Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[N:15]=[C:14]3[C:10]([N:11]=[C:12]([O:24]C)[N:13]3[CH2:16][CH2:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[C:9]([NH2:26])[N:8]=2)[CH2:3][CH2:2]1.Cl>CO.O1CCOCC1>[NH2:26][C:9]1[N:8]=[C:7]([O:6][CH2:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:15]=[C:14]2[C:10]=1[NH:11][C:12](=[O:24])[N:13]2[CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1
Reactant: COc1nc2c(N)nc(OCCC3CC3)nc2n1CCC1CCCCO1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1nc(OCCC2CC2)nc2c1[nH]c(=O)n2CCC1CCCCO1
Temperature: 25 °C
Reaction time: 20 h
Yield: 72 %

Procedure:
To a solution of 2-[(2-cyclopropylethyl)oxy]-8-(methyloxy)-9-[2-(tetrahydro-2H-pyran-2-yl)ethyl]-9H-purin-6-amine (84.7 mg, 0.234 mmol) in methanol (7.9 ml) at room temperature was added 4.0 M HCl in 1,4-dioxane (1.46 ml) to give a pale straw coloured solution. The reaction mixture was stirred at ambient temperature overnight (20 hours) and then evaporated in vacuo to give a colourless oil/gum. This material was re-dissolved in methanol and passed down a 5 g aminopropyl SPE cartridge (pre-conditioned in methanol), washed through with methanol and evaporated to give the title compound as a white solid (58.5 mg).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C:17]2[CH2:18][CH2:19][N:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:21][CH:22]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[F:27][C:28]([CH3:33])([CH3:32])[C:29](O)=O>>[F:2][C:3]1[CH:4]=[C:5]([C:17]2[CH2:22][CH2:21][N:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:19][CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11]1[CH2:12][CH2:13][N:14]([CH2:29][C:28]([F:27])([CH3:33])[CH3:32])[CH2:15][CH2:16]1
Reactant: CC(C)(F)C(=O)O
Reactant: CS(=O)(=O)N1CC=C(c2ccc(OCC3CCNCC3)c(F)c2)CC1
Agent: Cl
Product: CC(C)(F)CN1CCC(COc2ccc(C3=CCN(S(C)(=O)=O)CC3)cc2F)CC1

Procedure:
Prepared essentially as Example 2 starting from 4-[3-fluoro-4-(piperidin-4-ylmethoxy)-phenyl]-1-methanesulfonyl-1,2,3,6-tetrahydro-pyridine hydrochloride salt and 2-fluoro-2-methyl-propionic acid. MS (m/z) 443 (M+1).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([CH:7]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[C:4]([C:22]([OH:24])=[O:23])=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(C(C)=O)C>[CH2:31]([O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:4]3[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=3)=[CH:17][CH:16]=2)[C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=2[C:22]([O:24][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:23])=[CH:13][CH:12]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1ccccc1C(c1ccc(O)cc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(OCc1ccccc1)c1ccccc1C(c1ccc(OCc2ccccc2)cc1)c1ccc(OCc2ccccc2)cc1

Procedure:
In 500 ml of methyl ethyl ketone were dissolved 50 g of phenolphthalin and 75 g of anhydrous potassium carbonate, and the solution was ice cooled. Subsequently, 58 ml of benzyl bromide was added dropwise to the solution, and the mixture was heated under reflux for 24 hours. The temperature of the mixture was brought back to room temperature, and concentrated. Thereafter, water was added to the residue, and the aqueous mixture was extracted with ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with an aqueous 10% citric acid and then dried over anhydrous magnesium sulfate. The solvent was evaporated to give 114.61 g of the desired product.
Reaction SMILES: [C:1]1([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:8][CH2:9][C:10](=[CH2:13])[CH2:11]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Br)(Br)(Br)[Br:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[Br:27][CH2:11][C:10]([CH2:9][O:8][C:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH2:13]
Reactant: C=C(CO)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=C(CBr)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 99.2 %

Procedure:
To a solution of 10 (2.56 g; 7.74 mmol) in CH2Cl2 (75 ml), CBr4 (3.63 g; 10.83 mmol) and triphenylphosphine (2.47 g; 9.31 mmol) were added respectively at 0° C. and the reaction was stirred at room temperature for 40 min. Cooled to 0° C., ethyl acetate (100 mL) and saturated aqueous NaHCO3 (30 mL) were added. The organic layer was separated and washed by saturated aqueous NaCl, and dried over anhydrous Na2SO4. After evaporation of the solvent, the residue was purified by flash column chromatography over silica gel using CH2Cl2-hexane (1:5) as the eluent to afford 11 as white solid (3.02 g; 92% yield): 1H NMR (400 MHz, CDCl3) δ 7.42-7.48 (m, 6H, six of ArH), 7.27-7.33 (m, 6H, six of ArH), 7.20-7.27 (m, 3H, three of ArH), 5.37 (s, 1H, one of C═CH2), 5.31 (s, 1H, one of C═CH2), 4.01 (s, 2H, CH2Br), 3.75 (s, 2H, Ph2COCH2); 13C NMR (100 MHz, CDCl3) δ 143.6, 142.6, 128.4, 127.6, 126.9, 115.8, 86.9, 64.2, 33.5, (9).
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:15]3([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[O:14][C:13]3[C:21]([CH3:28])=[C:22]([CH3:27])[C:23]([OH:26])=[C:24]([CH3:25])[C:12]2=3)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[CH2:29]=O.[OH-].[Na+]>C(O)=O>[CH:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[C:15]3([CH2:16][CH2:17][N:18]([CH3:29])[CH2:19][CH2:20]3)[O:14][C:13]3[C:21]([CH3:28])=[C:22]([CH3:27])[C:23]([OH:26])=[C:24]([CH3:25])[C:12]2=3)=[CH:9][CH:10]=1)([CH3:4])[CH3:3]
Reactant: C=O
Reactant: Cc1c(C)c2c(c(C)c1O)C(c1ccc(C(C)C)cc1)C1(CCNCC1)O2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: Cc1c(C)c2c(c(C)c1O)C(c1ccc(C(C)C)cc1)C1(CCN(C)CC1)O2
Temperature: 100 °C
Reaction time: 15 h
Yield: 77 %

Procedure:
A mixture of 3-(4-isopropylphenyl)-4,6,7-trimethylspiro[benzofuran-2(3H),4′-piperidine]-5-ol hydrochloride (2.80 g, 6.97 mmol), formic acid (30 mL) and 37% formalin (30 mL) was stirred for 15 hours at 100° C. The reaction mixture was cooled to room temperature, made basic with 8N sodium hydroxide solution, and extracted twice with ethyl acetate. The organic layers were combined, washed with an aqueous saturated sodium hydrogencarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Chromatorex NH DM1020, Fuji Silysia Chemical LTD) (hexane/ethyl acetate=1/1) to obtain the title compound (2.05 g, yield 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH:6]=[CH:7][CH2:8][NH:9][CH2:10][CH2:11][NH:12][S:13]([C:16]2[C:17]3[CH:18]=[CH:19][N:20]=[CH:21][C:22]=3[CH:23]=[CH:24][CH:25]=2)(=[O:15])=[O:14])=[CH:4][CH:3]=1.Br[CH2:29][CH2:30]Br.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][CH2:8][N:9]2[CH2:30][CH2:29][N:12]([S:13]([C:16]3[C:17]4[CH:18]=[CH:19][N:20]=[CH:21][C:22]=4[CH:23]=[CH:24][CH:25]=3)(=[O:14])=[O:15])[CH2:11][CH2:10]2)=[CH:26][CH:27]=1
Reactant: BrCCBr
Reactant: O=S(=O)(NCCNCC=Cc1ccc(Cl)cc1)c1cccc2cnccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=S(=O)(c1cccc2cnccc12)N1CCN(CC=Cc2ccc(Cl)cc2)CC1
Reaction time: 24 h
Yield: 25.5 %

Procedure:
1.31 g of the product of Example 172 was dissolved in 3 ml of dimethylformamide, to the solution were added 644 mg of 1,2-dibromoethane and 1.13 g of anhydrous potassium carbonate at a room temperature, and the mixture was stirred for 24 hours. After adding 100 ml of ethyl acetate, the ethyl acetate layer was sequentially washed with water and a saturated sodium chloride aqueous solution twice in each case, and dried over magnesium sulfate. The solution was filtered and evaporated under a reduced pressure, and resulting residue was purified on a silica gel column (silica gel 50 g, eluant: 5% methanol in chloroform), to obtain 356 mg of the title compound in a colorless amorphous form, while recovering the residual starting material.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([O:15][C:16](=[O:32])[CH2:17][N:18]=[C:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:14])([CH3:13])[CH3:12].Br[CH2:34][C:35]1[CH:36]=[CH:37][C:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[N:39][CH:40]=1>C1COCC1.O>[C:19](=[N:18][CH:17]([CH2:34][C:35]1[CH:40]=[N:39][C:38]([NH:41][C:42]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:48])=[CH:37][CH:36]=1)[C:16]([O:15][C:11]([CH3:14])([CH3:12])[CH3:13])=[O:32])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CBr)cn1
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(CC(N=C(c2ccccc2)c2ccccc2)C(=O)OC(C)(C)C)cn1
Reaction time: 0.25 h
Yield: 103.8 %

Procedure:
84.64 ml (84.64 mmol) of a 1M solution of lithium bis(trimethylsilyl)amide in THF were added dropwise to a solution of 25.00 g (84.64 mmol) of N-(diphenylmethylene)glycine tert-butyl ester in 185 ml of THF under argon at 0° C. After stirring at this temperature for 15 min, 24.31 g (84.64 mmol) of tert-butyl (5-bromomethylpyridin-2-yl)carbamate were added as solid, and stirring was continued for 1 h. The reaction mixture was cautiously diluted with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated. 44.08 g of the crude product were obtained and were reacted further without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]#[N:14])=[C:11]([C:15]([O:17]C(C)(C)C)=[O:16])[N:10]=[C:9]2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]#[N:14])=[C:11]([C:15]([OH:17])=[O:16])[N:10]=[C:9]2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1nc(-c2ccc(Cl)cc2Cl)n(-c2ccc(Cl)cc2)c1C#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c(C(=O)O)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.7 %

Procedure:
To a solution of tert-butyl 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-cyano-1H-imidazole-4-carboxylate (2.57 gram, 5.73 mmol) in dichloromethane (40 mL) is added trifluoroacetic acid and the resulting solution is stirred at room temperature for 20 hours and concentrated in vacuo. The residue is crystallised from diisopropyl ether to give pure 1-(4-chlorophenyl)-5-cyano-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylic acid (1.95 gram, 87% yield). Melting point: 200-202° C. (dec.).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][CH2:8][C:9]#[C:10][CH2:11]Cl.[CH:13]1([C:17]2[C:22]([O:23]CC#N)=[N:21][N:20]3[C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[N:28][N:29]=[C:19]3[CH:18]=2)[CH2:16][CH2:15][CH2:14]1>CN(C=O)C>[Cl:7][CH2:8][C:9]#[C:10][CH2:11][O:23][C:22]1[C:17]([CH:13]2[CH2:16][CH2:15][CH2:14]2)=[CH:18][C:19]2[N:20]([C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:28][N:29]=2)[N:21]=1
Reactant: N#CCOc1nn2c(-c3ccccc3)nnc2cc1C1CCC1
Reactant: ClCC#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClCC#CCOc1nn2c(-c3ccccc3)nnc2cc1C1CCC1
Reaction time: 2 h

Procedure:
Potassium carbonate (311 mg, 2.2 mmol) and 1,4 dichloro-2-butyne (275 mg, 2.2 mol) in DMF (3 ml) were heated to 50° C. prior to the dropwise addition of the product from Example 185, Step a (200 mg, 0.75 mmol) in DMF (2 ml). The reaction mixture was left to stir for 2 hours. Cooled and partitioned (ethyl acetate/water). The organic layer was washed (H2O, brine), dried MgSO4) and evaporated in vacuo. Purified via silica gel chromatography using 50/50 ethyl acetate/hexane to elute. 1H NMR (250 MHz, CDCl3) δ1.93 (1 H, m), 2.11-2.16 (3 H, m), 2.42 (2 H, m), 4.2 (2 H, m), 5.10 (2 H, m), 7.50-7.59 (3 H, m), 7.84 (1 H, s), 8.47 (2 H, m).
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([OH:6])=[O:5].[C:9](O)([CH3:12])([CH3:11])[CH3:10].C1CCN2C(=NCCC2)CC1.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:9]([O:5][C:4](=[O:6])[C:3]([CH3:8])([CH3:7])[CH2:2][Cl:1])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)O
Reactant: CC(C)(CCl)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)C(C)(C)CCl
Temperature: 40 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
prepared as follows: To a solution of 3-chloro-2,2-dimethylpropionic acid (5.00 g; 36.6 mmol) in DMF (25 mL) was added N,N′-carbonyldiimidazole (5.94 g; 36.6 mmol) and the resulting mixture was stirred for 1 hour at 40° C. Subsequently, tert-butyl alcohol (7.1 mL; 73 mmol) and DBU (5.5 mL; 36.6 mmol) were added and the mixture stirred overnight at 40° C. After cooling to RT, 5% aqueous NaHCO3 solution (50 mL) was added to the mixture and stirred for another 15 minutes. The reaction mixture was extracted with EtOAc. The organic layer was dried (Na2SO4), concentrated in vacuo and purified by column chromatography (SiO2, Et2O:hexanes 1:1) to afford 3-chloro-2,2-dimethyl-propionic acid tert-butyl ester (3.34 g).
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][C:13]2([CH3:19])[CH2:17][O:16][C:15](=[O:18])[NH:14]2)(=O)=O)=CC=1.[CH3:20][O-].[Na+]>CO.O>[CH3:20][O:11][CH2:12][C:13]1([CH3:19])[CH2:17][O:16][C:15](=[O:18])[NH:14]1
Reactant: Cc1ccc(S(=O)(=O)OCC2(C)COC(=O)N2)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCC1(C)COC(=O)N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
To a round bottom flask containing (4-methyl-2-oxooxazolidin-4-yl)methyl 4-methylbenzenesulfonate (300 mg, 1.05 mmol) was added under a nitrogen atmosphere 3 ml of sodium methoxide in methanol solution (25% wt). The resulting thick suspension was stirred at ambient temperature for 24 hours, and then heated at 80° C. for 18 hours. The reaction was cooled to ambient temperature, diluted with water, and the pH was adjusted to neutral. The mixture was concentrated, and the resulting solids were extracted with DCM and EtOAc. The combined organic layer was concentrated to afford 4-(methoxymethyl)-4-methyloxazolidin-2-one (129 mg, 85%) as an oil.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].C(N(CC)CC)C.[OH:14][CH2:15][C@@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:31]=[C:30]3[C:25]([CH:26]=[C:27]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]([F:42])([F:41])[F:40])[NH:28][C:29]3=[O:32])=[CH:24][CH:23]=2)[CH2:17]1.[Cl-].[NH4+]>ClCCl>[O:21]=[C:19]1[N:18]([C:22]2[CH:31]=[C:30]3[C:25]([CH:26]=[C:27]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]([F:41])([F:40])[F:42])[NH:28][C:29]3=[O:32])=[CH:24][CH:23]=2)[CH2:17][C@H:16]([CH2:15][O:14][C:2](=[O:3])[O:4][CH2:5][CH3:6])[O:20]1
Reactant: CCOC(=O)Cl
Reactant: O=C1O[C@@H](CO)CN1c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)OC[C@H]1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 16.8 %

Procedure:
Ethyl chloroformate (5.7 μL, 0.059 mmol) and triethylamine (10.3 μL, 0.074 mmol) were added to a solution of 7-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in Step B of Example 1-14 (20 mg, 0.050 mmol) in dichloromethane, and the mixture was stirred at room temperature for 18 hours. Aqueous saturated ammonium chloride was added to the mixture, followed by extraction with dichloromethane. The extract was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by aminosilica gel column chromatography (methylene chloride:methanol=50:1) to obtain 4 mg (17%) of ethyl carbonate (R)-2-oxo-3-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]oxazolidin-5-ylmethyl ester as a colorless oil.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]3[CH2:21][CH2:20]O[CH2:18][CH2:17]3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[C:22]1(C2CCC(=O)CC2)C=CC=CC=1.N1CCOCC1.[O-2].[Al+3].[O-2].[O-2].[Al+3]>>[CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]3[CH2:21][CH2:20][CH2:22][CH2:18][CH2:17]3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1
Reactant: O=C1CCC(c2ccccc2)CC1
Reactant: CN[C@H]1CC[C@H](c2ccc(CN3CCOCC3)cc2)CC1
Agent: [Al+3]
Agent: [O-2]
Solvent: C1COCCN1
Product: CN[C@H]1CC[C@H](c2ccc(CN3CCCCC3)cc2)CC1

Procedure:
cis/trans-N-methyl-4-[4-(morpholinomethyl)phenyl]cyclohexylamine, from 4-phenylcyclohexanone and morpholine; colourless solid; Rf values 0.26 and 0.48 (aluminium oxide, petroleum ether/ethyl acetate=5:1, v:v)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8]([NH:10]C(=O)OCC)=S.Cl.NO.CC[N:21](C(C)C)C(C)C.C(O)C>CO>[N:7]1[C:8]([NH2:10])=[N:21][N:1]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=12
Reactant: CCOC(=O)NC(=S)Nc1cnccn1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: NO
Solvent: CO
Solvent: CCO
Product: Nc1nc2cnccn2n1
Temperature: 65 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 270a (6.00 g, 26.43 mmol, 1.0 eq.), hydroxylamine hydrochloride (3.32 g, 47.52 mmol, 1.8 eq.), DIPEA (12 mL), ethanol (40 mL), and methanol (40 mL). The reaction mixture was stirred at 65° C. for 16 hours. After the reaction was complete, it was cooled to room temperature and concentrated to a volume of around 20 mL under reduced pressure. The resulting suspension was collected by filtration and the solid was washed with 60:1 dichloromethane/ethanol (50 mL) to afford 270b (3.3 g, 92%) as a white solid. MS-ESI:[M+H]+ 136.3. 1H NMR (500 MHz, DMSO-d6) δ 8.84 (d, J=1.0 Hz, 1H), 8.70 (dd, J=1.0, 4.0 Hz, 1H), 7.98 (d, J=5.0 Hz, 1H), 6.47 (s, 2H).
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3].[CH3:24][NH:25][CH3:26]>>[CH3:24][N:25]([CH2:12][C:9]1[C:10](=[O:11])[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[N:6]=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:8]=1)[CH3:26]
Reactant: CC(C)Cn1nc(-c2ccccc2)cc(COS(C)(=O)=O)c1=O
Reactant: CNC
Product: CC(C)Cn1nc(-c2ccccc2)cc(CN(C)C)c1=O
Yield: 81.1 %

Procedure:
Following the procedure of Example 7, 2-isobutyl-4-methanesulfonyloxymethyl-6-phenyl-2H-pyridazin-3-one and dimethylamine were reacted to yield the title compound as a yellow oil (yield: 81.1%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:20])([CH3:19])[CH2:13][S:14]([O:16]CC)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C([O-])(=O)C.[Na+].[NH2:28]OS(O)(=O)=O>C(O)C.O>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:20])([CH3:19])[CH2:13][S:14]([NH2:28])(=[O:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOS(=O)CC(C)(C)NC(=O)OCc1ccccc1
Reactant: NOS(=O)(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(CS(N)(=O)=O)NC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 86 %

Procedure:
In ethanol (10 ml) was dissolved 0.60 g (2 mmol) of ethyl 2-(benzyloxycarbonylamino)-2-methylpropane-1-sulfinate, and 0.9 g (2.2 mmol) of 10% aqueous sodium hydroxide solution was slowly dropped thereinto under ice-cooling. The reaction was carried out at room temperature for 1 hour and then the ethanol was distilled off. Water (10 ml), 0.18 g (2.2 mmol) of sodium acetate and 0.25 g (2.2 mmol) of hydroxylamine-O-sulfonic acid were added to the residue, and the reaction was carried out at room temperature for 1 hour. The reaction mixture was poured into water, followed by three runs of extraction with ethyl acetate. The extract solution was washed with saturated aqueous sodium hydrogencarbonate solution and then saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off and 0.49 g (yield 86%) of the thus obtained crude 2-(benzyloxycarbonylamino)-2-methylpropane-1-sulfonamide was used without further purification in the subsequent reaction.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.CCN(CC)CC.[Si:19](OS(C(F)(F)F)(=O)=O)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>ClCCl>[Si:19]([NH:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: Nc1nc(Cl)c2cc[nH]c2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Nc1nc(Cl)c2cc[nH]c2n1
Temperature: -30 °C
Yield: 77.5 %

Procedure:
To a dichloromethane solution (100 mL) of 2-amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (8.7 g, 52 mmol) was added Et3N (26 g, 260 mmol) and the mixture was stirred at −30° C. After this time, TBDMSOTf (15.1 g, 57.2 mmol) was added in a slow dropwise manner and the resultant reaction was stirred at ambient temperature for 1.5 h. The observed solid material completely dissolved to form a light brown solution. The mixture was then quenched with 1 N NaOH (100 mL) and extracted with DCM (250 mL). The organic layer was washed with H2O (150 mL) and then with a brine solution (150 mL) and dried over Na2SO4. The solvents were removed in vacuo and the residue was purified by flash column chromatography (PE/EtOAc=10/1 to 5/1) to afford 2-(t-butyl-dimethylsilyl)amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (CXXII, 11.4 g, 79%) as a light yellow solid. LCMS: (ESI) m/z=283 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([NH:21][CH2:22][C:23]3[C:24]([NH:36][CH:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[C:25]4[CH:33]=[N:32][N:31]([CH2:34][CH3:35])[C:26]4=[N:27][C:28]=3[CH2:29][CH3:30])=[O:20])[CH:14]=2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:43]([C:45]1[CH:46]=[C:47](B(O)O)[CH:48]=[CH:49][CH:50]=1)=[O:44].C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[Cl:8][C:6]1[CH:5]=[C:4]([CH2:9][NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([NH:21][CH2:22][C:23]3[C:24]([NH:36][CH:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[C:25]4[CH:33]=[N:32][N:31]([CH2:34][CH3:35])[C:26]4=[N:27][C:28]=3[CH2:29][CH3:30])=[O:20])[CH:14]=2)=[O:12])[CH:3]=[C:2]([C:49]2[CH:48]=[CH:47][CH:46]=[C:45]([CH:43]=[O:44])[CH:50]=2)[CH:7]=1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(Cl)cc(Br)c2)c1
Reactant: O=Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(Cl)cc(-c3cccc(C=O)c3)c2)c1

Procedure:
N-[(3-Bromo-5-chlorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (300 mg, 0.459 mmol), (3-formylphenyl)boronic acid (68.8 mg, 0.459 mmol), potassium carbonate (190 mg, 1.376 mmol), and tetrakis(triphenylphosphine)palladium(0) (26.5 mg, 0.023 mmol) were placed in a 2-5 mL Biotage microwave vial along with a stir bar. Then 1,4-dioxane (3 mL) and water (1 mL) were added. The vial was capped and microwaved for 15 min at normal power in the SmithCreator microwave at 100° C. The reaction mixture was partitioned between ethyl acetate (50 mL) and water (10 mL). The organic phase was washed 3× with water (10 mL), 1× with brine (10 mL), and dried over anhydrous Na2SO4. The crude product was taken up in dichloromethane and absorbed on Isolute® Sorbent and purified using CombiFlash on a 40 g silica column eluted with 0-10% DCM/MeOH to afford the title compound as a pale yellow solid. LC-MS m/z 679.0 (M+H)+, 2.21 min (ret time); mp 123-127° C.; analytical HPLC shows 96.2% purity, (ret time 14.171 min).