Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([O:36][C:37]2[CH:45]=[CH:44][C:43]([O:46][C:47]([C:49]3[CH:54]=[CH:53][C:52]([O:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][O:62][C:63](=[O:66])[CH:64]=[CH2:65])=[CH:51][CH:50]=3)=[O:48])=[CH:42][C:38]=2[C:39]([OH:41])=[O:40])=[O:35])=[CH:30][CH:29]=1)(=[O:19])[CH:17]=[CH2:18].[C:67]([O:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][O:78][C:79]1[CH:84]=[CH:83][C:82]([C:85]([O:87][C:88]2[CH:93]=[CH:92][C:91]([CH2:94]O)=[CH:90][CH:89]=2)=[O:86])=[CH:81][CH:80]=1)(=[O:70])[CH:68]=[CH2:69].O>CN(C)C1C=CN=CC=1.ClCCl>[C:16]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]([O:36][C:37]2[CH:45]=[CH:44][C:43]([O:46][C:47]([C:49]3[CH:50]=[CH:51][C:52]([O:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][O:62][C:63](=[O:66])[CH:64]=[CH2:65])=[CH:53][CH:54]=3)=[O:48])=[CH:42][C:38]=2[C:39]([O:41][CH2:94][C:91]2[CH:92]=[CH:93][C:88]([O:87][C:85]([C:82]3[CH:83]=[CH:84][C:79]([O:78][CH2:77][CH2:76][CH2:75][CH2:74][CH2:73][CH2:72][O:71][C:67](=[O:70])[CH:68]=[CH2:69])=[CH:80][CH:81]=3)=[O:86])=[CH:89][CH:90]=2)=[O:40])=[O:35])=[CH:32][CH:33]=1)(=[O:19])[CH:17]=[CH2:18]
Reactant: C=CC(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(CO)cc2)cc1
Reactant: C=CC(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(OC(=O)c3ccc(OCCCCCCOC(=O)C=C)cc3)c(C(=O)O)c2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: C=CC(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(COC(=O)c3cc(OC(=O)c4ccc(OCCCCCCOC(=O)C=C)cc4)ccc3OC(=O)c3ccc(OCCCCCCOC(=O)C=C)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.3 %

Procedure:
0.2 g of N,N'-dicyclohexylcarbodiimide is added at room temperature while stirring to a solution of 0.6 g of 2,5-bis(4-[6-acryloyloxyhexyloxy]-phenylcarbonyloxy)-benzoic acid, 0.4 g [4-(4-[6-acryloyloxyhexyloxy]-phenylcarbonyloxy)phenyl]methanol and 0.04 g of 4-dimethylaminopyridine in 20 ml of dichloromethane. The reaction mixture is stirred at room temperature overnight, poured into 100 ml of water and then extracted three times with 50 ml of dichloromethane each time. The combined organic phases are washed twice with 100 ml of water each time, dried over magnesium sulphate, filtered and the filtrate is subsequently concentrated. Chromatographic purification of the residue on silica gel with hexane/ethyl acetate (vol. 1:1) and two-fold recrystallization from acetone of the fractions which are pure according to thin-layer chromatography gives 0.4 g of [4-(4-[6-acryloyloxyhexyloxy]-phenylcarbonyloxy)-phenyl]-methyl 2,5-bis(4-[6-acryloyloxyhexyloxy]-phenylcarbonyloxy)-benzoate.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:11][C:12]([CH3:17])=[CH:13][C:14](Cl)=[O:15].N1C=CC=CC=1>C(Cl)Cl>[CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:14](=[O:15])[CH:13]=[C:12]([CH3:17])[CH3:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(N)cc1
Reactant: CC(C)=CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)=CC(=O)Nc1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-isopropylaniline (5.0 g, 37.0 mmol) in 100 ml of anhydrous CH2Cl2 under argon at 0° C. was added 3,3-dimethylacryloyl chloride (4.12 ml, 37.0 mmol). Pyridine (3.0 ml, 40.6 mmol) was added, and the mixture was stirred at 25° C. for 12 hours. The reaction was quenched with water and extracted with ethyl ether. The organic layer was washed with water, and brine, dried over Na2SO4 and were in vacuo to give the title compound as a light brown solid.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16]([SH:20])[CH2:17][CH2:18][CH3:19].O>CC(N(C)C)=O>[CH2:16]([S:20][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH2:17][CH2:18][CH3:19]
Reactant: N#Cc1ccc(Cl)cc1
Reactant: CCCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCCCSc1ccc(C#N)cc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a well-stirred suspension of 41.27 g (0.3 mol) of 4-chlorobenzonitrile, 58.05 g (0.42 mol) of potassium carbonate and 200 ml DMA a solution of 27.06 g (0.3 mol) of 1-butanethiol in 50 ml of DMA are added under an atmosphere of nitrogen. The resulting mixture is heated to 80° C. and stirred at this temperature for 24 hours. Then, the reaction mixture is cooled to room temperature and poured into 750 ml of water. The crude product is extracted with 300 ml of ethyl acetate, washed with water, dried over MgSO4. Thereafter, ethyl acetate is removed. Then, fractional distillation yields 52.88 9 (80.4%) of colorless liquid 4-n-butylthio-benzonitrile.
Reaction SMILES: O[C:2]1([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][C:5]2[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:4]=2[CH2:3]1.Cl>C(O)(=O)C.[Pd]>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:4]2[CH2:3][CH:2]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[CH2:6][C:5]=2[CH:13]=1
Reactant: CCOC(=O)CC1(O)Cc2ccc(OC)cc2Cc2ccccc21
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)CC1Cc2ccc(OC)cc2Cc2ccccc21
Temperature: 35 °C
Reaction time: 18 h
Yield: 88.4 %

Procedure:
Ethyl (±)-10,11-dihydro-10-hydroxy-3-methoxy-5H-dibenzo[a,d]cycloheptene-10-acetate (101 g, 0.31 mole) was dissolved in glacial acetic acid (1.8 L) and 12 N HCl (28.5 mL, 0.34 mole) was added. The mixture was placed in a 2.5 L pressure bottle containing 5% Pd/C (20 g, 0.0094 mole), and the resulting mixture was shaken at 35° C. under hydrogen on a Parr hydrogenation apparatus equipped with a jacket heater. After 18 hr, the reaction was cooled to ambient temperature, and the catalyst was removed by filtration. The filtrate was concentrated to give a light yellow oil (85.1 g). This was chromatographed on silica gel (2 kg, step-gradient with 5% to 10% EtOAc/hexanes) to afford the title compound (69.1 g, 72%) as an oil: 1H NMR (250 MHz, CDCl3) δ7.05-7.22 (m, 4 H), 7.01 (d, J=8.2 Hz, 1 H), 6.76 (d, J=2.7 Hz, 1 H), 6.67 (dd, J=8.2, 2.7 Hz, 1 H), 4.30 (d, J=15.0 Hz, 1 H), 4.11-4.25 (m, 2 H), 3.85 (d, J=15.0 Hz, 1 H), 3.70-3.90 (m, 1 H), 3.77 (s, 3 H), 3.31 (dd, J=15.0, 4.1 Hz, 1 H), 2.93 (dd, J=15.0, 9.2 Hz, 1 H), 2.64 (dd, J=15.6, 5.0 Hz, 1 H), 2.52 (dd, J=15.6, 9.3 Hz, 1 H), 1.27 (t, J=7.1 Hz, 3 H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[C:4]([C:11]([OH:13])=O)[CH:3]=1.[C:14]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:15]C(C)=O.C(N(CC)CC)C>C(OC(=O)C)(=O)C>[CH2:21]([O:20][C:14]([CH:15]1[C:8](=[O:10])[C:5]2[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][C:4]=2[C:11]1=[O:13])=[O:19])[CH3:22]
Reactant: Cc1cc(C(=O)O)c(C(=O)O)cn1
Reactant: CCOC(=O)CC(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1C(=O)c2cnc(C)cc2C1=O
Reaction time: 8 h

Procedure:
6-Methyl-pyridine-3,4-dicarboxylic acid (440 mg) (see Emil J. Moriconi and Francis A. Spano, J. Am. Chem. Soc., Vol. 86, Pp. 38-46, 1964) was suspended in acetic anhydride (10 ml) and the mixture was refluxed for 10 minutes. Ethyl acetoacetate (0.325 ml) and triethylamine (0.745 ml) were dropwise added to the mixture at room temperature and the mixture was stirred overnight. The mixture was concentrated to dryness and purified by silica gel column chromatography developed by dichloromethane and by dichloromethane-methanol (15:1). The desired compound was obtained as a dark red oil which contained 1 equivalent of triethylamine. ESI−MS: m/z 234 (MH+); 1H-NMR (CDCl3): δ1.26-1.38 (15H, m), 2.63 (3H, s), 3.28 (6H, q, J=3.3 Hz), 4.22 (2H, q, J=4.2 Hz), 7.29 (1H, s), 8.58 (1H, s).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9](=[O:25])[C:10]([O:23][CH3:24])=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([C:19]([F:22])(F)F)[CH:13]=1.Br[CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:33][CH:32]=1>CN(C)C=O>[CH3:7][O:8][C:9](=[O:25])[C:10]([O:23][CH3:24])=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:27][CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:33][CH:32]=2)=[C:14]([CH2:19][F:22])[CH:13]=1
Reactant: COC(=O)C(=Cc1ccc(O)c(C(F)(F)F)c1)OC
Reactant: BrCCCOc1ccc(-c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(=Cc1ccc(OCCCOc2ccc(-c3ccccc3)cc2)c(CF)c1)OC
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
Potassium tert-butoxide (15 mg, 0.13 mmol) was added at 0° C. to a solution of 3-(4-hydroxy-3-trifluoromethyl-phenyl)-2-methoxy-acrylic acid methyl ester (35 mg, 0.126 mmol) in dry N,N-dimethylformamide (0.6 mL). The mixture was stirred for 0.5 hours and 4-(3-Bromo-propoxy)-biphenyl (example 23, Step D) (45 mg, 0.15 mmol) was added. The reaction was stirred for 6 hours at room temperature and quenched with a saturated solution of ammonium chloride (10 mL). The aqueous layer was separated and extracted with methylene chloride (5×10 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under vacuum. The residue was chromatographed (silica gel, hexanes/ethyl acetate 8:2) to produce 3-{4-[3-(biphenyl-4-yloxy)-propoxy]-3-fluoromethyl-phenyl}-2-methoxy-acrylic acid methyl ester as a colorless oil (35 mg, 57%). 1H-NMR (CDCl3, 200.15 MHz): δ 8.00 (d, 1H, J=1.6), 7.89 (dd, 1H, J=8.6, 1.6), 7.46–7.26 (m, 7H), 7.05–6.93 (m, 4H), 4.33–4.20 (m, 4H), 3.86 (s, 3H), 3.79 (s, 3H), 2.33 (qn, 2H, J=5.9).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:20]=[C:19]([OH:21])[CH:18]=[C:17](Br)[CH:16]=2)=[CH:9][C:8]=1[CH3:23])[CH3:2].[C:25]1([CH2:31][C:32]#[CH:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(N(CC)CC)C.CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu](I)I>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:16]=[C:17]([C:33]#[C:32][CH2:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:18]=[C:19]([OH:21])[CH:20]=2)=[CH:9][C:8]=1[CH3:23])[CH3:2]
Reactant: CCOC(=O)COc1ccc(SCc2cc(O)cc(Br)c2)cc1C
Reactant: C#CCc1ccccc1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(SCc2cc(O)cc(C#CCc3ccccc3)c2)cc1C

Procedure:
[4-(3-Bromo-5-hydroxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (2 g; 4.9 mmol), 3-phenyl-1-propyn (1.7 g; 14.6 mmol), bis(triphenylphosphine)palladium (II) chloride (0.27 g; 0.39 mmol) and copper iodide (0.056 g; 0.29 mmol) were dissolved in a mixture of triethylamine (5 mL) and DMF (10 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 100° C. for 1 h. Further 3-phenyl-1-propyn (1.7 g; 14.6 mmol) was added and the reaction mixture was reacted in a microwave oven at 100° C. for further 1 h. The reaction mixture was purified by preparative HPLC (method A). Yield: 0.8 g. HPLC-MS: m/z: 434.6 (M+1); Rt: 2.43 min.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH2:5].C(OC(C)C)(C)C.[F:13][C:14]([F:35])([S:31](F)(=[O:33])=[O:32])[C:15]([F:30])([F:29])[C:16]([F:28])([F:27])[C:17]([F:26])([F:25])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20]>>[NH2:1][CH2:2][CH2:3][CH2:4][NH:5][S:31]([C:14]([F:13])([F:35])[C:15]([F:29])([F:30])[C:16]([F:27])([F:28])[C:17]([F:25])([F:26])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])(=[O:33])=[O:32]
Reactant: NCCCN
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CC(C)OC(C)C
Product: NCCCNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 50 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
111 g (1.5 moles) of 1,3-diaminopropane and 300 g of fully dehydrated isopropyl ether were weighed in an atmosphere of nitrogen into a 2-liter three-necked round-bottomed flask equipped with a cooling condenser and stirrer. With sufficient stirring, 237 g (0.59 mole) of perfluorohexyl sulfonyl fluoride was added dropwise at room temperature from a dropping funnel. The mixture was stirred at 50° C. for 3 hours, and then the isopropyl ether was removed under reduced pressure. The oily residue was dissolved in 200 ml of ethanol, and gradually poured into 5 liters of distilled water with stirring. The resulting crystals were aged. The supernatant liquid was removed by decantation, and 1 liter of 0.5 N aqueous sodium hydroxide solution was added to wash the crystals. Decantation was performed for three more times using 5 liters of distilled water each time. The crystals were collected by filtration, washed with distilled water and dried at 60° C. under reduced pressure. There was obtained 268 g of N-(3 -aminopropyl)perfluorohexyl sulfonamide having a sufficient purity for use in the subsequent reaction.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C(F)=NC(F)=NC=1[F:16].N1C=CC=CC=1>C(Cl)Cl>[C:4]([O:3][C:1](=[O:2])[NH:8][C@H:9]([C:11]([F:16])=[O:13])[CH3:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: Fc1nc(F)nc(F)n1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)F
Temperature: -15 °C
Reaction time: 0.25 h

Procedure:
To an oven-dried, septaed 10 mL round-bottom flask, cooled under an argon atmosphere, and charged with (S)-N-BOC-alanine, 24c, (189.2 mg, 1.00 mmol) was added 2.5 mL freshly distilled CH2Cl2 under argon. The reaction was cooled to −15° C. and to the flask was added cyanuric fluoride (450 μL, 5 mmol). The reaction was stirred at −15° C. for 15 minutes then anhydrous pyridine (81 μL, 1.0 mmol) was added. Stirring was maintained at −15° C. for 90 minutes, with reaction progress indicated by the gradual formation of a precipitate. Without warming, the crude reaction was poured over ice, and immediately extracted twice with CH2Cl2. The combined CH2Cl2 extracts were washed once with water, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting colorless oil was dissolved in CH2Cl2, and precipitated with hexane to afford 163.5 mg of a mixture of 24c and 25c as white crystals. FTIR (film) 1842 cm−1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=1.[CH3:16][C:17]([CH3:19])=[O:18].CO.[OH-].[K+]>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11](/[CH:14]=[CH:16]/[C:17](=[O:18])[CH3:19])=[CH:12][CH:13]=1
Reactant: CC(C)=O
Reactant: O=Cc1ccc(-c2ccccc2F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)/C=C/c1ccc(-c2ccccc2F)cc1

Procedure:
200.2 Gm (1.0 mol) of 2'-fluoro-4-biphenyl-carboxaldehyde, 3500 gm (60.3 mols) of acetone and 200 ml of methanol were charged into a 6-liter three-neck-flask equipped with a stirrer, a dropping funnel and an internal thermometer. While thoroughly stirring the contents of the flask, a solution of 2.805 gm (0.05 mol) of potassium hydroxide in 16 ml of water was added dropwise thereto while maintaining a reaction temperature of 20° to 25°C, and the resulting mixture was stirred for three hours more. Thereafter, the precipitated solid side product was filtered off, the filtrate was made neutral by dropwise addition of glacial acetic acid, and the neutral solution was evaporated in vacuo. The residue was recrystallized three times from diisopropyl ether and then once from a mixture of ethyl acetate and diisopropyl ether (volumetric ratio 1:1) in the presence of activated charcoal, yielding 101.2 gm (42% of theory) of the fallow crystalline compound of the formula ##SPC20##
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][C:24](OC2C=CC=CC=2)=O)[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:41][C:42]1([O:45]C1)[CH3:43].O1CCCC1.[OH-].[K+]>CO>[Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:24][C:42]([OH:45])([CH3:43])[CH3:41])[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC1(C)CO1
Reactant: C[C@H](SC(=O)Oc1ccccc1)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](SCC(C)(C)O)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 81.8 %

Procedure:
Under the same conditions as in Example 3, 1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-phenoxycarbonylthiopregna-5,7,16-triene (83.0 mg, 0.143 mmol), isobutylene oxide (113 mg, 1.56 mmol), tetrahydrofuran (0.5 ml) and 1M KOH solution in methanol (0.5 ml) were reacted and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=1:1, developed once) to give the title compound as a colorless oil (62.3 mg, 82%).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@@H:8]([NH:9][C:10](=[O:25])[CH2:11][NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[CH2:7][CH2:6][C@@H:5]([N:26]([CH:34]([CH3:36])[CH3:35])C(=O)OC(C)(C)C)[CH2:4]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:1][CH2:2][C@@H:3]1[CH2:4][C@H:5]([NH:26][CH:34]([CH3:36])[CH3:35])[CH2:6][CH2:7][C@@H:8]1[NH:9][C:10](=[O:25])[CH2:11][NH:12][C:13](=[O:24])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1
Reactant: CC(C)N(C(=O)OC(C)(C)C)[C@@H]1CC[C@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)[C@H](CO)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N[C@@H]1CC[C@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)[C@H](CO)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
A solution of tert-butyl(1R,3R,4S)-3-(hydroxymethyl)-4-(2-(3-(trifluoromethyl)-benzamido)acetamido)cyclohexyl(isopropyl)carbamate (130 mg) in CH2Cl2 is treated with CF3COOH (7 ml) and stirred at room temperature for 2 hours. The solution was evaporated and the residue neutralized with 1 N NaOH and extracted into CH2Cl2. The extract was washed with water, brine, dried over Na2SO4, filtered and the solvent evaporated to give 100 mg of the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ(TMS): 8.12 (s, 1 H), 8.03 (d, J=7.8 Hz, 1 H), 7.94 (bt, 1 H), 7.75 (d, J=7.8 Hz, 1 H), 7.57 (t, J=7.8 Hz,l H), 7.39 (bd, 1 H), 4.31 (m, 1 H), 4.26 (dd, J=5 Hz, J=16 Hz, 1 H), 4.13 (dd, J=5 Hz, J=16 Hz, 1 H), 3.42 (m, 1 H), 3.27 (m, 1 H), 3.05 (m, 1 H), 2.84 (m, 1 H), 1.92-1.60 (m, 8 H), 1.12 (d, J=6.3 Hz, 6 H). MS found: (M+H)+=416.38.
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[CH:9][N:8]=[N:7][CH:6]=1)=[O:4].[CH3:11][P:12](=[O:17])([O:15][CH3:16])[O:13][CH3:14].C([N-]C(C)C)(C)C.[Li+]>C1COCC1>[O:4]=[C:3]([C:5]1[CH:10]=[CH:9][N:8]=[N:7][CH:6]=1)[CH2:11][P:12](=[O:17])([O:15][CH3:16])[O:13][CH3:14]
Reactant: COP(C)(=O)OC
Reactant: COC(=O)c1ccnnc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)c1ccnnc1)OC
Yield: 28.8 %

Procedure:
To a solution of methylpyridazine-4-carboxylate (1.00 g, 6.95 mmol) and dimethyl methylphosphonate (889 mg, 6.95 mmol) in THF (20 ml) was added a 2 M solution of lithium diisopropylamide (2 M in THF/heptane/ethylbenzene; 7.3 ml, 14.6 mmol) between −5° C. and 0° C. Then after 5 min the reaction mixture was carefully quenched with 4 M aq. hydrochloric acid solution to adjust the pH to ca. 6 and diluted with dichloromethane. The aqueous layer was separated and extracted 2 times with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (SiO2; gradient ethyl acetate to ethyl acetate/methanol 9:1) afforded the title compound (460 mg, 29%). Dark red oil; MS: 231.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][C:6]=12.C(=O)(O)[O-].[Na+].[N:22]#[C:23]Br>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:23]#[N:22])[CH2:13][CH2:12]3)=[N:7][C:6]=12
Reactant: Brc1cnn2ccc(N3CCNCC3)nc12
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: N#CN1CCN(c2ccn3ncc(Br)c3n2)CC1
Temperature: 0 °C

Procedure:
3-bromo-5-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidine (500 mg, 1.77 mmol) taken up in 20 mL DCM and stirred at 0° C. in an ice bath. Sodium bicarbonate (744 mg, 8.86 mmol) in 6 mL water added and stirred. Cyanogen bromide (225 mg, 2.12 mmol) added and stirred at 0° C. for 30 minutes then allowed to reach room temperature and stirred overnight. Reaction diluted with DCM washed with water, DCM layer dried over magnesium sulfate reduced in vacuo for 500 mg crude product for further reaction as is. LRMS (ESI) m/z 307/309 [(M+H)]+, calc'd for C11H11BrN6: 307.15.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)=[O:17])=[CH:11][CH:10]=2)[CH:3]=1.[CH3:29][NH2:30]>>[CH3:29][NH:30][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)=[O:17])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: CN
Reactant: O=C(Nc1ccc(Oc2cc(Cl)ncn2)cc1)Nc1cccc(C(F)(F)F)c1
Product: CNc1cc(Oc2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)ncn1
Temperature: 50 °C

Procedure:
1-[4-(6-Chloro-pyrimidin-4-yloxy)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea (Example 56) (42.7 mg, 0.1 mmol) is dissolved in methylamine (30% in EtOH, 1 mL) in a sealable tube and heated under Ar for 10 min at 50° C. After evaporating the solvent, the product is purified by preparative TLC (2 20×20 cm plates, acetone/CH2Cl2=3:7) to give the title compound as a white solid: M+H=404.1; 1H-NMR (400 MHz, CDCl3): 8.22 (s, 1H, pyridinyl), 7.84 (s/broad, 1H, NH), 7.62 (s, 1H, 3-CF3-phenyl), 7.52 (d, 8.0 Hz, 1H, CF3-phenyl), 7.35 (t, 8.0 Hz, 1H, 3-CF3-phenyl), 7.28 (m, 3H, CF3-phenyl/oxo-phenyl-amine), 6.97 (d, 9.5 Hz, 2H, oxo-phenyl-amine), 5.62 (d/broad, 2H, pyridinyl), 5.44 (s/broad, 1H, NH), 2.89 (s/broad, CH3—N); Rf (acetone/CH2Cl2=3:7): 0.36.
Reaction SMILES: OO.O[Li].O.C([C@@H]1COC(=O)N1[C:19](=[O:42])[C@H:20]([C@H:28]1[N:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:31]([CH3:41])([CH3:40])[CH2:30][CH2:29]1)[C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=1)C1C=CC=CC=1.[O-:43]S([O-])=O.[Na+].[Na+]>C1COCC1.O.C1COCC1>[Br:27][C:24]1[CH:25]=[CH:26][C:21]([C@@H:20]([C@@H:28]2[CH2:29][CH2:30][C:31]([CH3:40])([CH3:41])[N:32]2[C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])[C:19]([OH:43])=[O:42])=[CH:22][CH:23]=1
Reactant: O=S([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c2ccc(Br)cc2)CCC1(C)C
Agent: OO
Agent: [Li]O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)O)c2ccc(Br)cc2)CCC1(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87 %

Procedure:
30% H2O2 (0.67 mL, 7.0 mmol) was added to a solution of LiOH—H2O (0.24 g, 5.60 mmol) in THF/water (2:1, 93 mL), and the solution was stirred at room temperature for 10 minutes. The solution was then cooled to 0° C. and treated with a solution of (S)-tert-butyl 5-((S)-2-((R)-4-benzyl-2-oxooxazolidin-3-yl)-1-(4-bromophenyl)-2-oxo ethyl)-2,2-dimethylpyrrolidine-1-carboxylate (1.60 g, 2.80 mmol) in THF (10 mL). The reaction was stirred at 0° C. for 2 hours and allowed to warm to room temperature and stirred overnight. The reaction was then cooled to 0° C. and treated with 1M Na2SO3 (10 mL) and stirred for 10 minutes. The reaction was then warmed to room temperature and stirred for 10 minutes. The reaction was next concentrated and extracted with EtOAc (2×20 mL). The aqueous layer was then acidified with 1N HCl to a pH of about 1 to about 2 and extracted with DCM (2×20 mL). The combined DCM fractions were dried over sodium sulfate, filtered, and concentrated to give (S)-2-(4-bromophenyl)-2-((S)-1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl)acetic acid (1.01 g, 87% yield) as a solid. MS ESI (+) m/z 412 detected.