Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O-:2].[Na+].[Br:4][C:5]1[CH:6]=[C:7](F)[CH:8]=[C:9]([Br:21])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1>CN(C)C=O>[Br:4][C:5]1[CH:6]=[C:7]([O:2][CH3:1])[CH:8]=[C:9]([Br:21])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1
Reactant: C[O-]
Reactant: O=[N+]([O-])c1ccc(Oc2c(Br)cc(F)cc2Br)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(Br)c(Oc2ccc([N+](=O)[O-])cc2)c(Br)c1
Temperature: 100 °C
Yield: 52.4 %

Procedure:
Sodium methylate (2.2 g) was added to a solution of 3,5-dibromo-4-(4-nitrophenoxy)fluorobenzene (10 g) and dimethylformamide (25 mL). The reaction mixture was heated at 100° C. for 15 minutes. After cooling down to room temperature, concentration and purification on column (silica gel, ethyl acetate/petrolium ether, 1:9), 5.4 g of 3,5-dibromo-4-(4-nitrophenoxy)anisole was obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)=[C:16]([C:33]([F:36])([F:35])[F:34])[CH:15]=1)=[CH:10][C:9]([C:37]1[CH:38]=[N:39][C:40]3[C:45]([CH:46]=1)=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:8][CH:7]=2.Cl[C:48](Cl)([O:50]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[O:50]=[C:48]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:22][CH2:21]3)=[C:16]([C:33]([F:36])([F:35])[F:34])[CH:15]=2)[C:12]2[C:11]3[CH:10]=[C:9]([C:37]4[CH:38]=[N:39][C:40]5[C:45]([CH:46]=4)=[CH:44][CH:43]=[CH:42][CH:41]=5)[CH:8]=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[CH2:2][O:1]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3c(CO)cnc4ccc(-c5cnc6ccccc6c5)cc34)cc2C(F)(F)F)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N3C(=O)OCc4cnc5ccc(-c6cnc7ccccc7c6)cc5c43)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl 4-(4-(3′-(hydroxymethyl)-3,6′-biquinolin-4′-ylamino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate (35 mg, 0.05 mmol) in dichloromethane (5 mL) at 0° C. was added triphosgene (16 mg, 0.05 mmol), and the resultant solution was allowed to warm up to room temperature. The reaction was allowed to proceed for 4 h before quenching with a satd. aqueous sodium carbonate solution (3 mL). The reaction mixture was extracted with EtOAc (3×10 mL) and dried over Na2SO4. The crude product was taken onto the next step without further purification. LC-MS: (M+1)=656.30
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)=[C:9]([CH3:20])[S:8][C:7]=1[NH2:21])=[O:5])[CH3:2].[C:22]1(=O)[O:27][C:25](=[O:26])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([Br:19])=[CH:17][CH:18]=2)=[C:9]([CH3:20])[S:8][C:7]=1[N:21]1[C:25](=[O:26])[C:24]2[C:23](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:22]1=[O:27])=[O:5])[CH3:2]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCOC(=O)c1c(N)sc(C)c1CCc1ccc(Br)cc1
Solvent: CC(=O)O
Product: CCOC(=O)c1c(N2C(=O)c3ccccc3C2=O)sc(C)c1CCc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
A mixture of 2-Amino-4-[2-(4-bromophenyl)ethyl]-5-methyl-thiophene-3-carboxylic acid ethyl ester (2 mmol, Example 30, Part B) and phthalic anhydride (2.2 mmol) in glacial acetic acid (20 mL) is heated at reflux overnight. After cooling to room temperature, the acetic acid is removed in vacuo and the residue triturated with petroleum ether. The crude product is collected by filtration, suspended in acetyl chloride (5 mL), and heated to reflux for one hour. After removing the solvent in vacuo, the residue is dissolved in ethyl acetate (30 mL), washed sequentially with 5% aqueous NaHCO3 (10 mL), water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Recrystallization affords the desired product.
Reaction SMILES: [NH3:1].[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:13]2[N:14]=[C:15]([S:18][CH:19]([CH2:25][CH3:26])[C:20](OCC)=[O:21])[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1>CO>[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:13]2[N:14]=[C:15]([S:18][CH:19]([CH2:25][CH3:26])[C:20]([NH2:1])=[O:21])[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1
Reactant: N
Reactant: CCOC(=O)C(CC)Sc1ccc2nnc(-c3ccccc3F)n2n1
Solvent: CO
Product: CCC(Sc1ccc2nnc(-c3ccccc3F)n2n1)C(N)=O
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To 10 ml of dry methanol saturated with ammonia was added 0.5 mmol of ethyl 2-((3-(2-fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thio)butanoate. The pressure tube was stoppered tightly, and the solution was stirred for 16 hours at 50° C. The white precipitate was collected and washed with cold methanol to give 2-((3-(2-fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thio)butanamide.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:18]O>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([O:7][CH3:18])=[O:6]
Reactant: COc1ccc(C(=O)O)cc1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(OC)c(O)c1

Procedure:
A solution of 30.8 g (183 mmol) of 3-hydroxy-4-methoxybenzoic acid and 6 mL of conc sulfuric acid in 600 mL of methanol was refluxed overnight. Most of the solvent was removed and the remaining solution was poured into 600 mL of water containing 25 g of sodium bicarbonate. The product was extracted into ether, treated with Darco, dried and evaporated. The yield was 31.8 g of methyl 3-hydroxy-4-methoxybenzoate as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[NH:14][N:13]=[C:12]([CH3:17])[C:11]=2[C:10](=O)[CH2:9]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:30][NH:31][C:32]([NH:34][OH:35])=[NH:33].Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[NH:14][N:13]=[C:12]([CH3:17])[C:11]=2[C:10](=[N:30][NH:31][C:32](=[NH:33])[NH:34][OH:35])[CH2:9]1
Reactant: Cc1n[nH]c2c1C(=O)CC(c1ccccc1Cl)C2
Reactant: N=C(NN)NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Product: Cc1n[nH]c2c1C(=NNC(=N)NO)CC(c1ccccc1Cl)C2
Temperature: 85 °C
Reaction time: 1 h
Yield: 74.8 %

Procedure:
A mixture of 6-(2-chlorophenyl)-3-methyl-4-oxo-4,5,6,7-tetrahydroindazole (1.14 g), 1-amino-3-hydroxyguanidine p-toluenesulfonate (1.26 g) and concentrated hydrochloric acid (0.44 ml) in ethanol (12 ml) was stirred at 85° C. (bath temperature) for 1 hour. The reaction solution was concentrated under reduced pressure, and to the residue were added ethyl acetate (50 ml), tetrahydrofuran (20 ml) and an aqueous solution (20 ml) of anhydrous potassium carbonate (1.4 g). The mixture was shaken, and the separated upper layer was washed with an aqueous solution (10 ml) of anhydrous potassium carbonate (0.7 g) and water (10 ml, thrice). To the upper layer was added 2 N hydrochloric acid (2.3 ml), and the mixture was concentrated under reduced pressure. To the residue was added a mixture of ether (30 ml) and ethanol (15 ml), and the mixture was stirred at room temperature for 15 hours to give solidified powder. The powder was stirred in ethanol (4 ml) at 90° C. (bath temperature) for 1 hours, and precipitated crystals were filtered off. The filtrate was concentrated under reduced pressure, and the residue was dissolved in ethanol (12 ml). The solution was stirred at 90° C. (bath temperature) for 14 hours. The reaction solution cooled, and crystals precipitated while stirring were filtered, washed with ethanol and dried to give 6-(2-chlorophenyl)-4-(1-hydroxyguanidin-3-yl)imino-3-methyl-4,5,6,7-tetrahydroindazole hydrochloride (Compound 93) (604 mg) as pale yellow crystals.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][OH:16])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.C1N2CCN(CC2)C1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Si:1]([O:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][O:16][S:32]([C:29]2[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH2:13][CH2:14]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](CO)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: C1CN2CCN1CC2
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of trans-[4-(tert-butyldimethylsilanyloxy)cyclohexyl]methanol (555 mg, 2.24 mmol) in DCM (20 mL) at 0° C. was added DIPEA (0.59 mL, 3.37 mmol), DMAP (20 mol %, 54 mg), and p-toluene-sulfonyl chloride (570 mg, 2.68 mmol). The reaction mixture was stirred at room temperature for 2 h, DABCO (250 mg) was added. The reaction mixture was stirred overnight. The solution was diluted with DCM, washed with saturated aqueous sodium bicarbonate and brine, and dried over sodium sulfate. Solvent was removed in vacuo to give the title intermediate. 1H NMR (300 mHz, CD3OD): 7.75-7.77 (d, 2H), 7.40-7.42 (d, 2H), 3.80-3.81 (d, 1H), 3.45-3.51 (m, 1H), 2.40 (s, 3H) 1.78-1.82 (m, 2H), 1.62-1.71 (m, 2H), 1.48-1.58 (m, 1H), 1.30-1.33 (m, 1H), 1.15-1.21 (m, 2H), 0.85-1.00 (m, 2H), 0.85-0.90 (s, 9H), 0.00 (s, 6H).
Reaction SMILES: [Br-].[CH2:2]([O:9][CH2:10][CH2:11][CH2:12][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].[Br:38][C:39]1[CH:40]=[CH:41][C:42]([OH:47])=[C:43]([CH:46]=1)[CH:44]=O.O>C1COCC1>[CH2:2]([O:9][CH2:10][CH2:11][CH:12]=[CH:44][C:43]1[CH:46]=[C:39]([Br:38])[CH:40]=[CH:41][C:42]=1[OH:47])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1cc(Br)ccc1O
Reactant: c1ccc(COCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Oc1ccc(Br)cc1C=CCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
60.0 g (122 mmol) of (3-benzyloxypropyl)triphenylphosphonium bromide are initially introduced in 400 ml of THF, and a solution of 25.0 g (223 mmol) of potassium tert-butoxide in 100 ml of THF is added dropwise at −10° C. A solution of 20.0 g (99.5 mmol) of 5-bromo-2-hydroxybenzaldehyde in 200 ml of THF is subsequently added dropwise at 0° C., and the batch is stirred overnight at room temp. The reaction mixture is subsequently hydrolysed using water and extracted three times with MTB ether. The combined org. phases are washed with water and sat. sodium chloride soln. and dried over sodium sulfate. The solvent is removed in vacuo, and the residue is filtered through silica gel with heptane/ethyl acetate (4:1), giving a mixture of cis- and trans-2-(4-benzyloxybut-1-enyl)-4-bromophenol as a colourless oil, which is reacted without further purification.
Reaction SMILES: C[N:2]1[CH2:7][CH:6]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)([O-])O.[Na+]>C1C=CC=CC=1>[CH2:26]([O:25][C:23]([N:2]1[CH2:3][CH:4]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1)=[O:24])[CH3:27]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)C1=CCN(C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1=CCN(C(=O)OCC)CC1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 71.4 %

Procedure:
In 640 ml of benzene, 108.9 g of ethyl 1-methyl-1,2,3,6-tetrahydropyridine-4-carboxylate and 41.6 g of diisopropylethylamine were dissolved, and subsequently, 279.1 g of ethyl chloroformate was added dropwise thereto over 70 minutes. The reaction mixture was heated under reflux for 30 minutes, followed by cooling the reaction mixture to room temperature. A saturated aqueous solution of sodium hydrogencarbonate was poured thereinto. After the reaction mixture was extracted with ethyl acetate, the extract was washed with saturated brine and was then dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:1) to yield 104.4 g of ethyl 1-ethoxycarbonyl-1,2,3,6-tetrahydropyridine-4-carboxylate as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:18][CH:17]=2)[C:7]=1[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:5])[CH3:2].[Cl:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([Cl:32])[CH:38]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:24])[CH3:25])=[CH:18][CH:17]=2)[C:7]=1[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:5])[CH3:2]
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(OC(C)C)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3cccc(Cl)c3)ccc2n1-c1ccc(OC(C)C)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-5-hydroxy-1-(4-isopropoxyphenyl)indole-3-carboxylic acid ethyl ester (0.96 g, 2.26 mmol; see step (a) above) and 3-chlorophenylboronic acid (0.70 g, 4.52 mmol). Yield 100 mg (39%).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24]CC3C=CC=CC=3)=[CH:20][CH:19]=2)[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][CH:7]=1)(=[O:4])=[O:3].[H][H]>[C].[Pd].O1CCOCC1>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=2)[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][CH:7]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Oc1ccc(N(Cc2ccc(OCc3ccccc3)cc2)S(C)(=O)=O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: CS(=O)(=O)Oc1ccc(N(Cc2ccc(O)cc2)S(C)(=O)=O)cc1
Yield: 92.3 %

Procedure:
A mixture composed of 350 mg of 4-[N-(4-benzyloxybenzyl)-N-methylsulfonylamino]phenyl methanesulfonate, 350 mg of 10% palladium-carbon, and 10 ml of dioxane was stirred for 2 days under an atmospheric pressure of hydrogen. The reaction mixture was filtered to remove any insoluble matter, and the solvent was distilled off from the filtrate. Thus, there was obtained 260 mg of 4-[N-(4-hydroxybenzyl)-N-methylsulfonylamino]phenyl methanesulfonate.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:17](=[N:19][NH:20][C:21]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=2)=[O:22])[CH3:18])=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH3:15])=[CH:9][CH:8]=1.CO.[OH-].[Na+].Cl>O>[OH:1][C:2]1[C:3]([C:17](=[N:19][NH:20][C:21]([C:23]2[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=2)=[O:22])[CH3:18])=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][CH3:15])=[CH:11][CH:12]=1
Reactant: CCCc1ccc(-c2c(O)c(C(C)=NNC(=O)c3ccc(C(=O)OC)cc3)nn2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCc1ccc(-c2c(O)c(C(C)=NNC(=O)c3ccc(C(=O)O)cc3)nn2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.5 %

Procedure:
To methyl 4-[(2-{1-[4-hydroxy-1-methyl-5-(4-n-propylphenyl)-1H-pyrazol-3-yl]ethylidene}hydrazino)carbonyl]benzoate (0.166 mmol, 72.2 mg), methanol was added, and 1 M aqueous sodium hydroxide (5 eq., 0.831 mL) was added at room temperature. After 10 minutes of stirring at room temperature and 2 hours of stirring at 60° C., the reactor was cooled to room temperature, and 1 M hydrochloric acid (5 eq., 0.831 mL) and water were added. The precipitated solid was recovered by filtration, washed with water and dried by means of a vacuum pump, and the residue was further purified by silica gel thin layer chromatography (chloroform/methanol=10/1). After addition of chloroform/n-hexane, the precipitated solid was recovered by filtration and dried to give the desired product as a yellow solid (47.1 mg, yield 670).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[N+:24]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:11]([C:20]([F:21])([F:22])[F:23])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Product: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1N

Procedure:
The title compound was prepared from (5-morpholin-4-yl-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example C8) (1.83 g, 4.68 mmol) by hydrogenation with 10% Pd/C according to the general procedure J (method a). Obtained as an amorphous red substance (1.72 g, 102%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH2:11][CH3:12])[C:5]([C:6]([OH:8])=O)=[C:4]([CH2:13][CH3:14])[CH:3]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[Cl:48][C:49]1[CH:56]=[CH:55][C:52]([CH2:53][NH2:54])=[CH:51][CH:50]=1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:13][CH3:14])[C:5]([C:6]([NH:54][CH2:53][C:52]2[CH:55]=[CH:56][C:49]([Cl:48])=[CH:50][CH:51]=2)=[O:8])=[C:9]([CH2:11][CH3:12])[CH:10]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCc1cc(Br)cc(CC)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(Br)cc(CC)c1C(=O)NCc1ccc(Cl)cc1
Reaction time: 0.33 h
Yield: 75 %

Procedure:
To a solution of 4-bromo-2,6-diethyl-benzoic acid (0.30 g, 1.20 mmol) in dichloromethane (3.6 ml) are added diisopropylethylamine (0.58 ml, 3.56 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.54 g, 1.42 mmol) at 0° C. and the mixture is stirred for 20 min followed by the addition of 4-chloro-benzyl amine (0.17 ml, 1.42 mmol). The resulting mixture is stirred at room temperature for 16 h. After completion of the reaction (monitored by TLC) the reaction mixture is diluted with dichloromethane (20 ml) and washed with water (30 ml). The organic layer is dried over sodium sulfate and concentrated in vacuo. The resulting crude product is purified column chromatography (silica gel, 25% ethyl acetate/hexane) to obtain 4-bromo-N-[(4-chlorophenyl)-methyl]-2,6-diethyl-benzamide (0.34 g, 0.90 mmol, 75%).
Reaction SMILES: C[Si](I)(C)C.[CH:6]([C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16]2[N:25]=[CH:24][C:23]([CH2:26][C:27]3[CH:28]=[N:29][C:30]([O:33]C)=[CH:31][CH:32]=3)=[C:22]3[C:17]=2[CH:18]=[CH:19][CH:20]=[N:21]3)[CH2:11][CH2:10]1)([CH3:8])[CH3:7].CCOC(C)=O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH:6]([C@H:9]1[CH2:10][CH2:11][C@H:12]([NH:15][C:16]2[N:25]=[CH:24][C:23]([CH2:26][C:27]3[CH:28]=[N:29][C:30]([OH:33])=[CH:31][CH:32]=3)=[C:22]3[C:17]=2[CH:18]=[CH:19][CH:20]=[N:21]3)[CH2:13][CH2:14]1)([CH3:8])[CH3:7]
Reactant: COc1ccc(Cc2cnc(N[C@H]3CC[C@H](C(C)C)CC3)c3cccnc23)cn1
Agent: C[Si](C)(C)I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)[C@H]1CC[C@H](Nc2ncc(Cc3ccc(O)nc3)c3ncccc23)CC1
Reaction time: 12 h

Procedure:
Under a N2 atmosphere, 142 μl (1.02 mmol) of trimethylsilyl iodide are added to 400 mg (1.02 mmol) of trans 5-(4-isopropyl-cyclohexylamino)-8-[(6-methoxy-pyridin-3-yl)-methyl]-[1,6]naphthyridine in 7 ml of chloroform, and stirring is effected for 12 h at 70° C. The mixture is cooled, EtOAc and diluted NaHCO3 are added, stirring is effected until everything has dissolved, the organic phase is separated and washed with water and brine. The aqueous phases are extracted twice more with EtOAc. Drying (Na2SO4), concentrating by evaporation, column chromatography (SiO2, EtOAc/EtOH 5:1) and stirring with DIPE yield trans 5-(4-isopropyl-cyclohexylamino)-8-[(6-hydroxy-pyridin-3-yl)-methyl]-[1,6]naphthyridine; m.p. 232-235° C.; FAB-MS: (M+H)+=377.
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].S(=O)(=O)(O)O.[CH3:15]O>>[CH3:1][CH:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:15])=[O:7]
Reactant: CC(C)CCCC(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCCC(C)C

Procedure:
The 5-methyl-caproic acid (30 g) was treated with methanol (600 ml) and sulfuric acid (3 ml), and thus methyl 5-methylcaproate was obtained. Yield: 27 g (81%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]([OH:14])[CH3:13])=[CH:10][C:9]2[C:4](=[C:5]([F:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=1>[O-2].[O-2].[Mn+4].C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:11]([C:12](=[O:14])[CH3:13])=[CH:10][C:9]2[C:4](=[C:5]([F:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(O)c1cc2cccc(F)c2nc1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CC(=O)c1cc2cccc(F)c2nc1Cl
Temperature: 25 °C

Procedure:
To a round-bottomed flask containing toluene (183 mL) was added 1-(2-chloro-8-fluoroquinolin-3-yl)ethanol (6.2 g, 27.5 mmol) and manganese dioxide (19.1 g, 219.8 mmol, 8 eq). The reaction was heated to reflux for 2 h, cooled to rt, filtered concentrated. The product was diluted with hexanes and filtered to give as a white solid 1-(2-chloro-8-fluoroquinolin-3-yl)ethanone. 1H NMR (400 MHz, CDCl3) δ ppm 8.40 (d, J=1.6 Hz, 1H), 7.71 (br d, J=8.2 Hz, 1H), 7.56 (td, J=7.8, 5.1 Hz, 1H), 7.54 (ddd, J=9.8, 7.8, 1.6 Hz, 1H). Mass Spectrum (ESI) m/e=223.9 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:20].S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][N+:3]=1[O-:20]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(Oc2ccccc2)cn1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(Oc2ccccc2)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 86.3 %

Procedure:
A mixture of 2-methyl-5-phenoxy-pyridine (3.6 g, 19 mmol) described in Manufacturing Example 121-1-1, 3-chloroperoxybenzoic acid (5.6 g, 33 mmol), and methylene chloride (80 mL) was stirred at room temperature for 45 minutes. Aqueous sodium sulfite was added to the reaction solution, and the organic layer was separated and was washed with 5 N aqueous sodium hydroxide (7 mL). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under a reduced pressure to obtain 2-methyl-5-phenoxy-pyridine 1-oxide (3.3 g). 2-methyl-5-phenoxy-pyridine 1-oxide (3.3 g, 16 mmol) and acetic anhydride (20 mL) were stirred for 40 minutes at 115° C. Acetic anhydride was evaporated under a reduced pressure, aqueous sodium bicarbonate and ethyl acetate were added to the residue, and the organic layer was separated. The ethyl acetate solution was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain an acetic acid 5-phenoxy-pyridin-2-ylmethyl ester (3.0 g). Acetic acid 5-phenoxy-pyridin-2-ylmethyl ester (3.0 g, 12 mmol), 5 N aqueous sodium hydroxide (8.0 mL), and methanol (20 mL) were stirred for 20 minutes at 60° C. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under a reduced pressure to obtain the title compound (2.6 g, 65%).