Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[C:23]([O:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C:31]1([CH:38]=[O:39])[CH2:35][CH2:36][CH3:37])=[O:29])([CH3:26])([CH3:25])[CH3:24]>CCOCC>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:38]([C:31]3([CH2:35][CH2:36][CH3:37])[CH2:32][CH2:33][CH2:34][N:30]3[C:28]([O:27][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:29])[OH:39])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC1(C=O)CCCN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)n1ccc2cc(Br)ccc21
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CCCC1(C(O)c2ccc3c(ccn3C(=O)OC(C)(C)C)c2)CCCN1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
To a stirred solution of 5-bromo-indole-1-carboxylic acid tert-butyl ester (0.700 g, 2.37 mmol) in ether (20 mL) at −78° C. and under nitrogen was added tert-butyllithium (3.64 mL of 1.43 M solution in pentanes, 5.21 mmol) dropwise. After 30 minutes, a solution of 2-formyl-2-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.569 g, 2.37 mmol) in ether (5 mL) was added to the reaction mixture dropwise. The reaction mixture was stirred for one hour, then quenched by the addition of saturated aqueous NH4Cl, and extracted with EtOAc. The combined organic extracts were washed with saturated aqueous NaHCO3 and brine, then dried (MgSO4), filtered and concentrated in vacuo. Purification by chromatography (silica, 0-60% EtOAc in hexanes) gave 5-[(1-tert-butoxycarbonyl-2-propyl-pyrrolidin-2-yl)-hydroxy-methyl]-indole-1-carboxylic acid tert-butyl ester (0.466 g, 1.02 mmol, 43%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11](O)=[O:12])[C:5](=[CH:9][CH:10]=1)[C:6](O)=[O:7]>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([CH2:11][OH:12])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1C(=O)O
Solvent: C1CCOC1
Product: OCc1ccc(Br)cc1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.4 %

Procedure:
To a solution of 4-bromophthalic acid (3.0 g, 12.24 mmol) in 30 mL of THF was added a solution of borane-THF complex (1.0M) dropwise at 0° C. The solution was warmed to rt and stirred for 3 h. The reaction mixture was quenched by addition of HCl (2N) at 0° C. The product was extracted with ethyl acetate and washed with sat. NaCl, dried over Na2SO4, and concentrated under reduced pressure to afford 2.8 g (100%) of 4-bromo-2-hydroxymethylbenzyl alcohol as a colorless oil. 1H NMR (CDCl3) 7.28 (m, 2H), 7.26 (m, 1H), 4.69 (s, 4H), 2.80 (bs, 2H).
Reaction SMILES: S(=O)(=O)(O)O.[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:11]=[CH:12][C:13](=[O:25])[C:14](=[CH:19][C:20]1[O:21][CH:22]=[CH:23][CH:24]=1)[CH2:15][C:16]([OH:18])=[O:17].[CH3:26][CH2:27]OC(C)=O.C(=O)(O)[O-].[Na+]>C(O)C>[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:11]=[CH:12][C:13](=[O:25])[C:14](=[CH:19][C:20]1[O:21][CH:22]=[CH:23][CH:24]=1)[CH2:15][C:16]([O:18][CH2:26][CH3:27])=[O:17]
Reactant: CCOC(C)=O
Reactant: O=C(O)CC(=Cc1ccco1)C(=O)C=Cc1ccco1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC(=Cc1ccco1)C(=O)C=Cc1ccco1
Temperature: 25 °C
Yield: 88 %

Procedure:
To prepare a starting compound of Formula III, 12 g of levulinic acid (0.104 mol, 1.0 eq) was first dissolved in 66 mL of water. A solution of 15.4 g of sodium carbonate (0.146 mol, 2.8 eq of base relative to levulinic acid) was slowly added. The resulting suspension was stirred for 30 minutes at room temperature. The reaction mixture was heated to 90° C., and a solution of 25 g of furfural (0.260 mol, 2.5 eq) in 25 mL of ethanol was added dropwise. The reaction mixture was stirred at 90° C. until complete, as determined by thin layer chromatography (TLC) (sys 9:1 CHCl3/HOAc). The reaction mixture was cooled to room temperature, and the pH was carefully adjusted to pH=2 with concentrated HCl. The solids were removed by filtration and dissolved in ethyl acetate twice (400 ml). The ethyl acetate was treated with activated carbon, filtered and washed with ethyl acetate. Hexanes were added to the filtrate. The resulting slurry was filtered and washed with hexanes to give 6-(furan-2-yl)-3-(furan-2-ylmethylene)-4-oxohex-5-enoic acid as a brown solid (11.7 g, 41.3%, HNMR). A solution of 2 mL of sulfuric acid in 2 mL of ethanol was added to 10 g of 6-(furan-2-yl)-3-(furan-2-ylmethylene)-4-oxohex-5-enoic acid (0.0367 mol, 1.0 eq) in 100 mL of ethanol. The mixture was heated to reflux and stirred until complete, as determined by TLC (sys: 100% EtOAc). The reaction mixture was cooled to room temperature and poured slowly into a saturated sodium bicarbonate solution. The product was extracted with ethyl acetate, washed with saturated brine, treated with activated carbon and dried with sodium sulfate. The filtrate was evaporated to dryness to give ethyl 6-(furan-2-yl)-3-(furan-2-ylmethylene)-4-oxohex-5-enoate as an oil (9.7 g, 88% yield, HNMR, carbon nuclear magnetic resonance (13CNMR)).
Reaction SMILES: [ClH:1].[O:2]=[S:3]1(=[O:16])[N:7]([CH3:8])[CH2:6][CH2:5][N:4]1[C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1.O=S1(=O)N(C)CC[N:19]1C1C=CC([N+]([O-])=O)=CC=1>>[ClH:1].[O:16]=[S:3]1(=[O:2])[N:7]([CH3:8])[CH2:6][CH2:5][N:4]1[C:9]1[CH:15]=[CH:14][C:12]([NH:13][NH2:19])=[CH:11][CH:10]=1
Reactant: CN1CCN(c2ccc(N)cc2)S1(=O)=O
Reactant: CN1CCN(c2ccc([N+](=O)[O-])cc2)S1(=O)=O
Agent: Cl
Product: CN1CCN(c2ccc(NN)cc2)S1(=O)=O
Yield: 96 %

Procedure:
The title compound was prepared in 96% yield from 4-(1,1-dioxo-5-methyl-1,2,5-thiadiazolidin-2-yl)aniline hydrochloride using a similar method to that described for Intermediate 1 (step 1); yellow solid; δH (360 MHz, DMSO-d6) 7.15 (2H, d, J=8.9 Hz, Ar--H), 6.92 (2H, d, J=8.9 Hz, Ar--H), 3.74 (2H, t, J=6.4 Hz, --CH2 --), 3.42 (2H, t, J=6.4 Hz, --CH2 --), 2.68 (3H, s, --CH3); m/z (FAB) 243 (M+ +1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[C:4]([C:13]([OH:15])=O)=[C:3]1[CH3:16].C(Cl)(=O)C(Cl)=O.[CH2:23]([NH2:27])[CH:24]([CH3:26])[CH3:25]>>[CH2:23]([NH:27][C:13]([C:4]1[C:5]2[C:10](=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)[N:2]([CH3:1])[C:3]=1[CH3:16])=[O:15])[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)CN
Reactant: COc1ccc2c(C(=O)O)c(C)n(C)c2c1
Agent: O=C(Cl)C(=O)Cl
Product: COc1ccc2c(C(=O)NCC(C)C)c(C)n(C)c2c1

Procedure:
This material was prepared from 1,2-dimethyl-6-methoxy-1H-indole-3-carboxylic acid 16c, oxalyl chloride and isobutylamine in a manner as previously described for example 16d. 1H NMR (300 MHz, CDCl3) δ7.56 (1H, d, J=8.6 Hz), 6.85 (1H, dd, J=2.2, 8.6 Hz), 6.78 (1H, d, J=2.2 Hz), 3.87 (3H, s), 3.63 (3H, s), 3.32 (2H, m), 2.69 (3H, s), 1.93 (1H, m), 1.02 (3H, s), 1.00 (3H, s). LCMS (ESI+) [M+H]/z Calc'd 275, found 275.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[NH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:31][CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=3)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Reactant: NCCc1ccc(O)cc1
Product: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 4 from above was coupled with tyramine following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 456. 1H NMR (Varian 300 MHz, DMSO-d6, shifts relative to the solvent peak at 2.49 ppm) δ 8.5 (d, 1H) 8.1 (m, 2H) 8.0 (s, 2H) 7.6 (m, 2H) 7.4 s, 1H) 7.0 (d, 2H) 6.7 (d, 2H) 4.5 (s, 2H) 3.6 (m, 2H) 3.2 (m, 2H) 3.0 (s, 3H) 2.8 (m, 2H) 2.7 (m, 2H) 1.8 (m, 2H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]([CH:40]([CH3:42])[CH3:41])[CH:32]=1)=[O:30]>>[ClH:20].[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]([CH:40]([CH3:41])[CH3:42])[CH:32]=3)=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: CC(C)n1cc(C(=O)CCCCCBr)c2ccccc21
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2cn(C(C)C)c3ccccc23)CC1
Yield: 46.3 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.90 g) as starting compound and 6-bromo-1-(1-isopropyl-1 H-indol-3-yl)-1-hexanone (1.90 g) were reacted and treated in the same manner as in Example 199 to give 0.70 g of 4-amino-5-chloro-2-methoxy-N-((1-(6-(1-isopropyl-1H-indol-3-yl)-6-oxohexyl)-piperidin-4-yl)methyl)benzamide hydrochloride.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6]([SH:12])=[N:5][N:4]=1.I[CH2:14][CH3:15].C(N(CC)CC)C>C(O)C>[CH2:14]([S:12][C:6]1[N:7]([CH2:8][CH:9]([CH3:10])[CH3:11])[C:3]([CH2:2][OH:1])=[N:4][N:5]=1)[CH3:15]
Reactant: CC(C)Cn1c(S)nnc1CO
Reactant: CCI
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCSc1nnc(CO)n1CC(C)C
Yield: 87 %

Procedure:
A solution of 3-hydroxymethyl-4-isobutyl-5-mercapto-4H-1,2,4-triazole (1.0 g), iodoethane (1.0 g) and triethylamine (1.1 ml) in ethanol (10 ml) was stirred for 2 days at 70° C. The solvent was removed under reduced pressure, and the obtained residue was purified by column chromatography (ethanol:ethyl acetate 1:9→1:5), to give 5-ethylthio-3-hydroxymethyl-4-isobutyl-4H-1,2,4-triazole (1.0 g) as pale yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[CH3:33][C@@H:34]1[CH2:36][O:35]1>C(O)C>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH2:33][C@H:34]([OH:35])[CH3:36])[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Reactant: C[C@@H]1CO1
Solvent: CCO
Product: C[C@@H](O)CN1CCN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CC1
Yield: 16.5 %

Procedure:
To a solution of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (55 mg, 0.123 mmol) and (R)-2-methyl-oxirane (250 mg, 4.3 mmol) in 5 mL of ethanol is heated at 70° C. for 18 h. Following SiO2 chromatography, eluting with 0-10% (2M NH3 in MeOH)/dichloromethane] gave 7-cyclopentyl-2-{5-[4-((R)-2-hydroxy-propyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (10 mg, 16%). MS (ESI) m/z 493.3 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].F[C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=1>CC(N(C)C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][C:33]3[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(O)ccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2cc(Oc3ccc(C#N)cc3)ccc2C1
Temperature: 25 °C
Yield: 91.1 %

Procedure:
Combine in a round bottom flask equipped with a Dean Stark Trap 6-Hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.59 g, 6.36 mmol), toluene, dimethylacetamide (10 ml and 30 ml respectively), K2CO3 (1.25 g, 9.04 mmol), and 4-Fluorobenzonitrile (0.72 g, 6.04 mmol). Reflux the reaction under a Nitrogen atmosphere for 4 hours then cool to room temperature. Add water to the reaction mixture and extract the product from the water layer using ethyl acetate. The product, a white solid, precipitates out from the ethyl acetate to afford 1.93 g, 5.5 mmol (87% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 1.5 (9H, s), 2.75-2.85 (2H, m), 3.6-3.7 (2H, m), 4.5 (2H, s), 6.8-6.9 (2H, m), 6.9-7.0 (2H, m), 7.1-7.2 (1H, m), 7.5-7.6 (2H, m); MS m/z 249 (M+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:29][CH2:28][C:11]3([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:30][C@H:31]([C:36]2[CH:41]=[C:40](Br)[CH:39]=[CH:38][C:37]=2Br)[C:32]([F:35])([F:34])[F:33])[N:3]=1.[C:44]1(B(O)O)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[C:44]1([C:37]2[CH:38]=[CH:39][C:40]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:41][C:36]=2[C@@H:31]([O:30][C:4]2[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([N:8]3[CH2:29][CH2:28][C:11]4([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:12]4)[CH2:10][CH2:9]3)[CH:5]=2)[C:32]([F:33])([F:34])[F:35])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4cc(Br)ccc4Br)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4cc(-c5ccccc5)ccc4-c4ccccc4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OC(C)(C)C
Temperature: 90 °C

Procedure:
To a solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-1-(2,5-dibromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (660 mg, 0.95 mmol) in dioxane (12 mL) was added phenyl boronic acid (290 mg, 2.4 mmol), Pd2(dppf)Cl2 (70 mg, 0.095 mmol), and Na2CO3 (6.0 mL, 2.0 M, aq). The reaction mixture was heated to 90° C. for 2 h, then cooled to RT, concentrated in vacuo, and extracted with CH2Cl2. The combined organic layers were washed with brine, and dried over Na2SO4. Purification by normal phase silica gel column (EtOAc/heptane) provided (S)-2-tert-butyl 3-ethyl 8-(6-((R)-1-([1,1′:4′,1″-terphenyl]-2′-yl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Reaction SMILES: [OH:1][CH:2]1[NH:6][C:5](=[O:7])[CH:4]=[CH:3]1.[CH:8]1(O)[CH2:12][CH2:11][CH2:10][CH2:9]1>>[CH:8]1([O:1][CH:2]2[NH:6][C:5](=[O:7])[CH:4]=[CH:3]2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: OC1CCCC1
Reactant: O=C1C=CC(O)N1
Product: O=C1C=CC(OC2CCCC2)N1
Temperature: 60 °C

Procedure:
A mixture of 4.5 g of 1,5-dihydro-5-hydroxy-2H-pyrrol-2-one, 100 cm3 of cyclopentanol and 2.25 g of Amberlite IR 120 H is maintained for 8 hours at 60° C. It is then allowed to cool, is filtered, and evaporated to dryness. The residue is chromatographed on silica (eluent: ethyl acetate-n-hexane, 1--1). 3 g of the expected product is obtained, m.p.=77°-78° C. crystallized from cyclohexane. After recrystallizing from a mixture of isopropyl ether-n-hexane, 1--1, m.p.=81°-82° C.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6](=[O:26])[CH:7]([CH2:13][CH:14]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]1)[C:8]([O:10]CC)=[O:9])[CH3:4]>C(O)C>[CH2:3]([O:5][C:6](=[O:26])[CH:7]([CH2:13][CH:14]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]1)[C:8]([OH:10])=[O:9])[CH3:4]
Reactant: CCOC(=O)C(CC1CCN(C(=O)OC(C)(C)C)C1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(CC1CCN(C(=O)OC(C)(C)C)C1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
A solution of KOH (0.26 g; 4.6 mmol) in ethanol (7 mL) was added to a solution of 2-(1-tert-butoxycarbonyl-pyrrolidin-3-ylmethyl)-malonic acid diethyl ester (1.52 g; 4.4 mmol) in ethanol (7 mL) at 0° C. The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure and the residue was dissolved in water (500 mL). The aqueous layer was washed with diethyl ether, acidified to pH. 3 by 0.5 M HCl, and extracted with diethyl ether. The organic phase was dried and concentrated under reduced pressure to yield 2-(1-tert-butoxycarbonyl-pyrrolidin-3-ylmethyl)-malonic acid monoethyl ester (1.13 g, 81%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)=O.[NH2:20][C:21]1[CH:25]=[CH:24][NH:23][N:22]=1>C(O)(=O)C>[F:1][C:2]([F:19])([F:18])[C:3]1[N:22]2[N:23]=[CH:24][CH:25]=[C:21]2[N:20]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[CH:4]=1
Reactant: Nc1cc[nH]n1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)cc1
Solvent: CC(=O)O
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3nccc3n2)cc1
Temperature: 25 °C
Yield: 99 %

Procedure:
A mixture of 4,4,4-trifluoro-1-(4-trifluoromethyl-phenyl)-butane-1,3-dione (Example C.1, method 1, step 1) (2.84 g, 10 mmol) and 3-aminopyrazole (0.83 g, 10 mmol) in acetic acid (20 mL) were refluxed for 4 h. The reaction mixture was cooled to rt and poured into ice water (200 mL), extracted with EtOAc, dried over MgSO4, filtered and concentrated, and triturated with toluene, and dried to give 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (3.28 g, 99%) as a yellow solid. MS (ISP) 332.1 [(M+H)+]; mp 110-111° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][OH:39]>CS(C)=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([O:39][CH3:38])[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CO
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1

Procedure:
A mixture of 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide (0.1 mmol) and methanol (1.0 ml) in DMSO (0.5 ml) is heated using a microwave source at 180° C. for 5 min. The resulting mixture is diluted with CH2Cl2 (5 ml), washed with water, dried over Na2SO4 and concentrated. Purification of the residue by column chromatography on silica gel (50% EtOAc in hexane) gives 3-fluoro-N-{4-[(2-methoxypyrimidin-4-yl)oxy]-1-naphthyl}-5-morpholin-4-ylbenzamide as a white solid (31 mg). Mp: 216-217° C.; 1H NMR (300 MHz, CDCl3) δ 3.25(t, J=4.8 Hz, 4H), 3.84(s, 3H), 3.87(t, J=4.8 Hz, 4H), 6.53(d, J=5.7 Hz, 1H), 6.77(d, J=12 Hz, 1H), 7.06(d, J=8.4 Hz, 1H), 7.31-7.34(m, 2H), 7.49-7.60(m, 2H), 7.89-7.97(m, 3H), 8.15(s, 1H), 8.36(d, J=5.7 Hz, 1H);
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:37])[CH2:23][N:24]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25][C:26]([O:28]C)=[O:27])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1>[C:1]([O:5][C:6](=[O:38])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:37])[CH2:23][N:24]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25][C:26]([OH:28])=[O:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CN(CC(=O)NCCCCCCCCCCCCCCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCNC(=O)CN(CC(=O)O)C(=O)OC(C)(C)C
Reaction time: 16 h

Procedure:
15-[2-(tert-Butoxycarbonyl methoxycarbonylmethyl amino)acetylamino]pentadecanoic acid tert-butyl ester (0.22 g, 0.405 mmol) was dissolved in THF (5 mL) and 1 N NaOH (0.405 mL) was added. The mixture was stirred under nitrogen for 16 h. The mixture was concentrated under vacuum. The residue was suspended in AcOEt (ca 25 mL) and water (15 mL) and AcOH (3 mL) were added. The organic phase was isolated and washed with water (15 mL)+AcOH (1 mL), water (15 mL) and dried over magnesium sulphate, and concentrated under vacuum.
Reaction SMILES: C[C@H]1CO[C@@]2([O:9][C@H]3C[C@H]4[C@@H]5CC=C6C[C@@H](O)CC[C@]6(C)[C@H]5CC[C@]4(C)[C@H]3[C@@H]2C)CC1.[OH-].[K+].[CH2:33]([O:37][CH2:38][CH2:39][CH2:40]CCCCCCCCC)[CH:34]1[O:36][CH2:35]1>C1(C)C=CC=CC=1>[CH2:38]([O:37][CH2:33][CH:34]1[O:36][CH2:35]1)[CH:39]1[O:9][CH2:40]1
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC=C5C[C@@H](O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Reactant: CCCCCCCCCCCCOCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C(OCC1CO1)C1CO1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
In a 250 mL, round bottom 3-neck flask equipped with a condenser, a nitrogen in/out let, a mechanical stirrer, a thermo-watch, and a heating mantle, a mixture of 30 g of 10,000 Mw PEG and toluene (80 mL) was heated to 60° C. At this temperature, KOH (1.52 g, 0.04 mol, in 1.5 g of water) was added and the reaction mixture was stirred for 1 hour. Dodecyl glycidyl ether (5.81 g, 0.024 mole) was added and the reaction temperature was kept at 110° C. for 5 hours. After the reaction mass was cooled to 60° C., toluene (80 mL) was further added. The solution was precipitated into 300 mL of hexane. After filtration and washing with ethyl acetate (100 mL×3×) and drying in vacuum, a white polymer (31.8 g) was obtained. 1H NMR showed 11% hydrophobe incorporation. The Brookfield viscosity of a 5% aqueous solution of this oligomer was >400000 cps (BF LV, S-63, 0.3 rpm at 25° C.). Paint performance: SG10 M (standard formulation). The material was not soluble in this paint. For UCAR 379 G, TE %=0.52, VLT=−17 KU.
Reaction SMILES: [C:1]([CH:3]([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[CH:10]([C:12]([CH3:14])=[O:13])=[CH2:11]>C1(C)C=CC=CC=1>[O:13]=[C:12]([CH3:14])[CH2:10][CH2:11][C:3]([C:1]#[N:2])([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: C=CC(C)=O
Reactant: CCOC(=O)C(C)C#N
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C#N)CCC(C)=O
Yield: 86.2 %

Procedure:
A mixture of 127 mg (1.0 mmol) of ethyl 2-cyanopropanoate, 0.12 ml (1.5 mmol) of methyl vinyl ketone, and 9.4 mg (0.01 mmol) of Rh(acac)(CO)(L) obtained in Example 8 was stirred in 5 ml of toluene at 0° C. for 13 hours. The reaction mixture was concentrated to yield 170 mg (86%) of ethyl 5-oxo-2-cyano-2-methylhexanoate. The product was found to have an optical purity of 73% e.e. as analyzed by high performance liquid chromatography using a Chiralcel OJ column manufactured by Daicel Chemical Industries, Ltd.