Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])C)=[O:4].[N:22]1([CH2:28][CH2:29][O:30][C:31]2[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=2)CN)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>CO>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:7]2[S:6][C:5]3[C:3](=[O:4])[N:12]([CH2:14][C:33]4[CH:36]=[CH:37][CH:38]=[C:31]([O:30][CH2:29][CH2:28][N:22]5[CH2:23][CH2:24][O:25][CH2:26][CH2:27]5)[CH:32]=4)[CH:11]=[N:10][C:9]=3[CH:8]=2)=[CH:20][CH:19]=1
Reactant: NCc1cccc(OCCN2CCOCC2)c1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N=CN(C)C
Solvent: CO
Product: O=c1c2sc(-c3ccc(Cl)cc3)cc2ncn1Cc1cccc(OCCN2CCOCC2)c1
Temperature: 25 °C

Procedure:
5-(4-Chlorophenyl)-3-(dimethylamino-methyleneamino)-thiophene-2-carboxylic acid methyl ester (0.164 g, 0.508 mmol), 3-(2-morpholin-4-yl-ethoxy)-benzylamine (0.100 g, 0.423 mmol) and MeOH (1.5 mL) were heated by MW at 120° C. for 15 minutes. The reaction mixture was allowed to cool to r.t., the precipitate filtered, washed with MeOH, and dried in vacuo to give the product. Yield: 0.110 g (45%). 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.63 (d, 2H, J=8.42 Hz), 7.45 (s, 1H), 7.41 (d, 2H, J=8.42 Hz), 7.25 (m, 1H), 6.81-6.94 (m, 3H), 5.17 (s, 2H), 4.06 (t, 2H, J=6.12 Hz), 3.70 (t, 4H, J=4.68 Hz), 2.75 (t, 2H, J=5.58 Hz), 2.53 (t, 4H, J=4.51 Hz). MS (ESI+) 481.92 (M+1H+).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[C:5]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])[CH2:4][C@@H:3]1[CH3:25].[CH3:26][S:27](Cl)(=[O:29])=[O:28]>N1C=CC=CC=1>[CH3:26][S:27]([O:1][C@H:2]1[C@@H:3]([CH3:25])[CH2:4][C:5]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])=[CH:6][C@H:7]1[NH:8][C:9]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:15])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1CC(c2ccncc2[N+](=O)[O-])=C[C@@H](NC(=O)OC(C)(C)C)[C@H]1O
Solvent: c1ccncc1
Product: C[C@H]1CC(c2ccncc2[N+](=O)[O-])=C[C@@H](NC(=O)OC(C)(C)C)[C@H]1OS(C)(=O)=O
Reaction time: 0.08 h
Yield: 46 %

Procedure:
To a solution of (+/−)-tert-butyl ((1R,5S,6S)-6-hydroxy-5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-en-1-yl)carbamate (1.0 equiv.) in pyridine (0.20 M) was added MsCl (5.0 equiv.). The capped solution was stirred for 5 minutes and then the homogeneous solution was left standing at rt for 16 hrs. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and H2O. The organic layer was washed with 10% CuSO4, H2O, Na2CO3(sat.), NaCl(sat.), dried over MgSO4, filtered, concentrated and purified by ISCO SiO2 chromatography to yield (+/−)-(1S,2R,6S)-2-((tert-butoxycarbonyl)amino)-6-methyl-4-(3-nitropyridin-4-yl)cyclohex-3-en-1-yl methanesulfonate in 46% yield. LC/MS (m/z)=428.2 (MH+), Rt=0.89 min.
Reaction SMILES: [C:1]1(=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[O:17]1[CH2:18][CH2:19][N:14]([C:1]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)[CH2:15][CH2:16]1
Reactant: C1COCCN1
Reactant: O=C1CCCCCCCCCCC1
Product: C1=C(N2CCOCC2)CCCCCCCCCC1

Procedure:
Generally, the process described in U.S. Pat. No. 4,367,346 can be used to synthesize long chain carbon compounds. The Patent 4,367,346 synthesis route consists of: (a) reacting cyclododecanone with morpholine in the presence of a catalyst to form 1-morpholino-1-cyclododecene; (b) separating the 1-morpholino-1-cyclododecene and reacting it with an organic acid halide of 15-20 carbon atoms in the presence of a tertiary amine in an organic solvent while maintaining the reaction temperature at 0°-10° C. followed by (c) hydrolysis under acidic conditions, thereafter (d) separating the 2-n-alkyl-cyclotetradecanedione and reacting with a solution of alkali metal hydroxide and diethylene glycol at 90°-110° C. followed by (e) addition of hydrazine hydrate and the reaction mixture is refluxed at 125°-135° C., thereafter (f) the distillate is removed until the temperature of the reaction mixture climbs to 190°-210° C. where it is refluxed for 3 to 20 hours with slow stirring, and then (g) cooled to 110°-125° C. followed by addition of hot (80°-95° C.) water with rapid stirring followed by (h) neutralization with aqueous acid to a pH of 2 to yield the carboxylic acid which is separated and purified by recrystallization which is then (i) dissolved in tetrahydrofuran under an inert atmosphere and has added thereto the reducing agent, borane-methyl sulfide complex with stirring and heated to 40°-65° C. for 2 to 3 hours before cooling to ambient temperature followed by the sequential addition of ethanol and water to quench excess borane reagent followed by (k) separation and purification of the long chain alcohol.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[H-].[Na+].Cl[C:18]1[N:23]=[N:22][C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:20]2[S:29][C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)=[CH:31][C:19]=12.CCOC(C)=O>CN1C(=O)CCC1>[C:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][CH:2]([O:1][C:18]2[N:23]=[N:22][C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:20]3[S:29][C:30]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=4)=[CH:31][C:19]=23)[CH2:3]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCOC(=O)c1nnc(Cl)c2cc(-c3cccc(F)c3)sc12
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nnc(OC2CCCN(C(=O)OC(C)(C)C)C2)c2cc(-c3cccc(F)c3)sc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.2 %

Procedure:
tert-Butyl 3-hydroxypiperidine-1-carboxylate (100 mg, 0.5 mmol) was dissolved in dry NMP (5 mL) and NaH (20 mg, 60% in oil, 0.5 mmol) was added carefully. The mixture was stirred at room temperature for 10 min. Then, ethyl 4-chloro-2-(3-fluorophenyl)thieno[2,3-d]pyridazine-7-carboxylate (130 mg, 0.5 mmol) was added. The mixture was heated up to 80° C. and stirred for 30 min. After cooling to room temperature, EtOAc was added to dilute the reaction and washed with water and brine. The organics was dried over Na2SO4 and filtered, concentrated. The crude product was purified with column (silica gel) to give the product ethyl 4-(1-(tert-butoxycarbonyl)piperidin-3-yloxy)-2-(3-fluorophenyl)thieno[2,3-d]pyridazine-7-carboxylate (151 mg). HPLC-MS tR=2.17 min (UV254 nm); mass calculated for formula C25H28FN3O5S 501.2, observed LCMS m/z 502.2 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:39])[C:5]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[F:38])([CH3:30])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18](=[O:28])[N:17]2[CH3:29])=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)C>[CH2:21]([N:19]1[CH2:20][CH:16]([CH2:15][CH2:14][O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:5]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[F:38])([CH3:30])[C:4]([OH:39])=[O:3])=[CH:8][CH:9]=2)[N:17]([CH3:29])[C:18]1=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccccc3)C(=O)N2C)cc1)Oc1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1C(=O)N(Cc2ccccc2)CC1CCOc1ccc(CC(C)(Oc2ccccc2F)C(=O)O)cc1
Temperature: 25 °C

Procedure:
A solution of 3-{4-[2-(1-Benzyl-3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-(2-fluoro-phenoxy)-2-methyl-propionic acid ethyl ester and 5N NaOH (0.2 mL) in ethanol (2 mL) is refluxed under nitrogen for 1 h, cooled to ambient temperature, and concentrated in vacuo. The residue is diluted with 1N HCl, extracted with CH2Cl2, dried, concentrated in vacuo, and purified by LCMS to provide the title compound. 1H NMR (400 MHz, CDCl3): δ 7.55 (d, 1H, J=8.4 Hz), 7.34-7.21 (m, 6H), 7.10-7.01 (m, 4H), 6.74 (d, 2H, J=8.4 Hz), 4.46-3.36 (m, 2H), 3.96 (q, 2H, J=6.0 Hz), 3.74-3.65 (m, 1H), 3.45-3.39 (m, 1H), 3.28, 3.16 (ABq, 2H, J=14.7 Hz), 3.05 (q, 1H, J=8.6 Hz), 2.26-2.19 (m, 1H), 1.93-1.86 (m, 1H), 1.41 (s, 3H). MS [EI+] 507 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C([Li])CCC.CN(C)[CH:25]=[O:26]>C1COCC1.[Cl-].[NH4+]>[N:12]1([C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([CH:25]=[O:26])[CH:3]=3)[N:8]=[CH:7][CH:6]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CN(C)C=O
Reactant: Brc1ccc2nccc(N3CCOCC3)c2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=Cc1ccc2nccc(N3CCOCC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.5 %

Procedure:
To a solution of 6-bromo-4-morpholin-4-ylquinoline (1.06 g, 3.62 mmol) in THF (22 mL) was added dropwise a 2.5M solution of n-butyllithium in hexanes (1.74 mL, 4.34 mmol, 1.2 equiv.) at −70° C. During the addition, the color of the solution was turned into red and this solution was stirred for 1 h at this temperature. Then, a solution of dimethylformamide (0.558 mL, 7.23 mmol) in THF (2 mL) was added dropwise. After addition, the mixture was allowed to warm to room temperature and stirred for 2 h. Then, the mixture was diluted with saturated ammonium chloride solution and the two layers were separated. The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent under the vacuum gave the crude residue which was purified by using a Biotage silica gel column chromatography to afford 0.390 g (44.5% yield) of 4-morpholin-4-yl-quinoline-6-carbaldehyde as a white solid: EI-LRMS m/e calcd for C14H14N2O2 (M+) 243.1, found 243.1.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[CH2:19][CH2:20][O:21][C:22]4[CH:28]=[CH:27][C:26]([C:29]5[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=5)=[CH:25][C:23]=4[CH:24]=3)=[O:17])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:44])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[O-:44][N+:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[C:3]=1[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]2[CH2:19][CH2:20][O:21][C:22]3[CH:28]=[CH:27][C:26]([C:29]4[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=4)=[CH:25][C:23]=3[CH:24]=2)=[O:17])=[CH:13][CH:14]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(Cc4ncccc4O)cc2)CCO3)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(Cc4c(O)ccc[n+]4[O-])cc2)CCO3)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 63.3 %

Procedure:
To a suspension of N-[4-(3-hydroxypyridin-2-ylmethyl)phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (400 mg) in tetrahydrofuran (30 ml) was added 3-chloroperbenzoic acid (70%, 0.32 g) at 0° C., and the mixture was stirred at room temperature for 15 hours. To the mixture was added sodium thiosulfate, and the mixture was stirred for a few minutes and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried with magnesium sulfate, concentrated under reduced pressure and recrystallized from ethanol to give N-[4-(1-oxido-3-hydroxypyridin-2-ylmethyl)phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 175) (262 mg) as pale yellow crystals.
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[C:3]#[C:4][CH3:5].[Li]CCCC.CCCCCC.[Cl:19][C:20]1[C:25]2[N:26]([CH3:31])[C:27]([CH2:29]Cl)=[N:28][C:24]=2[CH:23]=[CH:22][CH:21]=1>C1COCC1>[Cl:19][C:20]1[C:25]2[N:26]([CH3:31])[C:27]([CH2:29][CH2:5][C:4]#[C:3][Si:2]([CH3:7])([CH3:6])[CH3:1])=[N:28][C:24]=2[CH:23]=[CH:22][CH:21]=1
Reactant: CC#C[Si](C)(C)C
Reactant: Cn1c(CCl)nc2cccc(Cl)c21
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cn1c(CCC#C[Si](C)(C)C)nc2cccc(Cl)c21
Reaction time: 1.5 h
Yield: 96.8 %

Procedure:
To a solution of the trimethyl(prop-1-ynyl)silane (0.21 mL, 1.4 mmol) in THF (4 mL), was added at −78° C. nBuLi 2.5M in hexane (0.56 mL, 1.3 mmol). After 90 min at −78° C., a solution of 7-chloro-2-(chloromethyl)-1-methyl-1H-benzo[d]imidazole (250 mg, 1.2 mmol) in THF (2 mL) was added. Mixture went from purple to orange and then dark brown. The reaction was quenched after 1 h at −78° C. with water and the solvent was evaporated to dryness to afford 338 mg of 7-chloro-1-methyl-2-(4-(trimethylsilyl)but-3-ynyl)-1H-benzo[d]imidazole (Yield: 100%) as a brown oily solid. It was carried through to the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:3]=1[C:4]([NH:6][CH2:7][CH:8]([N:16]1[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]1)[C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[N:13][CH:14]=1)=[O:5].C[N+]1([O-])CCOCC1>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[Cl:1][C:2]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:3]=1[C:4]([NH:6][CH2:7][CH:8]([C:9]1[CH:14]=[N:13][C:12]([CH3:15])=[N:11][CH:10]=1)[N:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1)=[O:5]
Reactant: Cc1ncc(C(CNC(=O)c2cccc(Cl)c2Cl)N2CCC(O)CC2)cn1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: Cc1ncc(C(CNC(=O)c2cccc(Cl)c2Cl)N2CCC(=O)CC2)cn1
Reaction time: 8 h
Yield: 23.8 %

Procedure:
To a solution of 2,3-dichloro-N-(2-(4-hydroxypiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide (130 mg, 0.32 mmol) in DCM (5 mL) was added 4 A molecular sieves (1.3 g), NMO (205 mg, 1.75 mmol) and TPAP (2.2 mg). The mixture was stiffed at room temperature overnight. The resulting mixture was filtered. The filtrate was washed with water, dried over Na2SO4 and concentrated. The residue was purified by preparative TLC (EtOAc:MeC)H=100:3) to give 2,3-dichloro-N-(2-(2-methylpyrimidin-5-yl)-2-(4-oxopiperidin-1-yl)ethyl)benzamide (31 mg, yield: 24%) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1>[C:10]([N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[N:4]([C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]1=[O:8])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: c1ccncc1
Product: O=C(c1ccccc1)n1cc(F)c(=O)n(C(=O)c2ccccc2)c1=O
Temperature: 70 °C
Yield: 50.3 %

Procedure:
2.6 g (0.02 mole) of 5-fluorouracil was suspended in 10 ml of absolute pyridine, and the suspension was stirred at 70° C to form a solution. 17 g (0.12 mole) of benzoyl chloride was added dropwise to the resulting solution followed by heating to 80° C for 1.5 hours while stirring. After completion of the reaction, the reaction mixture was concentrated under reduced pressure (25 mm Hg) to half its original volume, and 50 ml of ethyl acetate was added thereto. After the insoluble matter in the ethyl acetate was removed, the solution was washed twice with water, and dried over Glauber's salt, and the ethyl acetate removed therefrom under reduced pressure (25 mm Hg). Ethanol was then added to the residue, and the mixture heated to 80° C to form a solution followed by allowing the resulting solution to cool to precipitate crystals, which were then filtered to obtain 3.4 g of 1,3-di-N-benzoyl-5-fluorouracil in a yield of 51%.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:27]([CH3:42])([CH3:41])[C:28](=[O:40])[C@H:29]([CH3:39])[C@@H:30]([OH:38])[C@@H:31]([CH3:37])[CH2:32][CH2:33][CH2:34][CH:35]=[CH2:36])[CH2:10][C:11]([O:13][C@@H:14]([CH2:24][CH:25]=[CH2:26])/[C:15](/[CH3:23])=[CH:16]/[C:17]1[N:18]=[C:19]([CH3:22])[S:20][CH:21]=1)=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C(C)=CC=CC=1C.[Si:51](OS(C(F)(F)F)(=O)=O)([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52]>C(Cl)Cl>[Si:1]([O:8][C@H:9]([C:27]([CH3:41])([CH3:42])[C:28](=[O:40])[C@H:29]([CH3:39])[C@@H:30]([O:38][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52])[C@@H:31]([CH3:37])[CH2:32][CH2:33][CH2:34][CH:35]=[CH2:36])[CH2:10][C:11]([O:13][C@@H:14]([CH2:24][CH:25]=[CH2:26])/[C:15](/[CH3:23])=[CH:16]/[C:17]1[N:18]=[C:19]([CH3:22])[S:20][CH:21]=1)=[O:12])([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: C=CCCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@H](CC(=O)O[C@@H](CC=C)/C(C)=C/c1csc(C)n1)O[Si](C)(C)C(C)(C)C
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: C=CCCC[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C(=O)C(C)(C)[C@H](CC(=O)O[C@@H](CC=C)/C(C)=C/c1csc(C)n1)O[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
A solution of (3S,6R,7S,8S)-(S,E)-2-methyl-1-(2-methylthiazol-4-yl)hexa-1,5-dien-3-yl 3-((tert-butyldimethylsilyl)oxy)-7-hydroxy-4,4,6,8-tetramethyl-5-oxotridec-12-enoate (Nicolaou, K. C.; He, Y.; Vourloumis, D.; Vallberg, H.; Roschangar, F.; Sarabia, F.; Ninkovic, S.; Yang, Z.; Trujillo, J. I. J. Am. Chem. Soc. 1997, 119, 7960-7973) in DCM at −50° C. was treated with 2,6-lutidine (1.82 mL, 15.7 mmol) followed by TBSOTf (3.60 mL, 15.7 mmol). The reaction mixture was stirred at the same temperature for 0.5 h, quenched by NH4Cl (sat.) and extracted with DCM (3×). The combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure. Purification by chromatography on SiO2 (hexanes:ethyl ether=100:2 to 10:1) followed by the second chromatography (hexanes: diethyl ether=100:4 to 100:6 to 10:1) afforded 0.281 g (73%) of the title compound as a colorless oil.
Reaction SMILES: COC([C@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12](OC)=[O:13])[CH2:7][C@H:6]1[C:16](=[O:22])[N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=O.CC(C)([O-])C.[K+].O>C1(C)C=CC=CC=1>[CH2:18]([N:17]([CH2:20][CH3:21])[C:16]([C@@H:6]1[C@H:5]2[CH2:10][CH2:9][N:8]([CH2:11][C:12]2=[O:13])[CH2:7]1)=[O:22])[CH3:19]
Reactant: CCN(CC)C(=O)[C@@H]1CN(CC(=O)OC)CC[C@@H]1C(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCN(CC)C(=O)[C@H]1CN2CC[C@H]1C(=O)C2
Temperature: 25 °C
Yield: 30.7 %

Procedure:
A solution of 12 (159 g, 0.503 mole) in toluene (700 ml) was added dropwise over a period 2.5 hours to a solution of potassium t-butoxide (169 g, 1.51 mole) in toluene (1.9 L) at 110° C. under a nitrogen condition. The mixture was heated at reflux for 1 hour and cooled down to room temperature. Water (400 ml) was added then the layers were heated at reflux for 2 hours. After the organic layer was separated, the aqueous layer was neutralized and extracted with EtOAc for 15 hours with continuous extraction apparatus. The combined extracts were dried over MgSO4 and concentrated down. Recrystallization from EtOH gave 13 (34.6 g, 31%) as a colorless crystal. The stereochemistry was determined by X-Ray analysis, 13C and NMR.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].Cl.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]2[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=2)=[CH:16][CH:15]=1>COCCOC>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]2[CH:42]=[CH:41][C:37]([C:38]([CH:2]([C:3]([CH3:5])=[O:4])[C:1]([O:7][CH2:8][CH3:9])=[O:6])=[O:39])=[CH:36][CH:35]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: O=C(Cl)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(C(C)=O)C(=O)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1

Procedure:
A solution of 21.6 g. of ethyl acetoacetate and 10 ml. of 1,2-dimethoxyethane is added to a suspension of 4.0 g. of sodium hydride in 1,2-dimethoxyethane under argon. A solution of 17.3 g. of 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoyl chloride hydrochloride in 1,2-dimethoxyethane is then added. The reaction mixture is refluxed for 5 hours, cooled, poured on ice and extracted with ether. The ether solution is washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to dryness. Recrystallization from ether affords ethyl 2-{4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoyl}acetoacetate as a white solid.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].C(N(CC)CC)C.[Cl:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>ClCCl>[Cl:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])=[O:24])=[CH:26][CH:27]=1
Reactant: O=C(Cl)c1ccc(OCCCCl)cc1
Reactant: CC(C)(N)CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(CO)NC(=O)c1ccc(OCCCCl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-amino-2-methylpropanol (0.914 g, 10.2 mmol, 1.1 eq) and triethylamine (2.6 ml, 18.7 mmol, 2 eq) in dry dichloromethane (75 ml) is cooled (ice bath) and a solution of 4-(3-chloropropoxy)benzoyl chloride ax52 (2.95 g, 12.4 mmol, 1 eq) in dichloromethane (15 ml) is added dropwise, over 30 min. The mixture is then stirred at room temperature overnight. The suspension is washed with 1 M aqueous hydrochloric acid (2 times), an aqueous potassium carbonate solution (2 times) and brine, dried over magnesium sulfate and evaporated in vacuum to give 4-(3-chloropropoxy)-N-(2-hydroxy-1,1-dimethylethyl)benzamide ax53 (3.4 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)#[N:25]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:32][C:29]4[CH:30]=[CH:31][C:26]([C:24]#[N:25])=[CH:27][CH:28]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(C#N)cc4)ncnc32)CC1

Procedure:
4-[4-(4-Cyano-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure A by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19) with 4-cyanophenol (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA) in acetonitrile. 1H NMR (400 MHz, DMSO-d6) δ 1.43 (s, 9H), 1.94-2.04 (m, 4H), 2.95-3.05 (m, 2H), 4.08-4.11 (m, 2H), 4.98-5.04 (m, 1H), 7.58-7.60 (m, 2H), 7.99-8.01 (m, 2H), 8.37 (s, 1H), 8.56 (s, 1H). Mass spectrum MH+=421.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH:5]=[C:4]([Cl:16])[CH:3]=1.[C:17](=[O:19])=[O:18]>Cl.C(OCC)(=O)C>[Cl:16][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH:5]=1)[C:17]([OH:19])=[O:18]
Reactant: O=C=O
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1cc(Cl)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64 %

Procedure:
To “Rieke Mg” (0.21 mol; Rieke, R. D.; Bales, S. E.; Hudnall, P. M.; Bums, T. P.; Poindexter, G. S. Org. Synth. Collective Volume VI, 1988, 845.) in tetrahydrofiran (1000 mL) was added ether 13 (27.7 g, 0.10 mol). After the reaction mixture was stirred for 20 min at ambient temperature there was an exotherm observed. The exotherm. subsided within 5 min, and the reaction mixture was cooled to 20° C. with an ice bath. After 15 min, the reaction mixture was cooled to −78° C. To the cool reaction mixture was added CO2 gas for 30 min. The reaction mixture was warmed to ambient temperature, then diluted with cold (0° C.) 10% aqueous HCl (150 mL) and ethyl acetate (400 mL). The aqueous phase was extracted with ethyl acetate (400 mL). The combined organic phases were washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting solid was recrystallized from acetonitrile to provide 14 as fluffy white needles (19.3 g, 64%). 1H NMR (300 MHz, CDCl3) δ 7.70 (s, 1H), 7.43 (s, 1H), 7.08 (s, 1H), 0.99 (s, 9H), 0.23 (s, 6H). IR (KBr) 2957, 1697, 1578, 1434, 1297, 1266, 1115, 990,871 cm−1.