Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1[C@@H:19](OC([C@H](O)[C@@H](NC(C2C=CC=CC=2)=O)C2C=CC=CC=2)=O)[CH2:18][C@:14]2(O)[C:15](C)(C)[C:3]=1[C@@H:4]([O:59]C(C)=O)C([C@@]1(C)[C@H]([C@@H]2OC(C2C=CC=CC=2)=O)[C@]2(OC(C)=O)CO[C@@H]2C[C@@H]1O)=O.C(O)(=O)C.[Cl:67]CCl>C(OCC)(=O)C>[C:4]([Cl:67])(=[O:59])[C:3]1[CH:15]=[CH:14][CH:18]=[CH:19][CH:2]=1
Reactant: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Reactant: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(Cl)c1ccccc1

Procedure:
Before the C-4 sidechain can be added to the C-7 Cbz protected paclitaxel analog (9), the analog (9) must undergo protection of the 2-OH. The protection step is carried out by treating the reaction mixture containing analog (9) with an acid, preferably acetic acid to neutralize the reaction mixture. The dichloromethane in the neutralized reaction mixture is exchanged for ethyl acetate or other ester or amide organic solvent, and the resulting solution of 9 is treated with a strong base, preferably Li t-butoxide, and a benzoyl protecting agent, preferably benzoyl chloride, to form the 2-benzoyl (Bz) 7-hydroxy protected paclitaxel (10).
Reaction SMILES: [OH:1][CH:2]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23](I)=[CH:22][CH:21]=1)[CH:3]([CH2:7][CH2:8][N:9]1[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH3:16])[C:10]1=[O:17])[C:4]([OH:6])=[O:5].[C:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])[CH3:28].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.[Pd]>[C:27]([C:30]1[CH:35]=[CH:34][C:33]([C:23]2[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][CH:2]([OH:1])[CH:3]([CH2:7][CH2:8][N:9]3[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH3:16])[C:10]3=[O:17])[C:4]([OH:6])=[O:5])=[CH:21][CH:22]=2)=[CH:32][CH:31]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: Cn1c(=O)ccn(CCC(C(=O)O)C(O)CCc2ccc(I)cc2)c1=O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(-c2ccc(CCC(O)C(CCn3ccc(=O)n(C)c3=O)C(=O)O)cc2)cc1
Temperature: 150 °C
Yield: 61.5 %

Procedure:
A solution of 3-hydroxy-5-(4-iodophenyl)-2-[2-(3-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)ethyl]pentanoic acid (10 mg, 21 μmol) in dimethylformamide (0.5 mL) was added in one portion to a mixture of p-acetylbenzeneboronic acid (4.0 mg, 25 μmol) and fibrecat FC1001 (2.71% Pd; 8.3 mg, 2.0 μmol) in a Smith microwave reaction vial. Aqueous sodium carbonate solution (1.0 M; 53 μL, 53 μmol) was added and the vial capped. The crude reaction mixture was heated at 150° C. for 15 min using a Smith Synthesiser microwave reactor. On cooling the vial was opened and the contents filtered through a Whatman 5 μM filter tube, washing the filter cake with methanol (2×1 mL). The filtrate was evaporated and the resulting residue was purified using mass directed auto-preparative reverse phase HPLC to give the title compound (6.0 mg, 61%) as a white solid. LC/MS: 2.82 min; z/e 465, calcd (M+1) 465. H NMR (400 MHz: DMSO-d6): 8.00 (2H), 7.80 (2H), 7.60 (4H), 7.30 (2H), 6.65 (1H), 3.70 (3H), 3.10 (3H), 2.80 (1H), 2.60 (2H), 2.30 (1H), 1.85 (2H), 1.60 (1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[C:10]([CH3:16])=[CH:11][C:12](=O)[NH:13][N:14]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].CC1C(C2C=CC=C(C#N)C=2)=NNC(=O)C1.[Cl:33]C1C=C(C2C(C)CC(=O)NN=2)C=CC=1.P(Cl)(Cl)(Cl)=O>>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[N:13][C:12]([Cl:33])=[CH:11][C:10]=2[CH3:16])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CC1CC(=O)NN=C1c1cccc(Cl)c1
Reactant: Cc1cc(=O)[nH]nc1-c1cccc(C#N)c1
Agent: CC1CC(=O)NN=C1c1cccc(C#N)c1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)nnc1-c1cccc(C#N)c1

Procedure:
A 2.95 g. portion of 6-(m-cyanophenyl)-5-methyl-3(2H)-pyridazinone [prepared as described in Example 8 but employing 4,5-dihydro-5-methyl-6-(m-cyanophenyl)-3(2H)-pyridazinone (which in turn is prepared by employing 6-(m-chlorophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone in Example 44 of U.S. Pat. No. 3,824,271)] and 35 ml. of phosphorus oxychloride are heated on a steam bath for 5 hours. The mixture is concentrated free of excess phosphorus oxychloride and the concentrate is diluted with ice water. The resulting product, a tan solid, is recovered by filtration, washed with water and dried, m.p. 153°-155° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11][C:10]3[N:12]=[CH:13][CH:14]=[N:15][C:9]=3[NH:8][C:7]=2[CH:16]=1.[C-:17]#[N:18].[Na+].C(OCC)(=O)C>CS(C)=O>[N:15]1[C:9]2[NH:8][C:7]3[CH:16]=[C:3]([CH2:2][C:17]#[N:18])[CH:4]=[CH:5][C:6]=3[S:11][C:10]=2[N:12]=[CH:13][CH:14]=1
Reactant: [C-]#N
Reactant: ClCc1ccc2c(c1)Nc1nccnc1S2
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#CCc1ccc2c(c1)Nc1nccnc1S2
Yield: 104.2 %

Procedure:
To 50 ml of a solution of 5 g of 8-(chloromethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine in dimethyl sulfoxide was added 0.92 g of sodium cyanide and the resulting mixture was reacted at 60° C. for 1 hour. After adding ethyl acetate, the organic layer was washed with water and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, 4.7 g of the title compound was obtained as a yellow solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:20])[C:6](=[N:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][C@@H:14]([OH:19])[C@@H:15]2[NH-:18])=[CH:11][CH:10]=1)[CH3:7].C(OC(=O)N)(C)(C)C.C(N(CC)CC)C.O=C1CCC(=O)N1[O:43][C:44]([C:46]1[CH:51]=[CH:50][C:49]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[CH:48][CH:47]=1)=O>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:20])[C:6](=[N:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][C@@H:14]([OH:19])[C@@H:15]2[NH:18][C:44]([C:46]2[CH:51]=[CH:50][C:49]([C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)=[CH:48][CH:47]=2)=[O:43])=[CH:11][CH:10]=1)[CH3:7]
Reactant: COCCN(C)C(C)=Nc1ccc2c(c1)[C@@H]([NH-])[C@H](O)C2
Reactant: O=C(ON1C(=O)CCC1=O)c1ccc(-c2ccccc2)cc1
Agent: CC(C)(C)OC(N)=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCN(C)C(C)=Nc1ccc2c(c1)[C@@H](NC(=O)c1ccc(-c3ccccc3)cc1)[C@H](O)C2
Reaction time: 1 h
Yield: 50.9 %

Procedure:
Dissolve carbamic acid tert-butyl ester (R)-(6-(1-((2-methoxyethyl)methylamino)ethylideneamino)-2(R)-hydroxyindan-1-yl)amide (153.6 mg, 0.407 mmol) in excess TFA at 0° C. and allow to stir for 1 hour. Remove the solvent in vacuo. Dissolve the residue in 10 mL methylene chloride and add triethylamine (411.8 mg, 4.07 mmol) and biphenyl-4-carboxylic acid 2,5-dioxopyrrolidin-1-yl ester (118.3 mg, 0.400 mmol). Allow the reaction mixture to stir for 21 hours. Dilute the reaction mixture with methylene chloride and wash it with saturated aqueous sodium hydrogen carbonate (1×) and brine (1×). Dry the organic layer with magnesium sulfate. Filter and remove the solvent in vacuo to give 162.1 mg of crude product. Purify via Biotage chromatography (30% MeOH/EtOAc) to afford 93.1 mg of the titled product as an oil (50% yield). MS (ES): m/z 458.3(M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[OH:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[O:19][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: Cc1ccc(C)c(O)c1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C)c(Oc2ccc([N+](=O)[O-])cn2)c1
Temperature: 110 °C
Yield: 90.8 %

Procedure:
In a microwave vial, 2-chloro-5-nitropyridine (80 mg, 0.505 mmol) was dissolved in 2 mL of dry dimethylformamide. 2,5-dimethylphenol (80 mg, 0.505 mmol, 1 equiv) and potassium carbonate (418 mg, 3.03 mmol, 6 equiv) were added. The reaction mixture was heated under microwave irradiation for 1 hour at 110° C. (Biotage Initiator). The reaction mixture was filtered. The filtrated solid was washed with dichloromethane (5 mL). The volatiles were evaporated. The residue was dissolved in dichoromethane (10 mL) and brine was added (10 mL). The organic layer was extracted 2 times with dichloromethane (2×15 mL) and 2 times with ethylacetate (2×15 mL). The organic phase was dried over sodium sulphate. The solvent was removed to afford the title compound (112 mg)
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].CCOCC.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:21][N:22]2[CH2:25][CH:24]([OH:26])[CH2:23]2)=[C:17]([CH:20]=1)[C:18]#[N:19]>C1COCC1>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:21][N:22]2[CH2:23][CH:24]([OH:26])[CH2:25]2)=[C:17]([CH:20]=1)[CH2:18][NH2:19]
Reactant: N#Cc1cc(Cl)ccc1CN1CC(O)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: NCc1cc(Cl)ccc1CN1CC(O)C1
Yield: 70 %

Procedure:
1M LAH in ether (11.25 mL, 11.25 mmol) was added to a stirred solution of 5-chloro-2-[(3-hydroxyazetidin-1-yl)methyl]benzonitrile (1.67 g, 7.50 mmol) in THF (70 mL) at 0° C. After 1 h the reaction was quenched with EtOAc (5 ml) and concentrated. The residue was stirred with ether (150 mL) and this was then treated successively with water (0.43 mL), 15% NaOH (0.43 mL) and water (1.29 mL). After stirring for 15 min the mixture was filtered and evaporated to give 5-Chloro-2-[(3-hydroxyazetidin-1-yl)methyl]benzylamine (1.19 g) as a gum: 1H NMR (CDCl3, 400 MHz) δ 2.99 (m, 2H), 3.64 (m, 2H), 3.75 (s, 2H), 4.38 (d, J=5.3 Hz, 2H), 4.50 (m, 1H), 7.13 (d, J=8.0 Hz, 1H), 7.21 (dd, J=2.2, 9.7 Hz, 1H), 7.35 (d, J=2.2 Hz, 1H).
Reaction SMILES: F[C:2]1[C:11]2[O:10][CH:9]([C:12]([NH2:14])=[O:13])[CH2:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:15]C1C2OCCNC=2C=CC=1.CCC([O-])=O>>[Cl:15][C:2]1[C:11]2[O:10][CH:9]([C:12]([NH2:14])=[O:13])[CH2:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)C1CNc2cccc(F)c2O1
Reactant: Clc1cccc2c1OCCN2
Agent: CCC(=O)[O-]
Product: NC(=O)C1CNc2cccc(Cl)c2O1

Procedure:
This compound is obtained using the same experimental conditions as those used for the synthesis of intermediate 4b but replacing 3,4-dihydro-8-fluoro-2H-1,4-benzoxazine-2-ethyl carboxylate (5b) with 3,4-dihydro-8-chloro-2H-1,4-benzoxazine-2-ethyl carboxylate (5d), [73268-47-0]. The title compound of formula (4d) is obtained.
Reaction SMILES: [CH2:1]([C:3]1([CH2:18][CH2:19]O)[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][CH3:17])[CH3:2].CCN(S(F)(F)[F:27])CC>C(Cl)Cl>[CH2:1]([C:3]1([CH2:18][CH2:19][F:27])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][CH3:17])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CCO)OCC3
Solvent: ClCCl
Product: CCc1cccc2c3c([nH]c12)C(CC)(CCF)OCC3
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.7 %

Procedure:
To a stirred solution of compound 1 (136 mg, 0.5 mmol) in CH2Cl2 (2 mL) at −40° C. under argon, DAST (396 μL, 3.0 mmol, 6.0 eq) was slowly added in a dropwise manner. The resulting mixture was allowed to warm to room temperature and stirred for one hour before being cooled to 0° C. and quenched with MeOH (1 mL). The mixture was stirred an additional thirty minutes at room temperature, and then saturated NaHCO3 (10 mL) was added dropwise. The resulting aqueous layer was extracted three times with CH2Cl2. The combined organic phases were dried with Na2SO4, concentrated, and purified by column chromatography using 5:95:EtOAc:Hexane to give a yellow-white solid (45 mg, 33%): mp 118–119° C. 1HNMR (CDCl3, δ TMS): 0.88 (t, 3H), 1.37 (t, 3H), 1.94 (m, 2H), 2.29 (m, 2H), 2.78 (m, 2H), 2.86 (q, 2H), 3.99 (m, 2H), 4.57 (qq, 2H), 7.03–7.38 (m, 3H, Ar—H), 7.65 (br, 1H, NH). MS−: m/z 310 (MCl−), 274 ([M−H]−). Anal. (C17H22NOF): C, H, N.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:13]=[CH:12][C:11](B3OC(C)(C)C(C)(C)O3)=[CH:10][C:7]=2[C:8]#[N:9])[CH2:3][CH2:2]1.Br[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([Cl:30])[CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[Cl:30][C:26]1[CH:25]=[C:24]([C:11]2[CH:12]=[CH:13][C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)=[C:7]([CH:10]=2)[C:8]#[N:9])[CH:29]=[CH:28][N:27]=1
Reactant: CC1(C)OB(c2ccc(OCC3CC3)c(C#N)c2)OC1(C)C
Reactant: Clc1cc(Br)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: N#Cc1cc(-c2ccnc(Cl)c2)ccc1OCC1CC1
Temperature: 90 °C
Reaction time: 6 h
Yield: 73.8 %

Procedure:
A solution of 2-cyclopropylmethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (3.0 g, 0.010 mol) in acetonitrile (60 ml) and water (20 ml) is degassed for 10 min. 4-Bromo-2-chloropyridine (1.92 g, 0.010 mol), potassium carbonate (2.76 g, 0.02 mol) and tetrakis(triphenyl phosphine)palladium(0) (0.11 g, 0.0001 mol) are added. The reaction mixture is stirred at 90° C. for 6 h. The mixture is cooled to room temperature, filtered and evaporated in a rotary evaporator. The residue is taken up in ethyl acetate (200 ml), washed with water (2×200 ml) and saturated sodium chloride solution (1×200 ml). The mixture is subsequently dried over sodium sulfate, evaporated in a rotary evaporator and chromatographed for purification, giving 2.1 g of a pale-yellow solid;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[C:5]2[NH:28][CH:29]=[C:30]([C:31](=[O:51])[C:32](=[O:50])[N:33]3[CH2:38][CH2:37][N:36]([C:39]4[N:43]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=5)[N:42]=[N:41][N:40]=4)[CH2:35][CH2:34]3)[C:4]=12.Cl>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]3)=[CH:11][CH:10]=2)=[C:5]2[NH:28][CH:29]=[C:30]([C:31](=[O:51])[C:32]([N:33]3[CH2:38][CH2:37][N:36]([C:39]4[N:43]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=5)[N:42]=[N:41][N:40]=4)[CH2:35][CH2:34]3)=[O:50])[C:4]=12
Reactant: COc1cnc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)c2[nH]cc(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccn4)CC3)c12
Agent: Cl
Solvent: C1COCCO1
Product: COc1cnc(-c2ccc(N3CCNCC3)cc2)c2[nH]cc(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccn4)CC3)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
To a solution of tert-butyl 4-(4-(4-methoxy-3-(2-oxo-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)phenyl)piperazine-1-carboxylate (250 mg, 0.360 mmol) in 1,4-dioxane (2 mL) was added 4N HCl in 1,4-dioxane (0.450 mL, 1.802 mmol) at room temperature, the mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure. The resulting crude was purified by prep HPLC to give 1-(4-methoxy-7-(4-(piperazin-1-yl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (200 mg, 93%) as white solid. LCMS: m/e 594.55 (M+H)+, ret time 1.76 min (method 4). 1H NMR (500 MHz, MeOD) δ ppm 3.42-3.48 (m, 4H) 3.50 (m, 2H) 3.54 (m, 2H) 3.64-3.70 (m, 4H) 3.71 (m, 2H) 3.90 (m, 2H) 4.16 (s, 3H) 7.36 (d, J=8.54 Hz, 2H) 7.63 (dd, J=7.17, 5.04 Hz, 1H) 7.82 (d, J=8.85 Hz, 2H) 7.90 (d, J=8.24 Hz, 1H) 8.04 (s, 1H) 8.17 (t, J=7.63 Hz, 1H) 8.63-8.75 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Si:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][C:13]=2[F:22])=[N:9][C:8]([CH2:23][NH2:24])=[CH:7][N:6]=1)=[O:4].[C:25](OC(=O)C)(=[O:27])C>C(O)=O>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Si:18]([CH3:19])([CH3:20])[CH3:21])=[CH:14][C:13]=2[F:22])=[N:9][C:8]([CH2:23][NH:24][CH:25]=[O:27])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ncc(CN)nc1Nc1ccc([Si](C)(C)C)cc1F
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: COC(=O)c1ncc(CNC=O)nc1Nc1ccc([Si](C)(C)C)cc1F
Yield: 98.3 %

Procedure:
A solution of 5-aminomethyl-3-(2-fluoro-4-trimethylsilanyl-phenylamino)-pyrazine-2-carboxylic acid methyl ester (800 mg, 2.30 mmol) from above in formic acid (12 mL) and acetic anhydride (4 mL) was stirred at ambient temperature under N2 for 1.5 hour. The reaction mixture was concentrated in vacuo, and the residue was azeotroped with toluene. The resultant residue was diluted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium bicarbonate, water and brine, dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound as a yellow foam (850 mg, 98.3%). LCMS (method D1: RT=1.09 min, [M+H]+=377.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH2:12]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH2:19])[CH:13]([CH3:15])[CH3:14]>>[CH2:12]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH:19][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: Cc1ccc(CC(=O)O)cc1
Reactant: CC(C)COC(=O)[C@H](C)N
Product: Cc1ccc(CC(=O)N[C@@H](C)C(=O)OCC(C)C)cc1

Procedure:
Following General Procedure BI above, and using 4-methylphenylacetic acid (Aldrich) and L-alanine iso-butyl ester (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]1[N:13]2[CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[CH:16]=[C:12]2[C:11](=[O:24])[NH:10][CH2:9]1)(=O)=O.[N-:25]=[N+:26]=[N-:27].[Na+].O.C([O-])(O)=O.[Na+]>C(#N)C.CN(C=O)C>[N:25]([CH2:6][CH2:7][CH:8]1[N:13]2[CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[CH:16]=[C:12]2[C:11](=[O:24])[NH:10][CH2:9]1)=[N+:26]=[N-:27]
Reactant: CS(=O)(=O)OCCC1CNC(=O)c2cc(-c3cccc(Cl)c3)cn21
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: [N-]=[N+]=NCCC1CNC(=O)c2cc(-c3cccc(Cl)c3)cn21
Yield: 69.4 %

Procedure:
2-[1-oxo-7-(3-chlorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl]ethyl methanesulfonate 157 mg (0.42 mmol) were reacted with sodium azide (60 mg 0.924 mmol) in acetonitrile/DMF 10 ml/2 ml at 80° C. for 18 hours. The reaction was worked up with water, saturated NaHCO3 and extracted with ethyl acetate. The organic phase, dried on Na2SO4, was filtered and evaporated. The crude was dissolved with diethyl ether and after a while, a solid precipitated, which was filtered to give 92 mg (70%) of 4-(2-azidoethyl)-7-(3-chlorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:12]([F:13])[C:6]=2[CH2:5][O:4]1.[CH3:18][C:19]([CH3:23])([CH3:22])[CH2:20][NH2:21]>CCO>[F:13][C:12]1[C:6]2[CH2:5][O:4][CH:3]([CH2:2][NH:21][CH2:20][C:19]([CH3:23])([CH3:22])[CH3:18])[O:8][C:7]=2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=1
Reactant: CS(=O)(=O)c1cc(F)c2c(c1)OC(CBr)OC2
Reactant: CC(C)(C)CN
Solvent: CCO
Product: CC(C)(C)CNCC1OCc2c(F)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 34 using 2-(bromomethyl)-5-fluoro-7-(methylsulfonyl)-4H-1,3-benzodioxine (8.5 mg, 0.026 mmol), 2,2-dimethylpropan-1-amine (0.5 ml) and EtOH (3 ml). MS m/z (rel. intensity, 70 eV) 331 (M+, 1), 274 (74), 203 (20), 141 (32), 100 (bp), 72 (74).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[O:15])[N:11]=[C:10]2SC)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:18]([NH:21][C:22]([NH2:24])=[NH:23])([CH3:20])[CH3:19]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[O:15])[N:11]=[C:10]2[NH:24][C:22]([NH:21][CH:18]([CH3:20])[CH3:19])=[NH:23])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CSC1=NC(=O)C(=O)N1c1ccc(Cl)c(Cl)c1
Reactant: CC(C)NC(=N)N
Solvent: CN(C)C=O
Product: CC(C)NC(=N)NC1=NC(=O)C(=O)N1c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1-(3,4-dichlorophenyl)-2-methylsulfanyl-1H-imidazole-4,5-dione (15, 1.89 g, 6.54 mmol) was dissolved in 10 ml of dried DMF and cooled with an ice bath to 0° C. To the solution was added dropwise 40 ml of DMF solution containing guanidine 18 (1.369 g, 13.554 mmol). The solution was stirred at room temperature for 2 hours after addition and then further stirred at 50° C. for 24 hours. The solvent DMF was dried under vacuum and the crude product was suspended in 30 ml of chloroform. The yellow solid was collected, washed sequentially with 3×20 ml of CHCl3 and 10 ml of methanol to afford compound 4 as a white color powder (1.588 g, 6.54 mmol, 71%), mp 245° C.: NMR indicates that the compound exists in two tautomeric forms in the CDCl3 solution. 1H NMR (600 MHz, DMSO-d6) (Major tautomer): δ 8.74–8.69 (m, 1H), 7.79 (d, J=8.6 Hz, 1H), 7.76 (d, J=2.2 Hz, 1H), 7.44 (dd, J=8.6 and 2.2 Hz), 3.73 (m, 1H), 1.14 (d, J=6.4 Hz, 6H); 13C NMR: δ 168.60, 162.45, 161.15, 161.09, 134.01, 131.84, 131.48, 131.20, 130.29, 128.86. IR: 1757, 1722, 1645, 1595, 1551, 1535, 1480, 1304, 997, 754 cm−1; MS (m/z): 342 (M+), 271, 229, 187, 127. Anal. (C13H13Cl2N5O2.0.25H2O) C, H, Cl, N.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[C:13]=23)[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
Reactant: C1COCCN1
Reactant: ClCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: Clc1cc(Nc2ncnc3[nH]nc(OCCN4CCOCC4)c23)ccc1OCc1ccccn1
Yield: 40 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine and morpholine to give the title compound in 40% yield; NMR Spectrum: 2.50 (hidden by DMSO, 4H), 2.80 (t, 2H), 3.55 (br s, 4H), 4.44 (t, 2H), 5.29 (s, 2H), 7.25 (d, 1H), 7.37 (t, 1H), 7.55-7.58 (m, 2H), 7.86-7.92 (m, 2H), 8.29 (s, 1H), 8.45 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 482 (MH+).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[O:11])[CH2:8]2.[OH:12]N1C(=O)C2=CC=CC=C2C1=O.O=O>C(O)(=O)C>[OH:12][C:7]12[CH2:9][CH:3]3[CH2:4][CH:5]([CH2:10][CH:1]([C:2]3=[O:11])[CH2:8]1)[CH2:6]2.[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[O:11])[CH2:8]2
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=C1C2CC3CC(C2)CC1C3
Agent: O=O
Solvent: CC(=O)O
Product: O=C1C2CC3CC1CC(O)(C3)C2

Procedure:
A mixture of 0.1 mol of 2-adamantanone, 10 mmol of N-hydroxyphthalimide, 0.33 mmol of acetylacetonatovanadium V (AA)3, 0.17 mmol of acetylacetonatomanganese Mn(AA)3, and 250 ml of acetic acid was stirred at 85° C. in an oxygen atmosphere (1 atm) for 10 hours. The resulting reaction mixture was concentrated and was then extracted with ethyl acetate. A portion of an organic layer was concentrated and was then cooled for crystallization to yield 5-hydroxy-2-adamantanone of the following formula in a yield of 48% with a conversion rate from 2-adamantanone of 74%.