3.15 ml, 22.5 mmol) in an ice bath, and the mixture was stirred at room temperature for 1.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (2:1→1:1) as the eluant to afford [(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]carbamic acid benzyl ester (4.17 g, yield 88%) as a colorless oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][C:7](Cl)=[O:8].[CH3:10][N:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[CH2:20][CH2:21][C:22](=[O:23])[C:12]1=2>C(Cl)Cl>[Cl:5][CH2:6][C:7]([C:16]1[CH:17]=[CH:18][C:19]2[N:11]([CH3:10])[C:12]3[C:22](=[O:23])[CH2:21][CH2:20][C:13]=3[C:14]=2[CH:15]=1)=[O:8]
Reactant: O=C(Cl)CCl
Reactant: Cn1c2c(c3ccccc31)CCC2=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cn1c2c(c3cc(C(=O)CCl)ccc31)CCC2=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 53.1 %

Procedure:
Aluminum chloride (8.5g) was suspended in CH2Cl2 (20 ml) at 0° C., chloroacetyl chloride (7.2 g) was slowly added and the mixture was stirred for 5 minutes. This mixture was added dropwise to a stirred solution of 1,4-dihydro-4-methylcyclopent[b]indol-3(2H)-one (6.0 g) in 100 ml CH2Cl2 at 0° C. The mixture was stirred at 0° C. for 45 minutes and thereafter an additional equivalent of preformed solution of aluminum chloride and chloroacetyl chloride in methylene chloride was introduced in a dropwise manner. After 30 minutes the reaction mixture was slowly poured into a stirred ice/water mixture. The layers were separated and the CH2Cl2 layer was washed with NaHCO3, dried (Na2SO4) and concentrated to an oil. Purification by flash chromatography on silica gel eluting with hexane/acetone provided 7-chloroacetyl-1,4-dihydro-4-methylcyclopent[b]indol-3(2H)-one (4.5 g).
Reaction SMILES: [NH2:1][C:2]1([CH3:27])[CH2:6][CH2:5][N:4]([C:7]2[C:16]([F:17])=[C:15]3[C:10]([C:11](=[O:24])[C:12]([C:21]([OH:23])=[O:22])=[CH:13][N:14]3[CH:18]3[CH2:20][CH2:19]3)=[C:9](F)[C:8]=2[F:26])[CH2:3]1.[NH3:28]>>[NH2:28][C:9]1[C:8]([F:26])=[C:7]([N:4]2[CH2:5][CH2:6][C:2]([NH2:1])([CH3:27])[CH2:3]2)[C:16]([F:17])=[C:15]2[C:10]=1[C:11](=[O:24])[C:12]([C:21]([OH:23])=[O:22])=[CH:13][N:14]2[CH:18]1[CH2:19][CH2:20]1
Reactant: N
Reactant: CC1(N)CCN(c2c(F)c(F)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Product: CC1(N)CCN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Temperature: 100 °C

Procedure:
A mixture of 7-(3-amino-3-methyl-1-pyrrolidinyl)-1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (150 mg) and 28% aqueous ammonia (15 ml) was heated at 100° C. for 48 hours in a sealed tube. The reaction mixture was evaporated to dryness under reduced pressure and water was added to the residue. The resulting crystals were treated in the same manner as described in Example 10 (1) to give 5-amino7-(3-amino-3-methyl-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (93 mg), m.p. 271°-273° C (decomp.).
Reaction SMILES: [NH3:1].[F:2][C:3]1[CH:18]=[C:17](F)[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][C:4]=1[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].O>C1COCC1>[NH2:1][C:17]1[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][C:4]([C:5]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:6])=[C:3]([F:2])[CH:18]=1
Reactant: O=C(OCc1ccccc1)c1cc([N+](=O)[O-])c(F)cc1F
Reactant: N
Solvent: O
Solvent: C1CCOC1
Product: Nc1cc(F)c(C(=O)OCc2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2M Ammonia (25.6 mL, 51.2 mmol) was added to Benzyl 2,4-difluoro-5-nitro-benzoate in 200 mL THF at 0° C. and the mixture stirred for 16 h at ambient temperature. Then 100 mL water were added, the preticipate was filtered off, washed with water and dried at 60° C.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:16]CCl>O=P(Cl)(Cl)Cl>[Cl:16][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: ClCCl
Reactant: Oc1ccnc2cc(C(F)(F)F)ccc12
Solvent: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1ccc2c(Cl)ccnc2c1

Procedure:
A solution of 4-hydroxy-7-trifluoromethylquinoline (1 g) in dichloromethane (10 mL) and POCl3 (1 mL) was refluxed for half an hour. Then the reaction mixture was quenched with water (80 mL) and sodium bicarbonate to pH 7. The aqueous solution was extracted with dichloromethane (2×60 mL). The organic layers were combined, dried, evaporated to give 4-chloro-7-trifluoromethylquinoline. LCMS: ret. time: 31.51 min.; purity: 100%; MS (m/e): 232 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:8]2[CH:9]=[C:10]([O:15][CH3:16])[C:11]([O:13][CH3:14])=[CH:12][C:7]=2[N:6]([CH3:17])[C:5](=[O:18])[CH2:4][N:3]=1.[C:19]1(B(O)O)C=CC=C[CH:20]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[C:8]2[CH:9]=[C:10]([O:15][CH3:16])[C:11]([O:13][CH3:14])=[CH:12][C:7]=2[N:6]([CH2:17][CH2:19][CH3:20])[C:5](=[O:18])[CH2:4][N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1cc2c(cc1OC)N(C)C(=O)CN=C2Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN1C(=O)CN=C(Cl)c2cc(OC)c(OC)cc21
Temperature: 115 °C
Yield: 55.6 %

Procedure:
Heat at 115° C. for 12 hours under an inert atmosphere a mixture of 200 mg (0.74 mmol) of 5-chloro-7,8-dimethoxy-1-methyl-1,3-dihydro-1,4-benzodiazepin-2-one XVIIIaa, 109 mg (0.89 mmol) of benzene boronic acid, 182 mg (0.86 mmol) of K3PO4, 23 mg (0.020 mmol) of tetrakis(triphenylphosphine)Pd(0) in 5 ml of DMF. Allow to cool to room temperature. Add 80 ml of H2O and extract three times with 50 ml of Et2O. Dry the organic fractions on Na2SO4. Purify by chromatography (AcOEt). Recrystallize in EtOH. One obtains 122 mg of the abovenamed product in the form of colorless crystals.