Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][NH:9][C@H:10]([CH:13]([CH3:15])[CH3:14])[CH2:11][OH:12])[C:5]([F:16])=[CH:4][CH:3]=1.[CH:17]12[CH2:23][CH:20]([CH2:21][CH2:22]1)[CH:19]=[C:18]2B(O)O>C(O)C.C([O-])([O-])=O.[Cs+].[Cs+].[Pd]>[CH:17]12[CH2:23][CH:20]([CH2:21][CH2:22]1)[CH:19]=[C:18]2[C:2]1[N:7]=[C:6]([CH2:8][NH:9][C@H:10]([CH:13]([CH3:15])[CH3:14])[CH2:11][OH:12])[C:5]([F:16])=[CH:4][CH:3]=1
Reactant: OB(O)C1=CC2CCC1C2
Reactant: CC(C)[C@H](CO)NCc1nc(Br)ccc1F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Product: CC(C)[C@H](CO)NCc1nc(C2=CC3CCC2C3)ccc1F
Temperature: 120 °C

Procedure:
A microwave vial was charged with SiliaCat DPP-Pd (0.10 equivalent, 127 mg, purchased from Silicycle). A solution of Example 73A (100 mg, 0.30 mmol) in ethanol (1.0 mL) was added, followed by a solution of bicyclo[2.2.1]hept-2-en-2-ylboronic acid (41 mg, 0.30 mmol) in ethanol (1.0 mL) and 1 M aqueous Cs2CO3 (1.03 mL). The resulting mixture was heated in a microwave for 20 minutes at 120° C., filtered, and concentrated to provide (2R)-2-(((6-(bicyclo[2.2.1]hept-2-en-2-yl)-3-fluoropyridin-2-yl)methyl)amino)-3-methylbutan-1-ol. (2R)-2-(((6-(bicyclo[2.2.1]hept-2-en-2-yl)-3-fluoropyridin-2-yl)methyl)amino)-3-methylbutan-1-ol was subjected to hydrogenation (H2 atmosphere, Pd/C catalyst) then purified by reverse phase HPLC to provide the title compound. MS (ESI+) m/z 307 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][CH2:6][CH:7]([N:19]([CH3:36])[C:20](=[O:35])[C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)[CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)C.[OH-].[Li+]>CO.O1CCCC1.O>[CH3:36][N:19]([CH:7]([CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)[CH2:6][CH2:5][C:4]([OH:37])=[O:3])[C:20](=[O:35])[C:21]1[CH:22]=[C:23]([C:31]([F:33])([F:34])[F:32])[CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=1
Reactant: CCOC(=O)CCC(Cc1ccc2ccccc2c1)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CCC(=O)O)Cc1ccc2ccccc2c1

Procedure:
A solution of 19.5 g of 4-[N-methyl-N-(3,5-bistrifluoromethyl-benzoyl)-amino]-5-(naphth-2-yl)-pentanoic acid ethyl ester and 7.8 g of lithium hydroxide (monohydrate) in 212 ml of methanol, 148 ml of tetrahydrofuran and 60 ml of water is stirred at room temperature for 75 minutes and then concentrated by evaporation. The residue is dissolved in 150 ml of water, acidified to pH=2 with 0.1N hydrochloric acid and extracted three times with ethyl acetate. The combined organic phases are washed with water and saturated NaCl solution, dried (magnesium sulfate) and concentrated by evaporation. In this way the title compound is obtained in the form of a yellow foam. Rf value=0.50 (hexane/ethyl acetate 1:4). IR (CH2Cl2): 3053, 1712, 1639, 1406, 1341, 1278, 1183, 1141, 1108, 904, 849, 821 cm-1.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[N:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])[CH2:5][CH:4](C(OC)=O)[C:3]1=[O:19]>CC(O)=O.O>[CH3:1][C:2]1([CH3:20])[C:3](=[O:19])[CH2:4][CH2:5][N:6]1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: COC(=O)C1CN(C(=O)c2ccccc2)C(C)(C)C1=O
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)C(=O)CCN1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 42 h

Procedure:
A solution of methyl 5,5-dimethyl-4-oxo-1-(phenylcarbonyl)-3-pyrrolidinecarboxylate (2.5781 g, 9.364 mmol) in 10:1 HOAc-water (50 mL) was heated at 100° C. and stirred for 42 h. The solution was cooled to room temperature and concentrated in vacuo. The residue was dissolved in DCM (200 mL) and washed with sat. aq. NaHCO3. The organic phase was dried over anhydrous MgSO4, filtered, and concentrated in vacuo to afford crude 2,2-dimethyl-1-(phenylcarbonyl)-3-pyrrolidinone as a light yellow oil. LCMS: (M+H)+: 218.1.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].C1(P(C2C=CC=CC=2)(O[NH2:29])=O)C=CC=CC=1>CN(C=O)C>[NH2:29][N:14]1[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:12][C:13]1=[O:17]
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NN1CCN(C(=O)OCc2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
4-(Benzyloxycarbonyl)-2-piperazinone (4.685 g) was dissolved in DMF (170 ml) and combined with sodium hydride (800 mg, in oil) with cooling on ice. After stirring at room temperature for 30 minutes, O-diphenylphosphinyl hydroxylamine (4.896 g) was added and the mixture was stirred at 50° C. for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was combined with aqueous sodium bicarbonate and extracted with dichloromethane. The extract was dried and concentrated to obtain the title compound 1-amino-4-benzyloxycarbonyl-2-piperazinone (4.8 g) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][C@H:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2].[C:19]([O-])([O-])=O.[Cs+].[Cs+].CI.Cl>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][C@H:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][CH3:19])[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C[C@H]1OB(O)c2cc(O)cc(C)c21
Agent: Cl
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)C[C@H]1OB(O)c2cc(OC)cc(C)c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 33.6 %

Procedure:
To a solution of (3R)-(1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (2.0 g, 7.9 mmol) in anhydrous DMF (20 mL) were added Cs2CO3 (15.4 g, 47.4 mmol) and methyl iodide (1.43 g, 9.6 mmol) at 0° C. After stirring at room temperature for 4 hours the reaction mixture was cooled to 0° C. and acidified to pH 2 with concentrated HCl. The mixture was extracted with ethyl acetate and the organic extracts were washed with water, brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (30-100% EtOAc in hexane) to give (3R)-(1-hydroxy-6-methoxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester as a yellow foam (0.7 g, 35%). 1H NMR 400 MHz (DMSO-d6) δ9.12 (s, 1H), 7.07 (d, J=2.0 Hz, 1H), 6.85 (d, J=2.0 Hz, 1H), 5.46 (dd, J=9.2, 2.4 Hz, 1H), 4.09-4.03 (m, 2H), 3.74 (s, 3H), 3.17-3.07 (m, 1H), 2.26 (s, 3H), 2.23-2.17 (m, 1H), 1.16-1.12 (m, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[O:13][CH3:14])(=O)[CH3:2].Br[C:16]1[CH:21]=CC=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[K+]>[Cu].II.C1(C)C=CC=CC=1.C(O)CC(C)C>[C:1]1([NH:4][C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=2[O:13][CH3:14])[CH:18]=[CH:17][CH:16]=[CH:21][CH:2]=1
Reactant: Brc1ccccc1
Reactant: COc1ccc(NC(C)=O)c(OC)c1
Agent: [Cu]
Agent: II
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CC(C)CCO
Product: COc1ccc(Nc2ccccc2)c(OC)c1
Yield: 58.2 %

Procedure:
To a mixture of 58.5 g of N-acetyl-2,4-dimethoxyaniline and 70.7 g of bromobenzene, 29 g of anhydrous potassium carbonate, 2.1 g of copper powder and 0.8 g of iodine were added and reacted at a temperature of from 170° to 180° C. for 20 hours. Then, to this reaction mixture, 30 g of potassium hydroxide and 100 ml of isoamyl alcohol were added and reacted at a temperature of from 120° to 130° C. for 3 hours. To this reaction mixture, 300 ml of toluene was added, and the toluene layer was separated by liquid separation, washed with water, concentrated and then purified by distillation under reduced pressure, whereby 40 g of oily N-phenyl-2,4-dimethoxyaniline was obtained. The boiling point of this product was from 161° to 164° C./2 mmHg.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:18])[C:8]([CH3:10])([CH3:9])[O:7][B:6]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[O:5]1.[CH2:19](Cl)[O:20][CH3:21].O>CN(C=O)C>[CH3:19][O:20][CH2:21][O:17][C:14]1[CH:15]=[CH:16][C:11]([B:6]2[O:5][C:4]([CH3:18])([CH3:3])[C:8]([CH3:9])([CH3:10])[O:7]2)=[CH:12][CH:13]=1
Reactant: COCCl
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reaction time: 0.17 h

Procedure:
NaH (60% in oil, 4.00 g) was added portionwise at 0° C. to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (11.00 g) in DMF (125 mL). After stirring for 10 min, MOMCl (7.60 mL) was added dropwise, and the mixture was stirred for 1 h. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/AcOEt) to give the title compound (8.86 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[CH3:18][N:19]([CH3:30])[CH2:20][CH2:21][O:22][C:23]1[N:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:29][C:26]1[CH:27]=[N:28][C:23]([O:22][CH2:21][CH2:20][N:19]([CH3:30])[CH3:18])=[CH:24][CH:25]=1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: CN(C)CCOc1ccc(N)cn1
Product: CN(C)CCOc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cn1
Yield: 74.7 %

Procedure:
Following General procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (311 mg, 1 mmol) was reacted with 6-(2-(dimethylamino)ethoxy)pyridin-3-amine (340 mg, 1.8 mmol) to afford the desired product (340 mg, 75%) as a yellow solid: ESI MS m/z 455 [C22H23BrN4O2+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([N+:20]([O-:22])=[O:21])[CH2:11][CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])[CH:6]=[CH:7][CH:8]=1.Cl.[Cl-].[Na+].C(=O)([O-])O.[Na+]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([N+:20]([O-:22])=[O:21])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CC(CCC(=O)OC(C)(C)C)[N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: C1COCCO1
Product: COc1cccc(CC(CCC(=O)O)[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 97.7 %

Procedure:
To a solution of tert-butyl 5-(3-methoxyphenyl)-4-nitrovalerate (10.00 g) in 1,4-dioxane (10 ml) was added 4N hydrogen chloride in 1,4-dioxane (17.8 ml) in an ice bath. After stirring for 3 days at ambient temperature, ice water (60 ml) and sodium chloride (6 g) was added to the solution. The pH of the solution was adjusted to 9.5 with an aqueous saturated sodium hydrogencarbonate solution and the solution was washed with ethyl acetate. After the pH of the solution was adjusted to 1 with 6N hydrochloric acid, the solution was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, treated with silica gel (20 g), and evaporated in vacuo to give 5-(3-methoxyphenyl)-4-nitrovaleric acid (8.00 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[CH2:11]([NH2:14])[CH2:12][CH3:13]>>[CH2:11]([NH:14][C:6](=[O:8])[C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=1)[CH2:12][CH3:13]
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: CCCN
Product: CCCNC(=O)c1ccc(Br)cc1
Yield: 67 %

Procedure:
Using Preparation Method 1, 4-bromobenzoic acid was reacted with n-propylamine. The resulting reaction mixture was purified using SiO2 With 100% CH2Cl2 to give a white solid (67%). NMR1H (ppm, CDCl3): 7.61 (d, J3=8.60 Hz, 2H), 7.54 (d, J3=8.57 Hz, 2H), 6.06 (br. s., 1H), 3.43-3.37 (m, 2H), 1.62 (sext., J3=7.25 Hz, 2H), 0.97 (t, J3=7.39 Hz, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:6]=1[OH:14])(=[O:3])[CH3:2].[ClH:15]>[Pd].CO>[ClH:15].[C:1]([NH:4][C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:6]=1[OH:14])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc([N+](=O)[O-])ccc1O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(=O)Nc1cc(N)ccc1O

Procedure:
The 2-acetamido-4-nitrophenol thus prepared (6.6 g., 0.034 mol) in 200 ml. of methanol and 5.65 ml. of concentrated hydrochloric acid is hydrogenated with 0.50 g. of 10% palladium-on-carbon in a Parr apparatus for about one hour. The reaction mixture is filtered and the methanol removed in vacuo to yield 2-acetamido-4-aminophenol hydrochloride. The latter (4.8 g., 0.0236 mol) is dissolved in a minimum amount of methanol and treated with a solution of sodium bicarbonate (1.98 g., 0.0236 mol) in about 25 ml. of water. This solution is added to a solution of 5.0 g. (0.0236 mol) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in refluxing methanol and refluxed for 2.5 hours under nitrogen. The resulting mixture is stirred at room temperature overnight and then filtered. The solid is washed with ether, boiled with a large excess of dioxane and filtered. The solvent is reduced to about 150 ml., 100 ml. of acetonitrile is added and after cooling overnight the product is obtained, 3-[1-(3-acetamido-4-hydroxyphenylamino)ethylidene]-5-acetyl-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 248°-250° C. (dec.). Both the mono- and di-sodium salts are prepared upon treatment of the dione with sodium methoxide in methanol.
Reaction SMILES: [H-].[H-].[H-].[H-].[Al+3].[Li+].[CH2:7]([C@@H:9]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:18]=1)[C@@H:10]([CH3:16])[C:11]([N:13]([CH3:15])[CH3:14])=O)[CH3:8].[Al]>O1CCCC1.C1(C)C=CC=CC=1>[CH2:7]([C@@H:9]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:18]=1)[C@@H:10]([CH3:16])[CH2:11][N:13]([CH3:15])[CH3:14])[CH3:8]
Reactant: CC[C@@H](c1cccc(OCc2ccccc2)c1)[C@@H](C)C(=O)N(C)C
Agent: [Al+3]
Agent: [Al]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC[C@@H](c1cccc(OCc2ccccc2)c1)[C@@H](C)CN(C)C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
Lithium aluminum tetrahydride (730 mg, 20 mmol) was suspended in tetrahydrofuran (10 ml), the product of Example 5 (3.2 g, 10 mmol) was dissolved in toluene, cooled in an ice-water bath, the solution of red aluminum in toluene (9 mL, 30 mmol) was added dropwise, the reaction was carried out for 2 hours and then quenched by adding 10% NaOH aqueous solution. After the reaction solution was separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a pale yellow oil 2.8 g, yield: 90%. The HNMR spectrum data is the same as that in Example 6.
Reaction SMILES: [ClH:1].[NH:2]1[C@@H:10]2[C@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][C@H:3]1[C:11]([O:13]CC)=[O:12]>>[ClH:1].[NH:2]1[C@@H:10]2[C@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][C@H:3]1[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)[C@@H]1C[C@H]2CCCC[C@@H]2N1
Agent: Cl
Product: O=C(O)[C@@H]1C[C@H]2CCCC[C@@H]2N1

Procedure:
6 N hydrochloric acid (6 mL) was added to 0.42 g of (2S,3aR,7aS)-ethyl octahydro-1H-indole-2-carboxylate (16) and heated to reflux for NLT 4 hours. The mixture was concentrated and dried under vacuum to afford 0.42 g of (2S,3aR,7aS)-octahydro-1H-indole-2-carboxylic acid hydrochloride (5) as a crystalline solid.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:14](O)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH2:24][C:25]1[S:26][C:27]([N:30]2[CH:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:32]=[N:31]2)=[CH:28][N:29]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>C(Cl)Cl>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:14]([NH:24][C:25]3[S:26][C:27]([N:30]4[CH:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:32]=[N:31]4)=[CH:28][N:29]=3)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: CCOC(=O)c1cnn(-c2cnc(N)s2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCOC(=O)c1cnn(-c2cnc(NC(=O)C(OC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)s2)c1
Yield: 49.7 %

Procedure:
The compound of example A5 was obtained by similar method described in example A1 using 2-(4-cyclopropanesulfonyl-phenyl)-2-[(tetrahydro-pyran-4-yloxy)]-acetic acid (Preparation 4; 1.1 g, 3.23 mmol), ethyl 1-(2-aminothiazol-5-yl)pyrazole-4-carboxylate (Preparation 41; 0.924 g, 3.88 mmol), HOBt (0.524 g, 3.88 mmol), and EDCl (0.741 g, 3.88 mmol), N-methyl morpholine (0.815 g, 0.88 mmol) in DCM (20 mL) to provide the title compound (0.9 g).
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH2:13])=[N:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1)[NH2:2].[CH:14]1([CH2:17][C:18]([CH:20]2[C:25](=[O:26])[CH2:24][C:23]([CH3:28])([CH3:27])[CH2:22][C:21]2=O)=O)[CH2:16][CH2:15]1>CCO>[NH2:13][C:7]1[C:6]2[C:11](=[CH:12][C:3]([N:1]3[C:21]4[CH2:22][C:23]([CH3:28])([CH3:27])[CH2:24][C:25](=[O:26])[C:20]=4[C:18]([CH2:17][CH:14]4[CH2:16][CH2:15]4)=[N:2]3)=[CH:4][CH:5]=2)[N:10]=[CH:9][N:8]=1
Reactant: CC1(C)CC(=O)C(C(=O)CC2CC2)C(=O)C1
Reactant: NNc1ccc2c(N)ncnc2c1
Solvent: CCO
Product: CC1(C)CC(=O)c2c(CC3CC3)nn(-c3ccc4c(N)ncnc4c3)c2C1
Temperature: 50 °C
Reaction time: 22 h

Procedure:
7-Hydrazino-quinazolin-4-ylamine (0.092, 16 mg) is dissolved in 1 mL EtOH and 2-(2-Cyclopropyl-acetyl)-5,5-dimethyl-cyclohexane-1,3-dione (0.092 mmol, 20.4 mg) is added. The reaction is stirred at 50° C. for 22 h. The reaction is cooled and quenched by pouring into 20 mL H2O and extracted 3 times with 5 mL CH2Cl2. The combined organics are dried with Na2SO4, concentrated, and purified by silica gel chromatography on Biotage using a gradient of 0-15% MeOH in DCM. 1-(4-Amino-quinazolin-7-yl)-3-cyclopropylmethyl-6,6-dimethyl-1,5,6,7-tetrahydro-indazol-4-one is isolated (1 mg, LC/MS m/z=362 [M+H]+)) as a white powder.
Reaction SMILES: [F:1][C:2]1([F:23])[C:7]([F:9])([F:8])[C:6]2([CH2:12][CH2:13][CH3:14])[CH2:10][CH2:11][C:3]1([O:15]C(CCCCC)=O)[CH2:4][CH2:5]2.[OH-].[K+].O.Cl>C(OCC)(=O)C.C(O)C>[F:1][C:2]1([F:23])[C:7]([F:9])([F:8])[C:6]2([CH2:12][CH2:13][CH3:14])[CH2:5][CH2:4][C:3]1([OH:15])[CH2:11][CH2:10]2
Reactant: CCCCCC(=O)OC12CCC(CCC)(CC1)C(F)(F)C2(F)F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CCCC12CCC(O)(CC1)C(F)(F)C2(F)F
Temperature: 70 °C
Reaction time: 0.33 h

Procedure:
A mixture of 2,2,3,3-tetrafluoro-1-pentylcarbonyloxy-4-n-propylbicyclo[2.2.2]octane (11) (0.30 g), potassium hydroxide (0.10 g), water (0.5 mL), and ethanol (2.0 mL) was stirred at 70° C. for 20 minutes. The mixture was neutralized with hydrochloric acid, added with ethyl acetate (30 mL), and the organic layer was washed with aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then vaporized off under reduced pressure, to thereby obtain a crude product. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3:1), to thereby obtain 2,2,3,3-tetrafluoro-1-hydroxy-4-n-propylbicyclo[2.2.2]octane (12) (yield=0.20 g, yield ratio=94%) as a colorless clear solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][CH:19]([CH2:31][CH3:32])[C:20]([NH:22][CH2:23][C:24](OC(C)(C)C)=O)=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1.Cl.C(OC(=O)CN)(C)(C)C.NC1C=[CH:52][N:51]=[CH:50][CH:49]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][C@@H:19]([C:20]([NH:22][C:23]2[CH:24]=[CH:52][N:51]=[CH:50][CH:49]=2)=[O:21])[CH2:31][CH3:32])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1
Reactant: Nc1ccncc1
Reactant: CCC(NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)NCC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)CN
Agent: Cl
Product: CC[C@@H](NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)Nc1ccncc1

Procedure:
Instead of the starting material compound of Example 220, that is, glycine tert-butyl ester hydrochloride, 4-aminopyridine was used for the similar procedure as in Example 220 to obtain the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:9]=1[O:10][C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=O.[Cl-].[Al+3].[Cl-].[Cl-]>CN(C=O)C.C1COCC1>[CH3:15][C:11]1([CH3:16])[C:12](=[O:14])[C:17]2[CH:18]=[CH:19][C:20]([CH3:21])=[C:8]([CH3:7])[C:9]=2[O:10]1
Reactant: Cc1cccc(OC(C)(C)C(=O)O)c1C
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccc2c(c1C)OC(C)(C)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
Oxalyl dichloride (21 mL, 221 mmol) and DMF (3 drops) were sequentially added to a solution of THF (300 mL) containing 2-(2,3-dimethylphenoxy)-2-methylpropanoic acid (38.3 g, 184 mmol) synthesized in Reference Example 16 under ice-cooling condition, and the mixture was warmed to room temperature and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and then the residue was dissolved in methylene chloride (250 mL). To this solution, aluminium chloride (36.2 g, 276 mmol) was added at −78° C., and the mixture was warmed to room temperature and stirred for 15 hours. The reaction solution was concentrated under reduced pressure, and then water was added to the residue and extraction was performed using ethyl acetate. The extract was washed with saturated saline, and then dried using anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane-ethyl acetate 95:5 to 5/1) to give 26.4 g of the title compound (yield: 75%).
Reaction SMILES: N1C=NC=N1.[Na].ClC1C=CC([CH2:14][C:15]([C:18]2([CH:21]([N:23]3[CH:27]=[N:26][CH:25]=[N:24]3)[CH3:22])C[O:19]2)(C)C)=CC=1.O>C(O)CC>[N:23]1([CH:21]([CH3:22])[CH:18]([OH:19])[CH2:15][CH3:14])[CH:27]=[N:26][CH:25]=[N:24]1
Reactant: CC(n1cncn1)C1(C(C)(C)Cc2ccc(Cl)cc2)CO1
Agent: [Na]
Agent: c1nc[nH]n1
Solvent: CCCO
Solvent: O
Product: CCC(O)C(C)n1cncn1

Procedure:
3.6 g (0.052 mole) of 1,2,4-triazole are added to a solution of 0.1 g (0.043 mole) of sodium in 30 ml of n-propanol at room temperature, while stirring. A solution of 13.2 g (0.043 mole) of 2-(4-chlorophenyl-tert.-butyl)-2-[1-(1,2,4-triazol-1-yl)-ethyl]-oxirane in 20 ml of n-propanol is then added. The reaction mixture is heated under reflux for 20 hours and then cooled and poured onto 300 ml of water. The mixture is extracted with methylene chloride and the methylene chloride phase is washed with water, dried over sodium Sulphate and concentrated in vacuo. The residue is purified by column chromatography (silica gel; ethyl acetate:ether=3:1). 4 g (24.8% of theory) of 1-(4-chlorophenyl)-2,2-dimethyl-3-(1,2,4-triazol-1-yl)-methyl)-4-(1,2,4-triazol-1-yl)-3-pentanol of melting point 59° C. are obtained.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16]([NH2:23])[C:17]3[N:22]=[N:21][NH:20][C:18]=3[N:19]=2)=[N:6]1.[CH3:28]CN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.IC>CN(C)C=O>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16]([NH2:23])[C:17]3[N:22]=[N:21][N:20]([CH3:28])[C:18]=3[N:19]=2)=[N:6]1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]nnc12
Reactant: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1nnc2c(N)nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
250 mg (0.692 mmol) of the compound from example 53 and 190 mg (0.692 mmol) of BEMP were initially charged in 12 ml of dimethylformamide, and a solution of 98 mg (0.692 mmol) of iodomethane in 3 ml of dimethylformamide was added dropwise at 0° C. within 10 min. The mixture was stirred at 0° C. for 20 min. Subsequently, the reaction solution was concentrated under reduced pressure and the residue was purified by means of preparative HPLC (eluent: methanol/aqueous 0.1% ammonia solution=65:35). The residue was stirred with acetonitrile and filtered with suction, and the solids were dried under high vacuum. 78 mg of the title compound (30% of theory) and 50 mg of example 55 were obtained (19% of theory).