Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:20])=[C:7]([C:16]([O:18]C)=O)[C:8]([C:12]([O:14]C)=O)=[N:9]2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][NH2:29])=[CH:24][CH:23]=1.C(N(CC)CC)C.O>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:20])[C:7]3[C:16]([OH:18])=[N:29][N:28]([C:25]4[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=4)[C:12](=[O:14])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: COC(=O)c1nc2cc(Cl)ccc2c(O)c1C(=O)OC
Reactant: NNc1ccc(Cl)cc1
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=c1c2ccc(Cl)cc2[nH]c2c(=O)n(-c3ccc(Cl)cc3)nc(O)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.9 %

Procedure:
To a stirred suspension of dimethyl 7-chloro-4-hydroxyquinoline-2,3-dicarboxylate (2.50 g, 8.45 mM) and 4-chlorophenyl hydrazine (10.60 g, 59.20 mM) in ethanol (50 mL) was added triethylamine (9.43 mL) to give a brown solution. This solution was refluxed for 24 hours and then cooled to room temperature. Dilution with water (25 mL) gave a brown precipitate. This suspension was stirred for 16hours and filtered to remove the solids which were discarded. The filtrate formed another precipitate after standing for seven days. This solid was collected and washed with aqueous methanol (50%) and ether to give the 4-chlorophenyl hydrazine salt of the title compound as a brown powder (1.20 g). This material was refluxed in glacial acetic acid (25 mL) for 3 hours and cooled to room temperature. The resulting orange suspension was filtered, and the solids were washed with glacial acetic acid and ether togive the title compound (0.810 g, 25%) as a light orange powder, mp 399°-401° C.; MS(CI): 374 (M+H).
Reaction SMILES: [OH-].[Li+].O.[CH2:4]([N:11]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:12]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1)[C:13]([O:15]CC)=[O:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(O)(=O)C>C1COCC1>[CH2:4]([N:11]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:12]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1)[C:13]([OH:15])=[O:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)C(CCc1ccc(Cl)c(Cl)c1)N(Cc1ccccc1)C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)C(CCc1ccc(Cl)c(Cl)c1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
Lithium hydroxide (80 mg 1.8 mmol) and water (2 ml) were added to a solution of the product of step (c) (280 mg, 0.6 mmol) in THF (5 ml) and the mixture was stirred at room temperature for 16 hours. Acetic acid (0.5 ml) was added and the mixture was partitioned between ethyl acetate and water. The organic layer was dried (Na2SO4) and the solvent was evaporated under reduced pressure to give the title compound as a colourless foam (234 mg) m/e (CI+) 438 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8]C)[C:3]=1[C:10]1[NH:23][C:13]2=[CH:14][C:15]3[C:16](=[O:22])[NH:17][C:18](=[O:21])[C:19]=3[CH:20]=[C:12]2[N:11]=1.Cl.[F:25][C:26]1[C:31]([F:32])=[CH:30][C:29]([F:33])=[CH:28][C:27]=1[CH2:34][CH:35]([NH2:37])[CH3:36].C(N(CC)[CH:42]([CH3:44])[CH3:43])(C)C>O1CCOCC1.C(O)CCC>[O:8]=[C:4]1[C:3]([C:10]2[NH:11][C:12]3=[CH:20][C:19]4[C:18](=[O:21])[N:17]([CH:42]([CH3:43])[CH2:44][C:27]5[CH:28]=[C:29]([F:33])[CH:30]=[C:31]([F:32])[C:26]=5[F:25])[C:16](=[O:22])[C:15]=4[CH:14]=[C:13]3[N:23]=2)=[C:2]([NH:37][CH:35]([CH3:36])[CH2:34][C:27]2[CH:28]=[C:29]([F:33])[CH:30]=[C:31]([F:32])[C:26]=2[F:25])[CH:7]=[CH:6][NH:5]1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1nccc(Cl)c1-c1nc2cc3c(cc2[nH]1)C(=O)NC3=O
Reactant: CC(N)Cc1cc(F)cc(F)c1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CCCCO
Product: CC(Cc1cc(F)cc(F)c1F)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(C(C)Cc1cc(F)cc(F)c1F)C3=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
2-(4-Chloro-2-methoxypyridin-3-yl)imidazo[4,5-f]isoindole-5,7(1H, 6H)-dione (0.522 g, 1.59 mmol) was dissolved in 10 mL of 1,4-dioxane and 5 mL of concentrated HCl at rt. The reaction mixture was stirred at rt overnight. Then, the volatile was removed to give a yellow-brown solid. This solid was mixed with 1-(2,3,5-trifluorophenyl)propan-2-amine (0.30 g, 1.59 mmol), N,N-diisopropylethylamine (1.10 g, 9.54 mmol) and n-butanol (20 mL) in a flask. The reaction mixture was stirred and heated to reflux overnight under argon. Then, volatiles were removed under reduced pressure. The residue solid was purified by column chromatography (silica-gel, CH2Cl2/MeOH=9/1 v/v) to give a yellow-brown solid product, 0.78 g, 76.5% yield. MS: 640.2 [M+H]+. 1H NMR (DMSO-d6, 500 MHz): δ 13.38 (s, 1H), 11.32-11.29 (m, 1H), 10.94-10.91 (m, 1H), 8.06 (s, 1H), 7.84 (s, 1H), 7.64-7.60 (m, 1H), 7.37-7.34 (m, 1H), 7.08-6.99 (m, 2H), 6.14 (d, 1H, J=7.5 Hz), 4.50 (m, 1H), 4.18 (m, 1H), 3.37-3.32 (m, 1H), 3.15-3.01 (m, 3H), 1.57 (d, 3H, J=7.0 Hz), 1.35 (d, 3H, J=6.5 Hz).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][OH:18]>C(#N)C>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:16][CH2:17][OH:18])[CH2:5][CH2:4]1)[CH3:2]
Reactant: OCCBr
Reactant: CCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CCN(CCO)CC1
Temperature: 25 °C
Yield: 77.9 %

Procedure:
1-Ethylpiperazine (5.0 g, 43.8 mmol) was dissolved in 90 mL of acetonitrile, followed by the addition of powdered potassium carbonate (18.2 g, 131 mmol), and 2-bromoethanol (10.9 g, 87.6 mmol). This mixture was warmed to reflux for 16 hours, cooled to ambient temperature, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (10% MeOH/DCM/0.5% NH4OH) to give 5.4 g (78%) of 2-(4-ethylpiperazin-1-yl)ethanol as a light yellow oil.
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][N:13]([NH2:38])[CH2:14][C@H:15]([OH:37])[C@@H:16]([NH:24][C:25](=[O:36])[C@H:26]([C@H:32]([CH2:34][CH3:35])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.CN1CCOCC1.[CH3:46][O:47][C:48]([NH:50][C@H:51]([C:56](O)=[O:57])[C:52]([CH3:55])([CH3:54])[CH3:53])=[O:49].[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C>CN(C=O)C.C(OCC)(=O)C>[S:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]([CH2:12][N:13]([NH:38][C:56](=[O:57])[C@H:51]([C:52]([CH3:54])([CH3:53])[CH3:55])[NH:50][C:48]([O:47][CH3:46])=[O:49])[CH2:14][C@H:15]([OH:37])[C@@H:16]([NH:24][C:25](=[O:36])[C@H:26]([C@H:32]([CH2:34][CH3:35])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:10][CH:11]=2)=[CH:4][N:3]=[CH:2]1
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2cncs2)cc1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2cncs2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Under argon, 0.5 mmol of 1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-iso-leucyl)amino-6-phenyl-2-azahexane and 165 μl (1.5 mmol) of NMM in 4.8 ml of DMF are added to 113.5 mg (0.60 mmol) of N-methoxycarbonyl-(L)-tert-leucine (Example 2e) and 149 mg (0.50 mmol) of TPTU in 2.5 ml of DMF and the mixture is stirred at room temperature for 14 hours. Ice-water and and ethyl acetate are added; the aqueous phase is separated off and extracted with ethyl acetate. The organic phases are washed 2× with water and brine, dried (Na2SO4) and concentrated by evaporation. Column chromatography (SiO2; ethyl acetate) and crystallisation from ethyl acetate/ether/hexane yield the title compound: TLC: Rf=0.42 (methylene chloride/ethanol 10:1); HPLC20-100: tRet=14.8; FAB MS (M+H)+=711.
Reaction SMILES: [O:1]=[C:2]1[N:11]2[C:6]([CH:7]=[CH:8][CH:9]=[CH:10]2)=[C:5](C(O)=O)[CH:4]=[C:3]1[C:15]1[CH:16]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:19][CH:20]=1>Cl.C(O)(=O)C>[F:24][C:21]([F:22])([F:23])[C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:3]2[C:2](=[O:1])[N:11]3[C:6]([CH:7]=[CH:8][CH:9]=[CH:10]3)=[CH:5][CH:4]=2)[CH:16]=1
Reactant: O=C(O)c1cc(-c2cccc(C(F)(F)F)c2)c(=O)n2ccccc12
Agent: Cl
Solvent: CC(=O)O
Product: O=c1c(-c2cccc(C(F)(F)F)c2)ccc2ccccn12

Procedure:
0.83 g of 4-oxo-3-(α,α,α-trifluoro-m-tolyl)-4H-quinolizine-1-carboxylic acid was heated to reflux in a mixture of 13 ml of concentrated hydrochloric acid and 6.5 ml of acetic acid until the reaction was completed. The solution was evaPorated, whereupon 10 ml of water are added. The crystals were removed by filtration and dried. After chromatography on silica gel and recrystallization, there was obtained 3-(α,α,α-trifluoro-m-tolyl)4H-quinolizin-4-one as yellow crystals of m.p. 110°-111° (n-hexane/toluene).
Reaction SMILES: [CH:1]1([C:5]([NH:7][C@H:8]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](F)[CH:15]=2)[CH2:9][C:10](OC)=[O:11])=[O:6])[CH2:4][CH2:3][CH2:2]1.[H-].C([Al+]CC(C)C)C(C)C.CO.Cl>C(Cl)Cl>[O:11]=[CH:10][CH2:9][C@H:8]([NH:7][C:5]([CH:1]1[CH2:4][CH2:3][CH2:2]1)=[O:6])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)C[C@H](NC(=O)C1CCC1)c1cccc(F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CO
Solvent: ClCCl
Product: O=CC[C@H](NC(=O)C1CCC1)c1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirring solution of the methyl ester from Example 9, Step B (1.2 mmol, 330 mg) in 10 mL of DCM cooled to −78° C. was added dropwise over 20 min. diisobutylaluminum hydride (2.4 mmol, 2.4 mL of 1 M solution in DCM). The solution was stirred at −78° C. for 2 h. Methanol (2 mL) cooled to −78° C. was canulated dropwise to the reaction mixture over 5 min. After 10 min. the reaction was allowed to warm to room temperature, during which time a white precipitate formed. DCM (30 mL) was added, and the solution was poured into 2 N HCl (50 mL). The organic phase was collected and the aqueous phase was extracted with DCM (2×25 mL). The combined organic phase was dried with MgSO4 and the solvent removed under reduced pressure. The oily residue was dissolved in DCM and passed through a silica plug eluting with DCM. Removal of solvent under reduced pressure afforded the title compound as a clear oil. MS(ESI): m/z 250 (M+H). HPLC B: 1.31 min.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=O)[CH:10]=2)[NH:5][N:4]=1)[CH3:2].[C:14](/[CH:16]=[C:17](\[O-:19])/[CH3:18])#[N:15].[Na+].C(O)(=O)C.N1CCCCC1>ClCCl>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](/[CH:12]=[C:16](/[C:17](=[O:19])[CH3:18])\[C:14]#[N:15])[CH:10]=2)[NH:5][N:4]=1)[CH3:2]
Reactant: CCc1n[nH]c2ccc(C=O)cc12
Reactant: C/C([O-])=C/C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CCc1n[nH]c2ccc(/C=C(\C#N)C(C)=O)cc12
Yield: 87.4 %

Procedure:
A mixture of 0.50 g (2.87 mmol) 3-ethyl-1H-indazole-5-carbaldehyde (Example 6A), 0.33 g (3.16 mmol) sodium (1Z)-1-cyanoprop-1-en-2-olate, 0.21 ml (3.6 mmol) acetic acid and 0.028 ml (0.29 mmol) piperidine in dry dichloromethane (25 ml) containing 4 Å molecular sieve was stirred under reflux for 16 h. Upon cooling, a precipitate was formed which was collected by filtration and washed with saturated aqueous sodium bicarbonate solution and water. The solid was dissolved in ethanol, and the molecular sieve was filtered off. The filtrate was concentrated under reduced pressure, and the residue was treated with ethyl acetate and saturated aqueous sodium carbonate solution. The organic layer was washed with water, dried, and concentrated under reduced pressure to afford the title compound (0.60 g, 88% of th.) as a pale yellow solid which was used in subsequent steps without further purification.
Reaction SMILES: [C:1]1([CH2:7]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH:9]([OH:12])([CH3:11])[CH3:10].Cl.O.[C:15]1(C)C=CC=C[CH:16]=1>>[CH3:10][C:9]12[CH2:3][CH2:4][CH:5]([CH:15]([CH3:16])[CH2:11]1)[CH:6]([CH:1]([CH3:2])[CH3:7])[O:12]2
Reactant: Cc1ccccc1
Reactant: OCC1=CCCCC1
Reactant: CC(C)O
Agent: Cl
Solvent: O
Product: CC(C)C1OC2(C)CCC1C(C)C2

Procedure:
A solution of 130 grams of 2,4-dimethyl-alpha-isopropyl-3:cyclohexene methanol, 300 grams of isopropyl alcohol and 1000 ml of concentrated HCl is heated 21/2 hours at reflux. The reaction mass is cooled and 1500 ml of H2O and 100 ml of toluene is added with stirring. The aqueous layer is discarded and the organic layer is washed twice with water, neutralizing with aqueous caustic soda on the second wash. The organic layer is distilled through a 48" Vigreux column affording 25 grams of 1,5-dimethyl-3-isopropyl-2-oxabicyclo[2.2.2]octane (b.p. 55° C., 1.8 mm Hg pressure).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N:9]2[CH2:13][CH2:12][CH2:11][C@H:10]2[CH2:14][O:15][CH3:16])=[CH:4][C:3]=1[NH:17][C:18](=S)[NH:19][C:20]1[CH:21]=[C:22]([CH:34]=[CH:35][C:36]=1[Cl:37])[CH2:23][NH:24][C:25]([C:27]1([C:30]([F:33])([F:32])[F:31])[CH2:29][CH2:28]1)=[O:26].C(Cl)CCl.CN(C=O)C>[Cl-].[Na+].O>[Cl:37][C:36]1[CH:35]=[CH:34][C:22]([CH2:23][NH:24][C:25]([C:27]2([C:30]([F:33])([F:32])[F:31])[CH2:29][CH2:28]2)=[O:26])=[CH:21][C:20]=1[NH:19][C:18]1[NH:17][C:3]2[CH:4]=[C:5]([N:9]3[CH2:13][CH2:12][CH2:11][C@H:10]3[CH2:14][O:15][CH3:16])[C:6]([Cl:8])=[CH:7][C:2]=2[N:1]=1
Reactant: COC[C@@H]1CCCN1c1cc(NC(=S)Nc2cc(CNC(=O)C3(C(F)(F)F)CC3)ccc2Cl)c(N)cc1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC[C@@H]1CCCN1c1cc2[nH]c(Nc3cc(CNC(=O)C4(C(F)(F)F)CC4)ccc3Cl)nc2cc1Cl
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of (S)—N-(3-(3-(2-amino-4-chloro-5-(2-(methoxymethyl)pyrrolidin-1-yl)phenyl)thioureido)-4-chlorobenzyl)-1-(trifluoromethyl)cyclopropanecarboxamide (110 mg; 0.19 mmol), EDC (36 mg; 0.19 mmol) and DMF (4 mL) was stirred at 90° C. overnight. The mixture was poured into brine and extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and concentrated and the residue was purified by column chromatography.
Reaction SMILES: [H-].[Na+].[CH:3]1([C:6](=[O:10])[CH2:7][C:8]#[N:9])[CH2:5][CH2:4]1.[CH3:11][C:12]1[N:20]=[C:19]([N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)[CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH:3]1([C:6](=[O:10])[CH:7]([C:14]([C:13]2[C:12]([CH3:11])=[N:20][C:19]([N:21]3[CH:25]=[N:24][CH:23]=[N:22]3)=[CH:18][CH:17]=2)=[O:15])[C:8]#[N:9])[CH2:5][CH2:4]1
Reactant: Cc1nc(-n2cncn2)ccc1C(=O)Cl
Reactant: N#CCC(=O)C1CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(-n2cncn2)ccc1C(=O)C(C#N)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
A THF (2 ml) suspension of sodium hydride (0.06 g, 60% oil suspension, 18.78 mmol) was cooled in an ice bath, and a THF (2 ml) solution of 3-cyclopropyl-3-oxopropanenitrile was dripped thereto. To the obtained reaction solution, a THF (3 ml) solution of 2-methyl-6-(1H-1,2,4-triazol-1-yl) nicotinic acid chloride (0.16 g, 0.73 mmol) was dripped. The resultant was stirred at room temperature for 3 hours. The obtained reaction solution was made acidic with a citric acid aqueous solution, and the product was extracted with ethyl acetate. The obtained organic layer was washed with water, dried with magnesium sulfate and concentrated to obtain the desired product (0.14 g, yield 64%).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]([C@@H:11]1[CH2:14][C@H:13]([CH:15]([C:26]([O:28][CH3:29])=[O:27])[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:12]1)=[O:10].Br[CH2:31][C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1.Cl>O1CCCC1.C1(C)C=CC=CC=1>[CH3:29][O:28][C:26]([C:15]([C@H:13]1[CH2:14][C@@H:11]([C:9]([O:8][CH3:7])=[O:10])[CH2:12]1)([CH2:31][C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1)[C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])=[O:27]
Reactant: BrCc1cccc2ccccc12
Reactant: COC(=O)C(C(=O)OCc1ccccc1)[C@H]1C[C@@H](C(=O)OC)C1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)C(Cc1cccc2ccccc12)(C(=O)OCc1ccccc1)[C@H]1C[C@@H](C(=O)OC)C1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a stirred suspension of potassium t-butoxide (0.44 g, 3.93 mmol) in dry tetrahydrofuran (20 ml) cooled to 0° C. under a nitrogen atmosphere was added dropwise a solution of benzyl methyl cis-3-methoxycarbonylcyclobutylmalonate (1.25 g, 3.9 mmol) in dry tetrahydrofuran (20 ml) followed by dropwise addition of 1-(bromomethyl)naphthalene (2.58 g, 11.7 mmol) in dry toluene (15 ml). Stirring was continued at 0° C. for 4 hours, aqueous hydrochloric acid (2M, 15 ml) was then added and the mixture extracted with diethyl ether. The organic phase was dried, filtered and evaporated to an oil (2.5 g). The oil was dissolved in dichloromethane and filtered through a pad of flash silica, the solvent was removed and the resulting oil (2.0 g) purified by chromatography on silica using a Biotage Flash 40 eluting with dichloromethane to give the title compound as a colourless oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C@H:14]([C:19]([OH:21])=O)[CH2:15][C:16](=[O:18])[NH2:17])=[O:12].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[OH:54][C@H:55]([C@@H:73]([NH2:81])[CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)[CH2:56][N:57]([CH2:66][CH:67]1[CH2:72][CH2:71][CH2:70][CH2:69][CH2:68]1)[NH:58][C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60]>C1COCC1>[OH:54][C@H:55]([C@@H:73]([NH:81][C:19](=[O:21])[C@H:14]([CH2:15][C:16](=[O:18])[NH2:17])[NH:13][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)=[O:12])[CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)[CH2:56][N:57]([CH2:66][CH:67]1[CH2:68][CH2:69][CH2:70][CH2:71][CH2:72]1)[NH:58][C:59]([O:61][C:62]([CH3:65])([CH3:63])[CH3:64])=[O:60]
Reactant: CC(C)(C)OC(=O)NN(CC1CCCCC1)C[C@H](O)[C@@H](N)Cc1ccccc1
Reactant: NC(=O)C[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NN(CC1CCCCC1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
At 5° C., 940 mg (3.27 mmol) of quinoline-2-carbonyl-(L)-asparagine (in the form of the hydrochloride salt) are dissolved in 35 ml of THF, and 736 mg (3.57 mmol) of DCC are added. After 10 min, 482 mg (3.57 mmol) of HOBT, 0.82 ml (7.44 mmol) of NMM and 1.165 g (2.98 mmol) of 1-[2(S)-hydroxy-3(S)-amino-4-phenyl-butyl]-1-[cyclohexylmethyl]-2-[tert-butoxycarbonyl]-hydrazine are added and the mixture is stirred at RT for 18 h. The reaction mixture is filtered and the filtrate is concentrated by evaporation. The residue is partitioned between 3 portions of ethyl acetate, saturated NaHCO3 solution, water and brine, and the organic phases, which have been dried with Na2SO4, are concentrated by evaporation and subjected to column chromatography (SiO2, ethyl acetate) to yield the title compound: TLC Rf (O)=0.16; tRet (V)=16.5 min; FAB-MS (M+H)+ =661.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH2:29]([O:31][C:32]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][C:39]=1[F:40])=[O:33])[CH3:30]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[CH2:29]([O:31][C:32](=[O:33])[C:34]1[CH:35]=[C:36]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=4[CH:27]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)[CH:37]=[CH:38][C:39]=1[F:40])[CH3:30]
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: CCOC(=O)c1cc(B(O)O)ccc1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(Oc2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)ccc1F

Procedure:
In analogy to Example 5, 6-[(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (63 mg) was reacted with 3-ethoxycarbonyl-4-fluorophenylboronic acid, copper-(II)-acetate and pyridine to give the title compound (25 mg) as a white solid. MS (m/e)=582.0 [M+H+].
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]3[CH2:21][CH2:20]3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]3[CH2:21][CH2:20]3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:31]([C:30]3[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Nc1ncc(Br)c(N2CCN(CC3CC3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: COc1ccc(-c2nc3c(N4CCN(CC5CC5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 70 °C
Reaction time: 20 h

Procedure:
To a mixture of 5-bromo-4-(4-cyclopropylmethyl-piperazin-1-yl)-3-nitro-pyridin-2-ylamine (0.043 g, 0.12 mmol) and EtOH (3 ml) was added 4-methoxybenzaldehyde (0.027 g, 0.18 mmol) with the aid of EtOH (1 ml), followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.48 ml, 0.48 mmol). The reaction mixture was stirred at 70° C. for 20 h, then allowed to cool to room temperature and concentrated in vacuo. The residue was absorbed on silica gel, the free-running powder was placed on a 10 g isolute silica column and elution with a gradient of methanol (0 to 4%) in ethyl acetate/dichloromethane (v:v; 1:1) afforded a yellow solid. The title compound was obtained as a white solid after trituration with diethyl ether (0.012 g, 23%). 1H-NMR (500 MHz, DMSO-d6) 0.12 (m, 2H) and 0.50 (m, 2H) (cyclopropyl CH2), 0.90 (m, 1H, cyclopropyl CH), 2.27 (d, J=6.4 Hz, 2H, N—CH2cyclopropyl), 2.67 (br s, 4H, piperazine N(CH2)2), 3.66 (br s, 4H, piperazine N(CH2)2), 3.84 (s, 3H, OCH3), 7.10 (d, J=8.8 Hz, 2H) and 8.14 (d, J=8.8 Hz, 2H) (3,5-C6H4OMe and 2,6-C6H4OMe), 8.20 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.34 (br s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: C(OOC(C)(C)C)(C)(C)C.CO.[Br:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1Br>>[Br:13][CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCCc1ccccc1Br
Agent: CC(C)(C)OOC(C)(C)C
Solvent: CO
Product: BrC=Cc1ccccc1
Yield: 95 %

Procedure:
2 g di-t-butyl peroxide were dissolved in 100 g β-bromo ethyl bromo benzene. The mixture was added to the reactor in a manner described in Example 1, together with 25 g methanol and nitrogen at a flow rate of 2 l/h. The reactor was a glass spiral made of a 6 mm wide 5 m long tube heated to 300°-320°C. The products were collected as in Example 1 and consisted of 58 g bromostyrene and 12 g unconverted reactant. The yield was 95% bromostyrene.
Reaction SMILES: [NH2:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]3[C:14]([C:5]2=[N:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3.[CH:24](=O)[CH3:25].[BH4-].[Na+].O>C(O)C>[CH2:24]([NH:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]3[C:14]([C:5]2=[N:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[CH3:25]
Reactant: COc1ccc2ccn3c(N)c(-c4ccccc4C)nc3c2c1
Reactant: CC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCNc1c(-c2ccccc2C)nc2c3cc(OC)ccc3ccn12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5 g of 3-amino-9-methoxy-2-(2-methylphenyl)imidazo[2,1-a]isoquinoline (Compound 26) in 100 ml of ethanol was added 3.0 ml of acetaldehyde, and the mixture was stirred at room temperature for 3 hours. After 3.3 g of sodium borohydride was added to the mixture and refluxed for 2 hours, the reaction mixture was poured into water, and extracted with ethyl acetate. The extract was washed with saturated saline, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was removed under reduced pressure. The crude crystal was recrystallized from petroleum ether/ethyl acetate to give 5 g of the title compound as colorless needles.