Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@@H:3]1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19].[CH3:20][C:21]1[CH:22]=[CH:23][C:24]([C:30]2[N:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[C:25]([CH:29]=1)[C:26](O)=[O:27].CCN(C(C)C)C(C)C.CCCP(=O)=O>C(Cl)Cl>[CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:26](=[O:27])[C:25]2[CH:29]=[C:21]([CH3:20])[CH:22]=[CH:23][C:24]=2[C:30]2[N:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[C@@H:3]1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19]
Reactant: Cc1ccc(-c2cccnn2)c(C(=O)O)c1
Reactant: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(-c2cccnn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN2C(=O)c3ccccc3C2=O)c1
Temperature: 40 °C

Procedure:
To a mixture of 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione (1.09 g, 4.20 mmol), 5-methyl-2-(pyridazin-3-yl)benzoic acid (0.75 g, 3.5 mmol) and DIPEA (1.8 mL, 10.5 mmol) in DCM (20 mL) was added propylphosphonic anhydride (T3P) (50% in EtOAc, 4.2 mL, 7.0 mmol). The mixture was heated at 40° C. for 16 h. The mixture was cooled to rt and diluted with DCM. The mixture was washed with satd. aq. NaHCO3, brine, and dried (MgSO4). The solvent was removed in vacuo. The crude was purified by chromatography on silica gel (EtOAc/hexanes) to afford the title compound. ESI-MS (m/z): 455 [M+1]+.
Reaction SMILES: Br[CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:3]1.[O:17]1CCCC1>O.CCOCC.[B-](F)(F)(F)F.[Ag+]>[OH:17][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:3]1
Reactant: C1CCOC1
Reactant: O=C(O)CCCCCCC1=CC(Br)CC1=O
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: CCOCC
Solvent: O
Product: O=C(O)CCCCCCC1=CC(O)CC1=O
Reaction time: 1 h

Procedure:
To a stirred solution of 56.0 g. of crude 4-bromo-2-(6-(carboxyhexyl)cyclopent-2-en-1-one (Example 93) in 400 ml. of tetrahydrofuran and 133 ml. of water at 3° C. is added 44.1 g. (0.226 moles) of silver fluoborate during 25 minutes. The mixture is stirred at 0°-5° C. for 60 minutes, diluted with water and ether, and filtered. The aqueous portion of the filtrate is saturated with solid sodium chloride and extracted with additional ether. The combined organic phases are washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. Column chromatography of the residue gives the subject compound as a mixture with 4-hydroxy-2-(6-carboxyhexyl)-cyclopent-2-en-1-one, NMR (CDCl3) 3.60 (multiplet, 0-methylene hydrogens) and 4.60 f (multiplet, 0-methine hydrogen).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[C:8]([O:12][CH2:13][CH2:14][OH:15])(=[O:11])[CH:9]=[CH2:10].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>[Cl-].C[N+](C)(C)C>[C:8]([O:12][CH2:13][CH2:14][O:15][C:4]([CH2:3][CH2:2][C:1]([OH:6])=[O:7])=[O:5])(=[O:11])[CH:9]=[CH2:10]
Reactant: O=C1CCC(=O)O1
Reactant: C=CC(=O)OCCO
Agent: C[N+](C)(C)C
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Cl-]
Product: C=CC(=O)OCCOC(=O)CCC(=O)O
Temperature: 90 °C

Procedure:
In a separate vessel, succinic anhydride (30 g), 2-hydroxyethyl acrylate (34.2 g), tetramethylammonium chloride (0.2 g), and 2,6-di-t-butyl-4-methylphenol (0.15 g) were stirred and heated at 90° C. for 3 hours. The mixture was then cooled to give 3-(2-acryloyloxyethoxycarbonyl)propionic acid. This product (27.2 g) was mixed with 2,6-di-t-butyl-4-methylphenol (0.1 g) and added over 1 hour to the advanced resin at 100° C. The mixture was then stirred for a further 41/2 hours at 100° C., by with time its epoxide content had fallen to a negligibly low level.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH:11]([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:11]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)([CH3:13])[CH3:12]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(C=O)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 92.8 %

Procedure:
To a solution of 4-hydoxybenzaldehyde (4.0 g, 32.8 mmol) in dry DMF (100 mL) was added 2-bromopropane (6.0 g, 49.2 mmol) and potassium carbonate (6.8 g, 49.2 mmol). The resulting reaction was heated to 100° C. and stirred for 3 hours. The reaction was quenched by adding excess water and partitioned between ethyl acetate and brine. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated under vacuum. Purification on silica gel with 15% ether/hexane afforded the title compound (5.0 g, 93%).
Reaction SMILES: [S:1]1C=CC=[C:2]1[NH:6]C(O)=O.[OH-].[Na+].[CH3:12][C:13](Cl)([CH3:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:22][CH2:23][CH2:24][CH2:25][CH2:26]C>>[CH3:12][C:13]([CH3:20])([C:2]([N:6]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[S:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCCCCC
Reactant: CC(C)(Cl)c1ccccc1
Reactant: O=C(O)Nc1cccs1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C(=S)N1CCCCC1)c1ccccc1
Reaction time: 1.5 h

Procedure:
To the so obtained aqueous thiolcarbamic acid salt solution was added 7.2 kg (179 moles) of 40% sodium hydroxide at 50° to 60° C., following which 27.6 kg (179 moles) of α,α-dimethylbenzyl chloride was added dropwise at the same temperature over the course of 20 minutes. After repeating this operation four times, a further addition dropwise of 69.0 kg (447 moles) of α,α-dimethylbenzyl chloride was made over the course of 30 minutes. The reaction mixture was then stirred at 50° to 60° C. for 1.5 hours to complete the reaction. The pH of the system ranged from 9.5 to 12.5 during the reaction. After cooling the reaction mixture, 80 liters of hexane was added, and the organic layer and the aqueous layer were separated. The organic layer was then washed with 80 liters of 2% hydrochloric acid and 80 liters of water. After distilling the hexane off from this hexane solution, a 0.5 liter ethanol solution of 0.5 kg of p-toluenesulfonic acid was added, and the mixture was reacted and distilled under reduced pressure (10 to 20 mm Hg) at below 110° C. The intended N-(α,α-dimethylbenzylthio-carbonyl)piperidine (93 kg) was obtained in the residue. On analysis by gas chromatography, this product was found to have a purity of 96.0%, and its yield based on thiolcarbamic acid salt was 78.5%. The melting point was 34.5°-36.0° C.
Reaction SMILES: [BH4-].[Na+].C([O:5][C:6]([C:8]1[CH:21]=[C:11]2[C:12](=[O:20])[N:13]([CH2:16][CH:17]3[CH2:19][CH2:18]3)[CH2:14][CH2:15][N:10]2[N:9]=1)=O)C>C1COCC1.CO.O>[CH:17]1([CH2:16][N:13]2[CH2:14][CH2:15][N:10]3[N:9]=[C:8]([CH2:6][OH:5])[CH:21]=[C:11]3[C:12]2=[O:20])[CH2:18][CH2:19]1
Reactant: CCOC(=O)c1cc2n(n1)CCN(CC1CC1)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C1c2cc(CO)nn2CCN1CC1CC1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
Sodium borohydride (0.23 mL, 6.1 mmol) was added dropwise to a stirred solution of 5-cyclopropylmethyl-4-oxo-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine-2-carboxylic acid ethyl ester (0.32 g, 1.2 mmol) in a mixture of THF (4 mL) and MeOH (1 mL) under N2 at 0° C. The reaction mixture was stirred at 80° C. for 30 minutes and then diluted with water and extracted with DCM. The aqueous layer was acidified with a 1N solution of HCl and extracted with DCM. The organic layers were combined, dried (NaSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; 7 M solution of ammonia in methanol in DCM 0/100 to 10/90). The desired fractions were collected and the solvents evaporated in vacuo to yield 5-cyclopropylmethyl-2-hydroxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (0.21 g, 78% yield) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[CH3:7].[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1>[CH2:8]([C:4]1[O:3][C:2]([CH3:1])=[C:6]([CH3:7])[CH:5]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccoc1C
Solvent: C1CCOC1
Product: Cc1cc(Cc2ccccc2)oc1C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
At −78° C., to a stirred solution of commercial 2,3-dimethylfuran (50 g, 0.520 mol) in THF (2.6 L) was add dropwise 1.6M n-BuLi/hexanes (325 mL, 0.520 mol). After the addition was complete, the dry ice/acetone bath was removed and the reaction was stirred for 1 h. At −78° C., to the reaction was added dropwise commercial benzyl bromide (62 mL, 0.520 mol). After the addition was complete the reaction was stirred at −78° C. for 6 h, the dry ice/acetone bath was removed and the reaction was stirred for 7 days. The reaction was concentrated in vacuo and purified on silica gel eluting with hexane to give 75.70 g (78%) of the title compound as a clear oil; 1H NMR (DMSO-d6) δ1.83 (s, 3H), 2.08 (s, 3H), 3.83 (s, 2H), 5.83 (s, 1H), 7.16-7.30 (m, 5H). mass spectrum (EI), m/z 186 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.Cl[S:18]([OH:21])(=[O:20])=[O:19].S(=O)(=O)([O-])N.C(=O)([O-])[O-].[Na+:31].[Na+]>N1C=CC=CC=1C>[O:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:18](=[O:20])(=[O:19])[O-:21])=[CH:7][CH:6]=1.[Na+:31]
Reactant: Nc1ccc(-c2nc3ccccc3o2)cc1
Reactant: O=S(=O)(O)Cl
Agent: NS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccn1
Product: O=S(=O)([O-])Nc1ccc(-c2nc3ccccc3o2)cc1
Yield: 96 %

Procedure:
2(4'-Aminophenyl)benzoxazole was treated with chlorsulphonic acid in 2-picoline and sodium carbonate according to the above-described general procedure for preparation of sulphamate salts. Grey crystals were obtained in 96% yield, m.p. >340° C.
Reaction SMILES: OC1C=CC=CN=1.[C:8]([O:12][C:13](=[O:42])[NH:14][C@H:15]([C@@H:33]1[CH2:37][C@@H:36]([CH2:38][CH2:39][CH3:40])[C:35](=[O:41])[O:34]1)[CH2:16][N:17]1[CH2:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH2:19][C:18]1([CH3:32])[CH3:31])([CH3:11])([CH3:10])[CH3:9].O.[CH3:44][C:45]([CH3:49])([CH3:48])[CH2:46][NH2:47]>>[C:8]([O:12][C:13](=[O:42])[NH:14][C@@H:15]([CH2:16][N:17]1[CH2:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH2:19][C:18]1([CH3:32])[CH3:31])[C@@H:33]([OH:34])[CH2:37][C@H:36]([C:35](=[O:41])[NH:47][CH2:46][C:45]([CH3:49])([CH3:48])[CH3:44])[CH2:38][CH2:39][CH3:40])([CH3:11])([CH3:9])[CH3:10]
Reactant: CCC[C@@H]1C[C@@H]([C@H](CN2CC(=O)N(c3ccccc3Cl)CC2(C)C)NC(=O)OC(C)(C)C)OC1=O
Reactant: CC(C)(C)CN
Agent: Oc1ccccn1
Solvent: O
Product: CCC[C@H](C[C@H](O)[C@H](CN1CC(=O)N(c2ccccc2Cl)CC1(C)C)NC(=O)OC(C)(C)C)C(=O)NCC(C)(C)C
Temperature: 80 °C
Reaction time: 5 h
Yield: 94 %

Procedure:
3.8 mg of 2-hydroxypyridine (0.04 mmol) was added to a solution of 101 mg of {(S)-2-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-1-[(2S,4R)-5-oxo-4-propyltetrahydrofuran-2-yl]ethyl}carbamic acid t-butyl ester obtained in Example (116i) (0.2 mmol) in (2,2-dimethylpropyl)amine (1 ml), and the mixture was stirred at 80° C. for five hours. The reaction mixture was cooled and then water was added, followed by extraction with ethyl acetate. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=30/1-20/1) to obtain 111 mg of the title compound (yield: 94%).
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)=[O:8])[CH3:3].[BH4-].[Na+].C(Cl)(Cl)Cl>C(O)C.C(Cl)(Cl)(Cl)Cl>[CH2:2]([N:4]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])=[CH:11][CH:10]=1)[OH:8])[CH3:3]
Reactant: CCCCCCCN(CC)CCC(=O)c1ccc(NS(C)(=O)=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCCCCCCN(CC)CCC(O)c1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The crude mixture containing N-[4-[3-(ethylheptylamino)-1-oxopropyl]phenyl]methanesulfonamide hydrochloride from Preparation 16 (1.0 g, 2.6 mmol) is transferred to a reaction flask in ethanol-carbon tetrachloride, concentrated, treated with benzene and concentrated again in vacuo. The residue in 18 ml of ethanol, under nitrogen, is cooled in an ice bath and treated with powdered NaBH4 (0.23 g, 0.006 mol) in portions (foaming) over 20 min. The mixture is stirred for 15 min in the cold and for 2.5 hrs at room temperature. It is then treated with 20 ml of ice-water in portions over 5 min. Chloroform (10 ml) is added to the resultant suspension; the mixture is stirred 5 min; and, the layers are separated. The aqueous phase is extracted with additional chloroform (3×50 ml). (Each extract is backwashed with 5 ml of H2O). The pooled organic extract is washed with brine, dried (Na2SO4) and concentrated to give 0.85 g of crude material (two main spots by TLC). This material is chromatographed over 250 ml of silica gel with 0.5% NH4OH/7.5% MeOH/CHCl3 ; 16 ml fractions are collected. Fractions at approximately 36-54 give the title compound which is crystallized from ether-pentane; m.p. 74°-75° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[CH:9]([C:11]1[N:19]2[C:14]([C:15]([NH2:20])=[N:16][CH:17]=[N:18]2)=[CH:13][CH:12]=1)O)=[O:5])[CH3:2].C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[CH2:9][C:11]1[N:19]2[C:14]([C:15]([NH2:20])=[N:16][CH:17]=[N:18]2)=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CC1C(O)c1ccc2c(N)ncnn12
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1CC1Cc1ccc2c(N)ncnn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.2 %

Procedure:
A solution of 2-[(4-amino-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-hydroxy-methyl]-cyclopropanecarboxylic acid ethyl ester (1.75 g, 6.3 mmol) in dichloromethane (17.5 mL) was added dropwise into a mixture of triethylsilane (3 g, 25 mmol) and TFA (17.5 mL) in ice water bath. It was stirred at rt for overnight. 2N sodium carbonate solution (10 mL) was added and organic layer was separated, dried and concentrated. The residue was purified by Biotage® to give desired product 0.43 g (26). 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.75 (bs, 2 H), 6.80 (s, 1 H), 6.60 (m, 1 H), 4.0 (m, 2 H), 2.9 (d, 2 H), 1.5 (m, 2 H), 1.2 (t, 3 H), 1.0 (m, 2 H); ES-MS m/z 261.07 [M+H]+, HPLC RT (min) 2.03.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:20][C@@:18]2([CH3:19])[C@@H:14]([CH2:15][CH2:16][C:17]2=[O:21])[C@H:13]2[C@H:4]1[C:5]1[CH:6]=[CH:7][C:8]([OH:22])=[CH:9][C:10]=1[CH2:11][CH2:12]2.C1(C)C=CC(S(O)(=O)=[O:30])=CC=1.N1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1(C)C=CC=CC=1.O1CCCC1.O1C=CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C@H:3]1[CH2:20][C@@:18]2([CH3:19])[C@@H:14]([CH2:15][CH2:16][C:17]2=[O:21])[C@H:13]2[C@H:4]1[C:5]1[CH:6]=[CH:7][C:8]([O:22][CH:39]3[CH2:38][CH2:37][CH2:36][CH2:35][O:30]3)=[CH:9][C:10]=1[CH2:11][CH2:12]2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: c1ccncc1
Reactant: CO[C@H]1C[C@]2(C)C(=O)CC[C@H]2[C@@H]2CCc3cc(O)ccc3[C@H]21
Agent: C1=COCCC1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CO[C@H]1C[C@]2(C)C(=O)CC[C@H]2[C@@H]2CCc3cc(OC4CCCCO4)ccc3[C@H]21

Procedure:
A suspension of 2.0 g of 11β-methoxy-3-hydroxy-estra-1,3,5(10)-trien-17-one in 20 ml of toluene, 5 ml of tetrahydrofuran and 3.0 ml of dihydropyran is stirred with 20 mg of para-toluenesulfonic acid for 24 hours at room temperature. Then, 0.5 ml of pyridine is added, diluted with ethyl acetate, washed with sodium bicarbonate solution as well as with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/acetone. 1.9 g of 11β-methoxy-3-tetrahydropyranyloxy-estra-1,3,5(10)-trien-17-one is obtained as crystals with a melting point of 147° C., [α]D22 =+147.2° (c=0.5% in pyridine).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[CH:6][C:7]=1[CH3:8]>C(Cl)Cl.[O-2].[Mn+2]>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH3:8])[CH:9]=[O:10]
Reactant: Cc1ccc(CO)cc1Br
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1ccc(C=O)cc1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
(3-bromo-4-methylphenyl)methanol was oxidized as follows: To the primary alcohol (15 mmol) in methylene chloride (30 mL) was added 10 equivalents of activated manganese oxide (IV). The mixture was stirred at room temperature for 24 hours, the filtered through a bed of celite. Removal of the solvent left a yellow solid. Product was used crude in next step without further purification. The yield was 89%. 1H NMR (Varian 300 MHz CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 9.8 (s, 1H) 8.0 (s, 1H) 7.7 (d, 1H), 7.2 (d, 1H), 2.3 (s, 3H).
Reaction SMILES: C([O-])(=[O:3])C.[Na+].C(=O)(O)[O-].[Na+].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:32]=[CH:31][N:30]=[C:29]3[C:25]=2[N:26]=[C:27](Cl)[N:28]3[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:40]#[N:41])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>CS(C)=O>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:32]=[CH:31][N:30]=[C:29]3[C:25]=2[NH:26][C:27](=[O:3])[N:28]3[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:40]#[N:41])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3c2nc(Cl)n3Cc2ccccc2C#N)CC1
Reactant: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3c2[nH]c(=O)n3Cc2ccccc2C#N)CC1
Temperature: 135 °C
Yield: 45.9 %

Procedure:
Sodium acetate (0.168 g) and sodium bicarbonate (0.100 g) were added to a solution of 4-[8-chloro-9-(2-cyanobenzyl)-9H-purin-6-yl]-piperazine-1-carboxylic acid t-butyl ester (0.100 g) in dimethylsulfoxide (3 mL). This was then heated at 135° C. for 45 hours. The reaction solution was filtered, and then directly loaded onto a column for purification by reverse phase high performance liquid chromatography to give the title compound (0.044 g).
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2]1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>CO>[N:27]1([CH2:2][C:3]2([OH:1])[CH2:4][CH2:5][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:7][CH2:8]2)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)c(F)c2)C(=O)O1
Reactant: C1CNCCN1
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(CN4CCNCC4)CC3)c(F)c2)C(=O)O1
Yield: 80 %

Procedure:
The title compound was prepared by reacting (S)—N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.37 mmol) with piperazine (2.06 mmol) in methanol (10 ml) at a temperature 25° C. for 14 hours and by purifying the compound by silica gel column chromatography in 80% yield.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH3:26])[CH:21]=2)[CH:16]=1)=[NH:5])C.[NH2:27][NH:28][C:29](=O)[CH2:30][N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.C[O-].[Na+]>CO>[CH3:26][O:25][C:20]1[CH:19]=[CH:18][C:17]2[C:22](=[CH:23][CH:24]=[C:15]([C:9]3[C:13]4[C:12](=[CH:8][CH:7]=[C:6]([C:4]5[N:5]=[C:29]([CH2:30][N:31]6[CH2:35][CH2:34][CH2:33][CH2:32]6)[NH:28][N:27]=5)[CH:14]=4)[NH:11][N:10]=3)[CH:16]=2)[CH:21]=1
Reactant: CCOC(=N)c1ccc2[nH]nc(-c3ccc4cc(OC)ccc4c3)c2c1
Reactant: NNC(=O)CN1CCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2cc(-c3n[nH]c4ccc(-c5n[nH]c(CN6CCCC6)n5)cc34)ccc2c1
Temperature: 95 °C
Yield: 10.5 %

Procedure:
The title compound was prepared using the same procedure as for Example 423. To a suspension of ethoxy[3-(6-methoxy(2-naphthyl))(1H-indazol-5-yl)]methanimine (0.386 g, 1.01 mmol) in methanol (5 mL) was added N-amino-2-pyrrolidinylacetamide (0.433 g, 3.03 mmol) and 4.3 M sodium methoxide (0.518 mL, 2.23 mmol). The mixture was heated in a sealed tube at 95° C. for 16 h. The solvent was removed using a rotary evaporator which gave a solid residue. Purification of the residue by preparative HPLC (30–100%, acetonitrile/water) gave the title compound (0.045 g, 10% yield): 1H NMR (DMSO-d6) δ 13.41 (br s, 1H), 8.73 (s, 1H), 8.44 (s, 1H), 8.09 (t, 2H), 8.00 (t, 2H), 7.68 (d, 1H), 7.39 (d, 1H), 7.23 (dd, 1H), 3.91 (s, 3H), 3.75 (s, 2H), 2.53 (m, 4H), 2.49 (m, 4H); ES-MS (m/z) 425 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][CH2:10][CH2:11][C:12](O)=[O:13])[N:5]=[CH:4][C:3]=1[NH:15][C@@H:16]1[CH2:21][C@@H:20]2[CH2:22][C@@H:18]([C:19]2([CH3:24])[CH3:23])[C@H:17]1[CH3:25].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[N:45]1[CH:50]=[CH:49][C:48]([CH2:51][NH2:52])=[CH:47][CH:46]=1>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][CH2:10][CH2:11][C:12]([NH:52][CH2:51][C:48]2[CH:49]=[CH:50][N:45]=[CH:46][CH:47]=2)=[O:13])[N:5]=[CH:4][C:3]=1[NH:15][C@@H:16]1[CH2:21][C@@H:20]2[CH2:22][C@@H:18]([C:19]2([CH3:23])[CH3:24])[C@H:17]1[CH3:25]
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CCCC(=O)O)c(=O)c1Br)C2(C)C
Reactant: NCc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CCCC(=O)NCc3ccncc3)c(=O)c1Br)C2(C)C
Yield: 65.6 %

Procedure:
4-{5-Bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}butanoic acid (38 mg, 0.091 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (35 mg, 0.182 mmol), 1-hydroxybenzotriazole anhydride (12 mg, 0.091 mmol) and triethylamine (25 μL, 0.182 mmol) in N,N-dimethylformamide (1 mL) were stirred with 4-picolylamine (25 μL, 0.182 mmol) at room temperature for 24 hours. After completion of the reaction, ethyl acetate was added, and the organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform/methanol=15/1) to give the desired product (30 mg, 58% yield).
Reaction SMILES: CN(C)C=O.[CH2:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[CH3:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][CH2:30][OH:31]>C(OCC)(=O)C.O>[CH2:6]([C@H:8]1[CH2:9][CH2:10][C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH:30]([OH:31])[CH2:29][CH3:28])=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)[CH3:7]
Reactant: OCCCBr
Reactant: CC[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCC(O)Oc1ccc([C@H]2CC[C@H](CC)CC2)cc1
Temperature: 25 °C

Procedure:
In a 1-liter three-necked flask equipped with a condenser and a stirrer were placed 500 ml of dimethylformamide, 20.4 g (0.10 mol) of 4-(trans-4-ethylcyclohexyl)phenol and 41.4 g (0.30 mol) of potassium carbonate, followed by stirring at room temperature. Afterward, 18.1 g (0.13 mol) of 3-bromo-1-propanol was added thereto, and the solution was then vigorously stirred at 100° C. After reaction for 10 hours, this solution was poured into 2 liters of water, and extraction was then made with 1.5 liters of ethyl acetate. In succession, the resultant organic layer was washed with 3N hydrochloric acid three times, a 2N aqueous sodium hydroxide solution three times and water. The resultant ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure. Next, the resultant crystal was recrystallized from n-heptane twice to obtain 17.6 g (0.067 mol) of 4-(trans-4-ethylcyclohexyl)phenoxypropanol. Its melting point was in the range of 68.5° to 69.9° C.