Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]([N:6]([CH2:10][CH2:11][CH3:12])[CH2:7][CH2:8][CH3:9])=[CH:4][C:3]=1[N+:15]([O-])=O>CCOC(C)=O.[Pd]>[CH3:1][C:2]1[CH:14]=[CH:13][C:5]([N:6]([CH2:10][CH2:11][CH3:12])[CH2:7][CH2:8][CH3:9])=[CH:4][C:3]=1[NH2:15]
Reactant: CCCN(CCC)c1ccc(C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCN(CCC)c1ccc(C)c(N)c1
Reaction time: 18 h
Yield: 31.8 %

Procedure:
A mixture of 4-methyl-3-nitro-N,N-dipropylaniline (2.49 g, 10.5 mmol) and 10% Pd on carbon (1.00 g) in AcOEt (50 ml) was hydrogenated for 18 h. The catalyst was removed by filtration through Celite. The filtrate was concentrated under vacuum. The residue was purified by chromatography eluting with 10% AcOEt in n-hexane to afford 689 mg of the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH:18]1([NH2:21])[CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CO>CO>[CH:18]1([NH:21][CH:14]2[CH2:15][CH2:16][CH:11]([NH:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][N:2]=[CH:3]4)[CH2:12][CH2:13]2)[CH2:20][CH2:19]1
Reactant: NC1CC1
Reactant: O=C1CCC(Nc2ccc3[nH]ncc3c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: c1cc2[nH]ncc2cc1NC1CCC(NC2CC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 7.4 %

Procedure:
4-(1H-5-Indazolylamino)-1-cyclohexanone (intermediate 3) (57 mg) and cyclopropylamine (30 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (105 mg) was added by portions to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. Hydrochloric acid-methanol was then added thereto, and the mixture was stirred and was then concentrated. The residue was purified by HPLC [0.5% aqueous trifluoroacetic acid solution/acetonitrile]. A saturated aqueous sodium hydrogencarbonate solution (2 ml) was then added to fractions containing respective compounds, followed by extraction with chloroform-propanol (3/1). The organic layers were dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure to give an anti-form compound (5 mg) and a syn-form compound (12 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[C:5]([CH3:13])[C:4]=1[CH:14]([C:16]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][N:19]=[CH:18][C:17]=1[Cl:26])[OH:15]>[O-2].[O-2].[Mn+4].C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[C:5]([CH3:13])[C:4]=1[C:14]([C:16]1[C:21]([C:22]([F:25])([F:23])[F:24])=[CH:20][N:19]=[CH:18][C:17]=1[Cl:26])=[O:15]
Reactant: COc1cc(C)c(C(O)c2c(Cl)cncc2C(F)(F)F)c(OC)c1OC
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: COc1cc(C)c(C(=O)c2c(Cl)cncc2C(F)(F)F)c(OC)c1OC
Yield: 94.2 %

Procedure:
45 g of manganese dioxide was added to a toluene 220 ml solution of 15.9 g (40.6 mmol) of (2,3,4-trimethoxy-6-methylphenyl)(3-chloro-5-trifluoromethyl-4-pyridyl)methanol obtained in Step (b), followed by stirring under reflux with heating for 2 hours. The mixture was subjected to filtration, and the solvent was distilled off under reduced pressure to obtain 14.9 g (yield: 94%) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-3-chloro-5-trifluoromethylpyridine.
Reaction SMILES: [CH3:1][C:2]([CH:7]=[CH:8][CH2:9][CH:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:3][C:4]([OH:6])=[O:5].[C:18](Cl)(=O)C(Cl)=O.[CH:24]1[CH:29]=[CH:28]C=CC=1>>[CH3:1][C:2]([CH:7]=[CH:8][CH2:9][CH:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:3][C:4]([O:6][CH2:18][CH:29]([CH3:28])[CH3:24])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C=CCC(C)CCCC(C)C)=CC(=O)O
Reactant: c1ccccc1
Product: CC(C=CCC(C)CCCC(C)C)=CC(=O)OCC(C)C
Reaction time: 2 h

Procedure:
To a solution of 4.15 g. of 3,7,11-trimethyldodeca-2,4-dienoic acid in 100 ml. of dry benzene, under nitrogen, is added 5.1 ml. of oxalyl chloride. After 2 hours, solvent is removed under reduced pressure and 100 ml. of fresh dry benzene and 6.4 ml. of dry isobutyl alcohol is added. The reaction mixture is concentrated and the concentrate is stirred over 20 g. of activated alumina in pentane for 0.5 hr. and filtered. The filtrate is washed, dried and evaporated under reduced pressure to give isobutyl 3,7,11-trimethyldodeca-2,4-dienoate which can be purified by distillation.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6].[C:9]1(B(O)O)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1>CC([O-])=O.CC([O-])=O.[Cu+2]>[C:17]1([NH:6][C@@H:5]([CH3:7])[C:4]([O:3][CH3:2])=[O:8])[C:18]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)[C@H](C)N
Reactant: OB(O)c1cccc2ccccc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Product: COC(=O)[C@H](C)Nc1cccc2ccccc12
Reaction time: 48 h
Yield: 34.1 %

Procedure:
To a dry round bottom flask equipped with a stir bar was added L-alanine methyl ester hydrochloride (500 mg, 3.58 mmol), 1-Naphthalene boronic acid (1000 mg, 5.81 mmol), dry Cu(OAc)2 (715 mg, 3.93 mmol), 4 A° molecular sieves (1.34 g). The flask was sealed with septum, evacuated and back filled with O2 atmosphere. Triethyl amine (0.92 mL), and dry DCM (30 mL) were added at room temperature, stirred for 48 h. The reaction mixture was quenched with 13 mL 2M NH3 in methanol. The volatiles were removed in vacuo and the resulting crude oil was purified by silica gel flash chromatography ethyl acetate/n-hexane (10:90) to give 280 mg of the title compound as brown viscous oil (34% yield).
Reaction SMILES: [N+:1]([C:4]1[N:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[CH2:29]([NH2:32])[CH:30]=[CH2:31]>C1COCC1>[N+:1]([C:4]1[N:5]([CH2:9][C:10]([NH:32][CH2:29][CH:30]=[CH2:31])=[O:12])[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2]
Reactant: C=CCN
Reactant: O=C(O)Cn1ccnc1[N+](=O)[O-]
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: C=CCNC(=O)Cn1ccnc1[N+](=O)[O-]
Reaction time: 0.17 h
Yield: 47.6 %

Procedure:
2-(2-nitro-1H-imidazol-1-yl)acetic acid (1.71 g, 10 mmol) was added to N-methylmorpholine (1.01 g, 10 mmol) in 150 ml of dry THF under nitrogen at 0° C. and stirred for 10 minutes until completely dissolved. Isobutyl chloroformate (1.43 mL 11 mmol) added. After 30 minutes, allylamine hydrochloride (1.03 g, 11 mmol) and N-methylmorpholine (1.21 g, 12 mmol) added to the solution and the mixture stirred at room temperature overnight. The solution was then filtered and the organic solvent was evaporated to give a pale yellow solid. Purification by chromatography (silica gel, CH3OH/CHCl3=10:1) gave a white solid (1 g, 48%).
Reaction SMILES: C([O:4][C:5]1[CH:36]=[CH:35][CH:34]=[CH:33][C:6]=1[C:7]([NH:9][C:10]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28]C(=O)C)=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[O:8])(=O)C.C(=O)([O-])[O-].[Na+].[Na+].C(O)(=O)C>CO.O>[C:7]([NH:9][C:10]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:32])[C:22]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[OH:28])=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:8])[C:6]1[C:5](=[CH:36][CH:35]=[CH:34][CH:33]=1)[OH:4]
Reactant: COC(=O)c1cc(NC(=O)c2ccccc2OC(C)=O)ccc1NC(=O)c1ccccc1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc(NC(=O)c2ccccc2O)ccc1NC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
In 150 ml methanol was dissolved 5.3 g of methyl 2,5-bis(2'-acetoxybenzamido)-benzoate obtained in Example 3. To the solution was added 2.5 g of sodium carbonate dissolved in 40 ml of water and then the mixture was stirred at room temperature for 30 minutes. The mixture was poured into 500 ml of water containing 10 ml of acetic acid to precipitate crystals. The crystals were recovered by filtration, washed with water, dried and recrystallized from ethyl acetate to yield 3.8 g of methyl 2,5-bis(salicylamido)-benzoate having a melting point between 243° - 244°C.
Reaction SMILES: OC1[CH:3]=[C:4]2[C:9](=[CH:10]C=1OC)[CH2:8][CH2:7][CH2:6][CH2:5]2.[C:14]([O:17][C:18](=[O:20])[CH3:19])(=O)[CH3:15].C1C[O:24][CH2:23]C1>CN(C)C1C=CN=CC=1>[C:18]([O:17][C:14]1[CH:3]=[C:4]2[C:9](=[CH:10][C:15]=1[O:24][CH3:23])[CH2:8][CH2:7][CH2:6][CH2:5]2)(=[O:20])[CH3:19]
Reactant: C1CCOC1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2c(cc1O)CCCC2
Agent: CN(C)c1ccncc1
Product: COc1cc2c(cc1OC(C)=O)CCCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
A 250 mg (1.4 mmol) quantity of 6-hydroxy-7-methoxytetralin was dissolved in 1 mL of dry THF. To the solution of 6-hydroxy-7-methoxytetralin was added 4-dimethylaminopyridine (DMAP, 476 mg, 4.2 mmol) in 6 ml of dry THF and acetic anhydride 446 mg (4.37 mmol) in 1.5 mL, of dry THF. The reaction solution was stirred under a dry atmosphere at 25° C. for 18 hours, after which time the solvent was evaporated to dryness. The resulting residue was dissolved in EtOAc (40 mL) and the EtOAc layer washed with water (2×5 mL), 5% NaHCO3 (aq) (2×5 mL), 1 M HCl (5×5 mL), water (5 mL), and brine (2×5 mL). The organic layer was dried over MgSO4 and evaporated to dryness. The residue was purified by flash chromotography (hexane : EtOAc, 4:1) to give 290 mg (94% yield) of 6-acetoxy-7-methoxytetralin. IR 3003, 2930, 2860, 2840, 1767 (C═O str.), 1619, 1512, 1266, 1219, 1195, 1104, 1026; 1H NMR (CDCl13) δ6.73 (1H, s), 6.66 (1H, s), 3.79 (3H, s, —OCH3), 2.68-2.74 (4H, m), 2.30 (3H, s, —OCOCH3), 1.78 (4H, qn, J=3.25 Hz); 13C NMR (CDCl3) δ6.73 169.3, 148.6, 137.5, 135.3, 129.3, 122.8, 112.8, 55.8, 29.3, 28.4, 23.0, 20.5; LRMS EI m/z 220[M+], 178 [M+, base peak].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][N:8]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[N:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[N:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1>>[CH3:47][O:46][C:43]1[CH:42]=[CH:41][C:40]([CH2:39][N:8]([CH2:7][C:6]2[CH:48]=[CH:49][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([N:59]6[CH2:60][CH2:61][N:56]([C:51]7[CH:52]=[CH:53][CH:54]=[CH:55][N:50]=7)[CH2:57][CH2:58]6)=[O:35])=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:45][CH:44]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N4CCN(c5ccccn5)CC4)cc3)cn2)cc1
Yield: 120.5 %

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid (60.0 mg, 0.0909 mmol) obtained in Step A in Example 1-D-19 and 1-(2-pyridyl)piperazine (27.7 μl, 0.182 mmol) instead of 3-(aminomethyl)pyridine, amidation was carried out in the same manner as Step B in Example 1-D-19, to obtain a crude product of {4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-phenyl}-(4-pyridin-2-yl-piperazin-1-yl)-methanone as a brown solid (88.2 mg), and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-278) as a yellow powder (47.4 mg, 100%).
Reaction SMILES: [CH3:1][C:2]1([C:20]([O:22]CC)=[O:21])[CH2:7][CH2:6][N:5]([CH:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.[Li+].[OH-].Cl>C1COCC1>[CH2:18]([O:17][C:15]([N:11]1[CH2:12][CH2:13][CH2:14][CH:8]([N:5]2[CH2:6][CH2:7][C:2]([CH3:1])([C:20]([OH:22])=[O:21])[CH2:3][CH2:4]2)[CH2:9][CH2:10]1)=[O:16])[CH3:19]
Reactant: CCOC(=O)N1CCCC(N2CCC(C)(C(=O)OCC)CC2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCCC(N2CCC(C)(C(=O)O)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 193.8 %

Procedure:
Ethyl 4-[4-methyl-4-(ethoxycarbonyl)piperidin-1-yl]azepane-1-carboxylate (0.37 g, 1.09 mmol) was dissolved in THF (10 mL) at rt and 1M LiOH sol. (3.3 mL) was added. The reaction mixture was stirred at rt overnight. The pH was carefully adjusted to pH 6 by addition of concentrated hydrochloric acid, the solvents were removed in vacuo, to give 1-[1-(ethoxycarbonyl)azepan-4-yl]-4-methylpiperidine-4-carboxylic acid (0.66 g) as a viscous colourless oil, Intermediate 4, which was used crude in subsequent reactions.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][NH:6][C:7]([C:9]1O[CH:11]=[C:12]([Br:24])[C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:8].C(O)C.[CH3:31][O:32][CH:33]([O:36][CH3:37])[CH2:34][NH2:35]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][NH:6][C:7]([C:9]1[N:35]([CH2:34][CH:33]([O:36][CH3:37])[O:32][CH3:31])[CH:11]=[C:12]([Br:24])[C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:8]
Reactant: O=C(NCc1cccc(Cl)c1)c1occ(Br)c(=O)c1OCc1ccccc1
Reactant: COC(CN)OC
Solvent: C1CCOC1
Solvent: CCO
Product: COC(Cn1cc(Br)c(=O)c(OCc2ccccc2)c1C(=O)NCc1cccc(Cl)c1)OC
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 3-benzyloxy-5-bromo-4-oxo-4H-pyran-2-carboxylic acid 3-chlorobenzylamide (1.50 g) in tetrahydrofuran (10 ml)-ethanol (10 ml) was added aminoacetaldehyde dimethyl acetal (0.73 ml) and the mixture was stirred at 60° C. for 1 hr. The solvent was evaporated and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3–1:2) to give 3-benzyloxy-5-bromo-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (1.35 g).
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][C@H:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[C@H:23]([C:34](=[O:38])[N:35]([CH3:37])[CH3:36])[CH2:22]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(Cl)(Cl)[Cl:40].[ClH:43]>C(OCC)C>[ClH:40].[ClH:43].[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][C@H:21]4[CH2:26][CH2:25][NH:24][C@H:23]([C:34]([N:35]([CH3:37])[CH3:36])=[O:38])[CH2:22]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: ClC(Cl)Cl
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](Oc2cccc3ccc(-c4nnc5ccccn45)nc23)CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Product: CN(C)C(=O)[C@@H]1C[C@@H](Oc2cccc3ccc(-c4nnc5ccccn45)nc23)CCN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
To the product from Step A (0.080 g, 0.155 mmol) was added chloroform (1.6 mL) To the resulting solution was added hydrogen chloride (0.387 mL, 1.55 mmol, 4.0 M in 1,4-dioxane) causing the solution to turn yellow. The mixture was stirred at ambient temperature for 3 hours. Additional hydrogen chloride (0.387 mL, 1.55 mmol, 4.0 M in 1,4-dioxane) was added and the reaction stirred at ambient temperature for another 3 hours. The mixture was diluted with diethyl ether (5 mL) and filtered. The product was washed with Et2O and dried in vacuo to provide 0.068 g (86%) of the desired product as a yellow solid. MS ESI (+) m/z 417.1 (M+1) detected.
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([C:6](=[O:9])[CH2:7]Br)=[CH:4][C:3]=1[Cl:13].[CH3:14][C@@H:15]([NH2:27])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([NH2:26])=[O:25])=[CH:20][CH:19]=1>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([CH:6]([OH:9])[CH2:7][N:27]([CH2:7][CH:6]([OH:9])[C:5]2[CH:4]=[C:3]([Cl:13])[C:2]([NH2:1])=[C:11]([Cl:12])[CH:10]=2)[C@H:15]([CH3:14])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([NH2:26])=[O:25])=[CH:20][CH:19]=2)=[CH:4][C:3]=1[Cl:13]
Reactant: C[C@@H](N)CCc1ccc(C(N)=O)cc1
Reactant: Nc1c(Cl)cc(C(=O)CBr)cc1Cl
Solvent: ClC(Cl)Cl
Product: C[C@H](CCc1ccc(C(N)=O)cc1)N(CC(O)c1cc(Cl)c(N)c(Cl)c1)CC(O)c1cc(Cl)c(N)c(Cl)c1

Procedure:
A mixture of 13.6 g of 4-amino-3,5-dichlorophenacyl bromide and 4.6 g of (R)-1-methyl-3-(4-aminocarbonylphenyl)propylamine in 100 ml of chloroform was warmed to 50° for 3 hours. The mixture was evaporated in vacuo, the residue was dissolved in 200 ml of methanol was 70 ml of water and a solution of 3.0 g of sodium borohydride in 20 ml of water was added dropwise thereto while cooling with ice and stirring so that the temperature did not rise above 20°. After completion of the addition, the mixture was stirred at 5°-10° for a further 2 hours, then poured into ice-water and extracted with methylene chloride. The material isolated from the methylene chloride extract was chromatographed on silica gel. With chloroform/n-propanol/25% ammonia (1000:10:1) there was obtained pure p-[(R)-3-[bis-[(RS)-4-amino-3,5-dichloro-β-hydroxyphenethyl]amino]butyl]benzamide in amorphous form; [α]D20 =-46° (c=1.0% in methanol); ε242 =31080; ε302 =7250.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[CH3:17][O:18][C:19]1[CH:27]=[C:26]2[C:22]([CH2:23][C:24](=[O:28])[NH:25]2)=[CH:21][CH:20]=1>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=[C:23]1[C:22]2[C:26](=[CH:27][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)[NH:25][C:24]1=[O:28])([CH3:3])[CH3:2]
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Reactant: COc1ccc2c(c1)NC(=O)C2
Product: COc1ccc2c(c1)NC(=O)C2=Cc1cc(C(C)C)c(OC)c(C(C)C)c1

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 6-methoxy-2-oxindole to give 0.3 g of 3-(3,5-diisopropyl-4-methoxybenzylidene)-6-methoxy-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([NH:15][C:16](=[O:31])[C:17]2[CH:22]=[C:21]([N:23]3[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]3)[CH:20]=[C:19]([F:30])[CH:18]=2)=[CH:7][CH:6]=1)#[N:2].C[Si]([N:36]=[N+:37]=[N-:38])(C)C.C([Sn](=O)CCCC)CCC.CO>C1(C)C=CC=CC=1>[F:30][C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([N:23]2[CH2:24][CH2:25][CH:26]([CH3:29])[CH2:27][CH2:28]2)[CH:20]=1)[C:16]([NH:15][C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([O:4][CH2:3][C:1]2[N:36]=[N:37][NH:38][N:2]=2)=[CH:6][CH:7]=1)=[O:31]
Reactant: CC1CCN(c2cc(F)cc(C(=O)Nc3ccc(OCC#N)c4ccccc34)c2)CC1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: CO
Solvent: Cc1ccccc1
Product: CC1CCN(c2cc(F)cc(C(=O)Nc3ccc(OCc4nn[nH]n4)c4ccccc34)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 0 %

Procedure:
N-(4-Cyanomethoxynaphthalen-1-yl)-3-fluoro-5-(4-methylpiperidin-1-yl)-benzamide (54 mg, 129 mmol), trimethylsilylazide (0.1 ml, 760 mmol) and dibutyltin oxide (5 mg) are heated to reflux in anhydrous toluene (3 ml) for 5 hours. After cooling to room temperature methanol (5 ml) is then added and the mixture stirred at room temperature for 30 min. The mixture is then evaporated to dryness and the residue recrystalized from ethyl acetate/hexanes to give 3-fluoro-5-(4-methylpiperidin-1-yl)-N-[4-(2H-tetrazol-5-ylmethoxy)-naphthalen-1-yl]-benzamide as a grey powder (22 mg). 1H NMR 300 MHz (DMSO-d6) 10.3(s, 1H), 8.32(dd, 1H, J=8.7 and 2.7 Hz), 7.87(d, 1H, J=9.3 Hz), 7.54-7.62(m, 2H), 7.42-7.5(m, 2H), 7.17(dd, 1H, J=15.9 and 9.3 Hz), 6.97(d, 1H, J=13.2 Hz), 5.7(s, 2H), 3.85(d, 2H, J=19.8 Hz), 2.77(m, 2H), 1.5-1.78(m, 3H), 1.25(m, 2H), 0.95(d, 3H, J=6.6 Hz).
Reaction SMILES: [CH3:1][N:2]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([N+:21]([O-])=O)[CH:19]=2)[N:14]=[C:13]([CH3:24])[N:12]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH3:10])=[CH:5][CH:4]=1.ClC1C2C(=CC=C([N+]([O-])=O)C=2)N=C(C)N=1.CNC1C=CC(NC)=CC=1>CC(O)C.Cl>[CH3:24][C:13]1[N:12]=[C:11]([N:2]([CH3:1])[C:3]2[CH:4]=[CH:5][C:6]([NH:9][CH3:10])=[CH:7][CH:8]=2)[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([NH2:21])[CH:19]=2)[N:14]=1
Reactant: CNc1ccc(N(C)c2nc(C)nc3ccc([N+](=O)[O-])cc23)cc1
Agent: CNc1ccc(NC)cc1
Agent: Cc1nc(Cl)c2cc([N+](=O)[O-])ccc2n1
Agent: Cl
Solvent: CC(C)O
Product: CNc1ccc(N(C)c2nc(C)nc3ccc(N)cc23)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N,N′-Dimethyl-N-(2-methyl-6-nitro-quinazolin-4-yl)-benzene-1,4-diamine: To a mixture of 0.15 g (0.67 mmol) of 4-chloro-2-methyl-6-nitro-quinazoline in i-PrOH (10 mL) and concd HCl (0.2 mL) was added 0.1 g (0.73 mmol) of N,N′-dimethyl-benzene-1,4-diamine, and the mixture was stirred at ambient temperature for 18 hours. The precipitate occurred during the reaction was collected and washed with Et2O to give 0.19 mg of the title compound as the HCl salt. LC-MS (ESI+; 324 ([M+H]+)).
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[CH:10]=[C:11]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:12]([F:14])=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.Cl[C:41]([O:43][CH:44]([Cl:46])[CH3:45])=[O:42]>C(Cl)(Cl)Cl>[CH2:2]([N:3]1[C:9]2[C:8](=[CH:13][C:12]([F:14])=[C:11]([N:15]3[CH2:20][CH2:19][N:18]([C:41]([O:43][CH:44]([Cl:46])[CH3:45])=[O:42])[CH2:17][CH2:16]3)[CH:10]=2)[C:6](=[O:7])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:1]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)cc21
Reactant: CC(Cl)OC(=O)Cl
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: ClC(Cl)Cl
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C(=O)OC(C)Cl)CC3)cc21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Norfloxacin (6.4 g) was suspended in 300 ml of chloroform and 4.3 g of proton sponge® was added to it. The suspension was cooled in an ice bath and 4.0 g of 1-chloroethyl chloroformate was added. A clear solution resulted in half an hour. The reaction mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated in vacuum to about 150 ml. The crystals formed were filtered and washed with chloroform. The pure product weighed 5.3 g.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][C:15]=2[S:22]([NH2:25])(=[O:24])=[O:23])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[CH3:26][C:27]([CH3:31])([CH3:30])[C:28]#[CH:29]>>[CH3:26][C:27]([CH3:31])([CH3:30])[C:28]#[C:29][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][C:15]=2[S:22]([NH2:25])(=[O:24])=[O:23])(=[O:12])=[O:11])=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1cc(CO)ccc1NS(=O)(=O)CCc1ccc(Br)cc1
Reactant: C#CC(C)(C)C
Product: CC(C)(C)C#Cc1ccc(CCS(=O)(=O)Nc2ccc(CO)cc2S(N)(=O)=O)cc1
Yield: 5 %

Procedure:
The title compound was synthesized as described for Example 210 in 5% yield, starting from 2-[2-(4-bromo-phenyl)-ethanesulfonylamino]-5-hydroxymethyl-benzenesulfonamide and 3,3-dimethyl-1-butyne. Purification by preparative HPLC.
Reaction SMILES: [CH:1]([C:3]1[C:4]([NH:9]C(=O)C(C)(C)C)=[N:5][CH:6]=[CH:7][CH:8]=1)=[O:2].[OH-].[Na+].C(OCC)(=O)C>O1CCCC1>[NH2:9][C:4]1[C:3]([CH2:1][OH:2])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: CC(C)(C)C(=O)Nc1ncccc1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ncccc1CO
Yield: 53 %

Procedure:
A mixture solution of N-(3-formylpyridin-2-yl)-2,2-dimethylpropionamide described in Preparation Example J-2 (500 mg, 2.4 mmol) and an aqueous solution of 5N sodium hydroxide (7 mL) was refluxed for 90 minutes. After cooling, ethyl acetate and tetrahydrofuran were added for extraction, the organic layer was washed with brine, then, the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (methanol:ethyl acetate=1:5), and the title compound (160 mg, 1.2 mmol, 53%) was obtained as a pale yellow solid.