Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Br[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][N:8]=[C:7]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[C:17]([CH3:29])[CH:16]=1.[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1B(OC(C)C)OC(C)C>>[CH3:29][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[NH:14][C:7]1[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([C:31]3[S:30][CH:34]=[CH:33][CH:32]=3)[CH:5]=2)[N:10]=[CH:9][N:8]=1
Reactant: Cc1cc(Nc2ncnc3ccc(Br)cc23)ccc1OCc1ccccn1
Reactant: CC(C)OB(OC(C)C)c1cccs1
Agent: Cl
Product: Cc1cc(Nc2ncnc3ccc(-c4cccs4)cc23)ccc1OCc1ccccn1
Yield: 70 %

Procedure:
Using an analogous procedure to that described in Example 5, 6-bromo-4-[3-methyl-4-(2-pyridylmethoxy)anilino]quinazoline dihydrochloride salt was reacted with di-isopropyl 2-thienylboronate to give 4-[3-methyl-4-(2-pyridylmethoxy)anilino]-6-(2-thienyl)-quinazoline in 70% yield, m.p. 205°-206° C.;
Reaction SMILES: CN(C)[C:3](=[O:22])[CH2:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[NH:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([Cl:20])=[CH:15][C:14]=1[Cl:21].[OH-].[Na+].CCCC[OH:30].Cl>C1(C)C=CC=CC=1>[CH3:11][C:9]1[CH:8]=[CH:7][C:6]([NH:12][C:13]2[C:18]([CH3:19])=[CH:17][C:16]([Cl:20])=[CH:15][C:14]=2[Cl:21])=[C:5]([CH2:4][C:3]([OH:22])=[O:30])[CH:10]=1
Reactant: CCCCO
Reactant: Cc1ccc(Nc2c(C)cc(Cl)cc2Cl)c(CC(=O)N(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1ccc(Nc2c(C)cc(Cl)cc2Cl)c(CC(=O)O)c1
Temperature: 25 °C

Procedure:
N,N-dimethyl-5-methyl-2-(2′,4′-dichloro-6′-methylanilino)phenylacetamide (1.5 g, 4.3 mmol) is hydrolyzed with 6N NaOH (70 ml) as a two phase solution with n-BuOH (40 ml) at reflux temperature for 14 hours. After cooling to room temperature, the mixture is poured over ice (100 ml). Toluene (100 ml) is added and the mixture transferred to a separatory funnel. The aqueous phase is brought to a pH of 1 with 3 N HCl. The organic phase is separated and the aqueous phase re-extracted with toluene (100 ml). The combined organic solution is dried (MgSO4) and concentrated under high vacuum (35-50 mbar), on a rotovap, taking care not to warm above 50°. Upon crystallization from Et2O/hexane, 5-methyl-2-(2′,4′-dichloro-6′-methylanilino)phenylacetic acid is obtained as a tan solid, m.p. 137-141°.
Reaction SMILES: C(O[C:4](=[O:12])[C:5](=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[NH2:13][CH:14]([C:18]([NH2:20])=[O:19])[C:15]([NH2:17])=[O:16].[OH-].[Na+].C(O)C>O>[OH:16][C:15]1[C:14]([C:18]([NH2:20])=[O:19])=[N:13][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([OH:12])[N:17]=1
Reactant: NC(=O)C(N)C(N)=O
Reactant: CCOC(=O)C(=O)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1nc(C(N)=O)c(O)nc1O
Reaction time: 0.67 h

Procedure:
In 2.0 mL of water are suspended 0.65 mL of diethyl-2-oxomalonate and 0.5 g of 2-aminomalonamide. Under ice-cooling, 0.85 mL of 5 mol/mL sodium hydroxide is added thereto. The resulting solution is stirred for 40 minutes. Then, at ambient temperature, 2.55 mL of 5 mol/mL sodium hydroxide is added to the solution, which is then stirred for an additional 30 minutes. Ethanol is added to the reaction mixture and the precipitate is collected by filtration to obtain 0.24 g of 3,5-dihydroxy-6-ethoxycarbonyl-2-pyrazinecarboxamide.
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:37][CH2:36][C@@:35]2([CH3:38])[C:12](=[CH:13][CH:14]=[C:15]3[C@@H:34]2[CH2:33][CH2:32][C@@:31]2([CH3:39])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:30])[CH2:21][O:22][Si](C(C)(C)C)(C)C)[C:11]1([CH3:41])[CH3:40])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.Cl.C(=O)([O-])O.[Na+]>C(O)C>[C:1]([O:9][C@H:10]1[CH2:37][CH2:36][C@@:35]2([CH3:38])[C@@H:12]([CH2:13][CH2:14][C:15]3[C:16]4[C@:31]([CH3:39])([CH2:32][CH2:33][C:34]=32)[C@@H:19]([C@H:20]([CH3:30])[CH2:21][OH:22])[CH2:18][CH:17]=4)[C:11]1([CH3:40])[CH3:41])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](CO[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2C3=CC=C4C(C)(C)[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: C[C@H](CO)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](OC(=O)c2ccccc2)C(C)(C)[C@@H]1CC3
Yield: 67.2 %

Procedure:
vii)—A mixture of compound 8 (32.3 g), toluene (84 ml), ethanol (96%; 588 ml) and concentrated hydrochloric acid (84 ml) was heated under reflux for 3 h. The mixture was cooled and poured into a saturated aqueous solution of sodium hydrogen carbonate (1 l). The product was extracted into ethyl acetate; the combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Column chromatography afforded a 3:1 mixture (17.4 g) of (3β,5α,20S)-4,4,20-trimethylpregna-8,14-diene-3,21-diol 3-benzoate (9) and (3β,5α,20S)-4,4,20-trimethylpregna-6,8(14)-diene-3,21-diol 3-benzoate. The mixture was used as such in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:30])([CH2:24][N:25]1[CH:29]=[N:28][N:27]=[N:26]1)[C:10]([C:13]1[N:18]=[CH:17][C:16](/[CH:19]=[CH:20]\[C:21](=[O:23])[CH3:22])=[CH:15][CH:14]=1)([F:12])[F:11]>CO.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:30])([CH2:24][N:25]1[CH:29]=[N:28][N:27]=[N:26]1)[C:10]([C:13]1[N:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21](=[O:23])[CH3:22])=[CH:15][CH:14]=1)([F:11])[F:12]
Reactant: CC(=O)/C=C\c1ccc(C(F)(F)C(O)(Cn2cnnn2)c2ccc(F)cc2F)nc1
Agent: [Pd]
Solvent: CO
Product: CC(=O)CCc1ccc(C(F)(F)C(O)(Cn2cnnn2)c2ccc(F)cc2F)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
To a solution of 7 (30 mg, 0.071 mmol) in CH3OH (10 mL) was added 10% Pd/C (10 mg) under N2 atmosphere and the reaction mixture was stirred under hydrogen atmosphere at RT for 30 min. The reaction mixture was filtered through a pad of Celite®, the Celite® bed was washed thoroughly with EtOAc (3×10 mL) and then the filtrate was concentrated under vacuum. The crude material was purified by column chromatography (eluting with EtOAc/hexane) to afford 8 (16 mg, 0.037 mmol, 53%) as a colorless semi-solid. 1H NMR (500 MHz, DMSO-d6): δ 9.11 (s, 1H), 8.45 (s, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.24-7.21 (m, 2H), 7.17-7.12 (m, 1H), 6.89-6.85 (m, 1H), 5.61 (d, J=14.5 Hz, 1H), 5.06 (d, J=14.5 Hz, 1H), 2.81 (br s, 4H), 2.08 (s, 3H). MS (ESI): m/z 424 [M++1]. HPLC: 95.3%.
Reaction SMILES: [C:1]1([CH:7]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:8]([O:10]CC)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:19]>O1CCOCC1>[ClH:19].[C:1]1([CH:7]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:8]([OH:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(c1ccccc1)N1CCCCC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)C(c1ccccc1)N1CCCCC1
Yield: 86 %

Procedure:
Ethyl 2-phenyl-2-(piperidin-1-yl)acetate (985 mg, 3.98 mmol) was dissolved in dioxane (33 ml) and 37% HCl (10 ml) was slowly added. The reaction was refluxed for 48 hours and then it was evaporated under reduced pressure. The residue was triturated with acetonitrile (15 ml) and the solid was collected by filtration to obtain 2-phenyl-2-(piperidin-1-yl)acetic acid hydrochloride (876 mg, 86% yield) as a off-white solid. 1H NMR (300 MHz, DMSO-d6) ppm 10.57 (br. s., 1H), 7.33-7.67 (m, 5H), 5.27 (s, 1H), 2.84-3.21 (m, 4H), 1.64-1.98 (m, 4H), 1.31-1.64 (m, 2H)
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13](=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+].Cl>CO>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: CCOC(=O)C(=O)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)Cc1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.7 %

Procedure:
To a solution of ethyl [4-(cyclopropylsulfonyl)phenyl](oxo)acetate (20.1 g) in a mixed solvent of tetrahydrofuran (140 mL) and methanol (70 mL) was added 2M aqueous sodium hydroxide solution (70 mL), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was acidified with 1M hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was cooled to −78° C., hydrazine monohydrate (17.3 mL) was added, and the mixture was warmed to room temperature by stirring. The reaction mixture was stirred at 80° C. for 10 min and cooled to room temperature. Potassium hydroxide (12.0 g) was added to the reaction mixture, and the mixture was stirred at 100° C. for 16 hr. Water was added to the reaction mixture, and the aqueous layer was washed with diethyl ether. The aqueous layer was acidified with 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To a solution of the residue in ethanol (500 mL) was added thionyl chloride (6.23 mL) under ice-cooling, and the mixture was warmed to room temperature and stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from hexane-ether to give the title compound (13.7 g, yield 72%) as colorless crystals. melting point 102-104° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[NH:16][C:15]([CH3:20])=[CH:14][C:13]=3[NH:12][C:11]([CH3:21])=[C:10]2[C:22]([O:24][CH2:25][CH2:26][C:27]#[N:28])=[O:23])=[C:5]([O:29][CH3:30])[CH:4]=1)#[N:2].C(OCC)(OCC)O[CH2:33][CH3:34]>S(=O)(=O)(O)O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([CH3:20])=[N:16][C:17]=3[O:19][CH2:33][CH3:34])[NH:12][C:11]([CH3:21])=[C:10]2[C:22]([O:24][CH2:25][CH2:26][C:27]#[N:28])=[O:23])=[C:5]([O:29][CH3:30])[CH:4]=1)#[N:2]
Reactant: CCOC(OCC)OCC
Reactant: COc1cc(C#N)ccc1C1C(C(=O)OCCC#N)=C(C)Nc2cc(C)[nH]c(=O)c21
Agent: O=S(=O)(O)O
Product: CCOc1nc(C)cc2c1C(c1ccc(C#N)cc1OC)C(C(=O)OCCC#N)=C(C)N2
Temperature: 130 °C
Reaction time: 8 h

Procedure:
1.52 g (3.76 mmol) of the compound from Example 25A are suspended in 40 ml of triethyl orthoformate and heated to 130° C. Then, over a total period of 8 hours, 10 drops of concentrated sulfuric acid are added each hour to the reaction mixture. It is then stirred at the same temperature overnight. After cooling, excess orthoester is removed in a rotary evaporator, and the crude product is purified by column chromatography (silica gel; mobile phase: cyclohexane/ethyl acetate 1:1). The product fractions are combined, the solvent is removed, and the residue is taken up in a little methanol. The crystallizing product is filtered off. Drying under high vacuum results in 1.09 g (67% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][C@:8]2([CH3:28])[C:12](=[O:13])[O:11][C@@H](C3C=CC=CC=3)[N:9]2C(C2C=CC=CC=2)=O)=[CH:5][CH:4]=1>Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C@:8]([CH3:28])([C:12]([OH:13])=[O:11])[NH2:9])=[CH:29][CH:30]=1
Reactant: COc1ccc(C[C@]2(C)C(=O)O[C@@H](c3ccccc3)N2C(=O)c2ccccc2)cc1
Agent: Cl
Product: COc1ccc(C[C@@](C)(N)C(=O)O)cc1

Procedure:
Compound 2.3 (2.2 g, 0.0055 mol) were suspended in 20 mL of concentrated HCl solution. After nitrogen flush, the mixture was heated under reflux for 3 hours. After filtration and removal of the HCl solution, the white precipitate was dried. 1H NMR δ 7.24 (d, 2H, J=6 Hz), 6.91 (d, 2H, J=6 Hz), 3.77 (3H, s), 3.26 (d, 1H, J=14 Hz), 3.13 (d, 1H, J=14 Hz), 1.66 (s, 3H); C NMR 173.8, 161.3, 132.9, 115.9, 62.4, 56.4, 43.5, 23.2; ESI MS 210 (M+1). The product was used in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[C:5]([CH3:12])[C:4]=1[CH3:13].[H][H]>C(O)C.[C].[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([CH3:12])[C:4]=1[CH3:13]
Reactant: COc1ccc([N+](=O)[O-])c(C)c1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(N)c(C)c1C
Yield: 69.7 %

Procedure:
4-Methoxy-2,3-dimethylnitrobenzene (21.1 g, 0.15 mol) was dissolved in ethanol (300 mL), and 10% palladium carbon (50% hydrate, 1.36 g) was added. The mixture was reacted at 40° C. for 2 hours under the hydrogen atmosphere. After cooling, the catalyst was removed, ethanol was distilled off under reduced pressure, and the residue was diluted with ethyl acetate. The dilution was washed with 5% sodium hydrosulfite, dried over sodium sulfate, and purified by small amount silica gel column chromatography (ethyl acetate, 1:1). The solvent was distilled off under reduced pressure, followed by recrystallization from hexane, to obtain 15.8 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([Cl:18])[N:8]([C@@H:19]3[CH2:23][CH2:22][N:21]([C:24](OC(C)(C)C)=[O:25])[CH2:20]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C.[CH:47]1([N:50]([CH3:57])[CH2:51]/[CH:52]=[CH:53]/C(O)=O)[CH2:49][CH2:48]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=3)=[C:9]([Cl:18])[N:8]([C@@H:19]3[CH2:23][CH2:22][N:21]([C:24](=[O:25])/[CH:53]=[CH:52]/[CH2:51][N:50]([CH:47]4[CH2:49][CH2:48]4)[CH3:57])[CH2:20]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CN(C/C=C/C(=O)O)C1CC1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](n2c(Cl)c(-c3ccc(Cl)cc3)c3c(N)ncnc32)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C/C=C/C(=O)N1CC[C@@H](n2c(Cl)c(-c3ccc(Cl)cc3)c3c(N)ncnc32)C1)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.7 %

Procedure:
To a solution of (R)-tert-butyl 3-(4-amino-6-chloro-5-(4-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (37) (made according to procedures described in examples 1 and 2, using 4-chlorophenylboronic acid) (70 mg, 0.16 mmol) in DCM (4.0 mL) was added TFA (1 mL). The resulting mixture was stirred at r.t. for 1 hr before concentrated down to dryness under reduced pressure. The residue was dissolved in DMF (3 mL) and DIPEA (0.08 mL, 0.49 mmol), (E)-4-(cyclopropyl(methyl)amino)but-2-enoic acid (100 mg, 0.31 mmol), HBTU (60.4 mg, 0.16 mmol) were added, respectively. The resulting mixture was stirred at r.t. for 30 min. The solvents were evaporated. The crude product was directly purified by preparative HPLC (RP, C18, 10 to 95% acetonitrile in water (0.2% NH3H2O)) to afford (R,E)-1-(3-(4-amino-6-chloro-5-(4-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl)-4-(cyclopropyl(methyl)amino)but-2-en-1-one (38) (6.0 mg, 7.9% yield) as a white solid. LC-MS (ESI): m/z (M/M+2) 486.4/488.4. 1H NMR (400 MHz, DMSO) δ 8.17-8.12 (m, 1H), 7.56 (dd, J=8.4, 1.6 Hz, 2H), 7.48-7.40 (m, 2H), 6.77-6.60 (m, 1H), 6.37 (m, 1H), 6.10 (br, 1H), 5.49-5.28 (m, 1H), 4.24 (t, J=9.1 Hz, 1H), 4.17-3.93 (m, 1H), 3.91-3.75 (m, 1H), 3.69-3.53 (m, 1H), 3.05-2.59 (m, 3H), 2.38-2.27 (m, 1H), 2.20 (d, J=16.0 Hz, 3H), 1.82-1.46 (m, 1H), 0.48-0.36 (m, 2H), 0.32-0.18 (m, 2H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([C:20]4[N:24]([CH:25]([CH3:27])[CH3:26])[C:23]([CH3:28])=[N:22][CH:21]=4)[C:17]([F:29])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:3]1.[C:30](O)(=[O:34])[C@H:31]([CH3:33])[OH:32]>>[F:29][C:17]1[C:18]([C:20]2[N:24]([CH:25]([CH3:26])[CH3:27])[C:23]([CH3:28])=[N:22][CH:21]=2)=[N:19][C:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([N:4]3[CH2:5][CH2:6][C@@H:2]([NH:1][C:30](=[O:34])[C@@H:31]([OH:32])[CH3:33])[CH2:3]3)=[CH:12][CH:11]=2)=[N:15][CH:16]=1
Reactant: Cc1ncc(-c2nc(Nc3ccc(N4CC[C@@H](N)C4)cc3)ncc2F)n1C(C)C
Reactant: C[C@H](O)C(=O)O
Product: Cc1ncc(-c2nc(Nc3ccc(N4CC[C@@H](NC(=O)[C@H](C)O)C4)cc3)ncc2F)n1C(C)C

Procedure:
The title compound was prepared (15 mg, 6%), was prepared using a procedure analogous to Example 154 starting from N-{4-[(3R)-3-aminopyrrolidin-1-yl]phenyl}-5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidin-2-amine (Example 156; 220 mg, 0.556 mmol) and L—lactic acid (61 mg, 0.667 mmol). NMR: 1.20 (d, 3H), 1.36 (d, 6H), 1.89-2.01 (m, 1H), 2.14-2.22 (m, 1H), 2.43 (s, 3H), 3.02-3.10 (m, 1H), 3.14-3.48 (m, 3H), 3.92-4.03 (m, 1H), 4.34-4.46 (m, 1H), 5.35 (d, 2H), 5.41-5.53 (m, 1H), 6.49 (d, 2H), 7.30 (s, 1H), 7.32 (d, 2H), 8.40 (d, 1H), 9.05 (s, 1H); m/z 468.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14](Br)[N:13]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:19].[CH3:20][C@H:21]1[CH2:26][NH:25][CH2:24][C@@H:23]([CH3:27])[NH:22]1>CN1CCCC1=O.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:25]3[CH2:24][C@H:23]([CH3:27])[NH:22][C@H:21]([CH3:20])[CH2:26]3)[N:13]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:19]
Reactant: O=S(=O)(Nc1cccc(Br)n1)c1ccc(Br)c(F)c1
Reactant: C[C@@H]1CNC[C@H](C)N1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(c2cccc(NS(=O)(=O)c3ccc(Br)c(F)c3)n2)C[C@H](C)N1

Procedure:
A solution of 4-bromo-N-(6-bromo-2-pyridinyl)-3-fluorobenzenesulfonamide (D1) (300 mg, 0.73 mmol) and cis-2,6-dimethylpiperazine (600 mg, 5.4 mmol) in 1-methyl-2-pyrrolidinone (5 ml) and water (0.5 ml) was microwaved at 200° C. for 2000 sec. The reaction mixture was diluted with ethyl acetate (20 ml) and washed with water (3×10 ml). The organic phase was dried and evaporated. Purification by column chromatography eluting with 5% methanol in dichloromethane afforded the title compound (D2), MS (ES+) m/e 443, 445 [M+H]+.
Reaction SMILES: C([O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH:17]([N:21]2[CH:25]=[C:24]([C:26]3[C:27]4[CH:34]=[CH:33][N:32](COCC[Si](C)(C)C)[C:28]=4[N:29]=[CH:30][N:31]=3)[CH:23]=[N:22]2)[CH2:18][C:19]#[N:20])[CH2:12][CH:11]1[F:43])(=O)C1C=CC=CC=1.[OH-].[Li+].[C:46](#[N:48])[CH3:47]>O.C(OCC)(=O)C>[C:19]([CH2:18][CH:17]([N:21]1[CH:25]=[C:24]([C:26]2[C:27]3[CH:34]=[CH:33][NH:32][C:28]=3[N:29]=[CH:30][N:31]=2)[CH:23]=[N:22]1)[CH2:16][N:13]1[CH2:14][CH2:15][CH:10]([O:9][C:15]2[CH:14]=[C:47]([CH:12]=[C:11]([F:43])[CH:10]=2)[C:46]#[N:48])[CH:11]([F:43])[CH2:12]1)#[N:20]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCC(OC(=O)c5ccccc5)C(F)C4)c3)ncnc21
Reactant: CC#N
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: N#CCC(CN1CCC(Oc2cc(F)cc(C#N)c2)C(F)C1)n1cc(-c2ncnc3[nH]ccc23)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 1-{3-cyano-2-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}-3-fluoropiperidin-4-yl benzoate (0.389 g, 0.644 mmol) (diastereomer 2) in acetonitrile (2.0 mL) and water (1.0 mL) was added lithium hydroxide (30.8 mg, 1.29 mmol). The reaction solution was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give the desired product (0.322 g, 100%). The product was synthesized from diastereomer 1 using same procedure in 100% yield. LCMS (M+H)+: 500.3.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:12]1([Mg]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CN=CC=1>C1COCC1>[CH2:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: Br[Mg]c1ccccc1
Reactant: CCCCCCCCCCI
Solvent: C1CCOC1
Solvent: c1cnccn1
Product: CCCCCCCCCCc1ccccc1
Yield: 71 %

Procedure:
1-Iododecane (134.1 mg, 0.5 mmol) and a THF solution (0.77 mL, 0.97 M, 0.75 mmol) of phenylmagnesium bromide were used as starting materials, and reacted as in Entry 1. Conditions: The THF solution of phenylmagnesium bromide was added dropwise at 40° C. over 2 hours. 1H-NMR analysis was conducted using pyrazine (29.0 mg, 0.36 mmol) as an internal standard (yield 71%).
Reaction SMILES: [Mg].[CH3:2][C:3]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[CH:8][C:7]=1Br)([CH3:5])[CH3:4].[CH2:17]=[O:18]>O1CCCC1>[CH3:2][C:3]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[CH:8][C:7]=1[CH2:17][OH:18])([CH3:5])[CH3:4]
Reactant: C=O
Reactant: CC(C)(C)c1ccc(Br)c(C(C)(C)C)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CO)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 243 mg (10 mmoles) of magnesium turnings in 10 ml of tetrahydrofuran is added dropwise a solution of 2.69 grams (10 mmoles) of the title product of Example 9 in 5 ml of tetrahydrofuran. After the addition is complete, the mixture is refluxed for one hour. Paraformaldehyde (1.0 g, excess) is then added, and refluxing continued for one hour. The mixture is cooled to room temperature and partitioned between saturated ammonium chloride and diethyl ether. The aqueous layer is further extracted with ether, the combined organic extracts washed with brine, dried over sodium sulfate, filtered, and evaporated. Chromatography of the residue over silica gel using mixtures of ethyl acetate and hexane as eluents gives the title compound.
Reaction SMILES: [CH2:1]([P+:3]([CH2:8]O)([CH2:6]O)[CH2:4]O)O.[Cl-:10].[CH3:11][NH:12][C:13]([NH2:15])=[O:14]>C1(C)C=CC=CC=1>[Cl-:10].[CH3:11][NH:12][C:13](=[O:14])[NH:15][CH2:8][P+:3]([CH2:1][NH:15][C:13]([NH:12][CH3:11])=[O:14])([CH2:4][NH:15][C:13]([NH:12][CH3:11])=[O:14])[CH2:6][NH:15][C:13]([NH:12][CH3:11])=[O:14]
Reactant: OC[P+](CO)(CO)CO
Reactant: CNC(N)=O
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CNC(=O)NC[P+](CNC(=O)NC)(CNC(=O)NC)CNC(=O)NC
Yield: 100.2 %

Procedure:
Reaction of THPC (9.53 g, 0.05 mol) with N-methylurea (14.82 g, 0.2 mol) in toluene (75 ml), following Example 1, gave 20.78 g (100%) of tetrakis(3-methylureidomethyl)phosphonium chloride (I, R=R'=H, R"=CH3, X=Cl) as a brittle amber glass.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([N:19]([CH3:21])[CH3:20])=[CH:16][CH:17]=3)[C:11](=[O:12])[O:10]2)=[CH:5][CH:4]=1.[CH3:22][N:23]([CH3:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>[Cl-].[Zn+2].[Cl-]>[CH3:22][N:23]([CH3:30])[C:24]1[CH:29]=[CH:28][C:27]([CH:9]([C:18]2[CH:17]=[CH:16][C:15]([N:19]([CH3:21])[CH3:20])=[CH:14][C:13]=2[C:11]([OH:10])=[O:12])[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:26][CH:25]=1
Reactant: COc1ccc(C2OC(=O)c3cc(N(C)C)ccc32)cc1
Reactant: CN(C)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Product: COc1ccc(C(c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2C(=O)O)cc1

Procedure:
Following the procedure described in Example 26, part A, 9.9 g of 3-(4-methoxyphenyl)-6-dimethylaminophthalide, prepared as described in Example 12, part A above, and 89.0 ml of N,N-dimethylaniline were interacted in the presence of 9.5 g of anhydrous zinc chloride at room temperature to obtain 13.7 g of 2-(4-dimethylamino-4'-methoxybenzhydryl)-5-dimethylaminobenzoic acid as an off-white colored solid melting at 185°-190° C.
Reaction SMILES: [OH:1][CH:2]([CH3:18])[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][CH2:5]1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].CS(OCCN1CCC(NC(OC(C)(C)C)=O)CC1)(=O)=O.S([O-])(=O)(=O)C>>[CH3:26][S:27]([O:1][CH:2]([CH3:18])[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:17])[CH2:6][CH2:5]1)(=[O:29])=[O:28]
Reactant: CC(O)CN1CCC(NC(=O)OC(C)(C)C)CC1
Reactant: CS(=O)(=O)Cl
Agent: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Agent: CS(=O)(=O)[O-]
Solvent: CCN(CC)CC
Product: CC(CN1CCC(NC(=O)OC(C)(C)C)CC1)OS(C)(=O)=O

Procedure:
tert-Butyl [1-(2-hydroxypropyl)piperidin-4-yl]carbamate (Intermediate 224, 1.1 g, 4.3 mmol), triethylamine (0.90 mL, 6.5 mmol) and methanesulfonyl chloride (0.37 mL, 4.7 mmol). Were reacted as described for Intermediate 6. The crude mesylate was directly used for the next step.