Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Cl:9][C:10]1[C:11](F)=[CH:12][C:13]2[O:18][CH:17]([C:19]([F:22])([F:21])[F:20])[C:16]([C:23]([O:25]CC)=[O:24])=[CH:15][C:14]=2[CH:28]=1>>[Cl:9][C:10]1[C:11]([O:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:12][C:13]2[O:18][CH:17]([C:19]([F:21])([F:20])[F:22])[C:16]([C:23]([OH:25])=[O:24])=[CH:15][C:14]=2[CH:28]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: Oc1cccc(Cl)c1
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3cccc(Cl)c3)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 3-chlorophenol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 174.1-176.1° C. 1H NMR (acetone-d6/300 MHz) 7.91 (s, 1H), 7.73 (s, 1H), 7.48 (m, 1H), 7.29 (d, 1H, J=7.5 Hz), 7.17 (d, 1H, J=2.0 Hz), 7.08 (d, 1H, J=8.3 Hz), 6.73 (s, 1H), 5.85 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6/282 MHz) −79.4 (d, J=6.5 Hz) FABLRMS m/z 403 (M−H). ESHRMS m/z 402.9752 (M−H, Calc'd 402.9729). Anal. Calc'd for C17H9Cl2F3O4: C, 50.40; H, 2.24; Cl, 17.50. Found: C, 50.18; H, 2.00; Cl, 17.26.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[N:14]=[C:13](Cl)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1>C(Cl)Cl>[Cl:4][C:5]1[N:14]=[C:13]([NH:2][NH2:3])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: NN
Solvent: ClCCl
Solvent: O
Product: NNc1nc(Cl)nc2ccccc12
Reaction time: 8 h

Procedure:
87 g (1.74 moles) of hydrazine hydrate were added dropwise to a suspension of 86.5 g (0.43 mole) of 2,4-dichloroquinazoline in 1500 ml of methylene chloride at room temperature, while cooling with ice and stirring vigorously. After 8 hours at room temperature, the precipitate was filtered off under suction, washed with water and dried. Yield: 78.4 g (92%) of 2-chloro-4-hydrazinoquinazoline, mp.>280° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1.[C:32]1([NH:38]N)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:38][C:32]2[C:37]([C:9]=1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]1)=[CH:36][CH:35]=[CH:34][CH:33]=2
Reactant: NNc1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3I)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4I)[nH]c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(2-iodophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and phenylhydrazine: ESMS m/e: 606.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C@H:11]([CH2:13][CH3:14])[CH3:12])[CH:5]=[O:6].O.S(=O)(=O)(O)[OH:17]>CC(C)=O.[O-2].[Cr+6].[O-2].[O-2]>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C@H:11]([CH2:13][CH3:14])[CH3:12])[C:5]([OH:17])=[O:6]
Reactant: CC[C@H](C)Oc1ccc(C=O)cc1F
Reactant: O=S(=O)(O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(C)=O
Solvent: O
Product: CC[C@H](C)Oc1ccc(C(=O)O)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 130 mg (0.66 mmol) of 3-fluoro-4-(2-(S)-butoxy)benzaldehyde in 1 mL of acetone was treated with a 73 mg (0.73 mmol) of chromium (VI) oxide in a 3:1 v/v mixture of water/sulfuric acid at 0° C. The reaction was allowed to warm to rt and was stirred for 2 hr then extracted with 10 mL of EtOAc, washed with brine, dried over MgSO4 and concentrated to afford 130 mg of the title compound: 1H NMR (500 Mhz) δ 1.00 (t, J=7.6, 3H), 1.36 (d, J=6.2, 3H), 1.70 (m, 1H), 1.82 (m, 1H), 4.44 (m, 1H), 6.99 (t, J=8.2, 1H), 7.79 (d, J=8.2, 1H), 7.85 (s, 1H).
Reaction SMILES: C([O:4][C:5]([C@@H:7]1[C@@H:12]2[C@H:8]1[CH2:9][C@H:10]([F:23])[C@@:11]2([NH:16]C(OCC=C)=O)[C:13]([OH:15])=[O:14])=[O:6])C=C.[C:24](=[O:36])([O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[O:25][CH:26](Cl)[CH3:27]>>[NH2:16][C@@:11]1([C:13]([O:15][CH:26]([O:25][C:24]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:36])[CH3:27])=[O:14])[C@@H:10]([F:23])[CH2:9][C@@H:8]2[C@H:12]1[C@H:7]2[C:5]([OH:4])=[O:6]
Reactant: CC(Cl)OC(=O)OC1CCCCC1
Reactant: C=CCOC(=O)N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@@H]1F)[C@@H]2C(=O)OCC=C
Product: CC(OC(=O)OC1CCCCC1)OC(=O)[C@@]1(N)[C@H]2[C@@H](C[C@@H]1F)[C@@H]2C(=O)O
Yield: 14.4 %

Procedure:
(1S,2S,3S,5R,6S)-6-((Allyloxy)carbonyl) 2-(((allyloxy)carbonyl)amino)-3-fluorobicyclo[3.1.0]hexane-2-carboxylic acid (B-1-1, 701 mg) and 1-chloroethyl cyclohexyl carbonate (664 mg) were treated in the same manner as in Example A-8 (1), (2) to give the title compound (B-1, 115 mg) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Cl)=[CH:4][CH:3]=1.[C:10]([NH:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[N:18][CH:17]=1)([CH3:13])([CH3:12])[CH3:11].CO.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1COCC1>[C:10]([NH:14][C:15](=[O:23])[C:16]1[C:21]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:20][C:19]([Cl:22])=[N:18][CH:17]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: Fc1ccc([Mg]Cl)cc1
Reactant: CC(C)(C)NC(=O)c1ccc(Cl)nc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1cnc(Cl)cc1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 47.9 %

Procedure:
14.1 ml (14.1 mMol) 4-Fluoro-phenylmagnesium chloride solution (1M in THF) were added over 10 minutes to a solution of 1.0 g (4.7 mMol) N-tert.-butyl-6-chloro-nicotinamide in 5.0 ml THF cooled to 0° C. and the reaction mixture was stirred 18 hours at 35° C. After cooling to 0° C., 1.14 ml (28.2 mMol) methanol were added over 20 minutes, followed, after 15 minutes, by 1.17 g (5.2 mMol) 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. After 30 minutes at room temperature, the brown solution was concentrated under reduced pressure to about 10 g, heated to 50° C. and 20 ml tert.-butyl-methylether were added. The resulting suspension was stirred 1 hour at 55° C., then 1 hour at room temperature and filtered. The filtrate was concentrated under reduced pressure and digested in 5 ml n-hexane/ethyl acetate 4:1 to yield 0.69 g (48%) N-tert.-butyl-6-chloro-4-p-fluoro-phenyl-nicotinamide as a light brown powder of m.p.=168-173° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][C:18]=3[CH3:26])[C:13](=[O:27])[N:12]([C:28]3[CH:33]=[CH:32][C:31]([N+:34]([O-])=O)=[CH:30][C:29]=3[CH3:37])[C:11]2=[O:38])=[C:6]([CH3:39])[CH:5]=1)([O-])=O.Cl.O>C1COCC1.[Pd]>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([N:14]2[C:15](=[O:16])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][C:6]=3[CH3:39])[C:11](=[O:38])[N:12]([C:28]3[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][C:29]=3[CH3:37])[C:13]2=[O:27])=[C:18]([CH3:26])[CH:19]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1-n1c(=O)n(-c2ccc([N+](=O)[O-])cc2C)c(=O)n(-c2ccc([N+](=O)[O-])cc2C)c1=O
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(N)ccc1-n1c(=O)n(-c2ccc(N)cc2C)c(=O)n(-c2ccc(N)cc2C)c1=O
Yield: 79.2 %

Procedure:
1,3,5-tris-(4-nitro-2-methyl-phenyl)-[1,3,5]triazinane-2,4,6-trione (2.86 g, 5.4 mmol) was dissolved in THF (70 ml). HCl (4.5 ml, 6M), water (18 ml) and Pd/C (0.6 g, 10%) was added. The reaction vessel was evacuated and filled with argon in three cycles before hydrogenated on a Parr hydrogenation apparatus (60 psi). After 2 hours the excess hydrogen was evacuated with a membrane pump and the Pd/C (10%) was filtered off. The clear reaction solution was concentrated until no more THF remained and the pH adjusted to 7 with NaHCO3 (˜3.7 g). The aqueous phase was extracted with ethyl acetate (3×100 ml) and the combined organic phases were dried with MgSO4, filtered and concentrated to give a brown powder. The crude product was recrystallized from methanol to give the product as an off-white powder (1.9 g, 80%).
Reaction SMILES: [Br:1][C:2]([F:16])([F:15])[C:3]#[C:4][Si](C(C)C)(C(C)C)C(C)C.[CH:17](=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[Br:1][C:2]([F:15])([F:16])[C:3]#[C:4][CH:17]([OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCC=O
Reactant: CC(C)[Si](C#CC(F)(F)Br)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCCCC(O)C#CC(F)(F)Br
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
To a solution of (3-bromo-3,3-difluoro-prop-1-ynyl)-triisopropyl-silane (156 mg, 0.5 mmol) and hexanal (60 mg, 0.6 mmol) in THF (5 mL), TBAF (1M, 0.75 mL) was added dropwise at −90° C. After the addition was completed, the reaction mixture was stirred for 0.5 h and quenched with saturated aq. NH4Cl. The mixture was extracted with ether (20 mL×3) and washed with water (20 mL×2). After drying over Na2SO4 the solvent was removed and the product was purified by silica gel chromatography (AcOEt:hexane=1:20) to afford the title compound (82 mg, 65%) as colorless liquid. Colorless liquid, yield: 78%. IR (neat): 3320, 2934, 2261, 1223, 1096 cm−1. 1H NMR (500 MHz, CDCl3) δ 4.49-4.52 (m, 1H), 2.14 (bs, 1H), 1.74-1.77 (m, 2H), 1.45-1.47 (m, 2H), 1.33-1.38 (m, 4H), 0.91 (t, J=6.5 Hz, 3H); 19F NMR (470 MHz, CDCl3) δ −32.9 (s, 2F); 13C NMR (125 MHz, CDCl3) δ 101.5 (t, J=288 Hz), 91.5 (t, J=5.8 Hz), 77.3 (t, J=38 Hz), 62.2, 36.8, 31.4, 24.6, 22.6, 14.1; GCMS: 157, 137, 115, 104, 91.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].I[CH2:15][CH2:16][O:17][CH:18]([O:20][CH2:21][CH2:22]I)[CH3:19]>O1CCCC1>[C:3]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:15][CH2:16][O:17][CH:18]([O:20][CH2:21][CH2:22][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])[CH3:19])([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(OCCI)OCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCOC(C)OCCC(C(=O)OCC)C(=O)OCC)C(=O)OCC
Yield: 61.6 %

Procedure:
5.28 g (0.11 mol) of sodium hydride was added to 50 ml of dry tetrahydrofuran, and to this solution was added dropwise a mixed solution of 17.6 g (0.11 mol) of diethyl malonate and 10.0 g (0.027 mol) of bis(2-iodoethoxy)ethane, followed by 2-hour reflux under heating. After the reaction, the most part of tetrahydrofuran was distilled off and the residue was added with 10 ml of water, neutralized by adding 1N hydrochloric acid and extracted three times with 50 ml of ether. After drying the extract, ether was distilled off and the oily product was passed through a silica gel packed column and eluted with petroleum ether-ether (4:1) to obtain 7.23 g of bis(3,3-dicarboethoxypropoxy)ethane, (EtO2C)2CHCH2CH2OCH2CH2 -OCH2CH2CH(CO2Et)2 (yield: 60%). The property analyses of this compound showed the following results.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl-].[Cl-].[Cl-].[Al+3].[CH2:15]([C:18]1[N:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]2=[CH:20][N:19]=1)[CH2:16][CH3:17]>ClCCCl>[I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([C:20]1[N:19]=[C:18]([CH2:15][CH2:16][CH3:17])[N:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=12)=[O:6]
Reactant: O=C(O)c1ccccc1I
Reactant: CCCc1ncc2ccccn12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCCc1nc(C(=O)c2ccccc2I)c2ccccn12
Reaction time: 0.17 h
Yield: 14.7 %

Procedure:
To a solution of 2-iodobenzoic acid (487 mg, 1.83 mmol) in 1,2-dichloroethane (20 mL) was added aluminum trichloride (266 mg, 2.00 mmol). The mixture was allowed to stir for 10 min. then a solution of 3-propyl-imidazo[1,5-a]pyridine (139 mg, 0.87 mmol) in 1,2-dichloroethane (5 mL) was added. The mixture was stirred at ambient temperature for 30 min. then washed with saturated aqueous sodium bicarbonate and the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica to yield the title compound (50 mg, 15%). 1H NMR (DMSO-d6) δ 8.54 (1H), 8.10 (1H), 7.92 (1H), 7.50 (1H), 7.41 (2H), 7.22 (1H), 7.10 (1H), 3.00 (2H), 1.70 (2H), 0.94 (3H); m/z (M+H)=391.1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@@H:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][OH:7].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:26][S:27]([O:7][CH2:6][C@H:5]([NH:8][C:9]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:18])[CH2:4][CH2:3][CH2:2][O:1][S:27]([CH3:26])(=[O:29])=[O:28])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(N[C@@H](CO)CCCO)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCC[C@H](COS(C)(=O)=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of benzyl (1R)-4-hydroxy-1-(hydroxymethyl)butylcarbamate (1.5 g) in DCM (60 ml) was treated with triethylamine (3.3 ml) and stirred at room temperature for 10 min. Methanesulphonyl chloride (1.34 ml) was then added dropwise and the resultant mixture stirred at 0° C. for 75 min. Sodium bicarbonate solution was added and the reaction mixture allowed to reach room temperature over 1 h. The organic layer was separated, washed with brine, dried (over magnesium sulphate) and concentrated under reduced pressure to give a yellow oil. The oil was purified using Biotage™ chromatography (eluting with hexane:ethyl acetate 1:2, 1:3) to give the title compound (1.924 g) as a yellow oil
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6](=[O:28])[C:7]([CH3:27])=[C:8]([C@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[CH2:18][CH2:19][O:20]C3CCCCO3)[O:9]2)=[CH:4][CH:3]=1.CO.[ClH:31]>O>[ClH:31].[OH:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6](=[O:28])[C:7]([CH3:27])=[C:8]([C@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[CH2:18][CH2:19][OH:20])[O:9]2)=[CH:4][CH:3]=1
Reactant: Cc1c([C@H]2CCCN2CCOC2CCCCO2)oc2c(C)c(O)ccc2c1=O
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1c([C@H]2CCCN2CCO)oc2c(C)c(O)ccc2c1=O
Temperature: 55 °C
Reaction time: 20 h
Yield: 53 %

Procedure:
A mixture composed of 7-hydroxy-3,8-dimethyl-2-{(2R)-1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]pyrrolidin-2-yl}-4H-chromen-4-one (77 mg, 0.20 mmol) obtained in Example 4-1, methanol (6 mL), concentrated hydrochloric acid (0.5 mL), and water (1 mL) was heated with stirring at a bath temperature of 55° C. for 20 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse-phase HPLC. A 1 N aqueous hydrochloric acid solution (4 mL) was added to a fraction containing the compound of interest, and then the mixture was concentrated under reduced pressure. Diethyl ether and methanol were added to the obtained residue, and the mixture was powdered. The obtained solid was collected by filtration and then dried in a vacuum pump to obtain 40 mg of the title compound (yield: 53%).
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].C1C=C(Cl)C=C(C(OO)=[O:33])C=1>>[O-:33][N+:9]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[C:6]2[N:5]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:4]([CH2:1][CH2:2][CH3:3])=[N:16][C:7]=2[CH:8]=1
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCC(=O)OCC
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CCCc1nc2c[n+]([O-])c3ccccc3c2n1CCCC(=O)OCC

Procedure:
The general method described in Steps 9 and 10 of Example 1 was used to aminate ethyl 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyrate (8.20 g, 25.2 mmol, available from Step 3 of Example 17) by reaction with m-CPBA (14.1 g) to provide ethyl 4-(5-oxido-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyrate followed by reaction with p-toluenesulfonyl chloride (8.40 g, 44.1 mmol) and ammonium hydroxide solution (150 mL) to provide ethyl 4-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyrate as an off-white solid after recrystallization from aqueous methanol, mp 154-156° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.C([S:22][C@@H:23]1[CH2:28][O:27][C@@H:26](/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[O:25][CH2:24]1)(=O)C>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:10])([C@H:11]([S:22][C@@H:23]1[CH2:24][O:25][C@@H:26](/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[O:27][CH2:28]1)[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: CC(=O)S[C@H]1CO[C@H](/C=C/c2ccc(C(F)(F)F)cc2)OC1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/c2ccc(C(F)(F)F)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 70 %

Procedure:
Reaction and treatment were carried out in the same manner as in Example 1 using (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1 H-1,2,4-triazol-1-yl)methyl]oxirane and trans-5-(acetylthio)-2-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]-1,3-dioxane to obtain the desired compound having a melting point of 73 to 75° C. in a yield of 70%.
Reaction SMILES: [O:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3](=O)[CH2:2]1.[CH3:11][O:12][NH2:13].CC([O-])=O.[Na+]>CCO>[CH3:11][O:12][N:13]=[C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:1][CH2:2]1
Reactant: CON
Reactant: O=C1COc2ncccc21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CON=C1COc2ncccc21

Procedure:
To a solution of furo[2,3-b]pyridine-3(2H)-one (78.3 mmol) [J. Heterocyclic Chem., 23, 1465 (1986)] in 500 mL EtOH were added O-methyl-hydroxylamine (157 mmol) and NaOAc (157 mmol). After heating to reflux for 2 h the reaction mixture was concentrated in vacuo to half of its volume. Water and DCM were added and the aqueous phase was extracted 3 times with DCM. The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification by CC using Hept/EtOAc (5/1 to 1/1) gives the desired product as yellow oil;
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:29][CH3:30])=[C:10]([CH2:19][NH:20][C:21]([C:23]3([C:26](O)=[O:27])[CH2:25][CH2:24]3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH2:31][CH2:32][C:33]1[CH:34]=[CH:35][C:36]([F:60])=[C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]3[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C@@H:48]([CH3:59])[CH2:47]3)[CH:40]=2)[CH:38]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:29][CH3:30])=[C:10]([CH2:19][NH:20][C:21]([C:23]3([C:26]([NH:31][CH2:32][C:33]4[CH:34]=[CH:35][C:36]([F:60])=[C:37]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]6[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:56])([CH3:58])[CH3:57])=[O:53])[C@@H:48]([CH3:59])[CH2:47]6)[CH:40]=5)[CH:38]=4)=[O:27])[CH2:25][CH2:24]3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: C[C@H]1CN(Cc2cccc(-c3cc(CN)ccc3F)c2)CCN1C(=O)OC(C)(C)C
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)C1(C(=O)O)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)C1(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)[C@@H](C)C4)c3)c2)CC1

Procedure:
5-(Aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (30.0 mg, 0.1 mmol) and 1,1-cyclopropanedicarboxylic acid (0.1 mmol) was dissolved in DCM (3 mL), added in HOBt (1.0 eq, 14.0 mg), EDC (1.0 eq, 19.0 mg). The resultant solution was stirred overnight. The solution was purified by Gilson to yield 1-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-cyclopropanecarboxylic acid. 1-[({[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-cyclopropanecarboxylic acid was dissolved in 3 mL DCM with 1,1-dimethylethyl (2S)-4-{[5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate (41.3 mg, 0.1 mmol), added in HOBt (1.0 eq, 14.0 mg) and EDC (1.0 eq, 19.0 mg). The resultant solution was stirred overnight and then was purified by reverse phase hplc using a Gilson (0.1% TFA conditions) to yield 1,1-dimethylethyl (2S)-4-[(5′-{[({1-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]cyclopropyl}carbonyl)-amino]methyl}-2′-fluoro-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate.
Reaction SMILES: ClC(OCC(C)C)=O.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH:24]([CH2:32][CH2:33][CH:34]2[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]2)[C:25]([NH:27][CH2:28][C:29](O)=[O:30])=[O:26])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].CN1CCOCC1.Cl.[NH2:55][CH2:56][C@H:57]([NH:63][C:64]([O:66][CH2:67][C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1)=[O:65])[C:58]([O:60][CH2:61][CH3:62])=[O:59]>C(OCC)(=O)C>[C:43]([O:42][C:40]([N:37]1[CH2:36][CH2:35][CH:34]([CH2:33][CH2:32][CH:24]([C:25](=[O:26])[NH:27][CH2:28][C:29](=[O:30])[NH:55][CH2:56][C@@H:57]([C:58]([O:60][CH2:61][CH3:62])=[O:59])[NH:63][C:64](=[O:65])[O:66][CH2:67][C:68]2[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=2)[CH2:23][CH2:22][CH:19]2[CH2:20][CH2:21][N:16]([C:14]([O:13][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:15])[CH2:17][CH2:18]2)[CH2:39][CH2:38]1)=[O:41])([CH3:44])([CH3:45])[CH3:46]
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(CCC2CCN(C(=O)OC(C)(C)C)CC2)C(=O)NCC(=O)O)CC1
Reactant: CCOC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@H](CNC(=O)CNC(=O)C(CCC1CCN(C(=O)OC(C)(C)C)CC1)CCC1CCN(C(=O)OC(C)(C)C)CC1)NC(=O)OCc1ccccc1
Reaction time: 0.33 h
Yield: 90.9 %

Procedure:
Isobutyl chloroformate (13 g, 95.2 mmol) is added, at room temperature, to a solution of 2-[(4-[1-(tert-butoxycarbonyl)-4-piperidyl]-2-{2-[1-(tert-butoxycarbonyl)-4-piperidyl]ethyl}butanoyl)amino]acetic acid (compound 4) (46 g, 85.2 mmol) in 550 ml of ethyl acetate and N-methylmorpholine (19 g, 188 mmol), and a suspension is obtained. After stirring for 20 minutes, ethyl (2S)-3-amino-2-{[(benzyloxy)carbonyl]amino}propanoate hydrochloride (26.3 g, 86.9 mmol) is added. Stirring is continued for 18 hours at room temperature and the reaction medium is then washed with water, with 1N hydrochloric acid and with water and then dried over sodium sulphate and evaporated to give the crude product, which is purified by flash chromatography (20/1 dichloromethane/methanol) to give 61 g of a white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[NH2:3].[CH2:10]([N:17]=[C:18]=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCCC1.C(OCC)(=O)C>[CH3:1][N:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[NH:3][C:18](=[O:19])[NH:17][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)CN(C)N
Reactant: O=C=NCc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(C)NC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
To a solution of ethyl 2-(1-methylhydrazinyl)acetate (Compound XL-1) 10 ml (76 mmol) in tetrahydrofuran 40 ml, benzyl isocyanate 11.1 g (83.3 mmol) was added at 0° C. and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate 150 ml and washed with water 75 ml and brine 75 ml. The organic phase was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to obtain the title compound 15.2 g (76%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:8]2.[N:17]1[N:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]2=[C:19]([CH2:26][C:27](O)=O)[CH:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([N:13]([CH2:14][CH2:15][CH3:16])[CH2:27][CH2:26][C:19]1[CH:18]=[N:17][N:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=13)[CH2:9][CH2:8]2
Reactant: O=C(O)Cc1cnn2ccccc12
Reactant: CCCNC1CCc2cccc(OC)c2C1
Product: CCCN(CCc1cnn2ccccc12)C1CCc2cccc(OC)c2C1

Procedure:
Synthesis works according to the preparation of A4-1 or A4-4 when using N-(8-methoxytetralin-2-yl)-N-propylamine (A2-1: R=OMe) and 3-pyrazolo[1,5-a]pyridinyl acetic acid (A3-13: R=OMe, Cy=3-pyrazolo[1,5-a]pyridinyl) (synthesis according to literature: Gmeiner, P. Arch Pharm 1988, Vol 321, p 517) and subsequent reaction according to the synthesis of A5-1.