Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([Cl:13])[C:4]=1[C:5]([OH:7])=[O:6].ClC1C=CC(Cl)=CC=1Cl.ClC1C(Cl)=C(Cl)C=CC=1.ClC1C=CC(Cl)=CC=1O.[OH-].[Na+].C1(O)C=CC=CC=1.C(=O)=O>CO>[OH:2][C:3]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([Cl:13])[C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COc1c(Cl)ccc(Cl)c1C(=O)O
Agent: Clc1cccc(Cl)c1Cl
Agent: O=C=O
Agent: Oc1cc(Cl)ccc1Cl
Solvent: Oc1ccccc1
Solvent: CO
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: O=C(O)c1c(Cl)ccc(Cl)c1O

Procedure:
The compound 2-methoxy-3,6-dichlorobenzoic acid is a valuable herbicide and is used in commerce for the control of a variety of undesirable vegetation. The prior art discloses in U.S. Pat. No. 3,013,054 that the 2-methoxy-3,6-dichlorobenzoic acid is prepared from 1,2,4-trichlorobenzene in a three-stage process. The trichlorobenzene is first converted to 2,5-dichlorophenol with methanol and sodium hydroxide. The phenol is then treated with carbon dioxide under pressure to yield 2-hydroxy-3,6-dichlorobenzoic acid. The hydroxy acid is then methylated with dimethyl sulfate or methyl chloride to yield the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH:22]4[CH2:24][CH2:23]4)=[CH:20][C:19]([CH:25]4[CH2:27][CH2:26]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:3]=1.[CH2:32]([C@@H:34]1[CH2:38][O:37][C:36](=[O:39])[NH:35]1)[CH3:33]>>[CH:22]1([C:21]2[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:35]5[C@H:34]([CH2:32][CH3:33])[CH2:38][O:37][C:36]5=[O:39])=[CH:3][C:4]=4[S:28]([CH3:31])(=[O:30])=[O:29])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=[C:19]([CH:25]3[CH2:27][CH2:26]3)[CH:20]=2)[CH2:24][CH2:23]1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: CC[C@@H]1COC(=O)N1
Product: CC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C3CC3)CC2)c(S(C)(=O)=O)c1
Yield: 25.6 %

Procedure:
By reaction and treatment in the same manner as in Example 111 and using (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl]methanone (400 mg) described in Preparation Example 89 and (R)-4-ethyloxazolidin-2-one (91.3 mg) described in Preparation Example 26, the title compound (109.5 mg) was obtained.
Reaction SMILES: [CH2:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].Br[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)=[CH:20][CH:19]=1>>[CH2:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH:26]3[CH2:27][CH2:28][N:29]([C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]3)=[CH:22][CH:23]=2)=[CH:10][CH:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Reactant: CCCCNC(=O)c1ccc(B(O)O)cc1
Product: CCCCNC(=O)c1ccc(-c2ccc(OCC3CCN(C(=O)OC(C)C)CC3)cc2)cc1
Yield: 28.7 %

Procedure:
The title compound (26 mg, 23%) was prepared from {4-[(butylamino)carbonyl]phenyl}boronic acid (44 mg, 0.2 mmol) and 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 9, Step 2, 71 mg, 0.2 mmol) in a manner similar to Example 21, Step 3, and worked up in a manner similar to Example 9, Step 3. 1H NMR (400 MHz, CDCl3): δ 7.80 (d, 2H, J=8.6 Hz), 7.60 (d, 2H, J=8.6 Hz), 7.54 (d, 2H, J=8.9 Hz), 6.96 (d, 2H, J=8.8 Hz), 6.11 (t, 1H, J=5.7 Hz), 5.01-4.83 (m, 1H), 4.21 (bs, 2H), 3.85 (d, 2H, J=6.4 Hz), 3.53-3.39 (m, 2H), 2.83-2.73 (m, 2H), 2.05-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.67-1.55 (m, 2H), 1.46-1.37 (m, 2H), 1.36-1.25 (m, 2H), 1.24 (d, 6H, J=6.2 Hz), 0.96 (t, 3H, J=7.3 Hz); LRMS (ESI), m/z 453 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[N:16]2[C:17]3[N:12]([C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)=[CH:14][CH2:15]2)[N:11]=[CH:10][C:9]=3[C:8](=[O:28])[N:7]=1)=[O:4].[CH2:29]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[OH-].[Na+]>O1CCCC1>[O:28]=[C:8]1[N:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:39]2[CH2:40][CH2:41][N:36]([CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:37][CH2:38]2)[N:16]2[C:17]3[N:12]([C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=4)=[CH:14][CH2:15]2)[N:11]=[CH:10][C:9]1=3
Reactant: O=C(CCl)Nc1nc(=O)c2cnn3c2n1CC=C3c1cccc(C(F)(F)F)c1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(CN1CCN(Cc2ccccc2)CC1)Nc1nc(=O)c2cnn3c2n1CC=C3c1cccc(C(F)(F)F)c1

Procedure:
A 1.000 g amount of 2-chloro-N-[3-oxo-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,5a,8a-tetraazaacenaphthylen-5-yl]acetamide (prepared in the manner described in Example 31) was dissolved in 50 ml of dry tetrahydrofuran, then 430 mg of 1-benzylpiperazine was added to the mixture in one portion. The reaction mixture was heated at reflux for 16 hours. The mixture was cooled, made basic with 1N sodium hydroxide and extracted with chloroform. The solvent was evaporated and the solid was purified by conventional means to give 426 mg of the desired product as a brown solid.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][CH2:5][NH:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1.[OH-].[Li+]>O.O1CCCC1>[C:9]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=[C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:19])=[O:2])[CH:8]=1
Reactant: COC(=O)CCNc1cccc(-c2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCNc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 105.3 %

Procedure:
3-(Biphenyl-3-ylamino)-propionic acid methyl ester 1.6 g (6.3 mmol) was taken in 8 mL of water and 8 mL of tetrahydrofuran, to this solution was added 0.4 g (9.5 mmol) of lithium hydroxide, reaction stirred at room temperature for 5 hour. The solvent was removed from the mixture completely and 10 mL water was added and washed with ethyl acetate. The aqueous solution was acidified with 1 M HCl, and was extracted with ethyl acetate 3 times. Combined organic layer was washed with brine, dried over magnesium sulfate and concentrated under vaccum, yield to 1.6 g of acid used as crude for the next step.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[OH-].[Na+].[N+]([O-])([O-])=O.[Ag+:16]>O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[Ag:16]
Reactant: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: [Ag]
Temperature: 36 °C

Procedure:
A stirred reaction vessel was charged with 85 g of lime-processed gelatin, 25 g of phthalated gelatin, and 2000 g of deionized water. A solution containing 185 g of benzotriazole, 1405 g of deionized water, and 680 g of 2.5 molar sodium hydroxide was prepared (Solution B). The mixture in the reaction vessel was adjusted to a pAg of 7.25 and a pH of 8.0 by addition of Solution B, and 2.5 molar sodium hydroxide solution as needed, and maintaining it at temperature of 36° C. A solution containing 228.5 g of silver nitrate and 1222 g of deionized water (Solution C) was added to the kettle at the accelerated flow rate defined by: Flow=16(1+0.002t2) ml/min (where t is the time in minutes), and the pAg was maintained at 7.25 by a simultaneous addition of Solution B. This process was terminated when Solution C was exhausted, at which point a solution of 80 g of phthalated gelatin and 700 g of deionized water at 40° C. was added to the kettle. The mixture was then stirred and the pH was adjusted to 2.5 with 2 molar sulfuric acid to coagulate the silver salt emulsion. The coagulum was washed twice with 5 liters of deionized water, and re-dispersed by adjusting pH to 6.0 and pAg to 7.0 with 2.5 molar sodium hydroxide solution and Solution B. The resulting silver salt dispersion contained fine particles of silver benzotriazole salt.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[CH:7][N:6]=[C:5](O)[CH:4]=1.P(Cl)(Cl)([Cl:14])=O.N1C2C(=CC=CC=2)C=CC=1>C1(C)C=CC=CC=1.O>[Cl:14][C:5]1[CH:4]=[C:3]([C:2]([F:11])([F:10])[F:1])[N:8]=[CH:7][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc(C(F)(F)F)ncn1
Solvent: O
Solvent: c1ccc2ncccc2c1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cc(Cl)ncn1
Yield: 21.6 %

Procedure:
A solution of 6-(trifluoromethyl)pyrimidin-4-ol (5.0 g, 30.5 mmol), phosphoryl chloride (3.41 mL, 36.6 mmol), and quinoline (2.16 mL, 18.3 mmol) in toluene (50 mL) was stirred at 100° C. for 5 h. The reaction was diluted with water and extracted with ethyl acetate three times, dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography (10% EtOAc/Hexane) to yield the desired product (1.20 g, 21.6%). 1H NMR (400 Mflz, CDCl3): 9.21 ppm (1H, s), 7.78 (1H, s).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[C:13]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:23][CH:22]=3)=[C:14]([F:20])[C:15]([F:19])=[C:16]([CH3:18])[CH:17]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[H][H]>C1(C)C=CC=CC=1.[Pd]>[CH2:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]2[C:13]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:23][CH:22]=3)=[C:14]([F:20])[C:15]([F:19])=[C:16]([CH3:18])[CH:17]=2)=[CH:8][CH:9]=1)[CH2:2][CH3:3]
Reactant: CCCCCc1ccc(-c2c(C=Cc3ccc(CCC)cc3)cc(C)c(F)c2F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCCCCc1ccc(-c2c(CCc3ccc(CCC)cc3)cc(C)c(F)c2F)cc1
Yield: 60.3 %

Procedure:
0.33 g of Pd/C was added to 6.50 g of the compound (24) having been dissolved in 100 mL of toluene and 100 mL of Solmix, and under a hydrogen atmosphere, the mixture was stirred at room temperature until hydrogen was not absorbed. Pd/C was removed by filtration, and the solvent was distilled off. The residue was purified by silica gel column chromatography and recrystallization to obtain 3.94 g of 2-(4-propylphenyl)ethyl-2,3-difluoro-4-(4-pentylphenyl)toluene (Compound 1-2-3-3) as colorless crystals.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24](I)[CH:25]=4)[N:20]=[CH:19][N:18]=3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1.[C:31]([O:35][C:36](=[O:41])[NH:37][CH2:38][C:39]#[CH:40])([CH3:34])([CH3:33])[CH3:32].N(C(C)C)C(C)C>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:31]([O:35][C:36](=[O:41])[NH:37][CH2:38][C:39]#[C:40][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][N:18]=[C:17]2[NH:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:5]1[CH:28]=[CH:29][CH:30]=[C:3]([F:2])[CH:4]=1)[N:8]=[CH:9]2)([CH3:34])([CH3:33])[CH3:32]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: Fc1cccc(Cn2ncc3cc(Nc4ncnc5ccc(I)cc45)ccc32)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC#Cc1ccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.3 %

Procedure:
[1-(3-Fluoro-benzyl)-1H-indazol-5-yl]-(6-iodo-quinazolin-4-yl)-amine hydrochloride (0.334 g, 0.628 mmol) and Prop-2-ynyl-carbamic acid tert-butyl ester (113 mg, 1.16 equiv.) is treated with i-Pr2NH (2 equiv.) in dry THF (4 ml) under N2. Pd(PPh3)4 (25 mg, 0.0356 mmol, 5.7 mol %) and solid CuI (5 mol %) are added next, and the mixture is stirred at r.t. for 3 hours. Workup: THF is removed under reduced pressure and DCM (10 ml) is added. The organic layer is washed with sat. aq. NH4Cl solution and brine, dried and concentrated. Chromatography on silica (EtOAc/hexanes) affords the desired pure product (293 mg, 89%).
Reaction SMILES: [Br:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CCN=C=NCCCN(C)C.[C:22]([C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29])([CH3:25])([CH3:24])[CH3:23].C(=O)(O)[O-].[Na+]>ClCCl.O>[Br:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:29][C:28]1[CH:30]=[CH:31][CH:32]=[C:26]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:27]=1)=[O:6]
Reactant: O=C(O)c1cccnc1Br
Reactant: CC(C)(C)c1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1cccc(NC(=O)c2cccnc2Br)c1
Reaction time: 12 h
Yield: 59 %

Procedure:
To a stirred solution of 2-bromonicotinic acid (1.01 g, 5 mmol) dissolved in anhydrous dichloromethane (8 mL) were added EDCI (1.34 g, 7 mmol) and 3-tert-butylaniline (0.74 g, 5 mmol) at room temperature and the reaction mixture was stirred for 12 hours. The mixture was then diluted with dichloromethane, followed by saturated sodium bicarbonate and water wash. The dichloromethane layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography to obtain 2-bromo-N-(3-tert-butylphenyl)nicotinamide in 59% yield (950 mg). Rt: 2.44 min (20-100-5 method). MS: (ES) m/z 333, 335 (M+H+).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][O:7][CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.CCN(CC)CC.[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28](Cl)=[O:29]>>[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([NH:1][CH:2]1[CH2:8][O:7][CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1)=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCOCC(N)C1
Reactant: O=C(Cl)CCCCBr
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCOCC(NC(=O)CCCCBr)C1
Reaction time: 1 h

Procedure:
To an ice bath stirring solution of tert-butyl 6-amino-1,4-oxazepane-4-carboxylate 38.4 (1.01 g, 4.67 mmol) and Et3N (1.95 mL, 14.0 mmol) was added 5-bromo-pentanoyl chloride (0.62 mL, 4.7 mmol). The ice bath was removed and the solution was stirring for 1 h and then diluted with water and extracted with DCM. The organic phase was washed with diluted citric acid, water, sat. NaHCO3, dried (MgSO4), filtered and concentrated in vacuo to afford an oil which was purification by flash column chromatography (gradient EtOAc/hexanes). LCMS m/z 324.1 & 325.1 [M−tBu]+.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH:9]=2)=[CH:6][C:5]([C@H:34]([N:36]2[CH2:41][CH2:40][N:39]([S:42]([CH3:45])(=[O:44])=[O:43])[CH2:38][C@@H:37]2[CH3:46])[CH3:35])=[CH:4][N:3]=1.[F:47][C:48]1[CH:49]=[C:50]([NH2:56])[CH:51]=[N:52][C:53]=1[O:54][CH3:55].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[NH4+].[Cl-]>C1COCC1>[F:47][C:48]1[CH:49]=[C:50]([NH:56][C:2]2[C:7]([C:8]3[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[CH2:25][C:26]4[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=4)[CH:9]=3)=[CH:6][C:5]([C@H:34]([N:36]3[CH2:41][CH2:40][N:39]([S:42]([CH3:45])(=[O:44])=[O:43])[CH2:38][C@@H:37]3[CH3:46])[CH3:35])=[CH:4][N:3]=2)[CH:51]=[N:52][C:53]=1[O:54][CH3:55]
Reactant: COc1ncc(N)cc1F
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)C[C@@H]4C)cnc3F)nc(C)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)C[C@@H]4C)cnc3Nc3cnc(OC)c(F)c3)nc(C)n2)cc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 32.5 %

Procedure:
A solution of 6-(2-fluoro-5-((1R)-1-((2S)-2-methyl-4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-2-methyl-4-pyrimidinamine (0.130 g, 0.200 mmol) and 5-fluoro-6-methoxypyridin-3-amine (0.043 g, 0.301 mmol) in THF (2.00 mL) at −10° C. was treated with lithium bis(trimethylsilyl)amide (1.0 M solution in THF) (0.60 mL, 0.60 mmol). After 30 minutes, more lithium bis(trimethylsilyl)amide, (1.0 M solution in THF) (0.60 mL, 0.60 mmol) was added and the reaction mixture stirred for another 30 minutes at −10° C. Saturated NH4Cl (aq.) was added and the mixture was extracted with CH2Cl2 (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a silica gel column (4 g), eluting with a gradient of 0% to 100% EtOAc in hexane, to provide 6-(2-((5-fluoro-6-methoxy-3-pyridinyl)amino)-5-((1R)-1-((2S)-2-methyl-4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-2-methyl-4-pyrimidinamine (0.050 g, 0.065 mmol, 32.4% yield) as a brown oil. m/z (ESI, +ve) 771.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH:5]=[C:4]([Cl:16])[CH:3]=1.[C:17](=[O:19])=[O:18]>Cl.C(OCC)(=O)C>[Cl:16][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH:5]=1)[C:17]([OH:19])=[O:18]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(Cl)cc(Cl)c1
Reactant: O=C=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1cc(Cl)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64 %

Procedure:
To “Rieke Mg” (0.21 mol; Rieke, R. D.; Bales, S. E.; Hudnall, P. M.; Bums, T. P.; Poindexter, G. S. Org. Synth. Collective Volume VI, 1988, 845.) in tetrahydrofiran (1000 mL) was added ether 13 (27.7 g, 0.10 mol). After the reaction mixture was stirred for 20 min at ambient temperature there was an exotherm observed. The exotherm. subsided within 5 min, and the reaction mixture was cooled to 20° C. with an ice bath. After 15 min, the reaction mixture was cooled to −78° C. To the cool reaction mixture was added CO2 gas for 30 min. The reaction mixture was warmed to ambient temperature, then diluted with cold (0° C.) 10% aqueous HCl (150 mL) and ethyl acetate (400 mL). The aqueous phase was extracted with ethyl acetate (400 mL). The combined organic phases were washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting solid was recrystallized from acetonitrile to provide 14 as fluffy white needles (19.3 g, 64%). 1H NMR (300 MHz, CDCl3) δ 7.70 (s, 1H), 7.43 (s, 1H), 7.08 (s, 1H), 0.99 (s, 9H), 0.23 (s, 6H). IR (KBr) 2957, 1697, 1578, 1434, 1297, 1266, 1115, 990,871 cm−1.
Reaction SMILES: [O:1]([C:13]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:14]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40].O>CN(C)C=O>[O:1]([C:13]1[CH:18]=[C:17]([O:19][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH:16]=[CH:15][C:14]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: CCc1ccc(Cc2ccc(O)cc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCOc1ccc(Cc2ccc(CC)cc2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a suspension of 2-(4-ethylbenzyl)-5-hydroxyphenyl β-D-glucopyranoside (0.051 g) and cesium carbonate (0.13 g) in N,N-dimethylformamide (2 mL) was added ethyl 4-bromobutyrate (0.028 mL), and the mixture was stirred at 50° C. for 1 hour. After cooling to room temperature, to the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (eluent: dichloromethane/methanol=9/1) to give 5-[3-(ethoxycarbonyl)propyloxy]-2-(4-ethylbenzyl)phenyl β-D-glucopyranoside (0.028 g).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.C(Cl)(=O)C(Cl)=O.CCN(CC)CC.Cl.[CH3:25][NH:26][O:27][CH3:28]>C(Cl)Cl.O>[CH3:28][O:27][N:26]([CH3:25])[C:8]([CH:5]1[CH2:4][CH2:3][C:2](=[O:1])[CH2:7][CH2:6]1)=[O:10]
Reactant: CNOC
Reactant: O=C1CCC(C(=O)O)CC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.7 %

Procedure:
To a solution of 4-oxocyclohexanecarboxylic acid (4.2 g, 0.0293 mol) in CH2Cl2 (20 mL) was added oxalyl chloride (5.2 g, 0.44 mol) slowly, stirred at room temperature for 1 hour and concentrated, then 20 mL CH2Cl2 was added, followed by addition of Et3N (9 g, 0.116 mol) and N,O-dimethylhydroxylamine hydrochloride (3.5 g, 0.0359 mol). The reaction mixture was stirred for 2 hours, and then 100 mL water was added. The mixture was extracted with ethyl acetate. The extract was concentrated and purified by column chromatography to give the desired product (2.1 g, 39% yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]2[S:13][C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:11][C:10]=2[C:20]2[C:21]([F:38])=[C:22]([NH:26][S:27]([C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[F:37])(=[O:29])=[O:28])[CH:23]=[CH:24][CH:25]=2)[CH:6]=[CH:5][N:4]=1.[C:39](O)(=[O:41])[CH3:40]>>[F:37][C:31]1[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:30]=1[S:27]([NH:26][C:22]1[C:21]([F:38])=[C:20]([C:10]2[N:11]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[S:13][C:9]=2[C:7]2[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][NH:1][C:39](=[O:41])[CH3:40])[N:8]=2)[CH:25]=[CH:24][CH:23]=1)(=[O:28])=[O:29]
Reactant: NCc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Reactant: CC(=O)O
Product: CC(=O)NCc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 275 using N-{3-[5-[2-(aminomethyl)-4-pyrimidinyl]-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.1 g, 0.178 mmol) and acetic acid (0.053 g, 0.889 mmol), the title compound was obtained as a solid (30 mg, 27% yield). MS (ESI): 605 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:40]=[CH:39][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][O:20]C4CCCCO4)[C:12](=[O:27])[N:11]([CH3:28])[C:10]=3[N:9]=[C:8]2[O:29][CH2:30][CH2:31][O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[CH:4][CH:3]=1>Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][OH:20])[C:12](=[O:27])[N:11]([CH3:28])[C:10]=3[N:9]=[C:8]2[O:29][CH2:30][CH2:31][O:32][CH:33]2[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]2)=[CH:39][CH:40]=1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(OCCOC1CCCCC1)n2Cc1ccc(Cl)cc1
Agent: Cl
Product: Cn1c(=O)n(CCCO)c(=O)c2c1nc(OCCOC1CCCCC1)n2Cc1ccc(Cl)cc1
Yield: 60.9 %

Procedure:
A solution of 7-(4-chlorobenzyl)-8-(2-(cyclohexyloxy)ethoxy)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (123 mg, 0.214 mmol) in 1 mM ethanolic HCl (2 mL) was stirred at room temperature for 30 min. The reaction was concentrated to dryness to give a crude product, which was purified by preparative HPLC to give 7-(4-chlorobenzyl)-8-(2-(cyclohexyloxy)ethoxy)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (64 mg, 60.9% yield) as a white solid. 1H-NMR (CDCl3) δ 7.41-7.44 (d, 2H), 7.28-7.31 (d, 2H), 5.26 (s, 2H), 4.63-4.65 (m, 2H), 4.17-4.20 (t, 2H), 3.81-3.84 (m, 2H), 3.68-3.70 (br, 1H), 3.21 (m, 5H), 3.30-3.34 (m, 1H), 1.87-1.93 (m, 4H), 1.75-1.77 (t, 2H), 1.55-1.58 (m, 1H), 1.23-1.36 (m, 5H). LCMS retention time 2.893 min; LCMS MH+ 491.