Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:18])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:19]([O:21][C:22]([C:24]1([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36](B4OC(C)(C)C(C)(C)O4)=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)[CH2:26][CH2:25]1)=[O:23])[CH3:20]>>[CH2:19]([O:21][C:22]([C:24]1([C:27]2[CH:28]=[CH:29][C:30]([C:33]3[CH:34]=[CH:35][C:36]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=4[CH:8]([OH:18])[CH2:9][CH2:10][CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:37][CH:38]=3)=[CH:31][CH:32]=2)[CH2:26][CH2:25]1)=[O:23])[CH3:20]
Reactant: OC(CCCc1ccccc1)c1ccccc1Br
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4ccccc4C(O)CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 5, Step 2, using the following starting materials: 1-(2-bromo-phenyl)-4-phenyl-butan-1-ol and 1-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[CH:12]=1)[C:7]([OH:9])=[O:8])([O-])=O>CO.C1COCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(N2CCCC2=O)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cc(C(=O)O)cc(N2CCCC2=O)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To the solution of 2.19 g (8.75 mmol) 3-nitro-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid in 50 ml MeOH/THF 3/2 are added 0.2 g Pd/C (10% Engelhard 4505) and the reaction is stirred at rt under hydrogen (1 atm) for 18 h. After filtration through celite the solvent is evaporated at reduced pressure to give the product.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1>>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:20][CH:19]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCCCCOc1ccc(Br)cc1

Procedure:
Quantities: anhydrous potassium carbonate (60 g, 0.43 mol), 1-bromononane (45.3 g, 0.22 mol) and 4-bromophenol (34.6 g, 0.2 mol). The experimental procedure was as described in Example 119.
Reaction SMILES: C([O:8][CH2:9][CH2:10][N:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=[CH:13][C:12]1=[O:23])C1C=CC=CC=1.[H][H]>CO.[OH-].[Pd+2].[OH-]>[OH:8][CH2:9][CH2:10][N:11]1[CH2:16][CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][CH2:13][C:12]1=[O:23]
Reactant: [H][H]
Reactant: O=c1ccc(-c2ccccc2)cn1CCOCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=C1CCC(c2ccccc2)CN1CCO

Procedure:
A solution of 1-(2-(benzyloxy)ethyl)-5-phenylpyridin-2(1 H)-one (100 mg, 327 μmol) in MeOH (10 mL) was sparged with argon for 10 min. A portion of palladium hydroxide (46 mg, 327 μmol) was added and the reaction was subjected to 55 psi hydrogen in a Parr shaker for 1 hr. The mixture was filtered through a pad of Celite, and concentrated to a white solid under reduced pressure. MS (ESI pos. ion) m/z (MH+): 220. Calc'd exact mass for C13H17NO2: 219. 1H NMR (400 MHz, Chloroform-d) δ ppm 2.00-2.14 (m, 2 H) 2.46-2.67 (m, 2 H) 3.07-3.18 (m, 1H) 3.33 (br. s., 1 H) 3.42-3.56 (m, 3 H) 3.60-3.68 (m, 1 H) 3.83 (t, J=4.89 Hz, 2H) 7.21-7.30 (m, 3 H) 7.35 (t, J=7.24 Hz, 2 H). 13C NMR (101 MHz, Chloroform-d) δ ppm 27.75, 31.9, 40.37, 51.24, 55.88, 61.79, 126.99, 127.30, 128.85, 141.51, 171.78.
Reaction SMILES: [C:1]1([S:11]([O-:14])(=[O:13])=[O:12])[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([O-:10])(=[O:9])=[O:8])[CH:2]=1.[Na+:15].[Na+].S(=O)(=O)(O)O.[N+:22]([O-])([O-:24])=[O:23].[Na+]>>[N+:22]([C:5]1[CH:6]=[C:1]([S:11]([O-:14])(=[O:13])=[O:12])[CH:2]=[C:3]([S:7]([O-:10])(=[O:9])=[O:8])[CH:4]=1)([O-:24])=[O:23].[Na+:15].[Na+:15]
Reactant: O=[N+]([O-])[O-]
Reactant: O=S(=O)([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=[N+]([O-])c1cc(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c1
Temperature: 65 °C

Procedure:
A mixture of 141 g. of disodium benzene-1,3-disulfonate in 450 ml. of concentrated sulfuric acid is stirred and heated to 65° C. During the course of 31/4 hours, 120 g. of sodium nitrate are added in portions while the mixture is stirred and maintained at 70° C. After addition is complete, the mixture is cooled to 5° C. and 900 g. of ice are added with stirring. The mixture is filtered overnight with vacuum. The cake is warmed on a steam bath in 250 ml. of hot water, filtered and washed with hot water. The combined filtrate and wash is cooled to 5° C. and the resulting crystals are collected by filtration giving disodium 5-nitrobenzene-1,3-disulfonate.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([O:20][CH3:21])=[C:18]([NH:22][C:23]3[C:24]([CH3:33])=[N:25][C:26]([CH2:29][C:30](O)=[O:31])=[CH:27][CH:28]=3)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([O:20][CH3:21])=[C:18]([NH:22][C:23]3[C:24]([CH3:33])=[N:25][C:26]([CH2:29][CH2:30][OH:31])=[CH:27][CH:28]=3)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:2])[CH3:3]
Reactant: COc1c(Nc2ccc(CC(=O)O)nc2C)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1c(Nc2ccc(CCO)nc2C)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Reaction time: 2 h
Yield: 18.9 %

Procedure:
A solution of 4-[6-(6-carboxymethyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (TFA salt, 582 mg, 1.01 mmol) in 4 mL THF was cooled in an ice-water bath and lithium aluminum hydride (ca 190 mg, 5 mmol) was added in small portions. After 2 h, mixture was quenched with ice-water; solids were filtered off, and washed with THF. Filtrate was concentrated and purified by HPLC. Fractions containing product were partly concentrated and residue was extracted with 1 M NaOH and methylene chloride. Organic phases were dried over MgSO4, filtered, and concentrated to give 4-{6-[6-(2-hydroxy-ethyl)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester as a white solid (85.0 mg, 19%). 1HNMR (CDCl3, 400 MHz) δ 1.25-1.27 (d, J=6.2 Hz, 6H), 1.80-1.86 (m, 2H), 2.00-2.05 (m, 2H), 2.72 (s, 3H), 3.16-3.19 (t, J=5.6 Hz, 2H), 3.38-3.44 (m, 2H), 3.76-3.82 (m, 2H), 3.96-3.99 (t, J=5.6 Hz, 2H), 4.00 (s, 3H), 4.91-4.97 (m, 1H), 5.37-5.41 (m, 1H), 5.30 (s, 1H), 5.37-5.41 (m, 1H), 7.03 (s, 1H), 7.36-7.38 (d, J=8.5 Hz, 1H), 8.13 (s, 1H), 8.85 (s, 1H). Exact mass calculated for C22H31N5O5 445.23. found 446.1 (MH+).
Reaction SMILES: [CH2:1]=[CH:2][C@@H:3]([CH3:24])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.C(O[AlH-](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].O.[OH-].[Na+]>C1COCC1>[CH2:1]=[CH:2][C@@H:3]([CH3:24])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C@@H:13]([OH:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1
Reactant: C=C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)(C)O[AlH-](OC(C)(C)C)OC(C)(C)C
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4=C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 6 h

Procedure:
A suspension of 21-methylene-20(R)-methylpregn-4-en-3-one (5, 100.0 mg, 0.3063 mmol) and lithium tri-t-butoxyaluminohydride (319.4 mg, 1.256 mmol) in 5 ml of anh. THF was stirred under argon for 6 h, after which water (48 μL), 15% (w/w) sodium hydroxide (48 μL), and water (143 μL) were added. The mixture was filtered through diatomaceous earth and the residue was extracted four times with 5 ml aliquots of THF. Concentration of the combined filtrates under reduced pressure and two-fold recrystallization from aqueous ethanol gave white platelets (42.6 mg, 0.130 mmol, 42%), m.p. 121-123° C. TLC (25% ethyl acetate/hexanes on silica gel) shows major product at Rf 0.38 and minor product at Rf 0.43 (starting material Rf 0.50).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([B:23]([OH:25])[OH:24])=[CH:19][CH:18]=1.Cl>CC(C)=O.[I-].[K+].O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([B:23]([OH:25])[OH:24])=[CH:19][CH:18]=1
Reactant: OB(O)c1ccc(CBr)cc1
Reactant: Oc1cccc(Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Solvent: O
Product: OB(O)c1ccc(COc2cccc(Br)c2)cc1
Yield: 50.8 %

Procedure:
3-bromophenol (0.50 g) was dissolved in acetone, and to the resultant solution, potassium carbonate (1.49 g), potassium iodide (14 mg), and 4-bromomethylphenyl boronic acid (0.62 g) were added, followed by heating the resultant reaction mixture under reflux for 3 hours. The reaction mixture was left to be cooled down, and to the reaction mixture, water was added, and a 2M hydrochloric acid was added to adjust pH of the reaction mixture to 2 to 3, followed by extracting the reaction mixture with ethyl acetate. The organic phase was washed with saturated saline and was dried over anhydrous sodium sulfate. From the organic phase, the solvent was distilled off under reduced pressure, and the resultant residue was purified by silica gel column chromatography to obtain the subject compound (0.45 g) as a colorless solid.
Reaction SMILES: CS[C:3]1[N:4]=[C:5]([CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[NH:6][C:7](=[O:11])[C:8]=1[C:9]#[N:10].[CH3:18][O:19][CH2:20][CH2:21][NH2:22]>>[CH3:18][O:19][CH2:20][CH2:21][NH:22][C:3]1[N:4]=[C:5]([CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[NH:6][C:7](=[O:11])[C:8]=1[C:9]#[N:10]
Reactant: CSc1nc(Cc2ccsc2)[nH]c(=O)c1C#N
Reactant: COCCN
Product: COCCNc1nc(Cc2ccsc2)[nH]c(=O)c1C#N

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.38 mmol) of 4-(methylsulphanyl)-6-oxo-2-(3-thienylmethyl)-1,6-dihydropyrimidine-5-carbonitrile are reacted with 285 mg (3.80 mmol) of 2-methoxyethylamine to give 76 mg (69% of theory) of the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.O[N:14]=[C:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.N>>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[O:12][N:22]=[C:15]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[N:14]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1ccc2[nH]ncc2c1
Agent: N
Product: c1cncc(-c2noc(-c3ccc4[nH]ncc4c3)n2)c1

Procedure:
The title compound was prepared according to Method C using 1H-indazole-5-carboxylic acid (ABCR) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, DMSO-d6) δ 7.7 (dd, J=7.9, 4.8 Hz, 1H), 7.8 (d, J=8.7 Hz, 1H), 8.2 (dd, J=8.7, 1.6 Hz, 1H), 8.4 (s, 1H) 8.5 (dt, J=7.9, 1.8 Hz, 1H), 8.7 (s, 1H) 8.8 (dd, J=4.8, 1.6 Hz, 1H), 9.3 (d, J=2.0 Hz, 1H), 13.6 (s, 1H) ppm; MS (DCI/NH3) m/z 264 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[O:12][C:13]([CH3:16])=[CH:14][N:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:17]([O:20][CH2:21][C:22]1[C:23]([N:31]2[N:40]=[CH:39][C:38]3[C:33](=[C:34]([F:45])[CH:35]=[C:36]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:37]=3)[C:32]2=[O:46])=[N:24][CH:25]=[CH:26][C:27]=1B(O)O)(=[O:19])[CH3:18].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[C:17]([O:20][CH2:21][C:22]1[C:23]([N:31]2[N:40]=[CH:39][C:38]3[C:33](=[C:34]([F:45])[CH:35]=[C:36]([C:41]([CH3:43])([CH3:42])[CH3:44])[CH:37]=3)[C:32]2=[O:46])=[N:24][CH:25]=[CH:26][C:27]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[O:12][C:13]([CH3:16])=[CH:14][N:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OCc1c(B(O)O)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Reactant: Cc1cnc(Nc2cc(Br)cn(C)c2=O)o1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ncc(C)o3)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 90 °C
Yield: 39.5 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 125a (150 mg, 0.53 mmol), 3-(acetoxymethyl)-2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)pyridin-4-ylboronic acid 116c (438 mg, 1.06 mmol), Pd(dppf)Cl2 (39 mg, 0.053 mmol), K3PO4 (225 mg, 1.06 mmol), sodium acetate (87 mg, 1.06 mmol), water (0.5 mL), and acetonitrile (10 mL). After three cycles of vacuum/argon flush, the mixture was heated at 90° C. for 1 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (100:1 to 50:1) to afford 125b as a yellow solid (120 mg, 40%). MS-ESI: [M+H]+ 573.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:11]2[C:6]([C:7](=[O:31])[N:8]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=3)[C:9](=[O:19])[NH:10]2)=[CH:5][CH:4]=1.C(O)C.[H][H]>[C].[Pd].O1CCOCC1>[NH2:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][N:8]2[C:7](=[O:31])[C:6]3[C:11](=[C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[NH:10][C:9]2=[O:19])=[CH:23][CH:24]=1
Reactant: [H][H]
Reactant: CCCCCOc1c(OC)ccc2c(=O)n(CCc3ccc([N+](=O)[O-])cc3)c(=O)[nH]c12
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCO
Product: CCCCCOc1c(OC)ccc2c(=O)n(CCc3ccc(N)cc3)c(=O)[nH]c12
Temperature: 50 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
7-Methoxy-3-[2-(4-nitrophenyl)ethyl]-8-pentyloxy-1H-quinazoline-2,4-dione (45.0 g, 105 mmol) obtained in Example 7-39, ethanol (1300 ml) and dioxane (700 ml) were mixed, and 10% palladium-carbon catalyst (4.5 g) was added to this solution. The reaction mixture was stirred in a stream of hydrogen at room temperature for 16.5 hours, followed by filtration. Activated charcoal (2.6 g was added to the filtrate, and the reaction mixture was stirred at 50° C. for 1 hour and then filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (chloroform/ethyl acetate=3/1). The precipitated crude crystals were recrystallized from ethanol-hexane to give 3-[2-(4-aminophenyl)ethyl]-7-methoxy-8-pentyloxy-1H-quinazoline-2,4-dione (33.82 g, 81%) as pale-yellow crystals.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][N:19]([C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])[CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:32])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O.C(OCC)(=O)C>[Cl:30][C:24]1[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=1[C:22]([N:19]1[CH2:20][CH2:21][CH:16]([C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([F:32])[CH:11]=3)[CH:6]=[C:5]([CH2:4][C:3]([OH:33])=[O:2])[C:14]=2[CH3:15])[CH2:17][CH2:18]1)=[O:31]
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(C(=O)c3ccc(Cl)cc3Cl)CC2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1C1CCN(C(=O)c2ccc(Cl)cc2Cl)CC1
Reaction time: 15 h
Yield: 48.2 %

Procedure:
To a colorless solution of {4-[1-(2,4-dichloro-benzoyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (102 mg, 0.21 mmol) in THF (8.0 mL) was added a solution of lithium hydroxide monohydrate (100 mg, 4.2 mmol) in water (2.0 mL) at room temperature. The resulting colorless solution was stirred for 15 hours. The solvent was removed and the aqueous solution after dilution with water was neutralized with 1.0 N aqueous HCl. The resulting white precipitate was collected by filtration and washed with hexanes. After drying in the air, 62 mg of the crude product was isolated as a white solid. The crude product was dissolved in ethyl acetate (˜3 mL) with heating and the resulting solution was diluted with hexanes (˜20 mL). The solution was stored in the freezer for three days and the precipitated solids were collected by filtration and washed with hexanes. After drying in air, {4-[1-(2,4-dichloro-benzoyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid (48 mg, 48%) was isolated as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.42 (br. s, 1H), 7.85-7.97 (m, 1H), 7.81 (br. s, 1H), 7.75 (s, 1H), 7.69 (s, 1H), 7.51-7.63 (m, 1H), 7.41-7.50 (m, 1H), 7.35 (t, J=8.03 Hz, 1H), 4.71 (br. s, 1H), 3.78 (br. s, 4H), 3.40 (br. s, 2H), 2.42 (br. s, 3H), 1.77 (br. s, 2H), 1.60 (d, J=9.79 Hz, 2H). MS cald. for C25H23Cl2FNO3 [(M+H)+] 474, obsd. 474.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH2:11]([O:13][C:14](=[O:28])[CH:15]([CH2:19][C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:16](=O)[CH3:17])[CH3:12].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[CH:19]=[C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:1]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8](=[O:10])[CH3:9])[CH:3]=2)[C:16]=1[CH3:17])=[O:28])[CH3:12]
Reactant: CC(=O)c1cccc(N)c1
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2cccc(C(C)=O)c2)c1C

Procedure:
3′-Aminoacetophenone (5 mmol, 0.7 g), 3-oxo-2-(2-oxo-2-phenyl-ethyl)-butyric acid ethyl ester (5 mmol, 1.2 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The resulting oil was purified over silica and yielded the named product as a solid (m.p. 102° C.-104° C.).
Reaction SMILES: CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.[C:21]([O:25][C:26]([NH:28][C@@H:29]1[C:39]2[C:34](=[N:35][CH:36]=[CH:37][CH:38]=2)[C@@H:33]([CH2:40][C:41]([OH:43])=O)[CH2:32][CH2:31][C@H:30]1[C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([F:50])[C:45]=1[F:51])=[O:27])([CH3:24])([CH3:23])[CH3:22].[NH:52]1[CH2:57][CH2:56][CH:55]([N:58]2[C:66]3[C:61](=[N:62][CH:63]=[CH:64][CH:65]=3)[NH:60][C:59]2=[O:67])[CH2:54][CH2:53]1.C(N(CC)CC)C>C(OCC)(=O)C.CN(C)C=O>[F:51][C:45]1[C:46]([F:50])=[CH:47][CH:48]=[CH:49][C:44]=1[C@@H:30]1[CH2:31][CH2:32][C@H:33]([CH2:40][C:41](=[O:43])[N:52]2[CH2:53][CH2:54][CH:55]([N:58]3[C:66]4[C:61](=[N:62][CH:63]=[CH:64][CH:65]=4)[NH:60][C:59]3=[O:67])[CH2:56][CH2:57]2)[C:34]2=[N:35][CH:36]=[CH:37][CH:38]=[C:39]2[C@H:29]1[NH:28][C:26](=[O:27])[O:25][C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2cccnc2[C@@H](CC(=O)O)CC[C@H]1c1cccc(F)c1F
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1c2cccnc2[C@@H](CC(=O)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)CC[C@H]1c1cccc(F)c1F
Reaction time: 0.33 h
Yield: 89.5 %

Procedure:
DEPBT (0.115 g, 0.384 mmol) was added to a dimethylformamide (4 mL) solution of 2-((5S,6S,9R)-5-(tert-butoxycarbonylamino)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)acetic acid (0.111 g, 0.256 mmol), 1-(piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (0.084 g, 0.384 mmol) at room temperature. After stirring for 20 min, triethylamine (0.054 mL, 0.384 mmol) was added to the reaction mixture. The reaction was stirred overnight at room temperature. The reaction was diluted with ethyl acetate and washed three times with water. The ethyl acetate layer was separated, dried (sodium sulfate), filtered and concentrated. Flash chromatography using methanol in methylene chloride from 0 to 10% gave the desired product (145 mg, 90%):
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[CH2:10]([Mg]Cl)[CH3:11].C1COCC1.B(F)(F)F.CCOCC>CCOCC.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2([NH2:6])[CH2:11][CH2:10]2)[CH:7]=[CH:8][CH:9]=1
Reactant: N#Cc1cccc(Cl)c1
Reactant: CC[Mg]Cl
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: NC1(c2cccc(Cl)c2)CC1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-chlorobenzonitrile (1 g, 7.27 mmol) and titanium (IV) isopropoxide (2.34 mL, 8 mmol) in Et2O (35 mL) at −78° C. was added ethyl magnesium chloride in THF (5.71 mL, 15.99 mmol). The solution was stirred for 10 min at −78° C. then at 25° C. for 1 h. BF3.Et2O (1.82 mL, 14.54 mmol) was added and the solution was stirred for 1 h at 25° C. The reaction mixture was quenched with 1N HCl (22 mL) Et2O was added (100 mL). Then 10% aq. NaOH (70 mL) was added and the layers were separated. The organic layer was dried over Na2SO4, filtered and concentrated. The crude residue was purified by preparative HPLC (Waters SunFire C18-ODB, 5 μm, 19×50 mm, 5% CH3CN/H2O 2.5 min, 5-100% CH3CN/H2O in 10 min, CH3CN/H2O containing 0.1% HCOOH flow: 20 mL/min) to give after lyophilization of the purified fractions the title compound. MS (UPLC-MS): 170 [M+H]+, 168 [M−H]−; tR (HPLC conditions f): 1.22 min.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.[NH2:10][C@@H:11]([CH3:28])[CH2:12][N:13]1[CH:17]=[CH:16][C:15]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[C:19]=2[CH3:27])=[N:14]1>>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:10][C@@H:11]([CH3:28])[CH2:12][N:13]2[CH:17]=[CH:16][C:15]([C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[C:19]=3[CH3:27])=[N:14]2)=[O:9])[N:6]=1
Reactant: Cc1c(-c2ccn(C[C@H](C)N)n2)ccc(C#N)c1Cl
Reactant: Nc1nc(C(=O)O)cs1
Product: Cc1c(-c2ccn(C[C@H](C)NC(=O)c3csc(N)n3)n2)ccc(C#N)c1Cl
Yield: 16.65 %

Procedure:
(S)-2-amino-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)-propan-2-yl)thiazole-4-carboxamide was prepared using the method of Example 34(d) starting from 2-Aminothiazole-4-carboxylic acid (0.504 g 3.49 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile (0.8 g, 2.91 mmol). The product was purified by Flash-chromatography. Yield 16.65%. 1H-NMR (400 MHz; CDCl3): δ 1.24 (d, 3H), 2.58 (s, 3H), 4.30 (dd, 1H), 4.40 (dd, 1H), 4.53 (m, 1H), 4.86 (s, 2H), 7.44 (d, 1H), 7.35 (s, 1H), 7.51 (d, 1H), 7.54 (dd, 1H), 7.57 (d, 1H), 7.63 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH:10]([Mg]Cl)([CH3:12])[CH3:11].C(=O)(O)[O-].[Na+]>CCOCC>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([CH:10]([CH3:12])[CH3:11])[OH:7])=[CH:4][CH:3]=1
Reactant: CC(C)[Mg]Cl
Reactant: O=Cc1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)C(O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a solution of 9.0 g (0.048 mol) of 4-Bromobenzaldehyde in 150 mL of ether at 0° C. under argon, 2.0 M solution of isopropyl magnesium chloride in ether (29.2 mL) was added and stirred for 30 minutes. The solution was slowly warmed up to room temperature and stirred for an additional 4 hours. The mixture was then added to 150 mL of aqueous saturated sodium bicarbonate and extracted with 200 mL of ether. The organic extract was washed once with water, dried and evaporated to afford 9.8 g (95%) of the product as a gum.