Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)([OH:8])[CH2:5][CH:6]=[CH2:7].[N:16]([C@@H:19]([CH3:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:17]=[O:18].C1CCN2C(=NCCC2)CC1>C1COCC1.CCOC(C)=O>[CH2:5]([C:4]1([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[O:8][C:17](=[O:18])[N:16]([C@H:19]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH3:24])[CH2:2][CH2:3]1)[CH:6]=[CH2:7]
Reactant: C=CCC(O)(CCCl)c1ccc(F)cc1
Reactant: C[C@H](N=C=O)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: C=CCC1(c2ccc(F)cc2)CCN([C@@H](C)C(C)(C)C)C(=O)O1
Yield: 11.4 %

Procedure:
A mixture of 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol (500 mg, 2.19 mmol), (S)-3-isocyanato-2,2-dimethyl-butane (845 mg, 5.58 mmol), and DBU (681 mg, 5.9 mmol) in THF (10 mL) was heated to reflux for 25 h. The mixture was diluted with EtOAc and washed with 1 N aq HCl. The aqueous phase was extracted with EtOAc (3×). The combined organic phase was dried over Na2SO4. After the solvents were evaporated, the crude product was purified by column to give 6-allyl-3-((2S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (80 mg, crude).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10](=O)[CH3:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl.[F:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][O:20][NH2:21])=[CH:17][CH:16]=1>>[F:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][O:20]/[N:21]=[C:10](/[C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([OH:1])[CH:3]=2)\[CH3:11])=[CH:17][CH:16]=1
Reactant: COc1ccc(C(C)=O)cc1O
Reactant: NOCc1ccc(F)cc1
Agent: Cl
Product: COc1ccc(/C(C)=N/OCc2ccc(F)cc2)cc1O
Yield: 80.4 %

Procedure:
Acetophenone 12 (50 mg, 0.301 mmol) was condensed with O-(4-fluorobenzyl)hydroxylamine hydrochloride (29) (58 mg, 0.327 mmol) according to the general procedure II-B defined above. After being heated for 24 h the reaction mixture was cooled and the solvent removed under reduced pressure. The ensuing residue was dissolved in CH2Cl2 (15 mL) and the resulting solution washed with H2O (2×10 mL) then dried (MgSO4), filtered and concentrated under reduced pressure. The oil thus obtained was subjected to flash chromatography (1:19 v/v ethyl acetate/hexane elution) to afford the title compound CP30266 (70 mg, 80%) as a pale-purple waxy-oil, Rf 0.5 in 1:1 v/v ethyl acetate/hexane.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH3:31])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1.[Cl:37]CCl>C(O)CCC>[ClH:37].[ClH:37].[CH3:31][C:16]1[C:15]2[C:19](=[CH:20][CH:21]=[CH:22][C:14]=2[NH:13][C:11]([C:8]2[N:5]3[CH:6]=[CH:7][C:2]([N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:3][C:4]3=[N:10][CH:9]=2)=[O:12])[N:18]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=2)[N:17]=1
Reactant: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(F)ccn45)cccc32)n1
Reactant: ClCCl
Reactant: C1CCNC1
Solvent: CCCCO
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(N6CCCC6)ccn45)cccc32)n1
Product: Cl
Temperature: 120 °C

Procedure:
7-Fluoro-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (Example 53; 0.0144 g, 0.0347 mmol) was suspended in n-butanol (0.2 mL). To this was added pyrrolidine (7.25 μL, 0.0869 mmol) and the mixture was heated to 120° C. for 12 hours. The mixture was concentrated under reduced pressure and the resulting material was taken up in THF and concentrated three times to give a brown solid. This material was taken up in dichloromethane, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure (0.0127 g, 79%). The resulting material was treated with 2M HCl in diethyl ether to provide N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(pyrrolidin-1-yl)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride. MS (APCI), positive scan, m/z=466.3 (M+H).
Reaction SMILES: [C:1]1(=[O:13])[C:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[NH:5][C:4]=2[CH2:3][CH2:2]1.[CH2:14]([N:21]1[CH2:26][CH2:25][CH:24]([CH:27]=O)[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([N-]C(C)C)(C)C.[Li+].C(OC(=O)C)(=O)C>C1COCC1>[C:15]1([CH2:14][N:21]2[CH2:26][CH2:25][CH:24]([CH:27]=[C:2]3[CH2:3][C:4]4[NH:5][C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=5[C:12]=4[C:1]3=[O:13])[CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=CC1CCN(Cc2ccccc2)CC1
Reactant: O=C1CCc2[nH]c3ccccc3c21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: O=C1C(=CC2CCN(Cc3ccccc3)CC2)Cc2[nH]c3ccccc3c21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 1,2,3,4-tetrahydrocyclopent[b]-indol-1-one (440 mg, 2.6 mmol) and 1-benzylpiperidine-4-carboxaldehyde (581 mg, 2.86 mmol) in 90 ml dry THF was added 5.4 mmol of lithium diisopropylamide at -78° C. The mixture was stirred at -78° C. for 30 minutes, then warmed up to 0° C. for 1.5 hours, and then to r.t. for 15 minutes. Acetic anhydride (0.265 g, 2.6 mmol) was added, the mixture was stirred at r.t. for 1.5 hours and quenched ammonium chloride, water and extracted with chloroform. The organic layer was dried, concentrated, and purified through silica gel to give the title compound. 1HNMR (CDCl3)δ 1.45-1.7 (m, 3H), 1.8-2.3 (m, 4H), 2.8-3.0 (m, 2H), 3.46 (s, 2H), 3.55 (s, 2H), 6.5 (m, 1H), 7.1-7.4 (m, 8H), 7.9 (m, 1H), 9.2 (s, 1H) ppm.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:17][CH2:16][C@@H:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]2)(=O)=O)=CC=1.[CH3:26][CH:27]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]1>C(Cl)Cl>[CH3:26][CH:27]1[CH2:32][CH2:31][CH2:30][N:29]([CH2:12][C@H:13]2[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:20])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[CH2:14]2)[CH2:28]1
Reactant: CC1CCCNC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)C2)cc1
Solvent: ClCCl
Product: CC1CCCN(C[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)C2)C1
Temperature: 0 °C
Yield: 72.3 %

Procedure:
To a stirred solution of ((1S,3R)-3-(tert-butoxycarbonylamino)cyclopentyl)methyl 4-methylbenzenesulfonate (Intermediate 18-step 2, about 0.5 g) in DCM (50 ml) potassium carbonate (about 0.3 g) was added at room temperature and cooled to about 0° C. After ten minutes, 3-methylpiperidine (0.21 g) was added and stirred the reaction at room temperature for about 6 hours and completion of the reaction was monitored by TLC. The reaction mixture was neutralized and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure to furnish the title compound (0.29 g) as a pale yellow solid. 1H NMR (300 MHz, CDCl3: 1.08-1.09 (m, 3H); 1.24-1.29 (m, 1H); 1.39-1.40 (s, 9H); 2.29-2.60 (m, 6H); 2.79-2.80 (m, 8H); 3.70-3.73 (m, 4H); ES Mass: 297 (100%), [M+1].
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C:7]2[O:17][C:16]3[CH:15]=[C:14]([OH:18])[CH:13]=[C:12]([OH:19])[C:11]=3[C:9](=[O:10])[C:8]=2[OH:20])=[CH:5][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH3:29].[CH3:30][C:31](C)=O>>[CH2:30]([O:20][C:8]1[C:9](=[O:10])[C:11]2[C:16](=[CH:15][C:14]([O:18][CH2:28][CH3:29])=[CH:13][C:12]=2[OH:19])[O:17][C:7]=1[C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[CH3:31]
Reactant: CCBr
Reactant: CC(C)=O
Reactant: O=c1c(O)c(-c2ccccc2)oc2cc(O)cc(O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOc1cc(O)c2c(=O)c(OCC)c(-c3ccccc3)oc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
Galangin (27 mg, 0.1 mmol) was dissolved in dried acetone (20 mL), solid potassium carbonate (0.5 g) and bromoethane (1 mL) were added and the mixture was stirred overnight, at room temperature. The solution was filtered and evaporated, water (20 mL) and concentrated ammonium hydroxide (2 mL) were added and the solution was extracted with ethyl acetate (20 mL×2). The solution was dried and the solvent was evaporated. The residue was purified by preparative TLC plate (silica, ethyl acetate/petroleum ether 2:8) to give 21 mg product (64%). 1HNMR (CDCl3): d 1.34 (t, 3H, J=7.3 Hz, 3-CH3), 1.48 (t, 3H, J=7.1 Hz, 7-CH3), 4.14 (m, 4H, 2×OCH2), 6.38 (s, 1H, 6-H), 6.47 (s, 1H, 8-H), 12.64 (s, 1H, 5-OH). MS (CI/NH3): m/z 327 (MH+, base).
Reaction SMILES: C([Mg]Br)C.[Cl:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([SH:16])[CH:10]=[CH:9]2.[O:17]1[CH2:19][C@@H:18]1[C:20]([O:22][CH3:23])=[O:21].[Cl-].[NH4+]>C(OCC)C.C1COCC1>[Cl:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([S:16][CH2:19][C@@H:18]([OH:17])[C:20]([O:22][CH3:23])=[O:21])[CH:10]=[CH:9]2
Reactant: COC(=O)[C@H]1CO1
Reactant: Sc1ccc2cc(Cl)ccc2c1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)[C@H](O)CSc1ccc2cc(Cl)ccc2c1
Yield: 77 %

Procedure:
Under argon atmosphere, a 3 M solution of ethylmagnesium bromide in diethyl ether was added dropwise to THF (25 mL) with ice cooling. To this solution, a solution of 6-chloronaphthalene-2-thiol (5.0 g) in THF (50 mL) was added dropwise at 0C, and the mixture was mixed at room temperature for 30 minutes. To this solution, a solution of methyl (2R)-oxirane-2-carboxylate (2.3 mL) in THF (15 mL) was added dropwise, and the reaction solution was mixed at room temperature for 3 hours. To the reaction solution, an aqueous ammonium chloride solution (50 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from hexane/ethyl acetate (3:1) to give the title compound (5.9 g, 77%) as colorless needle-shaped crystals.
Reaction SMILES: F[C:2](F)(F)C([O-])=O.[NH:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:10][CH2:9]1.FC(F)(F)C(O)=O.S(Cl)([Cl:28])=O>ClCCl.CO>[ClH:28].[NH:8]1[CH2:9][CH2:10][CH:11]([O:14][CH2:15][C:16]([O:18][CH3:2])=[O:17])[CH2:12][CH2:13]1
Reactant: O=C([O-])C(F)(F)F
Reactant: O=S(Cl)Cl
Reactant: O=C(O)COC1CCNCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COC(=O)COC1CCNCC1
Product: Cl

Procedure:
By esterifying the trifluoroacetate of 4-piperidinyloxy-acetic acid (prepared by treating the product of Example 1c) with trifluoroacetic acid in dichloromethane) in methanol in the presence of thionyl chloride there is obtained methyl 4-piperidinyloxyacetate hydrochloride, MS (EI): 173 (M)+.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+].[CH2:13]([O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>C(O)C.O>[CH2:13]([O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[C:2]2[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1]2=[O:10])=[CH:22][CH:21]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C1CCc2ccccc21
Reactant: CCCCCCOc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCOc1ccc(C=C2Cc3ccccc3C2=O)cc1
Reaction time: 0.33 h

Procedure:
1-Indanone (4.17 g, 0.032 mol) was dissolved in ethanol (20 ml), and was added to sodium hydroxide (0.44 g, 0.011 mol) dissolved in water (8 ml) and ethanol (3 ml) and was left to stir for 20 min. 4-(Hexyloxy)benzaldehyde (6.4 ml, 0.031 mol), dissolved in ethanol (35 ml), was added to the mixture and was stirred for 4 hours. The product was isolated by vacuum filtration and was washed with cold ethanol (2×20 ml) and was dried in a vacuum oven. Yield=8.47 g, 85%. 1H NMR and 13C NMR gave expected signals.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[C:35]4[C:30](=[CH:31][C:32]([O:38][CH3:39])=[C:33]([O:36][CH3:37])[CH:34]=4)[N:29]=[CH:28][CH:27]=3)=[CH:21][CH:20]=2)=[O:17])=[CH:11][CH:10]=1)C1C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][C:26]3[C:35]4[C:30](=[CH:31][C:32]([O:38][CH3:39])=[C:33]([O:36][CH3:37])[CH:34]=4)[N:29]=[CH:28][CH:27]=3)=[CH:23][CH:24]=2)=[O:17])=[CH:11][CH:10]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(OCc5ccccc5)cc4)cc3)c2cc1OC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(O)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.7 %

Procedure:
N-(4-Benzyloxyphenyl)-N'-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}urea (228 mg) was dissolved in N,N-dimethylformamide/ethyl acetate (15 ml/20 ml), after the addition of triethylamine (4 ml), 20% palladium hydroxide (1.18 g) was added, and the admixture was stirred at room temperature under hydrogen for 15 hours. The reaction mixture was filtered using Celite, after which the filtrate was concentrated, and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 188 mg of the title compound (yield: 100%).
Reaction SMILES: [CH3:1][CH2:2][C:3]([O-:6])(C)[CH3:4].[Na+].[C:8](OC)(=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]CCCC.[C:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:31])[CH3:30]>>[C:29]([CH2:30][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:1][CH2:2][C:3]([CH3:4])=[O:6])(=[O:31])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC
Reactant: CC(=O)c1ccccc1
Reactant: CCC(C)(C)[O-]
Agent: [Na+]
Product: CC(=O)CCCCCCCCCCCCCCCCCC(=O)c1ccccc1
Temperature: 120 °C
Reaction time: 0.7 h

Procedure:
Xylenes (dry, 180 mL), sodium tert-pentoxide (17.9 g; 0.163 mol), and methyl stearate (41.5 g; 0.139 mol) were placed into a four-necked, round bottom, half-liter flask equipped with a stirrer, a thermometer, and a reflux condenser with a distillation valve. The mixture was heated to 120° C. and kept at that temperature under a blanket of nitrogen. Acetophenone (15.0 g; 0.125 mol) was added slowly over a period of 30 minutes by means of a syringe pump. After 42 minutes, the distillation valve was opened and the distillate was removed as the reaction proceeded. After 1:05 hours from the beginning of the addition of the ketone, the mixture was cooled down to room temperature. Aqueous sulfuric acid (16%) was added with stirring until the pH of the aqueous layer was acidic.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:31])[C:4](=[O:30])[C:5]([CH3:29])([CH3:28])[C@:6]([C:9]2[CH:10]=[C:11]([NH:16][CH:17]3[CH2:22][CH:21]4[CH2:23][CH:18]3[CH2:19][CH:20]4[O:24]C(=O)C)[CH:12]=[CH:13][C:14]=2[F:15])([CH3:8])[N:7]=1.[Li+].[OH-]>C1COCC1.CO.O>[NH2:1][C:2]1[N:3]([CH3:31])[C:4](=[O:30])[C:5]([CH3:29])([CH3:28])[C@:6]([C:9]2[CH:10]=[C:11]([NH:16][CH:17]3[CH2:22][CH:21]4[CH2:23][CH:18]3[CH2:19][CH:20]4[OH:24])[CH:12]=[CH:13][C:14]=2[F:15])([CH3:8])[N:7]=1
Reactant: CC(=O)OC1CC2CC1CC2Nc1ccc(F)c([C@@]2(C)N=C(N)N(C)C(=O)C2(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC3CC4CC3CC4O)ccc2F)N=C1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of acetic acid 5-[3-((S)-2-amino-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-4-yl)-4-fluoro-phenylamino]-bicyclo[2.2.1]hept-2-yl ester (example 93, 0.05 mmole) in THF (1 ml), MeOH (0.3 ml) and H2O (0.3 ml) was added LiOH 1N (0.1 mmole) and the reaction mixture was stirred at room temperature for 4 h. The mixture was concentrated in vacuo, the residue dissolved in aqueous HCl (0.5N) until pH=5 and washed with EtOAc. The aqueous phase was basified to pH=8 with a saturated aqueous NaHCO3 solution and extracted with EtOAc. The organic phase was separated, dried over Na2SO4 and evaporated to yield a mixture of isomers of the title compound as a colorless waxy solid. MS (ESI): m/z=389.3 [M+H]+.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]([CH3:25])[C@@H:10]([OH:24])[CH2:11][N:12]([CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH3:13])C1C=CC=CC=1.CC(O)=O>CO.CCOCC.[OH-].[OH-].[Pd+2]>[NH2:8][C@H:9]([CH3:25])[C@@H:10]([OH:24])[CH2:11][N:12]([CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)[CH3:13]
Reactant: C[C@H]([C@@H](O)CN(C)CCCc1ccc(F)cc1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: CO
Product: C[C@@H](N)[C@@H](O)CN(C)CCCc1ccc(F)cc1
Reaction time: 8 h
Yield: 84.7 %

Procedure:
Pd(OH)2 was carefully wetted down under N2 with 10 mL of MeOH then the product of Step f (1.15 g) dissolved in 40 mL of MeOH was added followed by 50 mL of HOAc. The mixture was hydrogenated overnight on a Parr shaker at 50 PSI. Worked up by filtering off the catalyst under N2 through a fiberglass filter paper and vacuum. The filtrate was stripped to obtain an oily residue which was dissolved in 25 mL of Et2O and washed 2 times with 1N NaOH, 1 time with brine, dried (Na2SO4) and stripped to give 0.57 g of a light yellow oil. MS (ESI) detects (M+H)+=255.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:23]([C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28])#[CH:24]>O1CCCC1.O.[Cu]I.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>[NH2:28][C:27]1[CH:26]=[C:25]([C:23]#[C:24][C:2]2[CH:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4][N:3]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)Nc1ccnc(I)c1
Reactant: C#Cc1cccc(N)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccnc(C#Cc2cccc(N)c2)c1
Temperature: 25 °C
Reaction time: 40 h
Yield: 88.4 %

Procedure:
tert-Butyl (2-iodopyridin-4-yl)carbamate (2.41 g, 7.5 mmol), copper(I) iodide (50 mg, 0.3 mmol) and bis(triphenylphosphine)palladium(II) chloride (200 mg, 0.3 mmol) were stirred in tetrahydrofuran (22 mL) with triethylamine (1.1 mL, 8.1 mmol) under N2 at rt. 3-Ethynylaniline (0.75 mL, 7.2 mmol) was added and the mixture was stirred at rt for 40 hours. The reaction mixture was diluted with water. After removal of the solvent, the aqueous residue was extracted with EtOAc three times, followed by drying, filtration, and concentration to give the desired product as a brown solid (1.97 g, 89%). LCMS for C18H20N3O2 (M+H)+: m/z=310.1.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.Br[C:17]1[CH:18]=[C:19]([C:22]#[N:23])[O:20][CH:21]=1>>[CH3:13][C:7]1([CH3:14])[C:6]2[CH:15]=[C:2]([C:17]3[CH:18]=[C:19]([C:22]#[N:23])[O:20][CH:21]=3)[CH:3]=[CH:4][C:5]=2[NH:11][C:10](=[O:12])[CH2:9][O:8]1
Reactant: CC1(C)OCC(=O)Nc2ccc(Br)cc21
Reactant: N#Cc1cc(Br)co1
Product: CC1(C)OCC(=O)Nc2ccc(-c3coc(C#N)c3)cc21

Procedure:
Prepared from 7-bromo-5,5-dimethyl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 4-bromofuran-2-carbonitrile generally according to the coupling procedure described in examples 82 and 1. 1H-NMR (DMSO-d6) δ 9.96 (s, 1H), 8.61 (s, 1H), 8.19 (s, 1H), 7.56 (d, J=1.9 Hz, 1H), 7.50 (dd, J=8.3, 2.0 Hz, 1H), 7.14 (d, J=8.4 Hz, 1H), 4.24 (s, 2H), 1.59 (s, 6H); MS (ES) m/z 283 (M+H)+.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[H-].[Na+].Cl[C:9]1[N:10]=[C:11]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:12]2[N:17]=[C:16](Cl)[N:15]=[C:14]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:13]=2[N:25]=1.[OH2:32]>C1COCC1>[OH:4][CH2:3][CH2:2][CH2:1][O:5][C:9]1[N:10]=[C:11]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:12]2[N:17]=[C:16]([O:32][CH2:1][CH2:2][CH2:3][OH:4])[N:15]=[C:14]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:13]=2[N:25]=1
Reactant: Clc1nc(N2CCCCC2)c2nc(Cl)nc(N3CCCCC3)c2n1
Reactant: OCCCO
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCCOc1nc(N2CCCCC2)c2nc(OCCCO)nc(N3CCCCC3)c2n1
Temperature: 25 °C
Yield: 51 %

Procedure:
1,3-Propane diol (0.73 ml, 10 mmol) was dissolved in dry THF (10 ml), added to sodium hydride (0.24 g, 10 mmol) and the mixture was stirred at room temperature for 6 hours 2,6-dichloro-4,8-dipiperidinopyrimidopyrimidine (0.184 g, 0.5 mmol) in dry THF (25 ml) was added and the mixture heated under reflux 72 hours. After cooling to room temperature, water (30 ml) was added and the product extracted into ethyl acetate (4×20 ml). The organic layers were combined, dried (MgSO4), filtered and solvent removed in vacuo. Purification was carried out by column chromatography on silica gel, with dichloromethane: methanol (95:5) as eluent. Subsequent recrystallisation from methanol/water gave the title compound as a cream solid (0.115 g, 51%), m.p. 154-156° C. Found: C, 59.23; H, 7.72; N, 18.79. C22H34N6O4 requires C, 59.17; H, 7.67; N, 18.82%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](=[O:39])[NH:25][C@H:26]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([OH:38])[CH:33]=3)[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].CC1C=CC(S(O[CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][F:65])(=O)=O)=CC=1.C1(C)C=CC=CC=1>CN(C=O)C>[F:65][CH2:64][CH2:63][O:62][CH2:61][CH2:60][O:59][CH2:58][CH2:57][O:38][C:34]1[CH:33]=[C:32]([C@@H:26]([NH:25][C:24]([C@@H:20]2[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][CH2:14][CH:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]3)[CH2:19]2)=[O:39])[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:37]=[CH:36][CH:35]=1
Reactant: COC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCF)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cccc(OCCOCCOCCF)c1
Temperature: 25 °C
Yield: 61.8 %

Procedure:
To tert-butyl-4-{3-[(3R)-3-{[(1S)-1-(3-hydroxyphenyl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (26 mg, 50 μmol) in DMF (6.6 mL) was added cesium carbonate (38.8 mg, 120 μmol) and 2-[2-(2-fluoroethoxy)ethoxy]ethyl 4-methylbenzenesulfonate (22 mg, 70 μmol) while stirring at room temperature. After 5 hours toluene was added and the mixture was concentrated in vacuum. The DMF free residue was purified by preparative thin layer chromatography on silica gel (dichloromethane in ethyl acetate 30%) to yield 21 mg of tert-butyl 4-{3-[(3R)-3-{[(1S)-1-(3-{2-[2-(2-fluoroethoxy)ethoxy]ethoxy}phenyl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: [CH2:1]([Br:4])[C:2]#[CH:3].[CH3:5][C:6]1[N:7]2[CH2:13][CH2:12][NH:11][CH:8]2[S:9][CH:10]=1>C(#N)C>[Br-:4].[CH2:1]([N:11]1[C:8]2[S:9][CH:10]=[C:6]([CH3:5])[N+:7]=2[CH2:13][CH2:12]1)[C:2]#[CH:3]
Reactant: C#CCBr
Reactant: CC1=CSC2NCCN12
Solvent: CC#N
Product: C#CCN1CC[n+]2c(C)csc21
Product: [Br-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 12 g. of propargyl bromide and 14 g. of 3-methyl-5,7-dihydroimidazo[2,1-b]thiazole (prepared by basification of 3-methyl-5,6-dihydroimidazo[2,1-b]thiazole hydrochloride with 5N sodium hydroxide solution) in 160 ml. of dry acetonitrile is allowed to stir at room temperature for 16 hrs. The solution is concentrated to a small volume and the precipitated product filtered. The purified product is obtained by recrystallization from acetonitrile-ethyl acetate, 21 g., m.p. 207°-208° C.