Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][S:11]([C:14]2[S:15][C:16]([Cl:19])=[CH:17][CH:18]=2)(=[O:13])=[O:12])=[O:9])=[CH:4][CH:3]=1.[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12>CN(C=O)C>[O:24]=[C:23]1[C:22]2[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=2[C:20](=[O:25])[N:1]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][S:11]([C:14]2[S:15][C:16]([Cl:19])=[CH:17][CH:18]=2)(=[O:13])=[O:12])=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(=O)NS(=O)(=O)c2ccc(Cl)s2)cc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CN(C)C=O
Product: O=C(NS(=O)(=O)c1ccc(Cl)s1)c1ccc(N2C(=O)c3ccccc3C2=O)cc1
Temperature: 110 °C
Yield: 55 %

Procedure:
A 22 mg portion (0.070) of (4-aminophenyl)-N-[(5-chloro(2-thienyl))sulfonyl]carboxamide was combined with 15 mg (0.10 mmol) of phthalic anhydride in 140 μL of DMF. After 18 h of heating at 110° C., the mixture was cooled and purified by RP-HPLC, to give 20 mg (55%) of the desired compound. ES-MS (M+H)+=447 (Cl).
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[C:10]2=[CH:11][C:12]3[N:13]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:14]4[C:19]([C:20]=3[CH:21]=[C:9]2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:18][C:17](B1OC(C)(C)C(C)(C)O1)=[CH:16][CH:15]=4.Br[C:40]1[CH:41]=[C:42]([C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([C:52]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[O:53])[CH:47]=2)[CH:43]=[CH:44][CH:45]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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>[C:52]([C:48]1[CH:47]=[C:46]([C:42]2[CH:43]=[CH:44][CH:45]=[C:40]([C:17]3[CH:18]=[C:19]4[C:14](=[CH:15][CH:16]=3)[N:13]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])[C:12]3[CH:11]=[C:10]5[C:2]([CH3:1])([CH3:38])[C:3]6[C:8]([C:9]5=[CH:21][C:20]4=3)=[CH:7][CH:6]=[CH:5][CH:4]=6)[CH:41]=2)[CH:51]=[CH:50][CH:49]=1)(=[O:53])[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: O=C(c1ccccc1)c1cccc(-c2cccc(Br)c2)c1
Reactant: CC(C)(C)OC(=O)n1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2c2cc3c(cc21)C(C)(C)c1ccccc1-3
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: [Na+]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)n1c2ccc(-c3cccc(-c4cccc(C(=O)c5ccccc5)c4)c3)cc2c2cc3c(cc21)C(C)(C)c1ccccc1-3

Procedure:
16.8 g (33.0 mmol) of tert-butyl 12,12-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-12H-10-azaindeno[2,1-b]fluorene-10-carboxylate, 13.4 g (40 mmol) of (3′-bromobiphenyl-3-yl)phenylmethanone and 11.6 g of sodium carbonate are suspended in 900 ml of dioxane, 900 ml of toluene and 400 ml of water. 4.2 g (3.6 mmol) of Pd(PPh3)4 are added to this suspension. The reaction mixture is heated under reflux for 7 h. After cooling, the precipitated solid is filtered off with suction and washed with water and ethanol and dried. The residue is extracted with hot toluene and recrystallised from toluene. Yield: 14.7 g (23 mmol), 70% of theory.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][CH:3]=1.[CH:11]([N:14](CC)C(C)C)(C)[CH3:12].BrCC#N>C(#N)C.C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH:8][CH2:12][C:11]#[N:14])=[CH:4][CH:3]=1
Reactant: NCCc1ccc(F)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: N#CCBr
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#CCNCCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a solution of 4-fluorophenethylamine (1.4 g) in acetonitrile (20 mL) was added dropwise N,N-diisopropylethylamine (2.6 mL) and bromoacetonitrile (0.84 mL). After stirring at room temperature for 50 minutes, the solution was diluted with ethyl acetate, the solution was washed with water, then with saturated sodium chloride water. After drying with anhydrous sodium sulfate, the solvent was removed by evaporation to provide the title compound (2.12 g) as a yellow oily substance.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([OH:10])=[O:9])[C:5](=[S:18])[NH:4][CH2:3]1.[O:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[S:31][C:30]([CH:32]=O)=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)[CH3:20].NCCC(O)=O.CO.C(Cl)Cl>C(O)(=O)C>[CH3:20][O:19][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[S:31][C:30]([CH:32]=[C:3]3[C:2](=[O:1])[N:6]([CH:7]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([OH:10])=[O:9])[C:5](=[S:18])[NH:4]3)=[CH:29][CH:28]=2)=[CH:25][CH:26]=1
Reactant: COc1ccc(-c2ccc(C=O)s2)cc1
Reactant: O=C(O)C(Cc1ccccc1)N1C(=O)CNC1=S
Agent: NCCC(=O)O
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(-c2ccc(C=C3NC(=S)N(C(Cc4ccccc4)C(=O)O)C3=O)s2)cc1
Temperature: 170 °C

Procedure:
To a mixture of 2-(5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid (0.080 g, 0.303 mmol) and 5-(4-methoxylphenyl)thiophene-2-carbaldehyde (0.066 g, 0.303 mmol) in acetic acid 5 mL is added β-alanine (2.69 mg, 0.030 mmol) and heat to 170° C. for 30 min under microwave irradiation. The resulting reaction mixture is cooled down and the solvent is removed. The pure product (0.075 g, 0.162 mmol, red solid) is obtained by column chromatography using MeOH/DCM, 2-7% ration solvent system. 1H-NMR (CD3OD/300 MHz): 7.62 (m, 2H), 7.45 (m, 1H), 7.33 (m, 5H), 7.27 (d, J=13.2 Hz, 1H), 6.94 (d, J=6.9 Hz, 2H), 6.70 (s, 1H), 5.50 (m, 1H), 3.82 (s, 3H), 3.53 (m, 2H). MS (ES+, m/z): 465.1 (M++1, 20.0).
Reaction SMILES: [NH2:1][C:2]([CH3:19])([CH2:5][N:6]1[C:14]([O:15][CH2:16][CH3:17])=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([Cl:18])=[CH:12]2)=[N:7]1)[C:3]#[N:4].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[S:27])=[CH:24][CH:23]=1>>[Cl:18][C:11]1[CH:10]=[CH:9][C:8]2[C:13](=[C:14]([O:15][CH2:16][CH3:17])[N:6]([CH2:5][C:2]([NH:1][C:26](=[S:27])[C:25]3[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:31])[F:32])=[CH:30][CH:29]=3)([C:3]#[N:4])[CH3:19])[N:7]=2)[CH:12]=1
Reactant: CCOc1c2cc(Cl)ccc2nn1CC(C)(N)C#N
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: CCOc1c2cc(Cl)ccc2nn1CC(C)(C#N)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(5-chloro-3-ethoxy-2H-indazol-2-yl)-2-methylpropionitrile (52 mg, described in Example 109) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (83 mg, 93%). MS (ES): M/Z [M+H]=483. 1H NMR: (400 MHz, DMSO-d6): 1.26 (t, J=7.0 Hz, 3H), 1.71 (s, 3H), 4.52 (q, J=7.0 Hz, 2H), 4.78 (d, 1H), 4.93 (d, 1H), 7.16 (dd, J=9.3, 1.9 Hz, 1H), 7.47 (d, J=9.3 Hz, 1H), 7.85-7.89 (m, 3H), 7.96 (d, J=8.8 Hz, 2H) and 8.99 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −42.0 (s, 3F).
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:23]=1[C:24](Cl)=[O:25]>ClCCl>[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:23]=1[C:24]([N:6]1[CH:7]=[C:2]([F:1])[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]1=[O:8])=[O:25]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: CN(C)C=Nc1nc(O)ncc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C=Nc1nc(=O)n(C(=O)c2c(Cl)cccc2Cl)cc1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To an 8 mL screw-cap vial were added dichloromethane (CH2Cl2; 4 mL), N′-(5-fluoro-2-hydroxy-pyrimidin-4-yl)-N,N-dimethylformamidine (100 mg, 0.54 mmol), and triethylamine (Et3N; 120 mg, 1.2 mmol). To this mixture was added 2,6-dichlorobenzoyl chloride (113 mg, 0.54 mmol), and the resulting mixture was shaken at room temperature for 24 h. After evaporation to dryness, the residue was taken up in N,N-dimethylformamide (DMF; 2 mL), filtered, and placed directly onto a reverse phase chromatography column. After elution, the title compound was isolated as a pale yellow solid (75 mg, 39%): mp 185-187° C.; 1H NMR (300 MHz, CDCl3) δ 8.80 (s, 1H), 8.20 (d, J=5.6 Hz, 1H), 7.31-7.20 (m, 3H), 3.23 (s, 3H), 3.21 (s, 3H); ESIMS m/z 357 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([OH:16])[C:8]2[O:9][C:10]([F:13])([F:12])[O:11][C:7]=2[CH:6]=1)=[O:4].Br[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][CH2:18][CH2:19][C:20]2[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=2)[C:8]2[O:9][C:10]([F:13])([F:12])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(O)c2c(c1)OC(F)(F)O2
Reactant: Cc1cccc(CCBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCCc2cccc(C)c2)c2c(c1)OC(F)(F)O2
Temperature: 80 °C
Reaction time: 3 h
Yield: 88.4 %

Procedure:
1.8 g of 2,2-difluoro-7-hydroxy-benzo[1,3]dioxole-5-carboxylic acid methyl ester, 4.6 g of 1-(bromo-ethyl)-3-methyl-benzene, and 3.2 g of K2CO3 were added to 70 ml of anhydrous DMF and the reaction mixture stirred at 80° C. for 3 h. The reaction mixture was then allowed to cool to room temperature, 300 ml of water added and extracted three times using 100 ml of EA each. The organic layer was then dried using MgSO4 and evaporated. Chromatography on silica gel using EA/HEP 1:4 yielded 2.4 g of the title compound, colorless oil. Rf (EA/HEP 1:4)=0.32
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([NH2:11])[CH:8]=[C:4]([C:5]([O-:7])=O)[C:3]=1[C:12]([O-:14])=[O:13].[Na+].[Na+].[CH3:17][C:18]1=[C:19]([CH3:25])[C:20]([O:22][C:23]1=[O:24])=O>O.C1(C)C=CC=CC=1>[CH3:25][C:19]1[C:20](=[O:22])[N:1]([C:2]2[CH:10]=[C:9]([N:11]3[C:5](=[O:7])[C:4]([CH3:8])=[C:3]([CH3:2])[C:12]3=[O:13])[CH:8]=[C:4]3[C:5]([O:14][C:12](=[O:13])[C:3]=23)=[O:7])[C:23](=[O:24])[C:18]=1[CH3:17]
Reactant: CC1=C(C)C(=O)OC1=O
Reactant: Nc1cc(N)c(C(=O)[O-])c(C(=O)[O-])c1
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1=C(C)C(=O)N(c2cc3c(c(N4C(=O)C(C)=C(C)C4=O)c2)C(=O)OC3=O)C1=O
Temperature: 100 °C
Yield: 115.7 %

Procedure:
7.20 g (0.039 mol) of disodium 3,5-diaminophthalate, dissolved in 200 ml of water, are added to a solution of 8.82 g (0.078 mol) of dimethylmaleic anhydride in 80 ml of toluene. This mixture is boiled under reflux for 1 hour. It is then evaporated to dryness in a rotary evaporator, the residue is dissolved, at 90° C, in 100 ml of N,N-dimethylacetamide and 50 ml of water and the solution is rendered acid to Congo Blue with 10% strength hydrochloric acid. After cooling, the slurry-like mixture is filtered and the residue is rinsed with acetone and then dried in vacuo at 80° C. The dry residue is then suspended in 100 ml of acetic anhydride and this mixture is warmed to about 100° C for 1 hour. It is then evaporated to dryness and the residue is recrystallised from 1,2-dichlorobenzene. 8.9 g (69% of theory) of 3,5-bis-(dimethylmaleimidyl)-phthalic anhydride are obtained; colour; light brownish; melting point 298° C (decomposition). H1NMR: (DMSO-d6, TMS = O) 2H (aromatic) 7.94 and 7.98 ppm, 12H (methyl protons 1.98 ppm). Analysis for C20H14N2O7 (molecular weight 394.12): calculated: C 60.92%; H 3.58%; N 7.11%. found: C 60.67%; H 4.44%; N 7.32%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[OH:10].[C:11]([OH:17])(=[O:16])[CH2:12][C:13]([OH:15])=O.O=P(Cl)(Cl)Cl.O>CCOCC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[O:10][C:13](=[O:15])[CH2:12][C:11]([O:17][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][C:4]=1[Cl:9])=[O:16]
Reactant: Oc1c(Cl)cc(Cl)cc1Cl
Reactant: O=C(O)CC(=O)O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: O=C(CC(=O)Oc1c(Cl)cc(Cl)cc1Cl)Oc1c(Cl)cc(Cl)cc1Cl

Procedure:
A mixture of 2,4,6-trichloro-phenol (157.6 g, 0.8 mol), malonic acid (52 g, 0.5 mol), and POCl3 (98 mL, 1.05 mol) is heated at reflux for 4 hours. The reaction mixture is cooled slightly and poured into a mixture of ice, water, and ether with stirring. The solid is collected by filtration and dried in vacuo to give malonic acid bis(2,4,6-trichloro-phenyl)ester.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[C:16]([O:17][CH3:18])=[C:15]([O:19][CH3:20])[C:14]([O:21][CH3:22])=[C:13]([CH3:23])[C:10]=1[CH:11]=[O:12].Cl>C(OCC)C.O>[CH3:7][O:8][C:9]1[C:16]([O:17][CH3:18])=[C:15]([O:19][CH3:20])[C:14]([O:21][CH3:22])=[C:13]([CH3:23])[C:10]=1[CH2:11][OH:12]
Reactant: COc1c(C)c(C=O)c(OC)c(OC)c1OC
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: COc1c(C)c(CO)c(OC)c(OC)c1OC
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
To a suspension of lithium aluminum hydride (2.37 g) in diethyl ether (150 ml) was dropwise added a solution of 2,3,4,5-tetramethoxy-6-methylbenzaldehyde (15.0 g) in diethyl ether (30 ml) with cooling with ice. After the reaction mixture was stirred for 30 min, 10% hydrochloric acid was added to the reaction mixture, which was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography (hexane to hexane:ethyl acetate=2:1) to yield the entitled compound (14.2 g) as an oil.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([OH:9])[CH2:5][C:6]([CH3:8])=[CH2:7].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C@@H:23]([N:25]=[C:26]=[O:27])[CH3:24])=[CH:19][CH:18]=1.C1CCN2C(=NCCC2)CC1>C1COCC1.CCOC(C)=O>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([C@@H:23]([N:25]2[CH2:2][CH2:3][C@:4]([CH2:5][C:6]([CH3:8])=[CH2:7])([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:9][C:26]2=[O:27])[CH3:24])=[CH:21][CH:22]=1
Reactant: C[C@H](N=C=O)c1ccc(Br)cc1
Reactant: C=C(C)CC(O)(CCCl)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C(C)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Yield: 30.1 %

Procedure:
A mixture of 1-chloro-5-methyl-3-phenylhex-5-en-3-ol (2.9 g, 13 mmol), (S)-1-bromo-4-(1-isocyanatoethyl)benzene (3.5 g, 16 mmol), and DBU (8 g, 33 mmol) in THF (80 mL) was heated at reflux overnight. The mixture was diluted with EtOAc, and washed with 1N aq HCl. The aqueous phase was extracted with EtOAc (3×), and the combined organic phase was dried over Na2SO4. After the solvents were evaporated, the crude product was purified by column chromatography to give (R)-3-((S)-1-(4-bromophenyl)-ethyl)-6-(2-methylallyl)-6-phenyl-1,3-oxazinan-2-one (1.62 g, yield: 30%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])=[N:4][C:5]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][N:14]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:15]3=[O:18])=[CH:11][C:10]=2[O:25][CH:26]([CH3:28])[CH3:27])=[N:6][CH:7]=1.C(OC([N:49]1[CH2:52][CH:51]([C:53](O)=[O:54])[CH2:50]1)=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:49]1[CH2:52][CH:51]([C:53]([N:22]2[CH2:21][CH2:20][CH:19]([N:14]3[CH2:13][C:12]4[C:16](=[CH:17][C:9]([NH:8][C:5]5[N:4]=[C:3]([NH:29][C:30]6[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=6[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])[C:2]([Cl:1])=[CH:7][N:6]=5)=[C:10]([O:25][CH:26]([CH3:28])[CH3:27])[CH:11]=4)[C:15]3=[O:18])[CH2:24][CH2:23]2)=[O:54])[CH2:50]1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: CC(C)Oc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)C(=O)N(C1CCNCC1)C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)C(=O)N(C1CCN(C(=O)C3CNC3)CC1)C2
Reaction time: 1 h

Procedure:
To a solution of 6-(5-chloro-4-(2-(isopropylsulfonyl)phenylamino)-pyrimidin-2-ylamino)-5-isopropoxy-2-(piperidin-4-yl)isoindolin-1-one C (41 mg, 0.07 mmol) in DMF (1.0 mL) was added 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (14 mg, 0.07 mmol), HATU (39 mg, 0.104 mmol), and DIEA (0.138 mmol, 24 μL) sequentially. The reaction mixture was stirred for 1 h, then partitioned between EtOAc and water. The organic extracts were dried (Na2SO4), and concentrated in vacuo. The crude product was stirred in a solution of DCM (1 mL) and TFA (1 mL) at room temperature for 1 h. The resulting solution was concentrated and then purified by preparative RP-HPLC to afford 2-(1-(azetidine-3-carbonyl)piperidin-4-yl)-6-(5-chloro-4-(2-(isopropylsulfonyl)phenyl-amino)pyrimidin-2-ylamino)-5-isopropoxyisoindolin-1-one.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]3[C@H:15]4[CH2:16][C@H:12]([CH2:13][CH2:14]4)[C@H:11]3[C:17]([N:19]([CH3:21])[CH3:20])=[O:18])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH:22]([N-]C(C)C)(C)C.[Li+].IC.O>O1CCCC1>[CH3:22][C:2]1[S:1][C:5]2[CH:6]=[CH:7][C:8]([C@H:10]3[C@H:15]4[CH2:16][C@H:12]([CH2:13][CH2:14]4)[C@H:11]3[C:17]([N:19]([CH3:21])[CH3:20])=[O:18])=[CH:9][C:4]=2[CH:3]=1
Reactant: CN(C)C(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1c1ccc2sccc2c1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: Cc1cc2cc([C@H]3[C@@H]4CC[C@@H](C4)[C@H]3C(=O)N(C)C)ccc2s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.7 %

Procedure:
To a stirred solution of (1S,2R,3S,4R)-3-(1-benzothien-5-yl)-N,N-dimethylbicyclo[2,2,1]heptane-2-carboxamide (200 mg, 0.67 mmol) in dry tetrahydrofuran (5 mL) at −78° C. was added lithium diisopropylamide (1.67 mL, 3.35 mmol). The mixture was stirred at this temperature for 1 hour before iodomethane (2.3 mL, 3.35 mmol) was added. The mixture was stirred for another 10 minutes at this temperature before it was allowed to warm to room temperature. After 1 hour, water was added and the layers were separated. The aqueous phase was extracted with ethyl acetate (2×10 mL) and the extracts were washed with water (2×10 mL) dried over magnesium sulphate and evaporated in-vacuo. Column chromatography with 20% ethyl acetate in hexane provided the (1S,2R,3S,4R)-3-(2-methyl-1-benzothien-5-yl)-N,N-dimethylbicyclo [2,2,1]heptane-2-carboxamide as a glass (140 mg, 66%). M/e 314 (M+H+).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].C[Si]([C:23]#[C:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]([CH3:35])[C:32]([NH2:34])=[O:33])(C)C>C1COCC1.C([O-])(O)=O.[Na+]>[C:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]([CH3:35])[C:32]([NH2:34])=[O:33])#[CH:23]
Reactant: CC(C(N)=O)c1ccccc1C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccccc1C(C)C(N)=O
Reaction time: 0.17 h

Procedure:
A 1.0 M solution of TBAF in THF (45.6 mL, 45.6 mmol) was added to a solution of 2-(2-((trimethylsilyl)ethynyl)phenyl)propanamide I15 (9.33 g, 38.0 mmol) in THF (200 mL) and the mixture was stirred for 10 minutes. The reaction mixture was diluted with sat. aq. NaHCO3 (200 mL), and the aqueous layer was extracted with DCM (3×150 mL). The combined organics were adsorbed onto silica and purified by silica gel column chromatography (Biotage Isolera, 120 g SiO2 cartridge, 0-80% EtOAc in petroleum benzine 40-60° C.) to yield the title compound K7 as a tan solid (5.11 g, 76%). LCMS-D: rt 3.03 min; m/z 174 [M+H]+.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:13])[CH2:9][C:10]([OH:12])=O)=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[CH3:53][C:54]1[CH:59]=[CH:58][C:57]([CH3:60])=[CH:56][C:55]=1[NH:61][CH:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1>CN(C=O)C.O>[C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:2]=[CH:3][C:4]([NH:7][C:8](=[O:13])[CH2:9][C:10]([N:65]2[CH2:66][CH2:67][CH:62]([NH:61][C:55]3[CH:56]=[C:57]([CH3:60])[CH:58]=[CH:59][C:54]=3[CH3:53])[CH2:63][CH2:64]2)=[O:12])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C)c(NC2CCNCC2)c1
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C)c(NC2CCN(C(=O)CC(=O)Nc3ccc(-c4ccccc4)cc3)CC2)c1
Reaction time: 8 h
Yield: 14.5 %

Procedure:
To a stirred solution of N-biphenyl-4-yl-malonamic acid (0.101 g, 0.00039 mole) in DMF (1 mL) was added DIPEA (0.233 g, 0.0018 mole), HOBt (0.053 g, 0.00039 mole) and EDCI.HCl (0.138 g, 0.00072 μmole). After 2 minutes (2,5-dimethyl-phenyl)-piperidin-4-yl-amine dihydrochloride (0.101 g, 0.00039 mole) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the resulting precipitate was isolated by filtration. Purification by column chromatography using silica gel 60-120 mesh (1% methanol in chloroform) afforded 0.025 g (16%) of N-biphenyl-4-yl-3-[4-(2,5-dimethyl-phenylamino)-piperidin-1-yl]-3-oxo-propionamide. LC-MS purity: 442.24 (M+1)+, 97.08%, 1H NMR (DMSO-d6): δ 10.1 (s, 1H), 7.7-7.5 (m, 6H), 7.4 (t, 2H), 7.35 (d, 1H), 6.9 (d, 1H), 6.5 (t, 2H), 4.5 (d, 1H), 4.0 (d, 1H), 3.7 (s, 1H), 3.5 (s, 2H), 3.4 (t, 2H), 3.1 (t, 1H), 2.3 (s, 3H), 2.2 (d, 2H), 2.1 (s, 3H), 1.5 (t, 2H).
Reaction SMILES: [CH:1](=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].B[O-].C(=O)C.[CH3:12][C:13]1[CH:18]2C(C)(C)C(C2)[CH2:15][CH:14]=1.B([O-])[O-].N(CCO)CCO>CCOCC.C1COCC1>[CH3:4][CH:3]([CH2:2][C@H:1]([OH:6])[CH2:18][C:13]([CH:14]=[CH2:15])=[CH2:12])[CH3:5]
Reactant: CC1=CCC2CC1C2(C)C
Reactant: CC(C)CC=O
Agent: B[O-]
Agent: CC=O
Agent: [O-]B[O-]
Solvent: OCCNCCO
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC(=C)C[C@@H](O)CC(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
Isovaleraldehyde (2.15 g, 2.68 mL, 25 mmol) in ether (6 mL) was added dropwise to a rapidly stirred solution of B-isoprenyldiisopinocampheylborane, dIpc2BIpn, maintained at -78° C. Stirring was continued for 1 h, when the 11B NMR spectrum of an aliquot showed a peak at δ52 ppm corresponding to a borinate indicating completion of the reaction. The reaction mixture was warmed to 0° C. and acetaldehyde (2.1 mL, 37.5 mmol) was added when one equiv of α-pinene was eliminated. 11B NMR showed a peak at δ32 ppm corresponding to a boronate. THF was substituted with EE and 1.1 equiv. of diethanolamine (2.6 mL, 27.5 mmol) was added and stirred for 2 h. The precipitated boron components were filtered and the filtrate was concentrated and distilled (92°-94° C./19 mm Hg) to yield 2.3 g (60%) of (+)-ipsenol. [α]D =+17.3° (c 1, MeOH) which corresponds to 93.7% ee. The spectral properties were identical to the racemic mixture of Example 6.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.O1CCOCC1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2].C(OCC)C>[F:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[C:16]1[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=[N+]([O-])c1cccc(F)c1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1cccc(F)c1-c1ccc(F)cc1
Temperature: 100 °C
Yield: 57.5 %

Procedure:
A microwave reaction vessel was charged with 2-chloro-3-fluoronitrobenzene (1.500 g, 8.5 mmol), 4-fluorophenylboronic acid (1.315 g, 9.4 mmol), sodium carbonate (2.717 g, 25.6 mmol), palladium diacetate (0.077 g, 0.3 mmol), tetrabutylammonium bromide (2.755 g, 8.5 mmol) in water (10 mL) and 1,4-dioxane (1 mL). The mixture was heated to 100° C. in a microwave reactor for 1 hr. The reaction was cooled to room temperature and poured into diethyl ether and 0.1N aqueous sodium hydroxide. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (10-30% methylene chloride/hexanes) to give the desired product as a yellow solid (1.15 g, 57%). 1H NMR (CDCl3, 300 MHz) δ 7.70 (dt, 1H, J=8.4, 1.5 Hz), 7.51 (td, 1H, J=8.4, 5.4 Hz), 7.41 (td, 1H, J=8.4, 1.2 Hz), 7.35-7.26 (m, 2H), 7.22-7.11 (m, 2H).