Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:3]=1.[Li]CCCC.CN([CH:25]=[O:26])C.[Cl-].[NH4+]>C1COCC1>[C:13]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])[CH:25]=[O:26])([CH3:16])([CH3:15])[CH3:14]
Reactant: CN(C)C=O
Reactant: CCN(CC)c1ccc(Br)cc1C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCN(CC)c1ccc(C=O)cc1C(C)(C)C
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 102.2 %

Procedure:
3.6 g (13 mmol) of (4-bromo-2-tert-butylphenyl)-diethylamine are diluted in 100 ml of THF, under a stream of nitrogen. The medium is cooled to −78° C. and then 7.8 ml (20 mmol) of a 2.5M solution of nBuLi are added. After stirring for 45 minutes, 1.5 ml (20 mmol) of DMF are added and the solution is brought back to ambient temperature. After 15 minutes, the mixture is poured into a saturated solution of ammonium chloride and then extracted twice with ethyl acetate. The organic phase is dried over sodium sulphate and then concentrated to dryness. 3.1 g of 3-tert-butyl-4-diethylaminobenzaldehyde are obtained in the form of a yellow oil (yield=100%).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)[CH2:16][CH2:15]1)[N:10]([C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=1[O:38][CH3:39])[CH:9]2[CH2:40][C:41]([O:43]C)=[O:42]>O1CCOCC1>[F:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([N:14]1[CH2:15][CH2:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)[CH2:18][CH2:19]1)[N:10]([C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=1[O:38][CH3:39])[CH:9]2[CH2:40][C:41]([OH:43])=[O:42]
Reactant: COC(=O)CC1c2cccc(F)c2N=C(N2CCN(c3cccc(OC)c3)CC2)N1c1cc(C(F)(F)F)ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cccc(N2CCN(C3=Nc4c(F)cccc4C(CC(=O)O)N3c3cc(C(F)(F)F)ccc3OC)CC2)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
At room temperature, 179.6 mg (4.49 mmol) of sodium hydroxide are added to 878 mg (1.5 mmol) of methyl {8-fluoro-2-[4-(3-methoxyphenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetate (Example 31A) in 40 ml of dioxane, and the mixture is stirred at 50° C. for 2 hours. The pH is then adjusted to 4–5. The product is filtered off, washed with water and dried under reduced pressure.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:3]=1.[CH3:19][O:20][C:21]1[CH:25]=[CH:24][S:23][C:22]=1[CH2:26][CH2:27][C:28]([CH3:31])([OH:30])[CH3:29]>>[CH3:19][O:20][C:21]1[CH:25]=[C:24]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]3[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]3)[N:3]=2)[S:23][C:22]=1[CH2:26][CH2:27][C:28]([CH3:31])([OH:30])[CH3:29]
Reactant: COc1ccsc1CCC(C)(C)O
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Product: COc1cc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)sc1CCC(C)(C)O

Procedure:
The title compound was prepared analogous to Method C, starting from (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine and 4-(3-methoxy-thiophen-2-yl)-2-methyl-butan-2-ol (prepared by Pd/C hydrogenation of (E)-3-(3-Methoxy-thiophen-2-yl)-acrylic acid methyl ester, followed by reaction with MeMgBr (Step A of Method A)).
Reaction SMILES: Br[C:2]1[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[N:4][N:5]2[C:10]=1[CH:9]=[CH:8][C:7]([O:11][CH:12]([F:14])[F:13])=[N:6]2.C(=O)([O-])[O-].[Na+].[Na+].[CH3:28][S:29]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)(=[O:31])=[O:30]>CN(C=O)C.C(OCC)(=O)C>[F:13][CH:12]([F:14])[O:11][C:7]1[CH:8]=[CH:9][C:10]2[N:5]([N:4]=[C:3]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[C:2]=2[C:35]2[CH:36]=[CH:37][C:32]([S:29]([CH3:28])(=[O:31])=[O:30])=[CH:33][CH:34]=2)[N:6]=1
Reactant: Fc1cccc(-c2nn3nc(OC(F)F)ccc3c2Br)c1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(-c2c(-c3cccc(F)c3)nn3nc(OC(F)F)ccc23)cc1
Yield: 38.1 %

Procedure:
To a stirred solution of 3-bromo-6-difluoromethoxy-2-(3-fluoro-phenyl)-pyrazolo[1,5-b]pyridazine (286 mg) in DMF(20 ml) was added 2N aq sodium carbonate (10 ml). To this mixture was added 4-methanesulfonyl-phenylboronic acid (180 mg) and tetrakis triphenylphosphine palladium(0) (34 mg). The resulting mixture was stirred and heated to reflux for 18 hours. The cooled reaction mixture was diluted with ethyl acetate (300 ml) and the organic solution washed with water (10×30 ml) and brine (30 ml), dried (Na2SO4) and evaporated to give a gum which was purified by flash column chromatography with chloroform:ethyl acetate (50:1 to 5:1) as eluant. Combination of appropriate fractions and concentration gave the title compound as an off-white solid (132 mg, 37%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH3:33][O:34][CH2:35][C:36]([NH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:37]
Reactant: COCC(=O)Cl
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c[nH]c23)c(OCC2CC2)c1
Product: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4ccc(OC)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from cis-4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A151) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:23]=[CH:22][C:9]2[N:10]([CH2:20][CH3:21])[C:11](=[O:19])[C:12]([CH3:18])([CH3:17])[C:13](=[O:16])[N:14]([CH3:15])[C:8]=2[CH:7]=1.[I-:24].[Na+].CC(C)=O>O>[CH2:20]([N:10]1[C:11](=[O:19])[C:12]([CH3:18])([CH3:17])[C:13](=[O:16])[N:14]([CH3:15])[C:8]2[CH:7]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][I:24])[CH:23]=[CH:22][C:9]1=2)[CH3:21]
Reactant: [I-]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCCl)ccc21
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCI)ccc21
Temperature: 25 °C
Yield: 99.7 %

Procedure:
7-(3-Chloropropoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione (2.18 g) and sodium iodide (4.8 g) were added to acetone (50 ml), and heated under reflux for 8.5 hours. The reaction mixture was cooled to room temperature, water was added, and extraction with ethyl acetate was performed. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1). The purified product was concentrated under reduced pressure to give the title compound (2.76 g) as a colorless oil.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10])=[C:2]=[O:3].[N:11]1[C:12]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:13][N:14]2[CH2:19][CH2:18][NH:17][CH2:16][C:15]=12.CCN(C(C)C)C(C)C>CN(C=O)C>[C:5]1([CH3:10])[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH:1][C:2]([N:17]1[CH2:18][CH2:19][N:14]2[CH:13]=[C:12]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:11]=[C:15]2[CH2:16]1)=[O:3]
Reactant: Cc1ccccc1N=C=O
Reactant: CCOC(=O)c1cn2c(n1)CNCC2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c(n1)CN(C(=O)Nc1ccccc1C)CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a vial containing 1-isocyanato-2-methylbenzene (0.0166 g, 0.125 mmol) was added ethyl 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (0.024 g, 0.125 mmol), DIPEA (0.0762 mL, 0.438 mmol), and DMF (1.5 mL). The solution was shaken at room temperature for 16 h, then concentrated to give crude ethyl 7-(o-tolylcarbamoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([CH2:21][CH2:22][CH3:23])[CH:12]2[CH2:20][CH2:19][C:15]3[N:16]=[CH:17][S:18][C:14]=3[CH2:13]2)=[CH:6][CH:5]=1.[OH-].[Na+].O>C(O)(=O)C>[CH2:21]([N:11]([CH2:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:24])=[O:2])=[CH:9][CH:8]=1)[CH:12]1[CH2:20][CH2:19][C:15]2[N:16]=[CH:17][S:18][C:14]=2[CH2:13]1)[CH2:22][CH3:23]
Reactant: CCCN(Cc1ccc(C(=O)OC)cc1)C1CCc2ncsc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CCCN(Cc1ccc(C(=O)O)cc1)C1CCc2ncsc2C1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 1.93 g (5.6 mmol) 42A, 840 mg (21 mmol) sodium hydroxide and 25 mL water is stirred for 4 hours at 80° C. The mixture is allowed to cool to room temperature and then neutralized with acetic acid and extracted three times with dichloromethane. The combined organic fractions are dried with sodium sulfate, and the solvent is evaporated in vacuum.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][CH2:6][C:7]1[N:8]=[C:9]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[C:23]([CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])=[O:14])[S:10][CH:11]=1)C>[Li+].[OH-]>[CH:25]1([C:23]([C:17]2[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=2[NH:15][C:13](=[O:14])[NH:12][C:9]2[S:10][CH:11]=[C:7]([CH2:6][CH2:5][C:4]([OH:30])=[O:3])[N:8]=2)=[O:24])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CCOC(=O)CCc1csc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)n1
Agent: [Li+]
Agent: [OH-]
Product: Cc1ccc(NC(=O)Nc2nc(CCC(=O)O)cs2)c(C(=O)C2CCCC2)c1
Yield: 93.4 %

Procedure:
3-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-propionic acid (15 mg, 88%) was prepared from 3-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-propionic acid ethyl ester (0.03 g, 0.04 mmol) and 2.5M LiOH (20 μL) following the general procedure J.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:15][O:16][C:17]([C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)=[O:18].O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([C:17]([O:16][CH3:15])=[O:18])[CH:24]=2)=[CH:4][N:3]=1
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: Clc1ncc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(-c2cnc(Cl)nc2)c1
Temperature: 110 °C
Reaction time: 10.5 h
Yield: 14.9 %

Procedure:
To a solution of 1.93 g (10.0 mmol) of 2-chloro-5-bromopyrimidine in 30 ml of toluene, 4.12 g (30.0 mmol) of potassium carbonate, 1.89 g (10.5 mmol) of 3-(methoxycarbonyl)phenylboronic acid and 1.0 g (0.87 mmol) of tetrakis(triphenyl phosphine)palladium (0) were added, and the reaction solution was stirred at 110° C. for 10.5 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride aqueous solution in order and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=95/5-0/100 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 0.37 g of the title compound as a yellow solid (yield: 14%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12]CC)=[O:11])=[CH:7][C:6]=2[CH:15]=1.[Br-].[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Zn+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=[O:11])=[CH:7][C:6]=2[CH:15]=1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2o1
Reactant: [Zn+]c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: O
Product: O=C(O)c1cc2cc(-c3ccccn3)ccc2o1
Temperature: 60 °C
Yield: 84.7 %

Procedure:
A mixture of ethyl 5-bromo-benzofuran-2-carboxylate (1.0 g, 3.8 mmol), (prepared as described herein in Preparation1), 2-pyridinyl zinc bromide (15 mL, 7.5 mmol), tetrakis(triphenylphosphine)palladium (0) (100 mg), was stirred under an argon atmosphere and heated to 60° C. overnight. The mixture was cooled, poured into water, extracted with ethyl acetate, washed with brine, dried (MgSO4), and evaporated. Purification by chromatography gave 770 mg of 5-pyridin-2yl-benzofuran-2-carboxylic acid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[OH-].[NH4+:14]>CO>[N:9]1[CH:10]=[CH:11][CH:12]=[C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][NH2:14])[CH:8]=1
Reactant: [NH4+]
Reactant: ClCCCCOc1cccnc1
Agent: [OH-]
Solvent: CO
Product: NCCCCOc1cccnc1
Temperature: 100 °C
Yield: 74.2 %

Procedure:
The 4-chloro-1-(3-pyridyloxy)butane (2.00 g, 10.8 mmol) was dissolved in methanol (25 mL) and added to concentrated ammonium hydroxide solution (29.7%, 14.8 M, 50 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100° C. (oil bath temperature) for 6 h. After cooling, the mixture was concentrated by rotary evaporation. Saturated NaCl solution (10 mL) was added to the residue, and the solution (pH 6) was extracted with ether (3×25 mL) to remove impurities. The aqueous layer was basified to pH 10 with 100% NaOH solution, and the mixture was extracted with chloroform (4×25 mL). The combined chloroform extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 1.25 g (74.2%) of an oil.
Reaction SMILES: [C:1]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4].[C:16]([O:25][CH3:26])(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[NH2:19]>>[C:1]([C:6](=[CH:12][NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[C:16]([O:25][CH3:26])=[O:24])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)C(=COCC)C(=O)OCC
Reactant: COC(=O)c1ccccc1N
Product: CCCC(=O)C(=CNc1ccccc1C(=O)OC)C(=O)OCC
Reaction time: 0.33 h

Procedure:
A mixture of ethyl 2-butyryl-3-ethoxyacrylate (21.4 g, 0.1 mol) and methyl anthranilate (12.9, ml, 0.1 mol) was heated to boiling for 20 minutes, then cooled and triturated with petroleum ether to obtain ethyl 2-butyryl3-(2-carbomethoxyphenylamino)acrylate as a mixture of E/Z isomers (18.0 g, 56%).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([O:31][C:32]3[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=3[F:39])[CH:26]=[N:25]2)[C:8]([NH:10][C:11]2[CH:15]=[CH:14][N:13]([CH2:16][C@H:17]3[CH2:21][O:20]C(C)(C)[O:18]3)[N:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH:1]1([CH2:6][CH:7]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([O:31][C:32]3[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=3[F:39])[CH:26]=[N:25]2)[C:8]([NH:10][C:11]2[CH:15]=[CH:14][N:13]([CH2:16][C@H:17]([OH:18])[CH2:21][OH:20])[N:12]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)OC[C@H](Cn2ccc(NC(=O)C(CC3CCCC3)n3ncc(Oc4c(F)cccc4F)cc3=O)n2)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: O=C(Nc1ccn(C[C@H](O)CO)n1)C(CC1CCCC1)n1ncc(Oc2c(F)cccc2F)cc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-propionamide (142.4 mg, 0.26 mmol) in methanol (2.6 mL, 0.10M) at 25° C. was treated with para-toluenesulfonic acid monohydrate (7.7 mg, 0.04 mmol). The reaction was stirred at 25° C. overnight. After this time, the reaction was concentrated in vacuo. Silica gel column chromatography (AnaLogix 8 g, 1-10% methanol/methylene chloride) afforded 3-cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-((S)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-propionamide (110.3 mg, 84%) as an off-white solid as a mixture of diastereomers; ES+-HRMS m/e calcd for C24H27N5O5F2 [M+H+] 504.2053 found 504.2053. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.03-1.18 (m, 1H) 1.22-1.76 (m, 8H) 1.88-2.01 (m, 1H) 2.17-2.35 (m, 1H) 3.19-3.32 (m, 2H) 3.70-3.80 (m, 1H) 3.82-3.93 (m, 1H) 4.09 (dd, J=13.3, 4.4 Hz, 1H) 4.70 (t, J=5.5 Hz, 1H) 4.94 (dd, J=5.5, 2.5 Hz, 1H) 5.40-5.51 (m, 1H) 6.03 (d, J=3.0 Hz, 1H) 6.36 (d, J=2.1 Hz, 1H) 7.35-7.43 (m, 2H) 7.44-7.51 (m, 1H) 7.53 (d, J=2.1 Hz, 1H) 8.28 (d, J=3.0 Hz, 1H) 10.83 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[C:10]=1[OH:11])[C:5]([OH:7])=[O:6].Cl.[CH2:16](Cl)Cl>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[C:10]=1[OH:11])[C:5]([O:7][CH3:16])=[O:6]
Reactant: O=C(O)c1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: ClCCl
Agent: Cl
Product: COC(=O)c1cc(O)c(O)c([N+](=O)[O-])c1
Reaction time: 3 h

Procedure:
1.0 g of 3,4-dihydroxy-5-nitrobenzoic acid is treated with 20 ml of methanolic hydrochloric acid, stirred at 45° for 3 hours and, after removing the solvent, the residue is taken up in methylene chloride. The organic phase is washed with sodium chloride solution, dried over sodium sulfate and evaporated. The crystalline product obtained is taken up in methylene chloride and filtered over a ten-fold amount of silica gel. The material obtained is recrystallized from ethyl acetate/n-hexane. There is obtained methyl 3,4-dihydroxy-5-nitrobenzoate in the form of yellow crystals of m.p. 144°-145°.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([CH3:11])([CH3:10])[C:5](=[O:9])[CH2:6][C:7]#[N:8].[OH-].[Na+].Cl.[NH2:15]O.Cl>C(O)C.O>[CH3:1][O:2][CH2:3][C:4]([C:5]1[O:9][N:8]=[C:7]([NH2:15])[CH:6]=1)([CH3:11])[CH3:10]
Reactant: COCC(C)(C)C(=O)CC#N
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COCC(C)(C)c1cc(N)no1
Temperature: 25 °C
Yield: 31.6 %

Procedure:
To a mixture of 5-methoxy-4,4-dimethyl-3-oxopentanenitrile (1 g, 6.5 mmol) in ethanol (100 mL), was added 96% sodium hydroxide (308 mg, 7.70 mmol). To this was added a solution of hydroxylamine hydrochloride (537 mg, 7.70 mmol) in water (100 mL). The resulting solution (pH 7.8) was stirred at 60° C. for 22 h, then cooled to room temperature. To this was added concentrated hydrochloric acid (3 mL, 36 mmol) and the mixture refluxed (80° C.) for 1 h. The reaction mixture was concentrated under reduced pressure to remove ethanol and the residue was mixed with 30% sodium hydroxide (2.1 g). The mixture was shaken with chloroform. The chloroform layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oil. Purification via silica gel chromatography afforded 5-(1-methoxy-2-methylpropan-2-yl)isoxazol-3-amine as a colorless solid (350 mg, 32%). 1H NMR (300 MHz, CDCl3) δ 5.60 (s, 1H), 3.39 (s, 2H), 3.32 (s, 3H), 2.94 (brs, 2H), 1.28 (s, 6H); LC-MS (ESI) m/z 171 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19](O)=[O:20])[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH:67]1([CH2:73][NH2:74])[CH2:72][CH2:71][CH2:70][CH2:69][CH2:68]1>ClCCl>[CH:67]1([CH2:73][NH:74][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][CH:24]=[C:16]([N:13]3[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][CH:7]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:15][CH2:14]3)[CH:17]=2)[CH2:72][CH2:71][CH2:70][CH2:69][CH2:68]1
Reactant: NCC1CCCCC1
Reactant: O=C(O)c1cccc(N2CCN(CCC(c3ccccc3)c3ccccc3)CC2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCC1CCCCC1)c1cccc(N2CCN(CCC(c3ccccc3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
The compound (0.12 g) prepared in step (c) of Example 1 was dissolved in dichloromethane (5 ml), and a BOP reagent (0.16 g) and diisopropylethylamine (0.078 ml) were added to the solution. The mixture was stirred at room temperature for 30 min. Cyclohexanemethylamine (0.057 ml) was then added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was extracted with ethyl acetate, followed by washing with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then removed by distillation under the reduced pressure. The residue was purified by preparative TLC (hexane:ethyl acetate=1:1) to give 0.13 g (91.6%) of N-cyclohexylmethyl-3-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]benzamide.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Cl:9])[CH:3]=1.[Mg].CON(C)[C:14]([C@@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1)=[O:15]>C1COCC1>[Cl:9][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([F:8])[CH:5]=1)[C:14]([C@@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1)=[O:15]
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: Fc1cc(Cl)cc(Br)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cc(F)cc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.5 %

Procedure:
A solution of 1-bromo-3-chloro-5-fluoro-benzene (31.5 g, 0.15 mol) in anhydrous THF (120 mL) was added dropwise to the Mg (5.4 g, 0.22 mol) at rt under nitrogen. The mixture was stirred at 50-60° C. for 1 hr until most of the magnesium was consumed. The resulting Grignard reagent was used for the next step. The Grignard reagent was added dropwise to a solution of (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (20.4 g, 0.075 mol) in anhydrous THF (200 mL) at −78° C. under nitrogen. After addition, the mixture was allowed to stir at rt for 1.5 hr. The mixture was quenched with saturated NH4Cl solution (300 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give crude (R)-tert-butyl 3-(3-chloro-5-fluorobenzoyl)piperidine-1-carboxylate (25 g, 98%), which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:3]=1[CH3:20].[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:29][C:28]=2[NH2:39])[CH2:23][CH2:22]1.Cl.O1CCOCC1>CO>[N:24]1([C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:29][C:28]=2[NH:39][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[F:12])[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:3]=2[CH3:20])[CH2:25][CH2:26][O:21][CH2:22][CH2:23]1
Reactant: Cc1c(-c2ccccc2F)nc2cccc(F)c2c1Cl
Reactant: Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1c(-c2ccccc2F)nc2cccc(F)c2c1Nc1cc(N2CCOCC2)ccc1N1CCOCC1

Procedure:
Prepared according to Procedure K, Method 1 using 4-chloro-5-fluoro-2-(2-fluorophenyl)-3-methylquinoline (137 mg, 473 μmol), 2,5-dimorpholinobenzeneamine (125 mg, 473 μmol) and 4N hydrochloric acid solution in dioxane (0.12 mL, 473 μmol) in MeOH (3.00 mL) to afford product as a colorless solid after purification by chromatography on silica gel, eluting with MeOH gradient in DCM. 1H NMR (400 MHz, chloroform-d) δ ppm 8.23-8.51 (1H, m), 7.96 (1H, d, J=8.2 Hz), 7.53-7.69 (2H, m), 7.42-7.53 (1H, m, J=7.8, 7.8, 5.5, 2.0 Hz), 7.31-7.40 (1H, m), 7.13-7.26 (2H, m), 7.10 (1H, d, J=8.6 Hz), 6.47 (1H, dd, J=8.4, 2.9 Hz), 6.12-6.27 (1H, m), 3.92 (4H, t, J=4.7 Hz), 3.75-3.87 (4H, m), 3.12-3.21 (2H, m), 3.00-3.12 (4H, m), 2.69-2.98 (2H, m), 2.11 (3H, d, J=2.3 Hz). Mass Spectrum (ESI) m/e=517.3 (M+1).