Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C12[N:8]([C:9]3C=N[C:16]4[C:11](=CC=[CH:14][CH:15]=4)[N:10]=3)CC1CCNC2.[Br:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([N:28]1[CH2:34][CH:33]2[CH:30]([CH2:31][NH:32]2)[CH2:29]1)=[O:27].ClC1N=C(C)C=CN=1>>[Br:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([N:28]1[CH2:34][CH:33]2[CH:30]([CH2:31][N:32]2[C:9]2[N:8]=[C:15]([CH3:14])[CH:16]=[CH:11][N:10]=2)[CH2:29]1)=[O:27]
Reactant: O=C(c1ccccc1Br)N1CC2CNC2C1
Reactant: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Agent: Cc1ccnc(Cl)n1
Product: Cc1ccnc(N2CC3CN(C(=O)c4ccccc4Br)CC32)n1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, Step A, using Intermediate 23 and 2-chloro-4-methylpyrimidine. MS (ESI) mass calcd. for C17H17BrN4O, 373.26; m/z found, 373.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:3]=1[CH2:4][N:5]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([O:22][CH2:23][CH3:24])[C:17]([O:19]CC)=[O:18])=[CH:11][CH:10]=1.[Li+].[OH-]>C1COCC1>[F:1][C:2]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:3]=1[CH2:4][N:5]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([O:22][CH2:23][CH3:24])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1
Reactant: CCCCCCCCN(Cc1ccc(F)cc1F)C(=O)COc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCCN(Cc1ccc(F)cc1F)C(=O)COc1ccc(C[C@H](OCC)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
To a solution of ethyl(2S)-3-(4-{2-[(2,4-difluorobenzyl)(octyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate (0.038 g, 0.071 mmol) in THF (3 mL) was added aqueous 0.10 M LiOH (2 mL) and the reaction mixture was stirred at room temperature overnight. After acidification with 5% HCl, the mixture was extracted with ethyl acetate (3×25 mL) and the combined organic phase was washed with brine (25 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to afford 0.035 g (98%) of a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([C:15]([O:17]CC)=[O:16])=[N:9]2)=[CH:4][CH:3]=1.[OH-].[K+].Cl>C(Cl)Cl.CC(O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([C:15]([OH:17])=[O:16])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nn(-c2ccc(F)cc2)cc1OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cn(-c2ccc(F)cc2)nc1C(=O)O
Temperature: 25 °C
Yield: 95.3 %

Procedure:
E1 (2 mmol, 1.0 eq.) and KOH (6 mmol, 3.0 eq.) in THF/H2O (1/1, 30 mL) were heated for 2 h at 60° C. The mixture was cooled to RT and then acidified with aq. HCl-solution (1N) to pH=1. The aq. phase was extracted with EtOAc. The combined organic phase was dried over Na2SO4. Removal of the solvent yielded the product E2 as a yellow solid (450 mg, 95%). 1H NMR (400 MHz, d6-DMSO, 300K) δ 3.80 (s, 3H), 7.37 (dd, J=J=9.0 Hz, 2H), 7.87 (dd, J=9.0 Hz, J=4.7 Hz, 2H), 8.40 (s, 1H), 12.72 (br s, 1H). MS (ES) C11H9FN2O3 requires: 236. Found: 237 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][N:13]([S:26]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)(=[O:28])=[O:27])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[CH:17][CH:16]=2)=[CH:8][CH:9]=1)=[O:4]>CCO>[N:31]1[CH:32]=[CH:33][CH:34]=[C:29]([S:26]([N:13]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[CH:19][CH:20]=2)[CH2:12][CH2:11][CH2:10][C:7]2[S:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=2)(=[O:27])=[O:28])[CH:30]=1
Reactant: COC(=O)c1ccc(CCCN(Cc2ccc(-c3nccs3)cc2)S(=O)(=O)c2cccnc2)s1
Solvent: CCO
Product: O=C(O)c1ccc(CCCN(Cc2ccc(-c3nccs3)cc2)S(=O)(=O)c2cccnc2)s1

Procedure:
The title compound was prepared following the method described in Example 1, Step C, from 5-{3-[(pyridine-3-sulfonyl)-(4-thiazol-2-yl-benzyl)-amino]-propyl}-thiophene-2-carboxylic acid methyl ester of Step B using EtOH in place of MeOH as solvent. 1H NMR (400 MHz, CDCl3) δ 9.12 (d, 1H, J=4 Hz), 8.81 (d, 1H, J=5 Hz), 8.17-7.21 (m, 9H), 6.61 (d, 1H, J=4 Hz), 4.41 (s, 2H), 3.25 (t, 2H, J=6.5 Hz), 2.72 (t, 2H, J=6.5 Hz), 1.73 (m, 2H); MS 498 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]3[CH2:25][CH2:24][CH:23]=[CH:22]3)[C:11](=[O:26])[C@:10]([CH2:28][CH:29]=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.CC(C)=[O:33].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]3[CH2:25][CH2:24][CH:23]=[CH:22]3)[C:11](=[O:26])[C@:10]([CH2:28][C:29]([OH:33])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: C[C@]1(CC=O)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C2C=CCC2)C1=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: C[C@]1(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C2C=CCC2)C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopent-2-enyl)-3-methyl-2-oxopiperidin-3-yl)acetaldehyde (Example 102, Step E) (267 mg, 0.604 mmol) in acetone (4 mL) was added freshly prepared Jones reagent (0.5 mL) at rt. The reaction mixture was stirred at room temperature for 15 min. before it was diluted with EtOAc and washed with water and sat. aq. NaCl solution. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 50 to 100% EtOAc in hexanes) to give the title compound as a colorless film as a 3.6:1 mixture of diastereomers.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([CH3:9])[C:7]=1[NH2:8].[CH3:11][O:12][CH2:13][CH2:14][C:15](O)=O.[OH-].[Na+]>CO>[CH3:11][O:12][CH2:13][CH2:14][C:15]1[NH:1][C:2]2[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([CH3:9])[C:7]=2[N:8]=1
Reactant: COCCC(=O)O
Reactant: Cc1cc(O)cc(N)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCCc1nc2c(C)cc(O)cc2[nH]1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
0.65 g (4.70 mmol) 3,4-diamino-5-methylphenol were placed in a little methanol and 0.94 mL (10.00 mmol) 3-methoxypropionic acid was added. First the methanol was distilled off and then the mixture was stirred for 2 h at 140° C. The reaction mixture was taken up in DMF/MeOH and purified by chromatography. The fractions containing product were combined and evaporated down i.vac. to leave the aqueous residue. This was neutralised with an aqueous 4M NaOH solution and extracted with ethyl acetate. The organic phase was dried and evaporated down i.vac. and dried.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][O:7][C@@H:6]1Br)(=[O:3])[CH3:2].[CH2:20]([OH:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Hg]C#N>C(#N)C.[Hg]Br>[C:1]([O:4][C@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][O:7][C@@H:6]1[O:27][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](Br)OC[C@H]1OC(C)=O
Reactant: OCc1ccccc1
Agent: Br[Hg]
Agent: N#C[Hg]
Solvent: CC#N
Product: CC(=O)O[C@@H]1[C@@H](OCc2ccccc2)OC[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 96.1 %

Procedure:
A solution of compound 2 (21 g, 61.9 mmol) in acetonitrile (200 ml) and benzyl alcohol (9.6 ml, 92.3 mmol) was vigorously stirred with molecular sieves (4 Å, 25 g), mercury bromide (25 g, 69.4 mmol), mercury cyanide (18.2 g, 12.0 mmol) under argon for 18 hours. The organic layer was filtered through celite and diluted with dichloromethane (250 ml) which was washed with water, aq. NaHCO3 and aq. NaCl and dried (Na2 SO4). The solvent was filtered and then evaporated under reduced pressure. The syrupy residue was chromatographed on silica gel (filter technique) using 1.5:1 hexane-ethyl acetate to give 3 (21.8 g, 90.0%).
Reaction SMILES: [CH3:1][C:2]1([CH3:43])[O:7][CH2:6][C:5]2[CH:8]=[C:9]([CH:12]([OH:42])[CH2:13][N:14]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)C(OCC3C=CC=CC=3)=O)[CH:10]=[CH:11][C:4]=2[O:3]1>CO.[Pd]>[CH3:1][C:2]1([CH3:43])[O:7][CH2:6][C:5]2[CH:8]=[C:9]([CH:12]([OH:42])[CH2:13][NH:14][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:10]=[CH:11][C:4]=2[O:3]1
Reactant: CC1(C)OCc2cc(C(O)CN(CCCCCCOCCCCc3ccccc3)C(=O)OCc3ccccc3)ccc2O1
Agent: [Pd]
Solvent: CO
Product: CC1(C)OCc2cc(C(O)CNCCCCCCOCCCCc3ccccc3)ccc2O1
Yield: 99 %

Procedure:
0.9 g (1.53 mmol) N-[2-(2,2-dimethyl-4H-benzo[1,3]-dioxin-6-yl)-2-hydroxyethyl]-N-benzyloxycarbonyl-6-(4-phenylbutoxy)hexylamine is hydrogenated with 0.1 g 5% Pd/C in 30 ml MeOH at atmospheric pressure and room temperature. Once 50 ml H2 have been absorbed, the catalyst is filtered off on decalite and the filtrate concentrated to dryness to give 0.69 g (99%) N-[2-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)-2-hydroxyethyl]-6-(4-phenylbutoxy)hexylamine.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]3)[CH2:4][CH2:3]1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:19]([O:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]3)[CH2:4][CH2:3]1)(=[O:21])[CH3:20]
Reactant: O=C1CCc2cc(N3CCC(O)CC3)ccc2N1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)OC1CCN(c2ccc3c(c2)CCC(=O)N3)CC1
Temperature: 25 °C
Reaction time: 40 h
Yield: 96.5 %

Procedure:
To a solution of 200 mg of 6-(4-hydroxypiperidino)-3,4-dihydrocarbostyril in 2 ml of pyridine were added 92 mg of acetic anhydride and 10 mg of 4-dimethylaminopyridine. After stirring at room temperature for 40 hr, the reaction mixture was concentrated under a reduced pressure, and the resulting residue was purified by a silica gel column chromatography to give 226 mg of 6-(4-acetoxypiperidino)-3,4-dihydrocarbostyril.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([CH2:14][N:15]([CH3:17])[CH3:16])[CH2:9]1)C1C=CC=CC=1.O.NN>C(O)C.[C].[Pd]>[CH3:16][N:15]([CH2:14][C@@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1)[CH3:17]
Reactant: CN(C)C[C@H]1CN(Cc2ccccc2)CCO1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: CN(C)C[C@H]1CNCCO1
Temperature: 25 °C
Yield: 88.1 %

Procedure:
(S)-4-Benzyl-2-(N,N-dimethylaminomethyl)morpholine (78.9 g) was dissolved in ethanol (800 ml) and 10% palladium carbon (31.1 g) and hydrazine monohydrate (22.1 g) were added with stirring at room temperature. The mixture was refluxed with stirring for 1 hour. After cooling, the reaction mixture was filtered through celite and the solvent was distilled off to give 42.8 g of (R)-2-(N,N-dimethylaminomethyl)morpholine as a pale-yellow oil.
Reaction SMILES: [F:1][CH2:2][CH:3]1[CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.[F:14][C:15]([F:20])([F:19])[C:16]([OH:18])=[O:17].C(Cl)Cl>>[F:14][C:15]([F:20])([F:19])[C:16]([OH:18])=[O:17].[F:1][CH2:2][CH:3]1[CH2:6][NH:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CC(CF)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FCC1CNC1

Procedure:
tert-Butyl 3-(fluoromethyl)azetidine-1-carboxylate (0.1 g, 0.53 mmol) and trifluoroacetic acid/DCM (1:1, 5.3 mL) was stir at room temperature for 30 min. Then the reaction mixture was concentrated on a rotary evaporator to afford 3-(fluoromethyl)azetidine 2,2,2-trifluoroacetate as clear oil. 1H NMR (DMSO-d6; TFA salt): δ 8.74 (br, 2H), 4.54 (dd, 2H), 4.08-3.98 (m, 2H), 3.84-3.76 (m, 2H), 3.20-3.06 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:21]3[CH:20]=[CH:19][C:18]4[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=4[C:16]=3[N:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]2[CH:29]=[CH:28][CH:27]=[CH:26][C:13]=23)=[CH:4][CH:3]=1.C1([N:36]2[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=3[N:38]=[C:37]2[C:45]2[CH:50]=[CH:49][C:48](B3OC(C)(C)C(C)(C)O3)=[CH:47][CH:46]=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O>[C:2]1([N:36]2[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=3[N:38]=[C:37]2[C:45]2[CH:46]=[CH:47][C:48]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[C:21]5[CH:20]=[CH:19][C:18]6[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=6[C:16]=5[N:15]=[C:14]5[C:9]=4[CH:10]=[CH:11][C:12]4[CH:29]=[CH:28][CH:27]=[CH:26][C:13]=45)=[CH:4][CH:3]=3)=[CH:49][CH:50]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(-c2c3ccc4ccccc4c3nc3c2ccc2ccccc23)cc1
Reactant: CC1(C)OB(c2ccc(-c3nc4ccccc4n3-c3ccccc3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: c1ccc(-n2c(-c3ccc(-c4ccc(-c5c6ccc7ccccc7c6nc6c5ccc5ccccc56)cc4)cc3)nc3ccccc32)cc1
Temperature: 80 °C
Reaction time: 36 h

Procedure:
6 (2.1 g, 4.8 mmol), 1-phenyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-benzo[d]imidazole (3.8 g, 9.6 mmol), Palladium tetrakis triphenylphoshine (830 mg) and 17 mL of a 1M potassium carbonate solution in water were introduced in a flask together with 35 mL degassed toluene. This mixture is stirred at 80° C. during 36 hours before being let cooled to room temperature and filtered. The solid is then dissolved in dichloromethane (600 mL) and filter over a Celite pad. The volatiles are removed by rotary evaporation and the solid is then dried overnight in a vacuum oven.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([I:9])=[CH:7][CH:8]=1)[NH2:2].[CH3:10][N:11]([C:13](Cl)=[N+](C)C)[CH3:12].F[P-](F)(F)(F)(F)F>CN(C=O)C>[I:9][C:6]1[CH:7]=[CH:8][C:3]2[N:4]([C:10]([N:11]([CH3:13])[CH3:12])=[N:2][N:1]=2)[N:5]=1
Reactant: NNc1ccc(I)nn1
Reactant: CN(C)C(Cl)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CN(C)c1nnc2ccc(I)nn12
Reaction time: 0.08 h
Yield: 82.4 %

Procedure:
The 3-hydrazinyl-6-iodopyridazine (1.00 g, 4.24 mmol, prepared using General Procedure D from Example #9, Step A with hydrazine) was dissolved in DMF (10 mL) then N-(chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate(V) (1.31 g, 4.66 mmol, Fluka) was added. The solution was stirred for about 5 min and then TEA (1.30 mL, 9.32 mmol) was added. The mixture was stirred at ambient temperature for about 1 h then at about 60° C. for about 2 h. The reaction was concentrated under reduced pressure then the mixture was partitioned between DCM (20 mL) and saturated aqueous NaHCO3. The layers were separated then the organic solution was dried over MgSO4, filtered and concentrated under reduced pressure. The material was purified by flash chromatography on silica gel with DCM/MeOH (95:5) as an eluent. The fractions were collected then concentrated under reduced pressure and the residue was triturated with Et2O (20 mL). The solid was collected by filtration and dried overnight under vacuum to give the title compound (1.01 g, 90%): LC/MS (Table 1, Method g) Rt=1.60 min; MS m/z: 289.8 (M+H)+.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:6]([CH3:15])=[CH:5][C:4]=1[NH:16][C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[C:20]([CH3:30])=[CH:19][N:18]=1.[F:31][C:32]([F:37])([F:36])[C@@H:33]1[CH2:35][O:34]1>CN(C=O)C>[CH3:15][C:6]1[CH:5]=[C:4]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=3)[C:20]([CH3:30])=[CH:19][N:18]=2)[C:3]([CH3:2])=[CH:8][C:7]=1[CH:9]1[CH2:14][CH2:13][N:12]([CH2:35][C@H:33]([OH:34])[C:32]([F:37])([F:36])[F:31])[CH2:11][CH2:10]1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3C)ncc2C)n[nH]1
Reactant: FC(F)(F)[C@@H]1CO1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(C[C@H](O)C(F)(F)F)CC4)cc3C)ncc2C)n[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N2-(2,5-dimethyl-4-(piperidin-4-yl)phenyl)-5-methyl-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine hydrochloride (36.0 mg, 0.084 mmol) in DMF (0.5 mL) were added TEA (23.4 μL, 0.168 mmol) and (S)-2-(trifluoromethyl)oxirane (72.8 μL, 0.84 mmol). The reaction mixture was stirred at room temperature overnight, and purified by preparative RP-HPLC to provide (S)-3-(4-(2,5-dimethyl-4-(5-methyl-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)phenyl)piperidin-1-yl)-1,1,1-trifluoropropan-2-ol; ESMS m/z 504.3 (M+H+).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[S:12](=[O:14])(=[O:13])[NH:11][C:10](=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:35][O:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41]O)=[CH:39][CH:38]=1.N(C([O-])=O)=NC([O-])=O>C1COCC1>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[S:12](=[O:14])(=[O:13])[N:11]([CH2:41][C:40]3[CH:43]=[CH:44][C:37]([O:36][CH3:35])=[CH:38][CH:39]=3)[C:10](=[O:15])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C1CN(c2ccc(I)cc2)S(=O)(=O)N1
Reactant: COc1ccc(CO)cc1
Agent: O=C([O-])N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)CN(c3ccc(I)cc3)S2(=O)=O)cc1

Procedure:
The title compound of Example 45, 5-(4-iodo-phenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (355.9 mg, 1.05 mmol) is dissolved in THF (20 mL) in a 40 mL capacity septum capped vial, and stirred under argon balloon. Triphenylphosphine (552 mg, 2.11 mmol) is added as a solid and stirred until dissolved, then 4-methyoxybenzyl alcohol (0.156 mL, 1.26 mmol) is added by syringe. The stirred reaction is cooled in an ice bath, and disopropyl azodicarboxylate (0.415 mL, 2.11 mmol) is added slow dropwise by syringe. After two h, the reaction is concentrated in vacuo and the residue is taken up in CH2Cl2. Chromatography on a 35 g silica gel RediSep column (Isco, Inc.) with a 30 mL/min gradient elution of 10:90 (EtOAc:hexane) to 30:70 over 15 min gives 5-(4-iodo-phenyl)-2-(4-methoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one as a white solid. 1H-NMR (300 MHz, CDCl3) 3.80 (s, 3H), 4.37 (s, 2H), 4.79 (s, 2H), 6.89 (d, J=7.5, 2H, aryl), 7.03 (d, J=7.5, 2H), 7.41 (d, J=7.5, 2H), 7.73 (d, J=7.5, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C@H:7]2[N:8](C(C3C=CC=CC=3)C)[CH2:9][C@H:4]([O:5][C:6]2=[O:18])[CH2:3]1.[H][H]>[Pd].CO>[CH3:1][C:2]1([CH3:19])[C@H:7]2[NH:8][CH2:9][C@H:4]([O:5][C:6]2=[O:18])[CH2:3]1
Reactant: CC(c1ccccc1)N1C[C@H]2CC(C)(C)[C@@H]1C(=O)O2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC1(C)C[C@@H]2CN[C@H]1C(=O)O2
Yield: 94.8 %

Procedure:
To a small Parr shaker bottle was added of (1R,4R)-8,8-Dimethyl-5-(1-phenyl-ethyl)-2-oxa-5-aza-bicyclo[2.2.2]octan-3-one (compound of formula XXXV, 1.04 g, 4.01 mmol), methanol (50 ml) and 0.12 g of 10% Palladium on charcoal. The mixture was shaken under about 50 psi of hydrogen for about 19 hours. The mixture was filtered and concentrated, affording 0.59 g of (1R,4R)-8,8-dimethyl-2-oxa-5-aza-bicyclo[2.2.2]octan-3-one (compound of formula XXXVI) as a filmy solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=O)[C:9]([CH3:12])([CH3:11])[O:10][C:6]=2[C:5]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]2=[O:26])=[C:4]([Cl:27])[CH:3]=1.[CH3:28][O:29][NH3+:30].[Cl-].C(O)C.N1C=CC=CC=1>C(OCC)(=O)C>[Cl:1][C:2]1[C:7]2[C:8](=[N:30][O:29][CH3:28])[C:9]([CH3:11])([CH3:12])[O:10][C:6]=2[C:5]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]2=[O:26])=[C:4]([Cl:27])[CH:3]=1
Reactant: CO[NH3+]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(Cl)cc(Cl)c3c2OC(C)(C)C3=O)c1=O
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CON=C1c2c(Cl)cc(Cl)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2OC1(C)C
Yield: 21.2 %

Procedure:
In a flask were placed 3.20 g (0.0076 mole) of 3-(4,6-dichloro-2,3-dihydro-2,2-dimethylbenzofuran-3-on-7-yl)-1-methyl-6-trifluoromethyluracil, 1,20 g (0.0144 mole) of 0-methylhydroxylamine hydrochloride, 4 mL of ethanol, and 4 mL of pyridine. This mixture was heated at reflux for five hours and then was evaporated under reduced pressure, leaving a residue. The residue was dissolved in ethyl acetate, and this solution was washed with water. The aqueous washings were then extracted twice with ethyl acetate, and these extracts were combined with the ethyl acetate solution of the product. The combined extracts and solution was dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated from the filtrate under reduced pressure, leaving a light reddish, viscous oil as a residue. This oil was passed through a column of silica gel, eluting with methylene chloride. Product-containing fractions were combined, and the solvent evaporated under reduced pressure, leaving 0.73 g of 3-(4,6-dichloro-2,3-dihydro-2,2-dimethyl-3-methoxyiminobenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil (Compound 26) as an off-white, fluffy solid, m.p. 145°-149° C. The NMR and IR spectra were consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](Cl)=[CH:4][CH:3]=1.P.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:16][C:17]([CH3:19])=[O:18]>C(Cl)C=CC1C=CC=CC=1.[Pd]>[C:2]1([CH3:1])[CH:7]=[CH:6][C:5]([CH2:16][C:17](=[O:18])[CH3:19])=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: Cc1ccc(Cl)cc1
Agent: [Pd]
Agent: ClCC=Cc1ccccc1
Agent: O=C([O-])[O-]
Product: CC(=O)Cc1ccc(C)cc1
Yield: 68 %

Procedure:
This reaction is carried out in the same manner as the reaction in example 3. The difference is that, the reactants are p-methylphenyl chloride (127.0 mg, 1.0 mmol), palladium cinnamyl chloride (7.9 mg, 0.015 mmol), 2-Methoxy-6-(N-methyl-N-phenyl-amino) henyldicyclohexyl)phosphine (24.3 mg, 0.060 mmol), Cs2CO3 (652.2 mg, 2.0 mmol) in 4.0 mL acetone at 90° C. for 18 h. 1-(p-tolyl)-2-propanone (100.5 mg) was obtained with a yield of 68% as liquid. 1H NMR (300 MHz, CDCl3) δ 7.19-7.05 (m, 4H, ArH), 3.66 (s, 2H, CH2), 2.34 (s, 3H, ArCH3), 2.15 (s, 3H, COCH3); 13C NMR (75 MHz, CDCl3) δ 206.7, 136.6, 131.1, 129.4, 129.2, 50.6, 29.1, 21.0; IR (neat) v (cm−1) 3023, 3004, 2922, 2857, 1714, 1615, 1514, 1417, 1356, 1229, 1158, 1040, 1023; MS (70 eV, EI) m/z (%): 149 (M++1, 3.90), 148 (M+, 31.26), 105 (100).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=O>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=3)[CH:27]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1cccc(-c2ccccn2)c1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2ccccn2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 3-(pyridin-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.62 min.; [M+H]+: 403.37 g/mol.