Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[S:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30](O)=[O:31])=[CH:29][C:24]=2[N:23]=[CH:22]1>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:30]([C:28]3[CH:27]=[CH:26][C:25]4[S:21][CH:22]=[N:23][C:24]=4[CH:29]=3)=[O:31])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: O=C(O)c1ccc2scnc2c1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc2scnc2c1

Procedure:
Benzothiazole-5-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate D and benzothiazole-5-carboxylic acid. MS calcd. for C24H17ClN3O2S [(M+H)+] 446.1, obsd. 445.9.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=2)[CH:17]=[CH:16][N:15]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: FC(F)(F)c1ccc(Br)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: COc1cc(-c2ccc(C(F)(F)F)cn2)ccn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
2-Bromo-5-trifluoromethylpyridine (410 mg, 2.13 mmol), 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (500 mg, 1.81 mmol), K2CO3 (749 mg, 5.43 mmol) and PdCl2(dppf) (140 mg, 0.18 mmol) were stirred in DMSO (10 mL). The reaction mixture was degassed, then back-filled with N2. The reaction mixture was stirred at 80° C. in a pre-heated oil bath for 2 hours. After cooling, the reaction was quenched with water and extracted with CH2Cl2. The organic layer was washed with H2O and 5% LiCl, dried with Na2SO4, filtered and concentrated. Flash chromatography (silica gel, hexanes/EtOAc, 100:0 to 50:50) afforded the title compound title compound (337 mg, 62%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.96 (s, 1H), 8.31 (d, J=5.4 Hz, 1H), 8.04 (dd, J=8.3, 2.1 Hz, 1H), 7.87 (d, J=8.3 Hz, 1H), 7.51 (dd, J=5.4, 1.4 Hz, 1H), 7.36 (s, 1H), 3.52 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:11]=[C:12]([NH2:19])[CH:13]=[C:14]2[C:18]=1[NH:17][N:16]=[CH:15]2.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:19][C:12]2[CH:13]=[C:14]3[C:18](=[C:10]([CH3:9])[CH:11]=2)[NH:17][N:16]=[CH:15]3)[CH:7]=1
Reactant: Cc1cc(N)cc2cn[nH]c12
Reactant: Clc1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Nc2cc(Cl)ncn2)cc2cn[nH]c12
Temperature: 25 °C

Procedure:
500 mg (3.40 mmol) 4,6-dichloropyrimidine, 500 mg (3.40 mmol) 7-methyl-1H-indazol-5-ylamine and 1.30 mL (7.60 mmol) DIPEA were combined in 5.0 mL DMF and refluxed for 5 h. The reaction mixture was cooled to RT and evaporated down i.vac. The residue was taken up in EtOAc and extracted several times with saturated sodium chloride solution. The organic phases were combined, dried on magnesium sulphate, filtered and evaporated down. The residue was stirred with DIPE, suction filtered and dried i. vac.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH3:16])=[CH:10][C:11]([O:13]CC)=O)=[CH:4][CH:3]=1.OS(O)(=O)=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:8]=[C:9]([CH3:16])[CH:10]=[C:11]2[OH:13])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C=C(C)Cc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Product: Cc1cc(O)c2cc(Br)ccc2c1
Temperature: 50 °C

Procedure:
A flask containing the crude ethyl 4-(4-bromophenyl)-3-methylbut-2-enoate from above (˜30 grams) was treated with concentrated H2SO4 (120 mL) and warmed to 50° C. for 2.5 h. The reaction was poured onto ˜500 mL of crushed ice. Once the ice had thawed, the brown suspension was extracted with two portions of EtOAc (500 mL and 100 mL, respectively). The two extracts were combined, washed with saturated NaHCO3, dried (MgSO4), filtered, and concentrated to ˜55 mL. The residue was treated with DCM and loaded onto a silica gel column and purified by flash chromatography (ethyl acetate/hexanes) giving the desired product. 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J=1.9 Hz, 1H), 7.57 (d, J=8.6 Hz, 1H), 7.50 (dd, J=8.6, 2.0 Hz, 1H), 7.17 (s, 1H), 6.67 (s, 1H), 2.42 (s, 3H).
Reaction SMILES: N#N.[N+:3]([C:6]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=[O:9])([O-:5])=[O:4].[N+:16]([CH2:19][CH3:20])([O-:18])=[O:17].[F-].[K+]>O.C(O)(C)C>[N+:3]([C:6]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]([OH:9])[CH:19]([N+:16]([O-:18])=[O:17])[CH3:20])([O-:5])=[O:4]
Reactant: COc1cccc(C=O)c1[N+](=O)[O-]
Reactant: CC[N+](=O)[O-]
Agent: N#N
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: COc1cccc(C(O)C(C)[N+](=O)[O-])c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
To a 2 L round-bottomed flask equipped with a magnetic stirrer and a N2 bubbler were added 2-nitro-3-methoxybenzaldehyde (125.7 g, 0.6939 mol), nitroethane (73 g, 0.97 mol), 18-C-6 (18 g), isopropanol (420 mL) and KF (20 g). The mixture was stirred at RT for 16 h. The solvent was removed under vacuum to give an oil. Isopropanol (100 mL) and water (250 mL) were added. The mixture was placed under vacuum to give a slurry. The slurry was stirred for 1 h and filtered. The cake was washed with water (4×100 mL) and dried to give 1-(2-nitro-3-methoxyphenyl)-2-nitropropanol as a diastereomeric mixture in a ratio of 3:2 (170.3 g, 96% yield). 1H NMR for major isomer (CDCl3) δ1.38 (d, J=6.9 Hz, 3H), 2.94 (s, 1H), 3.92 (s, 3H), 4.90 (m, 1H), 5.08 (d, J=8.6 Hz, 1H), 7.05-7.52 (m, 3H). 1H NMR for minor isomer (CDCl3) δ1.55 (d, J=6.9 Hz, 3H), 2.94 (s, 1H), 4.80 (m, 1H), 5.46 (d, J=3.0 Hz), 7.05-7.52 (m, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([NH:10][C:11]2[CH:26]=[CH:25][C:14]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18](C(N)=O)[CH:17]=3)=[CH:13][CH:12]=2)=[O:9])[C:4](=[O:27])[N:3]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.CCOC(C)=O.CC#[N:57].O>>[NH2:57][C:18]1[CH:17]=[C:16]([O:15][C:14]2[CH:25]=[CH:26][C:11]([NH:10][C:8]([C:5]3[C:4](=[O:27])[N:3]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:2]([CH3:1])[C:6]=3[CH3:7])=[O:9])=[CH:12][CH:13]=2)[CH:21]=[CH:20][N:19]=1
Reactant: CC#N
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3)cc2)c(=O)n(-c2ccccc2)n1C
Solvent: O
Solvent: Ic1ccccc1
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)cc2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
To a solution of 4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)phenoxy)picolinamid (1.773 g, 3.998 mmol) in EtOAc/MeCN/H2O (20 mL/20 mL/10 mL) was added iodobenzene diacetate (1.6 g, 4.96 mmol) at 0° C. The reaction was stirred at rt overnight, then concentrated in vacuo and diluted with EtOAc (100 mL). The mixture was washed with saturated aq. NaHCO3 (60 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (v/v)=30/1) to give the title compound as a yellow solid (799 mg, 48%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH:4]=[N:5][O:6][CH2:7][C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=[O:10].S(=O)(=O)(O)O.[CH3:23]O>>[Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH:4]=[N:5][O:6][CH2:7][C:8]([CH3:13])([CH3:12])[C:9]([O:11][CH3:23])=[O:10]
Reactant: CO
Reactant: CC(C)(CON=Cc1ccccc1Cl)C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)(C)CON=Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 2-(2-chlorobenzylideneaminooxymethyl)-2-methylpropanoic acid (31.6 grams; 0.12 mole) and concentrated sulfuric acid (2 mL) in methanol (100 mL) was heated at reflux for two hours and then stirred for 48 hours at ambient temperature. The reaction mixture was then heated for an additional four hours. The reaction mixture was concentrated under reduced pressure. Water (30 mL) and methylene chloride (30 mL) were added to the residue. The mixture was then neutralized with aqueous sodium carbonate and extracted with methylene chloride. The dried (magnesium sulfate) extract was concentrated under reduced pressure to yield 27.0 grams of methyl 2-(2-chlorobenzylideneaminooxymethyl)-2-methylpropanoate.
Reaction SMILES: [N:1]([CH2:4][C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=1[O-])([F:7])[F:6])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH2:34]>C1COCC1>[F:6][C:5]([F:7])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH2:4][NH2:1]=[O:34]
Reactant: [N-]=[N+]=NCC(F)(F)c1cccc[n+]1[O-]
Reactant: O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: [O-][NH2+]CC(F)(F)c1ccccn1
Reaction time: 1 h
Yield: 96 %

Procedure:
To the solution of 2-(2-azido-1,1-difluoro-ethyl)-pyridine N-oxide (example 60a, 2.7 g, 13.5 mmol) in THF (40 mL) was slowly added triphenylphosphine (3.9 g, 14.9 mmol) at 0° C. After stirred for 1 h, water (5 mL) was added. The reaction mixture was stirred at 55° C. for 2 h and at room temperature for 12 h. After removal of solvent, the crude was puried by flash chromatography (Merck Silica gel 60, 70-230 mesh, 0%-20% methanol in methylene chloride in 30 min) to give 2,2-difluoro-2-pyridin-2-yl-ethylamine N-oxide (2.2 g, 96%) as a white solid. LC-MS m/e 175 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:11]([O:13][CH:14]([O:17][CH2:18][CH3:19])[CH2:15]Br)[CH3:12]>CN(C)C=O.C(OCC)C>[CH2:11]([O:13][CH:14]([O:17][CH2:18][CH3:19])[CH2:15][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[CH3:12]
Reactant: Oc1cccc(Br)c1
Reactant: CCOC(CBr)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(COc1cccc(Br)c1)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.7 %

Procedure:
A solution of 10 gm (57.8 mMol) 3-bromophenol in 25 mL dimethylformamide was added dropwise to a mixture of 2.8 gm (70 mMol) sodium hydride (60% suspension in mineral oil) in 30 mL dimethylformamide. The reaction mixture was stirred for one hour after the addition was complete. To the reaction mixture was then added 9.7 mL (64.5 mMol) bromoacetaldehyde diethyl acetal and the resulting mixture was stirred at 153° C. for 2 hours. The reaction mixture was then allowed to cool to room temperature and was diluted with 300 mL diethyl ether. This mixture was then washed with two 150 ml portions of water, washed with 50 mL saturated aqueous sodium chloride, dried over magesium sulfate and concentrated under reduced pressure to provide about 17 gm of the desired compound.
Reaction SMILES: Br[CH:2]([CH3:16])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11](=[O:13])[N:10]([CH3:14])[C:9]=2[CH:15]=1)=O.[NH2:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=1>>[CH3:16][C:2]1[N:19]2[CH:20]=[CH:21][C:22]([CH3:24])=[CH:23][C:18]2=[N:17][C:3]=1[C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11](=[O:13])[N:10]([CH3:14])[C:9]=2[CH:15]=1
Reactant: CC(Br)C(=O)c1ccc2oc(=O)n(C)c2c1
Reactant: Cc1ccnc(N)c1
Product: Cc1ccn2c(C)c(-c3ccc4oc(=O)n(C)c4c3)nc2c1
Yield: 46 %

Procedure:
5-(3,7-Dimethylimidazo[1,2-a]pyridin-2-yl)-3-methyl-2-benzoxazolinone (1.35 g) was prepared in the substantially same manner as that of Example 4 from 5-(2-bromopropionyl)-3-methyl-2-benzoxazolinone (2.84 g) and 2-amino-4-methylpyridine (3.24 g).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][C@H:6]([N:8]([C:13]([C:15]2[C:16]([NH:25][CH2:26][C:27]3[O:28][CH:29]=[CH:30][CH:31]=3)=[N:17][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[N:19][CH:20]=2)=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:5][N:4]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:3]1.C(N(CC)CC)C.[C:46](OC(=O)C)(=[O:48])[CH3:47].Cl>ClCCCl>[C:46]([NH:1][C@@H:2]1[CH2:7][C@H:6]([N:8]([C:13]([C:15]2[C:16]([NH:25][CH2:26][C:27]3[O:28][CH:29]=[CH:30][CH:31]=3)=[N:17][C:18]([C:21]([CH3:24])([CH3:22])[CH3:23])=[N:19][CH:20]=2)=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:5][N:4]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[CH2:3]1)(=[O:48])[CH3:47]
Reactant: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@H]1C[C@@H](N)CN(C(=O)OC(C)(C)C)C1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(=O)N[C@@H]1C[C@H](N(CC(C)C)C(=O)c2cnc(C(C)(C)C)nc2NCc2ccco2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (3R,5S)-3-amino-5-[({2-tert-butyl-4-[(furan-2-ylmethyl)amino]pyrimidin-5-yl}carbonyl)(2-methylpropyl)amino]piperidine-1-carboxylate (70 mg) in 1,2-dichloroethane (3 ml) were successively added triethylamine (55 μl) and acetic anhydride (35 μl), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was acidified with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane-methanol (50:50:0-85:0:15) was concentrated under reduced pressure to give the object compound (28.5 mg).
Reaction SMILES: C([O:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6])(=O)C.[OH-].[Na+]>P([O-])([O-])([O-])=O>[C:7]1([C@@H:5]([OH:4])[CH3:6])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(=O)OC(C)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: C[C@H](O)c1ccccc1

Procedure:
For the preparative resolution, racemic 1-phenylethyl acetate (50 mmol/l) in 10 mmol/l phosphate buffer pH 7.0 is incubated at 30° C. with the esterase according to the invention (1 unit esterase per 1 mmol ester) that was isolated according to example 1. The pH value is kept constant during the reaction by means of an automatic burette which titrates 0.1 mol/l NaOH. The reaction course is monitored by the consumption of sodium hydroxide. The enantiomeric excess of the product 1-phenylethanol as well as of the substrate 1-phenylethyl acetate is determined by HPLC on a chiral column (Chiracel OJ, Daicel Company). Once a 50% conversion is achieved, the enantiomeric excess of the retained substrate (R)-1-phenylethyl acetate is 96% and that of the product (S)-1-phenylethanol is 94% (enantioselectivity E>100). The reaction is terminated by extracting several fold with ethyl acetate. The organic phases are pooled and concentrated by evaporating the solvent. The (S)-1-phenylethanol obtained is separated from non-converted (R)-1-phenylethyl acetate by chromatography on silica gel.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.[H-].[Na+].Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21].O>CN(C=O)C>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:19]=1[C:20](=[O:21])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)n1c(C(=O)c2ccccc2)c(N)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
To a solution of 4-chloro-2-(ethoxycarbonylamino)benzonitrile (10.8 g) in DMF (50 ml) cooled to 0° C. was added sodium hydride (60% w/w dispersion in mineral oil, 2.0 g, 50 mmol). The mixture was stirred for 30 min at 0° C. and then 2-bromoacetophenone (9.9 g, 50 mmol) was carefully added. After stirring for an additional 15 h at 0° C., the mixture was poured into water (500 ml) and extracted with diethyl ether (500 ml×2). After drying (MgSO4) and removal of solvent, the crude product was purified by flash chromatography eluting with ethyl acetate/hexane (1:5) to afford 11.8 g (72%) of the title compound as a brown amorphous solid.
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:19][C:20]3[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=3)=[C:15](Br)[CH:16]=[N:17][C:10]=2[N:9]([CH3:30])[C:8]1=[O:31])=O.[Cl:32][C:33]1[CH:34]=[C:35]([OH:39])[CH:36]=[CH:37][CH:38]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C)CC(O)=O>O1CCOCC1.[Cu]I>[Cl:32][C:33]1[CH:34]=[C:35]([CH:36]=[CH:37][CH:38]=1)[O:39][C:15]1[CH:16]=[N:17][C:10]2[N:9]([CH3:30])[C:8](=[O:31])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:12](=[O:13])[C:11]=2[C:14]=1[CH2:19][C:20]1[CH:21]=[N:22][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:25]=1
Reactant: Cn1c(=O)n(CCCOC=O)c(=O)c2c(Cc3ccc(C(F)(F)F)nc3)c(Br)cnc21
Reactant: Oc1cccc(Cl)c1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cn1c(=O)n(CCCO)c(=O)c2c(Cc3ccc(C(F)(F)F)nc3)c(Oc3cccc(Cl)c3)cnc21
Temperature: 25 °C
Yield: 12.5 %

Procedure:
To a mixture of 3-(6-bromo-1-methyl-2,4-dioxo-5-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (40 mg, 0.08 mmol) and 3-chlorophenol (26 mg, 0.2 mmol) in dioxane (2 mL) was added Cs2CO3 (78 mg, 0.24 mmol), 2-(dimethylamino)acetic acid (4.1 mg, 0.04 mmol) and CuI (1.9 mg, 0.01 mmol). The reaction was degassed with nitrogen (3×), heated at 130° C. (MW) for 1.5 h, cooled to RT, diluted with water (10 mL) then extracted with EA (2×10 mL). The combined organic layers were dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 6-(3-chlorophenoxy)-3-(3-hydroxypropyl)-1-methyl-5-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (5.2 mg, 12.5% yield) as a white solid. 1H NMR (CDCl3) δ: 8.66 (s, 1H), 8.39 (s, 1H), 7.79 (d, J=7.2 Hz, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.30-7.25 (overlap with CDCl3, 1H), 7.12 (dd, J=8.0, 0.8 Hz, 1H), 6.87-6.79 (m, 2H), 4.81 (s, 2H), 4.23 (t, J=6.4 Hz, 2H), 3.72 (s, 3H), 3.55-3.58 (m, 2H), 2.95 (brd s, 1H), 1.95-1.90 (m, 2H). LCMS: MH+ 521 and TR=3.068 min.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([C:26]#[N:27])[C:17]2=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=1)=[O:7].C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:36][OH:37]>C(O)C>[CH3:1][N:2]([CH3:28])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([C:26](=[NH:27])[NH:36][OH:37])[C:17]2=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: CN(C)CCNC(=O)c1cccc2nc3ccc4c(C#N)cccc4c3nc12
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CN(C)CCNC(=O)c1cccc2nc3ccc4c(C(=N)NO)cccc4c3nc12
Yield: 91.8 %

Procedure:
A mixture of 4-cyano-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide (20 mg), potassium carbonate (37 mg) and hydroxylamine hydrochloride (19 mg) was heated to reflux in ethanol (5 mL) for 18 hours. The reaction mixture was filtered, and the filtrate was collected and the solvent removed in vacuo to yield the title compound (20 mg).
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][C:16]=4[CH:6]2[CH2:5][CH:4]([C:18]([OH:20])=[O:19])[CH2:3]1)[NH:11][CH:10]=3.[OH-].[K+].CN(C=O)C.[C:28]1(C)[CH:33]=[CH:32]C(S(OC(CC)CC)(=O)=O)=[CH:30][CH:29]=1>O>[CH2:29]([CH:28]([N:11]1[C:12]2[C:17]3[C:9]([CH2:8][C@@H:7]4[C@@H:6]([C:16]=3[CH:15]=[CH:14][CH:13]=2)[CH2:5][CH:4]([C:18]([OH:20])=[O:19])[CH2:3][N:2]4[CH3:1])=[CH:10]1)[CH2:33][CH3:32])[CH3:30]
Reactant: CCC(CC)OS(=O)(=O)c1ccc(C)cc1
Reactant: CN1CC(C(=O)O)CC2c3cccc4[nH]cc(c34)CC21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)n1cc2c3c(cccc31)[C@H]1CC(C(=O)O)CN(C)[C@@H]1C2
Yield: 57 %

Procedure:
To a 50 ml, three-neck round bottom flask was added 1.0 g (3.4 mmol) of 92% pure 9,10-dihydrolysergic acid, 1.03 g (15.8 mmol) of 86% pure powdered potassium hydroxide and 15 ml of DMF. This mixture was agitated until the solids were dissolved, and 1.79 g (7.4 mmol) of p-toluenesulfonic acid, 1-ethylpropyl ester was added. The reaction mixture was stirred for 19 hours at room temperature, and 35 ml of water was added. The reaction mixture was washed into a 250 ml erlenmeyer flask with deionized water, and the mixture was washed with 50 ml of methylene chloride. The aqueous layer was separated, saturated with an aqueous sodium chloride solution and washed with methylene chloride. The emulsified aqueous layer and the second organic layer were combined and the pH was adjusted to 6. The organic layer was separated and filtered by vacuum filtration. The resulting solid was washed with methylene chloride and dried in vacuo to provide 0.66 g of the title compound. The purity of the solid was 96.8% as determined by high performance liquid chromatography (HPLC). mp =187° -189° C. Exact mass: theory 341.22290; found 341.22261.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:21])[N:5]([CH:12]1[CH2:17][CH:16]([OH:18])[C:15](=[O:19])[NH:14][C:13]1=[O:20])[C:6]2=[O:11].[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH:27]=O.[BH4-].[Na+]>C(O)(=O)C>[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27][NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:21])[N:5]([CH:12]1[CH2:17][CH:16]([OH:18])[C:15](=[O:19])[NH:14][C:13]1=[O:20])[C:6]2=[O:11]
Reactant: O=Cc1ccco1
Reactant: Nc1cccc2c1C(=O)N(C1CC(O)C(=O)NC1=O)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=O)C(N2C(=O)c3cccc(NCc4ccco4)c3C2=O)CC1O

Procedure:
A solution of 3-(4-amino-1,3-dioxoisoindolin-2-yl)-5-hydroxypiperidine-2,6-dione (0.82 g, 3.0 mmol) and 2-furaldehyde (0.34 g, 3.5 mmol) in acetic acid (10 mL) is heated at reflux for 4 hours. To the mixture is added sodium borohydride (130 mg, 3.5 mmol) at room temperature and this mixture is maintained for 18 hours. The mixture is worked up to give 3-(4-fur-2-ylmethylamino-1,3-dioxoisoindolin-2-yl)-5-hydroxypiperidine-2,6-dione which is further purified by column chromatography.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@:9]2([CH3:21])[C:13](=[O:14])[N:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:11](=[O:20])[NH:10]2)=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].[CH3:24]I>CN(C)C=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@:9]2([CH3:21])[C:13](=[O:14])[N:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:11](=[O:20])[N:10]2[CH3:24])=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)CN1C(=O)N[C@@](C)(c2ccc(C#N)cc2)C1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)N(C)[C@@](C)(c2ccc(C#N)cc2)C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3 g of methyl (S)-(4-(4-cyanophenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetate (10.4 mmol) were dissolved in 15 ml of anhydrous dimethylformamide under argon. 11.4 mmol of sodium hydride in the form of a dispersion in mineral oil were added in an argon countercurrent. The reaction mixture was stirred at room temperature for 15 minutes. It was then treated with 721 μl of methyl iodide (11.4 mmol). The mixture was stirred at room temperature for 4 hours and then allowed to stand at room temperature overnight. The solution was concentrated. For purification, the substance was chromatographed on silica gel using methylene chloride/ethyl acetate (9.5:0.5). The fractions containing the pure substance were concentrated.
Reaction SMILES: Br.Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH2:14])[S:12][CH:13]=2)=[CH:5][CH:4]=1.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[CH:26]=2)=[O:24])=[CH:18][C:17]=1B1OC(C)(C)C(C)(C)O1>>[NH2:14][C:11]1[S:12][CH:13]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:17]3[C:16]([CH3:15])=[CH:21][CH:20]=[C:19]([NH:22][C:23]([C:25]4[CH:30]=[CH:29][N:28]=[C:27]([N:31]5[CH2:32][CH2:33][CH2:34][CH2:35]5)[CH:26]=4)=[O:24])[CH:18]=3)=[CH:4][CH:5]=2)[N:10]=1
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Nc1nc(-c2ccc(Br)cc2)cs1
Agent: Br
Product: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1-c1ccc(-c2csc(N)n2)cc1

Procedure:
Example 9 was prepared using using 4-(4-bromophenyl)-2-thiazolamine monohydrobromide and N-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)phenyl]-2-(1-pyrrolidinyl)-4-pyridinecarboxamide (Intermediate 20).