Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:6]=[C:5]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)[C:4](=[O:29])[CH:3]=1.[CH3:30][Si](C=[N+]=[N-])(C)C>CO>[CH3:30][O:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:17])[F:16])[CH:9]=2)[N:6]=[C:5]([C:18]2[N:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:21]=[CH:20][CH:19]=2)[C:4](=[O:29])[CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=c1cc(O)n(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1
Solvent: CO
Product: COc1cc(=O)c(-c2ccnn2-c2ccccc2)nn1-c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 9.6 %

Procedure:
To a solution 6-hydroxy-3-(1-phenyl-1H-pyrazol-5-yl)-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (0.23 g, 0.58 mmol) in MeOH (10 mL) was added dropwise trimethylsilyldiazomethane (2 M solution in diethylether, 8.0 mL, 16.0 mmol) at 0° C., and the mixture was stirred at 0° C. for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with AcOEt/hexane (20/80-100/0) and recrystallized from AcOEt/hexane to give the title compound (0.023 g, 10% yield) as white crystals: mp 139-141° C.; NMR (300 MHz, CDCl3): δ ppm 3.90 (3H, s), 6.14 (1H, s), 6.97-7.02 (1H, m), 7.13 (1H, s), 7.22 (1H, d, J=1.9 Hz), 7.31-7.44 (6H, m), 7.56-7.61 (1H, m), 7.76 (1H, d, J=1.9 Hz). LC-MS (ESI) m/z 413 [M+H]+. Anal. Calcd for C21H15F3N4O2: C, 61.17; H, 3.67; N, 13.59.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14]Cl)=[CH:9][C:8]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:39].[CH2:40]([NH:42][CH2:43][CH2:44][OH:45])[CH3:41].O>CN(C)C(=O)C>[Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][N:42]([CH2:43][CH2:44][OH:45])[CH2:40][CH3:41])=[CH:9][C:8]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:39]
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(OCCCCl)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: CCNCCO
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCN(CCO)CCCOc1cc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c(c1Cl)CNC2=O
Temperature: 90 °C
Reaction time: 72 h
Yield: 80.8 %

Procedure:
4-Chloro-5-(3-chloropropoxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (90.4 mg, 0.158 mmol) was dissolved in N,N-dimethylacetoamide (1.0 mL), and the solution was added with 2-(ethylamino)ethanol (0.321 mL, 2.37 mmol), followed by stirring at 90° C. for 72 hours. The reaction mixture was added with water. The obtained solid was collected by filtration and washed with water, followed by drying under reduced pressure to obtain 4-chloro-5-[3-[N-ethyl(2-hydroxyethyl)amino]propoxy]-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (79.8 mg, yield 81%).
Reaction SMILES: CN(C=O)C.[CH3:6][C:7]1([CH3:33])[C:19]2[O:18][C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[C:15]=2[C:14](=[O:24])[C:13]2[C:8]1=[CH:9][C:10](OS(C(F)(F)F)(=O)=O)=[CH:11][CH:12]=2.[CH3:34][C:35]1([CH3:42])[O:39][CH:38]([CH:40]=[CH2:41])[CH2:37][O:36]1.C([O-])(O)=O.[Na+]>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:34][C:35]1([CH3:42])[O:39][CH:38](/[CH:40]=[CH:41]/[C:10]2[CH:9]=[C:8]3[C:13](=[CH:12][CH:11]=2)[C:14](=[O:24])[C:15]2[C:16]4[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=4[O:18][C:19]=2[C:7]3([CH3:33])[CH3:6])[CH2:37][O:36]1
Reactant: C=CC1COC(C)(C)O1
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1oc1ccccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OCC(/C=C/c2ccc3c(c2)C(C)(C)c2oc4ccccc4c2C3=O)O1
Temperature: 100 °C
Reaction time: 8 h
Yield: 45.8 %

Procedure:
To the DMF solution (4 ml) of trifluoro-methanesulfonic acid 6,6-dimethyl-11-oxo-6,11-dihydro-benzo[b]naphtho[2,3-d]furan-8-yl ester (300 mg), 2,2-dimethyl-4-vinyl-[1,3]dioxolane (469 mg) and PdCl2(PPh3)2 (103 mg), sodium hydrocarbonate (184 mg) was added, and the mixture was stirred at 100° C. overnight under nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium bicarbonate and saturated brine, and then concentrated under reduced pressure. The resulting residues were purified by silica gel column (ethyl acetate/hexane) to obtain the title compound (130 mg, 46%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[Cl:9]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][Cl:9])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccnc(Cl)n1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: ClCc1ccnc(Cl)n1
Temperature: 25 °C

Procedure:
The mixture of 2-Chloro-4-methyl-pyrimidine (51) (6.48 g, 50 mmol), N-chloro succinimide (8.0 g, 60 mmol), and benzoyl peroxide (2.42 g, 10 mmol) in carbon tetrachloride (100 ml) was refluxed for 22 hr. After cooling to room temperature, the mixture was filtered and the filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ether:hexane (1:2)) to afford 3.3 g (40%). 1H NMR (200 MHz, CDCl3) δ: 4.57 (2H, s), 7.50 (1H, d, J=5.2 Hz), 8.65 (1H, d, J=5.2 Hz).
Reaction SMILES: [CH3:1][C@@H:2]1[O:7][C@@H:6]([O:8][C@H:9]2[C@H:14]([O:15][C:16]3[CH:17]=[C:18]([OH:36])[C:19]4[C:25](=[O:26])[CH2:24][C@@H:23]([C:27]5[CH:28]=[CH:29][C:30]([O:34][CH3:35])=[C:31]([OH:33])[CH:32]=5)[O:22][C:20]=4[CH:21]=3)[O:13][C@H:12]([CH2:37][OH:38])[C@@H:11]([OH:39])[C@@H:10]2[OH:40])[C@H:5]([OH:41])[C@H:4]([OH:42])[C@H:3]1[OH:43].[H][H]>[OH-].[Na+].[Ni]>[CH3:1][C@@H:2]1[O:7][C@@H:6]([O:8][C@H:9]2[C@H:14]([O:15][C:16]3[CH:17]=[C:18]([OH:36])[C:19]([C:25]([CH2:24][CH2:23][C:27]4[CH:28]=[CH:29][C:30]([O:34][CH3:35])=[C:31]([OH:33])[CH:32]=4)=[O:26])=[C:20]([OH:22])[CH:21]=3)[O:13][C@H:12]([CH2:37][OH:38])[C@@H:11]([OH:39])[C@@H:10]2[OH:40])[C@H:5]([OH:41])[C@H:4]([OH:42])[C@H:3]1[OH:43]
Reactant: [H][H]
Reactant: COc1ccc([C@@H]2CC(=O)c3c(O)cc(O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O[C@@H]4O[C@@H](C)[C@H](O)[C@@H](O)[C@H]4O)cc3O2)cc1O
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(CCC(=O)c2c(O)cc(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](O)[C@H]3O)cc2O)cc1O
Reaction time: 15 h
Yield: 94.7 %

Procedure:
18.9 g (0.030 mol) of neohesperidin are dissolved in 90 ml of 2-N sodium hydroxide and treated with 1.2 g of Raney-nickel. The mixture is hydrogenated under normal pressure for 15 hours. The hydrogen uptake corresponds to 30 mmol. The solution is filtered and adjusted to pH 6 with 36 ml of 5-N hydrochloric acid while cooling with ice and stirring. The resulting clear yellow solution is left in a refrigerator for 48 hours and then filtered under suction. The white residue is washed with cold water and dried overnight in a high vacuum. There are obtained 17.4 g (95% yield) of neohesperidin dihydrochalcone of melting point 150°C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[NH:14][C:15]([NH2:24])=[C:16]2[C:20]([N:21]=1)=[N:19][C:18]([O:22][CH3:23])=[N:17]2)[CH2:9][CH2:10][CH3:11].Br[CH2:26][CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1>>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: BrCCCC1CCCCO1
Reactant: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCO3)c2n1

Procedure:
Prepared similarly to Intermediate 216 from 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 2-(3-bromopropyl)tetrahydro-2H-pyran.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:15]=[C:14]([NH:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[O:18])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]>C(=O)([O-])[O-].[Na+].[Na+]>[F:5][C:6]1[CH:15]=[C:14]([NH:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[O:18])[C:13]([N+:1]([O-:4])=[O:2])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(NC(=O)c2ccccn2)cc1F
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1cc([N+](=O)[O-])c(NC(=O)c2ccccn2)cc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
With cooling with ice, fuming nitric acid (110 ml) was gradually added to methyl 2-fluoro-4-[(2-pyridinylcarbonyl)amino]benzoate (27.7 g), and stirred at room temperature for 1.5 hours. With cooling with ice, the reaction liquid was gradually added to an aqueous solution (2000 ml) of sodium carbonate (138 g), and the formed solid was taken out through filtration. After dried under reduced pressure, the entitled compound was obtained as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12](O)=O)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH2:21][CH2:22][C:23]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([OH:27])[CH2:24][CH2:25][CH3:26]>>[CH3:1][C:2]1[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]1[O:27][C:23]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([CH2:24][CH2:25][CH3:26])[CH2:22][N:21]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CCCC(O)(CN)c1ccccc1
Reactant: Cc1c(-c2ccccc2)nc2ccccc2c1C(=O)O
Product: CCCC1(c2ccccc2)CN=C(c2c(C)c(-c3ccccc3)nc3ccccc23)O1

Procedure:
Following essentially the procedure of Example 39, (3-methy-2-phenylquinolin-4-yl)carboxylic acid and 1-amino-2-phenyl-2-pentanol are converted to the titled compound.
Reaction SMILES: [F:1][C@H:2]1[C@H:6]([OH:7])[CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)=[O:9])[CH2:3]1.C(Cl)Cl.[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>CN(C1C=CN=CC=1)C.O>[F:1][C@H:2]1[C@H:6]([O:7][S:32]([C:29]2[CH:30]=[CH:31][C:26]([CH3:25])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)=[O:9])[CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(OCc1ccc2ccccc2c1)N1C[C@@H](O)[C@H](F)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CN(C(=O)OCc3ccc4ccccc4c3)C[C@H]2F)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 44.1 %

Procedure:
A flask was charged with (trans)-naphthalen-2-ylmethyl 3-fluoro-4-hydroxypyrrolidine-1-carboxylate (237 mg, 0.819 mmol), TEA (0.343 ml, 2.458mmol) and DMAP (10.0 mg, 0.082 mmol) in DCM (4.3 ml, 0.86 mmol). The reaction mixture was cooled to 0° C., and 4-methylbenzene-1-sulfonyl chloride (234 mg, 1.23 mmol) was added. The reaction was warmed to ambient temperature and stirred for 3 hours. The reaction was diluted with water and extracted with DCM. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography, eluting with 0-5% MeOH in DCM to give the product as an oil (160 mg, 44% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O=S(Cl)Cl.C(Cl)Cl>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:9](=[O:11])[CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:19][CH:18]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: Fc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cc1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-(4-fluorophenyl)acetic acid (5.0 g, 32.5 mmol, 1.00 equiv) in SOCl2 (30 mL) was heated for 3 hr at reflux in a 50-mL round-bottom flask. Most of SOCl2 was removed under vacuum, and the residue was added dropwise into a solution of AlCl3 (12.8 g, 96.2 mmol, 3.00 equiv) and fluorobenzene (6.1 g, 63.54 mmol, 2.00 equiv) in DCM (20 mL) at 0° C. The resulting solution was allowed to react, with stirring, for 2 hrs at room temperature.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[N:7]([CH2:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:8](=[O:23])[C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Br:22])=[CH:11][CH:10]=2)=[O:5].C(N(CC)CC)C.[C:38](OC(=O)C)(=[O:40])[CH3:39]>O1CCCC1>[CH3:2][O:3][C:4]([C:6]1[N:7]([CH2:24][CH:25]2[CH2:30][CH2:29][N:28]([C:38](=[O:40])[CH3:39])[CH2:27][CH2:26]2)[C:8](=[O:23])[C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Br:22])=[CH:11][CH:10]=2)=[O:5]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1CC1CCNCC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1CC1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36 %

Procedure:
To a solution of 6-bromo-1-oxo-4-phenyl-2-(piperidin-4-ylmethyl)-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester hydrochloride (49 mg) in tetrahydrofuran (5 ml) were added triethylamine (0.03 ml) and acetic anhydride (0.05 ml) and the mixture was stirred at room temperature for 16 hrs. The solvent was evaporated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by preparative HPLC to give the title compound (18 mg, 36%).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[O:16][NH:15][CH:14]([CH2:17][OH:18])[CH:13]=[C:12]2[CH3:19])=[CH:7][CH:6]=1)[CH3:3].C(N(CC)CC)C.[C:27]([NH:30][C:31]1[CH:40]=[CH:39][C:34]([S:35](Cl)(=[O:37])=[O:36])=[CH:33][CH:32]=1)(=[O:29])[CH3:28]>ClCCl>[C:27]([NH:30][C:31]1[CH:32]=[CH:33][C:34]([S:35]([N:15]2[CH:14]([CH2:17][OH:18])[CH:13]=[C:12]([CH3:19])[CH:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:2][CH3:3])=[CH:10][CH:9]=3)[O:16]2)(=[O:37])=[O:36])=[CH:39][CH:40]=1)(=[O:29])[CH3:28]
Reactant: CCOc1ccc(C2ONC(CO)C=C2C)cc1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1ccc(C2ON(S(=O)(=O)c3ccc(NC(C)=O)cc3)C(CO)C=C2C)cc1
Reaction time: 4 h

Procedure:
To a stirred solution of 3,6-dihydro-6-(4-ethoxyphenyl)-3-hydroxymethyl-5-methyl-2H-1,2-oxazine hydrochloride (1.31 g, 4.59 mmol) and triethylamine (1.34 ml, 9.63 mmol) in dichloromethane (50 ml) was added 4-N-acetylsulphanilyl chloride (1.07 g, 4.59 mmol). After 4 h at room temperature, the reaction mixture was washed twice with water and brine. The organic phase was dried over magnesium sulphate, filtered and evaporated to a foam, purified on flash silica eluting with ethylacetate to give 2-(4-acetamidobenzenesulphonyl)-3,6-dihydro-6-(4-ethoxyphenyl)-3-hydroxymethyl-5-methyl-2H-1,2-oxazine as a white foam. 1H NMR (CDCl3)δ 1.39(3H, t), 2.21(3H, s), 3.85(2H, m), 4.00(2H, q), 4.54(1H, m), 5.32(1H, s), 5.70(1H, m), 6.80(2H, d), 7.09(2H, d), 7.54(1H, bs) 7.63(2H, d), 7.85(2H, d).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([CH2:19][Br:21])=[CH:17][CH:18]=2)=[CH:9][CH:8]=1)=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-c2ccc(C(=O)OC(C)(C)C)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)c1ccc(-c2ccc(CBr)cc2)cc1
Temperature: 25 °C
Yield: 62.4 %

Procedure:
To a solution of tert-butyl-4-(4-tolyl)benzoate (32 g, 0.12 mol) in carbontetrachloride (500 mL) was added N-bromosuccinimide (23.3 g, 0.13 mol) and benzoyl peroxide (4.0 g). The reaction mixture was refluxed for 10 h. After cooling to RT, the reaction mixture was filtered. The filtrate was concentrated and the crude was recrystallised from petEther to give 4-(4-tert-butoxycarbonylphenyl)benzylbromide (26 g, 69%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:17]=1[C:18]([N:20]=[C:21]=[O:22])=[O:19]>C(OCC)(=O)C>[F:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:17]=1[C:18]([NH:20][C:21]([NH:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:2]([CH3:1])[N:7]=1)=[O:22])=[O:19]
Reactant: Cc1nc(N)ccc1-c1ccccc1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: CCOC(C)=O
Product: Cc1nc(NC(=O)NC(=O)c2c(F)cccc2F)ccc1-c1ccccc1

Procedure:
6-Methyl-5-phenyl-2-pyridylamine (500 mg) and 2,6-difluorobenzoyl isocyanate (650 mg) were reacted in 25 ml ethyl acetate. A precipitate formed which was filtered, dried, and identified as the desired product by NMR, m.p. 206°-208° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]=[O:11].[CH3:12][N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](=[O:22])[CH2:19][C:20]#[N:21].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:12][N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](=[O:22])[CH:19]([C:10](=[O:11])[NH:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8])[C:20]#[N:21]
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: Cn1cccc1C(=O)CC#N
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cn1cccc1C(=O)C(C#N)C(=O)Nc1c(Cl)cccc1Cl
Reaction time: 8 h

Procedure:
To the filtered solution of 4.4 g of 2,6-dichlorophenylisocyanate in 30 ml of toluene is added 2.5 g of 1-methyl-β-oxo-2-pyrrolpropionitrile and 2.1 g of triethylamine while stirring. The mixture is allowed to stand overnight at room temperature, whereupon it is filtered. The solids are washed with toluene and diethyl ether, taken up in 50 ml of methanol and the solution poured into the mixture of 6 ml of 5 N hydrochloric acid and 300 ml of water. The crystals formed are collected, washed with water, dried, triturated with ethanol, and recrystallized from methanol, to yield the 1-methyl-β-oxo-α-(2,6-dichlorophenylcarbamoyl)-2-pyrrolpropionitrile melting at 196°-199°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:14])=[C:4]([C:8]2([OH:13])[CH2:12][CH2:11][NH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:15]=O>C(O)=O>[Cl:1][C:2]1[C:3]([F:14])=[C:4]([C:8]2([OH:13])[CH2:12][CH2:11][N:10]([CH3:15])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OC1(c2cccc(Cl)c2F)CCNC1
Reactant: C=O
Solvent: O=CO
Product: CN1CCC(O)(c2cccc(Cl)c2F)C1

Procedure:
Preparation according to Example 26: 3-(3-chloro-2-fluorophenyl)-pyrrolidin-3-ol (0.6 g, 2.78 mmol), formic acid (8.1 mL), aqueous formaldehyde (40%, 7.2 mL). Purification by flash chromatography on silica gel (ethyl acetate/methanol, 2:8 to 3:8) and by HPLC on Waters OBD C18, 5 μm (MeOH/33 mM NH3, 20:80 to 100:0). Yield: 0.3 g. The amine was converted to the fumaric acid salt and evaporated to a solid residue: MS m/z (relative intensity, 70 eV) 229 (M+, 10), 157 (8), 129 (5), 58 (28), 57 (bp).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH:7]=[O:8].[Na+].[C:10]1([S:16]([O-:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CS(C)=O>[C:10]1([S:16]([C:2]2[N:3]=[CH:4][S:5][C:6]=2[CH:7]=[O:8])(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1scnc1Cl
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: CS(C)=O
Product: O=Cc1scnc1S(=O)(=O)c1ccccc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
A mixture of 4-chlorothiazole-5-carbaldehyde (0.15 g), benzenesulfinic acid sodium salt (0.25 g) and dimethyl sulfoxide (7.0 mL) was stirred at 100° C. for 30 minutes. The mixture was cooled to room temperature, poured onto ice/water (50 mL) and extracted with ethyl acetate. The combined organic extract was washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure to afford the title compound as a tan oil (0.23 g).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C@H:5]([NH2:22])[C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]2[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:8]=2[N:7]=1)[CH3:2].Cl[C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][N:28]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[CH2:1]([O:3][CH2:4][CH:5]([NH:22][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][NH:28]2)[C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]2[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:8]=2[N:7]=1)[CH3:2]
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: CCOC[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOCC(Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 90 °C
Yield: 22.3 %

Procedure:
A mixture of (R)-2-ethoxy-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine (510 mg, 1.7 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (410 mg, 1.7 mmol) and DIPEA (1.5 mL, 8.5 mmol) in n-butanol (6 mL) was heated at 90° C. for 18 h in a sealed vial. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford 200 as a white solid (158 mg, 22%). LCMS (Method K): RT 3.80 min [M+H]+ 418.1. 1H NMR (DMSO-d6, 400 MHz): δ 12.60 (1H, s), δ 8.22-8.05 (2H, m), 7.87 (1H, br s), 7.75-7.49 (6H, m), 7.11 (1H, td, J=9.32, 2.48 Hz), 6.89 (1H, dd, J=8.92, 2.50 Hz), 5.63 (1H, br s), 3.88 (2H, br d, J=6.76 Hz), 3.40-3.33 (2H, m), 1.01-0.91 (3H, m)
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[CH2:7][C:8]1([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[O:25])[CH:12]([CH3:13])[CH2:11][N:10]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>CCCCCC.C(O)C>[C:1]([O:5][C:6](=[O:36])[CH2:7][C@@:8]1([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[O:25])[C@H:12]([CH3:13])[CH2:11][N:10]([C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(COC(=O)C2(CC(=O)OC(C)(C)C)CN(C(=O)OCc3ccccc3)CC2C)cc1
Solvent: CCO
Solvent: CCCCCC
Product: COc1ccc(COC(=O)[C@@]2(CC(=O)OC(C)(C)C)CN(C(=O)OCc3ccccc3)C[C@H]2C)cc1
Yield: 40.5 %

Procedure:
1-Benzyl 3-(4-methoxyphenyl)methyl (3RS,4SR)-3-[2-(tert-butoxy)-2-oxoethyl]-4-methylpyrrolidine-1,3-dicarboxylate obtained in Example 2h (7.2 g, 14.5 mmol) was optically resolved repeatedly by HPLC(CHIRALPAK AD-H (2 cm diameter×25 cm), elution solvent: hexane/ethanol=85/15, flow rate: 8-10 ml/min.) to give a chiral form corresponding to the peak with a shorter retention time (2.92 g, yield: 40.5%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=O)[N:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH:5]2[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:34]2)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[S:34])[N:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH:5]2[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)CC1c2cc(C)c(C)cc2C(=O)N1c1cccnc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1c2cc(C)c(C)cc2C(=S)N1c1cccnc1
Yield: 167.6 %

Procedure:
5,6-Dimethyl-3-ethoxycarbonylmethyl-2-(3-pyridyl)-isoindolin-1-one [IUPAC name: ethyl 2-[5,6-dimethyl-3-oxo-2-(3-pyridinyl)-2,3-dihydro-1H-isoindol-1-yl]acetate] (0.10 g, 0.31 mmol) and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (69 mg, 0.17 mmol) were heated under reflux in toluene (1.5 ml) under an argon atmosphere for 1 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:acetone=10:1) to give 97 mg of the title compound.