Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Cr+3:2].[Cl-].[Cl-].[O:5]=[C:6]1[O:12][C@H:11]([C@H:13]([CH2:15][OH:16])[OH:14])[C:9]([OH:10])=[C:7]1[OH:8]>O>[O:5]=[C:6]1[O:12][C@H:11]([C@H:13]([CH2:15][OH:16])[OH:14])[C:9]([O-:10])=[C:7]1[OH:8].[Cr+3:2].[O:5]=[C:6]1[O:12][C@H:11]([C@H:13]([CH2:15][OH:16])[OH:14])[C:9]([O-:10])=[C:7]1[OH:8].[O:5]=[C:6]1[O:12][C@H:11]([C@H:13]([CH2:15][OH:16])[OH:14])[C:9]([O-:10])=[C:7]1[OH:8]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: [Cr+3]
Agent: [Cl-]
Solvent: O
Product: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Half gram (1.85 mmole) of chromium chloride (CrCl3) was dissolved in 30 ml of deionized water to get a green solution. 1.0 g (5.5 mmole) of ascorbic acid (Asc) dissolved in 40 ml of deionized water, was added to the solution. The pH of the reaction mixture was adjusted to 4.5 (pK(Asc)4.2), and the reaction mixture was stirred for 3 hours at 50° C. to get a dark green solution. The solution was concentrated in vacuum and the large volume of ethanol 90% was added to get a green sediment. UV-VIS Spectrum for Cr-Asc showed two main absorbance peaks at 263 and 592 nm.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)=[N:4][N:5]([CH:7]([CH3:9])[CH3:8])[CH:6]=1.[CH3:17][NH:18][CH3:19].[O:20]1[CH2:24]CCC1>>[Br:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:24](=[O:20])[N:18]([CH3:19])[CH3:17])=[CH:12][CH:11]=2)=[N:4][N:5]([CH:7]([CH3:9])[CH3:8])[CH:6]=1
Reactant: CNC
Reactant: C1CCOC1
Reactant: CC(C)n1cc(Br)c(-c2ccc(N)cc2)n1
Product: CC(C)n1cc(Br)c(-c2ccc(NC(=O)N(C)C)cc2)n1

Procedure:
Following the procedure described in Example 5a using {4-[4-bromo-1-(1-methylethyl)-1H-pyrazol-3-yl]phenyl}amine and 2M dimethylamine in tetrahydrofuran provided the title compound. ESMS [M+H]+: 351.2
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:13])[C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:14]F>C(#N)C.ClC(Cl)(Cl)C(F)(F)F>[C:1]1([CH:7]([F:14])[C:8](=[O:13])[C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: FF
Reactant: COC(=O)C(=O)Cc1ccccc1
Solvent: CC#N
Solvent: FC(F)(F)C(Cl)(Cl)Cl
Product: COC(=O)C(=O)C(F)c1ccccc1

Procedure:
In the same manner as in Example 1, methyl 3-phenylpyruvate (35.62 g; 0.2 mol) is dissolved in a mixture of acetonitrile (240 g) and trichlorotrifluoroethane (1.6 L) and reacted with fluorine at -10° C. After the same work-up as in Example 1, the residue is rectified to give methyl 3-phenyl-3-fluoropyruvate (11.8 g). The silyl enol ether obtained by the treatment of the above product with bis-(trimethylsilyl)acetamide (BSA) in methylene chloride shows boiling point 93°-95° C./1 mmHg and 19F NMR (CDCl3), δ (int. C6F6)+31.5 (s).
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.C1N=CN([C:31]([N:33]2C=N[CH:35]=[CH:34]2)=[O:32])C=1.[Si:38]([O:45][C:46]1[CH:52]=CC(N)=[CH:48][C:47]=1[CH3:53])([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39]>CN(C=O)C>[Si:38]([O:45][C:46]1[CH:52]=[CH:35][C:34]([NH:33][C:31]([NH:6][CH2:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[CH2:11]3)=[O:32])=[CH:48][C:47]=1[CH3:53])([C:41]([CH3:42])([CH3:43])[CH3:44])([CH3:40])[CH3:39]
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: Cc1cc(N)ccc1O[Si](C)(C)C(C)(C)C
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CS(=O)(=O)O
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)ccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
A mixture of 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione methanesulfonate (0.74 g, 2.0 mmol) and CDI (0.32 g, 2.0 mmol) in DMF (30 mL) was stirred at room temperature for 3 h, and then the product from Step 2 (0.47 g, 2.0 mmol) was added. The mixture was heated to 70° C. for 30 h. Then, the mixture was cooled to room temperature and quenched with 1N HCl (30 mL), resulting in solid precipitate. This solid was purified by chromatography on a silica gel column, using a methylene chloride-methanol gradient, and providing 0.59 g of 1-(4-(tert-butyldimethylsilyloxy)-3-methylphenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)urea as an off-white solid, in 55% yield; 1H NMR (DMSO-d6) δ 0.16 (s, 6H), 0.97 (s, 9H), 1.88-2.06 (m, 1H), 2.10 (s, 3H), 2.25-2.47 (m, 1H), 2.53-2.70 (m, 1H), 2.80-3.02 (m, 1H), 4.31 (d, J=17.4 Hz, 1H), 4.36-4.52 (m, 3H), 5.11 (dd, J=4.9, 13.2 Hz, 1H), 6.51-6.74 (m, 2H), 7.08 (dd, J=2.5, 8.6 Hz, 1H), 7.18 (d, J=2.3 Hz, 1H), 7.43 (d, J=7.7 Hz, 1H), 7.50 (s, 1H), 7.69 (d, J=7.7 Hz, 1H), 8.35 (s, 1H), 10.98 (s, 1H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:27])[CH2:18][C:19]3[CH:24]=[CH:23][C:22](Br)=[C:21]([CH3:26])[CH:20]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:28][C:29]1[CH:34]=[C:33]([Sn](CCCC)(CCCC)CCCC)[CH:32]=[CH:31][N:30]=1.CS(C)=O>CN(C=O)C.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:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:27])[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:33]4[CH:32]=[CH:31][N:30]=[C:29]([CH3:28])[CH:34]=4)=[C:21]([CH3:26])[CH:20]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(C)c1
Reactant: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(Br)c(C)c3)nc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(-c4ccnc(C)c4)c(C)c3)nc2)CC1
Temperature: 110 °C
Reaction time: 20 h

Procedure:
To the mixture of N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-bromo-3-methylphenyl)acetamide 159-1 (65 mg, 0.15 mmol) and 2-methyl-4-(tributylstannyl)pyridine 159-2 (58 mg, 0.15 mmol) in DMF (0.8 mL) was added [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (30 mg, 0.036 mmol). The reaction was stirred at 110° C. for 20 hours. After cooling down to room temperature, the reaction mixture was diluted into DMSO and purified by reverse-phase HPLC to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(3-methyl-4-(2-methylpyridin-4-yl)phenyl)acetamide 159 as off-white solid. MS m/z 444.2 (M+1); 1H NMR 400 MHz (DMSO-d6) δ10.47 (s, 1H), 8.41 (d, 1H), 7.97 (d, 1H), 7.88 (d, 1H), 7.37 (dd, 1H), 7.21-7.18 (m, 2H), 7.16 (s, 1H), 7.12-7.09 (m, 2H), 3.61 (s, 2H), 3.52 (m, 4H), 3.08 (t, 2H), 3.02 (t, 2H), 2.17 (s, 3H), 1.97 (s, 3H).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([C:10]#[C:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15])=[N:5]2.[C:19]1([CH3:28])[CH:24]=[CH:23][CH:22]=[C:21]([C:25](O)=[O:26])[CH:20]=1.Cl.CN(C)CCCN=C=NCC.CO.C(Cl)Cl>ClC(Cl)C.CN(C)C1C=CN=CC=1>[N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([C:10]#[C:11][C:12]1[CH:13]=[C:14]([NH:15][C:25](=[O:26])[C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([CH3:28])[CH:20]=3)[CH:16]=[CH:17][CH:18]=1)=[N:5]2
Reactant: Cc1cccc(C(=O)O)c1
Reactant: Nc1cccc(C#Cc2ccc3nccn3n2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CC(Cl)Cl
Product: Cc1cccc(C(=O)Nc2cccc(C#Cc3ccc4nccn4n3)c2)c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a mixture of 3-(imidazo[1,2-b]pyridazin-6-ylethynyl)aniline (93.6 mg, 0.4 mmol, 1 eq) and m-toluic acid (55 mg, 1 eq) in anhydrous dichloroethane (4 mL) under nitrogen atmosphere was added 4-(dimethylamino)pyridine (10 mg, 0.2 eq) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (92.2 mg, 1.2 eq). After the reaction was stirred at 60° C. for four hours and was cooled to room temperature, white precipitates were observed. It was filtered directly to give a white solid. This solid was further subject to a gradient column chromatography (MeOH-DCM 1:50 to 1:20) to yield N-[3-(imidazo[1,2-b]pyridazin-6-ylethynyl)phenyl]-3-methylbenzamide as a white solid in amount of 85 mg.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]3[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=3[O:13][N:12]=2)=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[2H][C:28]1([2H])[C:33]([2H])([2H])[C:32]([2H])([2H])[N:31]([2H])[C:30]([2H])([2H])[C:29]1([2H])[2H].C(#N)C>O>[F:20][C:18]1[CH:17]=[CH:16][C:15]2[C:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:31]4[CH2:32][CH2:33][CH2:28][CH2:29][CH2:30]4)=[CH:6][CH:7]=3)=[N:12][O:13][C:14]=2[CH:19]=1
Reactant: Fc1ccc2c(-c3ccc(OCCBr)cc3)noc2c1
Reactant: [2H]N1C([2H])([2H])C([2H])([2H])C([2H])([2H])C([2H])([2H])C1([2H])[2H]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Fc1ccc2c(-c3ccc(OCCN4CCCCC4)cc3)noc2c1
Temperature: 25 °C
Yield: 73.9 %

Procedure:
Combine 3-[4-(2-bromo-ethoxy)-phenyl]-6-fluoro-benzo[d]isoxazole (550 mg, 1.63 mmol), potassium carbonate (500 mg, 3.62 mmol), piperidine- d11 (630 mg, 6.55 mmol) and 5% aqueous acetonitrile. Under a nitrogen atmosphere, heat to reflux overnight. Cool to room temperature and pour the reaction mixture into water resulting in white solid precipitation. Collect the solid and dry in vacuo. Dissolve the solid in ethyl acetate and filter to remove the insoluble materials and concentrate in vacuo. Take the solid up in diethyl ether, filter and precipitate the hydrochloride salt out of solution by addition of hydrogen chloride in diethyl ether. Collect the desired salt and dry in vacuo to give the title compound as a solid (410 mg, 67% Yield).
Reaction SMILES: CS(C)=O.Cl[C:6]1[N:7]([CH2:29][CH:30]2[CH2:32][CH2:31]2)[C:8]2[C:13]([N:14]=1)=[C:12]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[N:11]=[C:10]([C:21]1[CH:22]=[N:23][C:24]([NH:27][CH3:28])=[N:25][CH:26]=1)[N:9]=2.[CH3:33][C@H:34]1[CH2:39][NH:38][CH2:37][C@@H:36]([CH3:40])[NH:35]1>ClCCl.CO>[CH:30]1([CH2:29][N:7]2[C:6]([N:38]3[CH2:37][C@H:36]([CH3:40])[NH:35][C@H:34]([CH3:33])[CH2:39]3)=[N:14][C:13]3[C:8]2=[N:9][C:10]([C:21]2[CH:22]=[N:23][C:24]([NH:27][CH3:28])=[N:25][CH:26]=2)=[N:11][C:12]=3[N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:32][CH2:31]1
Reactant: CNc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC4CC4)c3n2)cn1
Reactant: C[C@@H]1CNC[C@H](C)N1
Solvent: CO
Solvent: ClCCl
Solvent: CS(C)=O
Product: CNc1ncc(-c2nc(N3CCOCC3)c3nc(N4C[C@@H](C)N[C@@H](C)C4)n(CC4CC4)c3n2)cn1
Reaction time: 5 h
Yield: 89.2 %

Procedure:
A dimethyl sulfoxide solution (1.0 ml) of 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]-N-methylpyrimidin-2-amine (112.3 mg, 0.23 mmol) and cis-2,6-dimethylpiperazine (105.7 mg, 0.93 mmol) was heated at 140° C., stirred for 5 hours, and left standing to cool followed by the addition of dichloromethane-methanol (10:1) and the resulting mixture was washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (dichloromethane:methanol=10:1) to give the title compound (98.2 mg, 89%) as a light brown solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([OH:18])=O)[C:5]2[CH:6]=[N:7][N:8](C3CCCC3)[C:9]=2[CH:10]=1.C1C[N:22]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.NCC1C(=O)NC(C)=CC=1CO[Si](C(C)(C)C)(C)C.O>CS(C)=O>[NH:8]1[C:9]2[CH:10]=[CH:2][CH:3]=[C:4]([C:16]([NH2:22])=[O:18])[C:5]=2[CH:6]=[N:7]1
Reactant: O=C(O)c1cc(Br)cc2c1cnn2C1CCCC1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cc1cc(CO[Si](C)(C)C(C)(C)C)c(CN)c(=O)[nH]1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1cccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 115.8 %

Procedure:
To a solution of 6-bromo-1-cyclopentyl-1H-indazole-4-carboxylic acid (2.3 g, 7.5 mmol) in DMSO (30 mL), PyBOP (5.82 g, 11.20 mmol) was added and reaction stirred at room temperature for 15 min. 3-(Aminomethyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridin-2(1H)-one (2.52 g, 8.96 mmol) was then added and reaction mixture stirred overnight. On completion, water was added and the resulting precipitate filtered and washed with water. This solid was then stirred with acetonitrile for 10 min and filtered again to obtain 6-bromo-1-cyclopentyl-N-44-(hydroxymethyl)-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indazole-4-carboxamide (1.4 g, 40.9%).
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH:14]=[C:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C:16]3=[CH:17][CH2:18][C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-:38].[Na+].ClC1C=CC=C(C(OO)=O)C=1.O>COC(C)(C)C>[C:1]([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH:14]=[C:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C@@:16]43[O:38][C@H:17]4[CH2:18][C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC=C2C3=CC[C@H]4C[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@@]21C
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Product: CC(C)CCC[C@@H](C)[C@H]1C[C@@H]2O[C@@]23C2=CC[C@H]4C[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]2CC[C@]13C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 24.55 kg amount of (3β,5α)-cholesta-7,14-dien-3-ol benzoate (2) (prepared in the manner described in Example 1) and 6.41 g of sodium bicarbonate were suspended under nitrogen with good agitation in 240 liters of t-butyl methyl ether in a 200-gallon reactor and chilled to 0° C. A solution of 13.0 kg of m-chloroperbenzoic acid in 100 liters of t-butyl methyl ether at about 20° C. was added to the steroid-bicarbonate suspension over a 10 minute period. A mild exothermic reaction which raised the reaction mixture temperature to 10° C. was noted. The mixture was stirred for 2 hours then 150 liters of water were added. The mixture was stirred an additional hour and agitation was halted to allow separation of the phases. The lower aqueous layer was drained off and the remaining organic phase was treated with 50 liters of water, agitated vigorously, and then the aqueous portion was drained off. The product was filtered at about 10° C., washed with three 10 liter portions of methanol and air-dried to yield 19.1 k9 of (3) batch-A.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Br[CH2:10][CH2:11][CH2:12][Cl:13]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:10][CH2:11][CH2:12][Cl:13]
Reactant: ClCCCBr
Reactant: Fc1ccccc1S
Product: Fc1ccccc1SCCCCl

Procedure:
Prepared by Procedure R and Scheme Z using 2-fluorobenzenethiol and 1-bromo-3-chloropropane.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:27])=[CH:16][C:17]=3[O:19][CH:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[N:12]=[CH:11][N:10]=2)=[C:6]2[O:28][CH2:29][O:30][C:5]2=[CH:4][CH:3]=1.[F:31][CH2:32][CH2:33]O>>[Cl:1][C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:27][CH2:33][CH2:32][F:31])=[CH:16][C:17]=3[O:19][CH:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[N:12]=[CH:11][N:10]=2)=[C:6]2[O:28][CH2:29][O:30][C:5]2=[CH:4][CH:3]=1
Reactant: OCCF
Reactant: CN1CCC(Oc2cc(O)cc3ncnc(Nc4c(Cl)ccc5c4OCO5)c23)CC1
Product: CN1CCC(Oc2cc(OCCF)cc3ncnc(Nc4c(Cl)ccc5c4OCO5)c23)CC1

Procedure:
Using an analogous procedure to that described in Example 51, 4-(6-chloro-2,3-methylenedioxyanilino)-7-hydroxy-5-(N-methylpiperidin-4-yloxy)quinazoline was reacted with 2-fluoroethanol to give the title compound; NMR Spectrum: (CDCl3) 2.0–2.1 (m, 2H), 2.15–2.3 (m, 2H), 2.35 (s, 3H), 2.3–2.4 (m, 2H), 2.8 (br s, 2H), 4.32 (m, 1H), 4.4 (m, 1H), 4.65 (m, 1H), 4.8 (m, 1H), 4.9 (m, 1H), 6.05 (s, 2H), 6.6 (s, 1H), 6.75 (d, 1H), 6.85 (s, 1H), 7.0 (d, 1H), 8.55 (s, 1H), 9.3 (s, 1H); Mass Spectrum: M+H+ 475 and 477.
Reaction SMILES: Cl.[CH2:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]([C:15]([OH:17])=[O:16])[CH2:4][NH:3]1.S(Cl)([Cl:20])=O.[CH3:22]O>>[ClH:20].[CH2:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]([C:15]([O:17][CH3:22])=[O:16])[CH2:4][NH:3]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1CNCc2[nH]c3ccccc3c21
Reactant: CO
Agent: Cl
Product: COC(=O)C1CNCc2[nH]c3ccccc3c21
Temperature: 0 °C
Reaction time: 24 h

Procedure:
1,2,3,4-Tetrahydro-β-carboline-4-carboxylic acid hydrochloride (3 g, 0.012 mole) (TR-8025) prepared in Example 3 was mixed with 50 ml of methanol. It was cooled at 0° C. Then thionylchloride (2 ml, 0.028 mole) was added dropwise. The mixture was stirred at room temperature for 24 hours. The solvent was removed in vacuo. The residue was partitioned in ethyl acetate/6% K2CO3 solution. The organic phase was dried over MgSO4, filtered and treated with 4 NHCl in dioxane to pH=5. A white solid was collected. Yield: 2 g (62%) mp 246°-247° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][Br:8].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:19]2[C@H:28]3[C@H:23]([CH2:24][CH2:25][CH2:26][CH2:27]3)[C:22](=[O:29])[N:21](CCCCBr)[N:20]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]>>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:19]2[C@H:28]3[C@H:23]([CH2:24][CH:25]=[CH:26][CH2:27]3)[C:22](=[O:29])[N:21]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][Br:8])[N:20]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: COc1ccc(C2=NN(CCCCBr)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: BrCCCCCCBr
Product: COc1ccc(C2=NN(CCCCCCBr)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC

Procedure:
Prepared from compound C and 1,6-dibromohexane as described for compound 58. M.p. 55°-56° C.
Reaction SMILES: [CH:1]([N:4]1[C:30](=[O:31])[C:29]2[N:12]3[CH2:13][CH2:14][C:15]4[CH:16]=[C:17]([O:27][CH3:28])[C:18]([C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:19][C:20]=4[C:11]3=[C:10]([C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)[C:9]=2[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl>O1CCOCC1.CO.C([O-])(O)=O.[Na+]>[CH:1]([N:4]1[C:30](=[O:31])[C:29]2[N:12]3[CH2:13][CH2:14][C:15]4[CH:16]=[C:17]([O:27][CH3:28])[C:18]([C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:19][C:20]=4[C:11]3=[C:10]([C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)[C:9]=2[CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: COc1cc2c(cc1-c1cccnc1)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)C)CCN(C(=O)OC(C)(C)C)C3
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: COc1cc2c(cc1-c1cccnc1)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)C)CCNC3
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 50 mg of 10m in 1 ml of dioxane was added 150 μl of 4N HCl in dioxane and a few drops of methanol. The mixture was stirred for 3 hr at RT. The reaction mixture was diluted with 5 ml of 5% aq NaHCO3 and the product was extracted with ethyl acetate. The organic layer was washed with water, dried, concentrated and the residue was treated with diisopropyl ether, to give 35 mg of white crystalline 10n; Mp: 227-229° C.; Rf: 0.60 (CH2Cl2/methanol 80/20).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][O-:13].[Na+]>CO>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([O:13][CH3:12])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
18.4 g (83.64 mmol) of 2-fluoro-4-bromonitrobenzene (Aldrich) are almost fully dissolved in 300 mL of anhydrous methanol. 19.9 mL (106.22 mmol) of a 30% solution of sodium methoxide in methanol are added dropwise and the mixture is stirred overnight at room temperature. The methanol is evaporated off under reduced pressure, the medium is taken up in ethyl acetate and water, and the aqueous phase is then acidified by adding aqueous 1N HCl. After separation of the phases by settling, the organic phase is washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated under vacuum. 17.4 g of the expected product are obtained in the form of a yellow solid. Yield=89.7%.
Reaction SMILES: [OH-].[Li+].FC(F)(F)C(O)=O.C([O:12][C:13]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]3[C:33]([Cl:34])=[CH:32][N:31]=[C:30]([NH:35][C:36]4[CH:37]=[CH:38][C:39]5[NH:45][C:44](=[O:46])[CH2:43][CH2:42][C:41]([CH3:48])([CH3:47])[C:40]=5[CH:49]=4)[N:29]=3)=[C:23]([N:50]3[CH:54]=[CH:53][CH:52]=[N:51]3)[CH:22]=2)[CH2:17][CH2:16]1)=[O:14])C.CO.Cl>O>[Cl:34][C:33]1[C:28]([NH:27][C:24]2[CH:25]=[CH:26][C:21]([N:18]3[CH2:19][CH2:20][CH:15]([C:13]([OH:14])=[O:12])[CH2:16][CH2:17]3)=[CH:22][C:23]=2[N:50]2[CH:54]=[CH:53][CH:52]=[N:51]2)=[N:29][C:30]([NH:35][C:36]2[CH:37]=[CH:38][C:39]3[NH:45][C:44](=[O:46])[CH2:43][CH2:42][C:41]([CH3:47])([CH3:48])[C:40]=3[CH:49]=2)=[N:31][CH:32]=1
Reactant: CCOC(=O)C1CCN(c2ccc(Nc3nc(Nc4ccc5c(c4)C(C)(C)CCC(=O)N5)ncc3Cl)c(-n3cccn3)c2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC1(C)CCC(=O)Nc2ccc(Nc3ncc(Cl)c(Nc4ccc(N5CCC(C(=O)O)CC5)cc4-n4cccn4)n3)cc21

Procedure:
To a room temperature solution of Lithium hydroxide (53 mg, 2.2 mmol) in Water (3 mL), was added 1-{4-[5-Chloro-2-(5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-7-ylamino)-pyrimidin-4-ylamino]-3-pyrazol-1-yl-phenyl}-piperidine-4-carboxylic acid ethyl ester; compound with trifluoro-acetic acid (47 mg, 0.063 mmol) followed by Methanol (12 mL). After 72 hours 1 N HCl (2 mL) was added to the reaction to neutralize the base, then the mixture was concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC to yield the desired 1-{4-[5-Chloro-2-(5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-3-pyrazol-1-yl-phenyl}-piperidine-4-carboxylic acid as a lyophylate (20%); 1H NMR (400 MHz, DMSO-d6) δ 9.81 (s, 1H), 9.39 (s, 1H), 9.32 (s, 1H), 8.26 (s, 1H), 8.09 (s, 1H), 7.97 (m, 1H), 7.83 (s, 1H), 7.57 (d, J=7.07 Hz, 1H), 7.42 (s, 1H), 7.12 (s, 1H), 6.97 (d, J=9.86 Hz, 1H), 6.79 (d, J=8.34 Hz, 1H), 6.54 (s, 1H), 3.75 (m, 2H), 2.8 (m, 2H), 2.6 (m, 1H), 2.15 (m, 2H), 1.99 (m, 4H), 1.70 (m, 2H), 1.2 (s, 6H); MS (m/e) 601.56 (M+H).
Reaction SMILES: [CH3:1][C@H:2]([NH2:12])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[C:13](O)(=[O:22])[C@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[OH:15].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>ClCCl.CO.CN(C)C=O>[OH:15][CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13]([NH:12][CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:22]
Reactant: O=C(O)[C@@H](O)c1ccccc1
Reactant: C[C@H](N)CCCc1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(CCCc1cccnc1)NC(=O)C(O)c1ccccc1

Procedure:
Under the conditions outlined in Example 14a, 76.2 g of the amine was reacted with 74.2 g of (S)-mandelic acid in the presence of 105.2 g of 1,3-dicyclohexylcarbodiimide and 78.4 g of 1-hydroxybenzotriazole in 1L of dimethylformamide. A similar workup furnished 109 g of [S-(S*,S*)]-alpha-hydroxy-N-[1-methyl-4-(3-pyridinyl)butyl]benzeneacetamide, mp 143°-145° C., [α]D25 +27.8° (c, 1.0, MeOH).
Reaction SMILES: C[Si](C)(C)[O:3][C:4]([O:13][Si](C)(C)C)=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.[F:20]OC(F)(F)F>C(Cl)(Cl)(Cl)F>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]([F:20])[C:4]([OH:13])=[O:3])=[CH:7][CH:8]=1
Reactant: FOC(F)(F)F
Reactant: C[Si](C)(C)OC(=Cc1ccc(Cl)cc1)O[Si](C)(C)C
Solvent: FC(Cl)(Cl)Cl
Product: O=C(O)C(F)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52.4 %

Procedure:
A solution of 29.92 g (0.095 mol) of the aforesaid β,β-bis(trimethylsiloxy)p-chlorostyrene in 300 ml of CFCl3 was cooled to -70° C. and 9.88 g (0.095 mol) of trifluoromethyl hypofluorite were passed into the solution over a period of 2 hours. The mixture was allowed to warm to room temperature and evaporated to dryness under reduced pressure. The resultant white solid residue was stirred with 10 ml of water for approximately 10 minutes. The solids were recrystallized from 1 l of hexane to give 9.38 g (53% yield) of p-chlorophenylfluoroacetic acid as shiny white crystals, mp 66°-68° C.; 1H NMR (CDCl3) δ5.75 (d, J≅47 Hz, 1H), δ7.35 ppm (s, 4H), δ10.95 (s, 1H); 19F NMR (CDCl3) δ-182.60 (d, J≅47 Hz).