Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:20][C:21]([OH:23])=O)[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11].[CH2:24]([NH:26][CH2:27][C:28]1[CH:29]=[N:30][C:31]2[C:36]([CH:37]=1)=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH3:25]>>[CH2:24]([N:26]([CH2:27][C:28]1[CH:29]=[N:30][C:31]2[C:36]([CH:37]=1)=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:21](=[O:23])[CH2:20][N:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:11])=[O:12])[CH3:25]
Reactant: CCNCc1cnc2ccccc2c1
Reactant: COc1ccccc1N(CC(=O)O)S(=O)(=O)c1ccccc1C
Product: CCN(Cc1cnc2ccccc2c1)C(=O)CN(c1ccccc1OC)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of [(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-acetic acid with ethyl-quinolin-3-ylmethyl-amine
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10][NH2:11])=[CH:8][CH:9]=1.[F:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH:39]([CH3:41])[CH3:40])[N:34]=[C:33]([CH:42]=O)[CH:32]=[CH:31]2>C(O)C>[F:26][C:2]([F:25])([F:1])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[CH2:13]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10]/[N:11]=[CH:42]/[C:33]2[CH:32]=[CH:31][C:30]3[C:35](=[CH:36][C:37]([O:38][CH:39]([CH3:41])[CH3:40])=[C:28]([F:27])[CH:29]=3)[N:34]=2)=[CH:8][CH:9]=1
Reactant: CC(C)Oc1cc2nc(C=O)ccc2cc1F
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc(NN)nc2)C(F)(F)F)C1
Solvent: CCO
Product: CC(C)Oc1cc2nc(/C=N/Nc3ccc([C@@H](N4CC[C@H](NC(=O)OC(C)(C)C)C4)C(F)(F)F)cn3)ccc2cc1F

Procedure:
tert-Butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (451 mg, 1.20 mmol) and 6-fluoro-7-isopropoxyquinoline-2-carbaldehyde (280 mg, 1.20 mmol) in ethanol (5 mL) were stirred at ambient temperature for 24 hours. After concentration, the residue was used in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([NH2:14])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:23][CH3:24]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([NH:14][CH2:23][CH3:24])[CH:5]=1
Reactant: CCI
Reactant: COC(=O)c1cc(N)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCNc1cc(C(=O)OC)cc(C(F)(F)F)c1
Temperature: 65 °C
Reaction time: 14 h

Procedure:
A mixture of 3-amino-5-(trifluoromethyl)-benzoic acid methyl ester (J. Med. Chem. (1969) 12, 299-303; 4.23 g, 19.3 mmol), potassium carbonate (8.0 g, 57.9 mmol) and iodoethane (3.12 mL, 38.6 mmol) in 20 mL N,N-dimethylformamide is stirred at 65° C. for 14 hours in a tightly closed vessel. After cooling, the reaction mixture is filtered and the filtrate evaporated to dryness under reduced pressure. The residue is treated with water and extracted three times with ethyl acetate. The combined extracts are dried (Na2SO4) and the solvent is evaporated off under reduced pressure. The resulting residue is purified by column chromatography on silica gel, eluent hexane/methylene chloride (1:1).
Reaction SMILES: [CH2:1]([NH:8][C@H:9]([C:14]([NH:16][C@@H:17]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C@H:18]([OH:33])[C:19]([N:21]1[CH2:32][CH2:31][CH2:30][C@H:22]1[C:23]([NH:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:20])=[O:15])[CH2:10][C:11](=[O:13])[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:41]=O>>[CH2:1]([N:8]([CH3:41])[C@H:9]([C:14]([NH:16][C@@H:17]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C@H:18]([OH:33])[C:19]([N:21]1[CH2:32][CH2:31][CH2:30][C@H:22]1[C:23]([NH:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:20])=[O:15])[CH2:10][C:11](=[O:13])[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=O
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NCc1ccccc1
Product: CN(Cc1ccccc1)[C@@H](CC(N)=O)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)N1CCC[C@H]1C(=O)NC(C)(C)C
Yield: 73.2 %

Procedure:
Following a procedure similar to that described in Example 67, but using 200 mg (0.36 mmol) of 1-[(2S,3S)-3-(N2 -Benzyl-L-asparaginyl)amino-2-hydroxy-4-phenylbutyryl]-N-t-butyl-L-prolinamide (prepared as described in Example 86) and 41 μl (0.54 mmol) of 37% formalin, 149 mg of the title compound were obtained as a colorless powder, melting at 97°-100° C.
Reaction SMILES: [Na].[C:2]([O:6][CH2:7][CH3:8])(=[O:5])[CH2:3][SH:4].[Cl:9][C:10](Cl)=[CH:11][C:12](OCC)=[O:13].CC[O-].[Na+]>C(O)C>[CH2:7]([O:6][C:2]([C:3]1[S:4][C:10]([Cl:9])=[CH:11][C:12]=1[OH:13])=[O:5])[CH3:8]
Reactant: CCOC(=O)CS
Reactant: CCOC(=O)C=C(Cl)Cl
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1sc(Cl)cc1O
Reaction time: 0.25 h

Procedure:
A solution of 23.6 mm of the sodium salt of ethyl thioglycolate in 100 ml of ethanol was added over 5 minutes at 30° C. to a a mixture of 4 g of ethyl dichloroacrylate in 50 ml of ethanol and the mixture was stirred at 25°-30° C. for 15 minutes and was then returned to room temperature. A mixture of 3.22 g of sodium ethylate in 75 ml of ethanol was added thereto and the mixture was stirred for 18 hours. The mixture was concentrated and poured into water and the mixture was extracted with ether. The aqueous phase was acidified with hydrochloric acid and was extracted with ether. The ether phase was evaporated to dryness and the 4.2 g of residue was chromatographed over silica gel. Elution with benzene yielded 1.75 g of 2-ethoxycarbonyl-3-hydroxy-5-chloro-thiophene with Rf = 0.4-0.5.
Reaction SMILES: [C:1]([O:20][CH2:21][C@@H:22]1[CH2:24][O:23]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][C@@H:26]1[C@@H:31]([O:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:30][CH2:29][NH:28][CH2:27]1>C(O)C>[OH:23][C@H:22]([CH2:21][O:20][C:1]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:24][N:28]1[CH2:29][CH2:30][C@H:31]([O:32][C:33](=[O:38])[C:34]([CH3:36])([CH3:35])[CH3:37])[C@@H:26]([CH3:25])[CH2:27]1
Reactant: c1ccc(C(OC[C@@H]2CO2)(c2ccccc2)c2ccccc2)cc1
Reactant: C[C@H]1CNCC[C@@H]1OC(=O)C(C)(C)C
Solvent: CCO
Product: C[C@H]1CN(C[C@H](O)COC(c2ccccc2)(c2ccccc2)c2ccccc2)CC[C@@H]1OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 23 h

Procedure:
(S)-2-Trityloxymethyl-oxirane (636 mg, 2 mmol) and 2,2-dimethyl-propionic acid (3S,4S)-3-methyl-piperidin-4-yl ester (17, 400 mg, 2 mmol) are dissolved in 7 ml of ethanol and stirred at room temperature for 23 h. The white suspension is heated to 40° C. and stirred for additional 2 h. The reaction mixture is evaporated under reduced pressure and the crude product is purified by Flash-chromatography. (silica gel, 20% ethyl acetate in cyclohexane).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][C:10]([CH3:15])([N+:12]([O-:14])=[O:13])[CH3:11].[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1>[CH3:11][C:10]([N+:12]([O-:14])=[O:13])([CH3:15])[CH2:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1
Reactant: C1CNCCN1
Reactant: CC(C)(COc1ccccc1Br)[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(C)(COc1ccccc1N1CCNCC1)[N+](=O)[O-]
Yield: 73.2 %

Procedure:
A solution of 1-bromo-2-(2-methyl-2-nitro-propoxy)-benzene (2.30 g, 8.4 mmol), piperazine (1.8 g, 20 mmol), Pd2dba2 (384 mg, 0.4 mmol), BINAP (784 mg, 1.26 mmol), and NaOtBu (1.13 g, 12 mmol) in 34 mL of toluene was heated to 90° C. for 5 hrs. The solution was concentrated, dissolved in CH2Cl2 and filtered through celite. Purification by silica gel chromatography (4×20 cm SiO2, 0,1,2,3,4,5,7,9,11% 2M NH3 in MeOH/CH2Cl2 step gradient, 12 min each at 35 mL/min) afforded 1.72 g (6.15 mmol, 73%) of 1-[2-(2-methyl-2-nitro-propoxy)-phenyl]-piperazine as a yellow oil. LRMS (electrospray): 280.1 [M+1].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5](Br)=[CH:4][N:3]=1.[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1>O>[NH2:1][C:2]1[CH:7]=[N:6][C:5]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][N:3]=1
Reactant: C1CCNC1
Reactant: Nc1cnc(Br)cn1
Solvent: O
Product: Nc1cnc(N2CCCC2)cn1
Temperature: 180 °C
Yield: 37.1 %

Procedure:
A solution of 0.6 g (3.45 mmol) of 2-amino-5-bromopyrazine and of 3 mL (36 mmol) of pyrrolidine, placed in a sealed tube, is heated in a microwave oven for two hours at 180° C. and 200 W. 100 mL of water is added to the reaction mixture and it is extracted three times with 50 mL of ethyl acetate. The organic phases are combined, washed three times with 20 mL of water and then once with 20 mL of a saturated aqueous solution of sodium chloride, dried over sodium sulfate and then concentrated at reduced pressure. The product obtained is then purified by chromatography on a silica column, eluting with a mixture of dichloromethane and methanol. We obtain 0.21 g of the expected compound in the form of a brown solid.
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[NH2:44][NH2:45]>C(O)CC>[CH2:1]([S:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([NH:44][NH2:45])=[O:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCSCCCCCCCCCCC(=O)O
Reactant: NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCO
Solvent: O
Product: CCCCCCCCCCCCCCCCSCCCCCCCCCCC(=O)NN
Temperature: 25 °C

Procedure:
22.1 Grams of 11-(hexadecylthio)undecanoic acid, 1.0 g of p-toluenesulfonic acid monohydrate and 200 ml of n-propanol were charged in a flask equipped with a stirrer, a condenser and a calcium chloride drying tube and refluxed with heating for 4 hours. Thereafter, to the solution was added 12.5 g of hydrazine monohydrate, followed by refluxing with heating for further 20 hours. The reaction mixture was cooled to room temperature and the precipitated crystal was filtered off under reduced pressure and washed with distilled water. The crystal was recrystallized from 2-propanol to obtain 16.0 g of the desired product. m.p. 108° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]([CH3:22])[N:13]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:23]I.[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]([CH3:22])[N:13]=2)[CH3:23])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2nc(C)nc3ccccc23)cc1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C)c2nc(C)nc3ccccc23)cc1OC

Procedure:
The title compound was prepared from (3,4-dimethoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine (288 mg, 0.98 mmol), methyl iodide (0.094 ml, 1.47 mmol), sodium hydride (60 mg, 1.5 mmol) in DMF similar to example 21 to give 70 mg (23%) of off white solids. 1H NMR (CDCl3): 7.75-7.72 (m, 1H), 7.56-7.50 (m, 1H), 7.05-6.94 (m, 2H), 6.85 (d, J=7.5 Hz, 1H), 6.76-6.71 (m, 2H), 3.92 (s, 3H)), 3.78 (s, 3H), 3.61 (s, 3H), 2.73 (s, 3H).
Reaction SMILES: [C:1](Br)#[N:2].[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1>C(OCC)C>[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:1]#[N:2])=[CH:8][CH:7]=1
Reactant: N#CBr
Reactant: COc1ccc(N)cc1
Solvent: CCOCC
Product: COc1ccc(NC#N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of cyanobromide (0.6 eq) in diethyl ether, a solution of 4-methoxy phenyl amine (1.0 eq) in diethyl ether was added and the reaction mixture was stirred at room temperature for 2 h. Salt separated out was filtered and the filtrate was concentrated to afford the desired 4-methoxy-phenyl-cyanamide in good yield.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:23]2[O:27][N:26]=[C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:24]=2)[C:5]([N:8](C(OC(C)(C)C)=O)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:42]2[CH:47]=[CH:46][C:45]([S:48]([CH:51]3[CH2:56][CH2:55][CH2:54][N:53]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:52]3)(=[O:50])=[O:49])=[CH:44][CH:43]=2)O1.O.C([O-])([O-])=O.[Na+].[Na+]>CC#N>[C:11]([O:10][C:9]([NH:8][C:5]1[N:6]=[CH:7][C:2]([C:42]2[CH:47]=[CH:46][C:45]([S:48]([CH:51]3[CH2:56][CH2:55][CH2:54][N:53]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:52]3)(=[O:50])=[O:49])=[CH:44][CH:43]=2)=[N:3][C:4]=1[C:23]1[O:27][N:26]=[C:25]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:24]=1)=[O:15])([CH3:12])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCCC(S(=O)(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1cc(-c2ccccc2)no1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ncc(-c2ccc(S(=O)(=O)C3CCCN(C(=O)OC(C)(C)C)C3)cc2)nc1-c1cc(-c2ccccc2)no1
Temperature: 65 °C
Yield: 109.6 %

Procedure:
tert-butyl (5-bromo-3-(3-phenylisoxazol-5-yl)pyrazin-2-yl)-N-tert-butoxycarbonyl-carbamate (750 mg, 1.393 mmol) and tert-butyl 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]sulfonylpiperidine-1-carboxylate (691.5 mg, 1.532 mmol) were suspended in MeCN (7.500 mL)/water (7.500 mL) and Na2CO3 (1.393 mL of 2 M, 2.786 mmol) was added. The reaction mixture was degassed with 3× nitrogen/vacuum cycles. Pd(tBu3P)2 (71.19 mg, 0.1393 mmol) was added and the reaction mixture again degassed 3 times then heated to 65° C. (Dry Syn Temp) for 1.5 hours. The reaction mixture was cooled to ambient temperature and diluted with ethylacetate/water. The aqueous layer was extracted with ethylacetate (×1) and the combined organic extracts washed with brine (×2), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 80 g column, eluting with 0 to 30% Petroleum/Petroleum Ether, loaded in DCM) to give tert-butyl 3-((4-(5-((tert-butoxycarbonyl)amino)-6-(3-phenylisoxazol-5-yl)pyrazin-2-yl)phenyl)sulfonyl)piperidine-1-carboxylate as a yellow solid (1.01 g, 93% Yield). H NMR (400.0 MHz, DMSO) δ 9.53 (s, 1H), 8.67 (d, 2H), 8.12 (d, 2H), 8.05-8.03 (m, 3H), 7.60-7.57 (m, 3H), 3.76 (br d, 1H), 3.47-3.41 (m, 1H), 3.02-2.95 (m, 1H), 2.81-2.77 (m, 1H), 2.09-2.04 (m, 1H), 1.77-1.63 (m, 2H) and 1.42-1.21 (m, 29H) ppm
Reaction SMILES: [C:1](=[N:4][OH:5])([NH2:3])[CH3:2].[H-].[Na+].CO[C:10](=O)[C@H:11]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].O>C1COCC1>[C:16]([O:15][C:13]([NH:12][CH:11]([C:10]1[O:5][N:4]=[C:1]([CH3:2])[N:3]=1)[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(N)=NO
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1noc(C(Cc2ccccc2)NC(=O)OC(C)(C)C)n1
Yield: 48.7 %

Procedure:
To a solution of acetamide oxime [2.67 g, J. Saunders et al., J. Med. Chem., 33, 1128 (1990)] in THF (125 ml) was added 60% sodium hydride (1.44 g) in oil, and the mixture was refluxed under heating for 1 hour. Then, the reaction mixture was allowed to cool, and a solution of N-tert-butoxycarbonyl-L-phenylalanine methyl ester (8.38 g) in THF (40 ml) was added at room temperature. The mixture was refluxed under heating for 20 minutes. The mixture was allowed to cool, and water (10 ml) was added, which was followed by concentration under reduced pressure. A 10% aqueous citric acid solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=3/1 v/v) to give 4.43 g of N-tert-butoxycarbonyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)-2-phenylethylamine. This compound was added to a 4N hydrogen chloride-dioxane solution (50 ml), and the mixture was stirred at room temperature for 2 hours. Toluene was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Ether was added to the residue for crystallization to give the title compound (3.25 g, yield 47%).
Reaction SMILES: [C:1]([OH:8])(=O)[CH2:2][CH2:3][C:4]([CH3:6])=O.[CH2:9]([NH2:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>O>[CH3:6][CH:4]1[N:17]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:1](=[O:8])[CH2:2][CH2:3]1
Reactant: CC(=O)CCC(=O)O
Reactant: CCCCCCCCN
Solvent: O
Product: CCCCCCCCN1C(=O)CCC1C
Temperature: 150 °C

Procedure:
The feedstock used in examples 39 through 77, except for example 40, was 20% of the ammonium salt of levulinic acid, 40% octylamine, and 40% water, by weight. For the reaction in example 40, the weight ratio of the feedstock was 30% of the ammonium salt of levulinic acid, 30% octylamine, and 40% water. The temperature and pressure of the reactions were maintained at 150° C. and 6.9 MPa. Water was used as the solvent medium for the reactions. The results are set forth in the following table.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[N:15]([C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=[N:13][CH:12]=1)=[O:10].[CH2:35]([Mg]Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>ClCCl>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[N:15]([C:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:14]=[N:13][CH:12]=1)([OH:10])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Br[Mg]Cc1ccccc1
Reactant: Cc1cccc(C(=O)c2cncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C
Solvent: ClCCl
Product: Cc1cccc(C(O)(Cc2ccccc2)c2cncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of (2,3-dimethylphenyl)(I-trityl-1H imidazol-5-yl)methanone (450 mg, 1.01 mmol) in dichloromethane (25 mL) at room temperature was treated with benzyl magnesium bromide (1.51 mmol) and allowed to react at room temperature and the reaction mixture was then stirred at room temperature for 5 hours. The mixture was quenched with water (10 mL) and a sat. solution of ammonium chloride (10 mL). The residue was isolated in a typical aqueous to give 1-(2,3-dimethylphenyl)-2-phenyl-1-(1-trityl-1H-imidazol-5-yl)ethanol (Intermediate 8) crude, which was taken to the next step without any purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[O:14][C:11]([CH2:15][CH:16](C(OC)=O)[C:17]([O:19][CH3:20])=[O:18])([CH2:12][CH2:13]2)[CH2:10][CH2:9]3)=[CH:4][CH:3]=1.[Cl-].[Li+]>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[O:14][C:11]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])([CH2:10][CH2:9]2)[CH2:12][CH2:13]3)=[CH:6][CH:7]=1
Reactant: COC(=O)C(CC12CCC(c3ccc(Br)cc3)(CC1)O2)C(=O)OC
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)CCC12CCC(c3ccc(Br)cc3)(CC1)O2
Temperature: 180 °C
Reaction time: 0.33 h

Procedure:
To a solution of dimethyl 2-((4-(4-bromophenyl)-7-oxabicyclo[2.2.1]heptan-1-yl)methyl)malonate (305 mg, 0.77 mmol) in DMSO (3.0 mL) and water (0.03 mL) was added lithium chloride (98 mg, 2.3 mmol) and the reaction was stirred in a microwave reactor at 180° C. for 20 min. The resulting yellow reaction mixture was diluted with water and extracted with EtOAc. The organic phase was dried over MgSO4, filtered and concentrated by rotary evaporation in vacuo to afford 289 mg of a crude clear yellow film. Purification of the crude material by column chromatography (24 g silica gel, 0-30% EtOAc:Hept, monitor 230 nm) afforded 194 mg colorless film that solidified upon standing and which was used without further purification. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.54-1.67 (m, 4H), 1.68-1.79 (m, 2H), 2.04-2.16 (m, 4H), 2.42-2.48 (m, 2H), 3.61 (s, 3H), 7.31 (d, J=8.6 Hz, 2H), 7.53 (d, J=8.6 Hz, 2H). ESI-MS m/z: 341.1 [M+H]+, retention time 1.59 min (condition E).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([O:23][C:24]2[N:32]=[CH:31][N:30]=[C:29]3[C:25]=2[N:26]=[C:27](I)[N:28]3[CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].COCCOC.[Cl:46][C:47]1[CH:56]=[C:55]2[C:50]([C:51](B3OC(C)(C)C(C)(C)O3)=[CH:52][CH:53]=[N:54]2)=[CH:49][CH:48]=1.[OH-].[Ba+2].[OH-].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([O:23][C:24]2[N:32]=[CH:31][N:30]=[C:29]3[C:25]=2[N:26]=[C:27]([C:51]2[C:50]4[C:55](=[CH:56][C:47]([Cl:46])=[CH:48][CH:49]=4)[N:54]=[CH:53][CH:52]=2)[N:28]3[CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2ccnc3cc(Cl)ccc23)OC1(C)C
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2ncnc3c2nc(I)n3C2CCCCO2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2ncnc3c2nc(-c2ccnc4cc(Cl)ccc24)n3C2CCCCO2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 90 °C

Procedure:
To a solution of 6-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy)-8-iodo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (258.4 mg, 0.0003752 mol) in 1,2-Dimethoxyethane (3.0 mL, 0.029 mol) was added 7-chloroquinoline-4-boronic acid pinacol ester (0.158 g, 0.000546 mol), barium hydroxide (0.228 g, 0.00133 mol), water (0.5 mL, 0.03 mol) and Tetrakis(triphenylphosphine)palladium(0) (0.02 g, 0.00002 mol), and the mixture was heated at 90° C. overnight. The reaction was cooled, quenched by addition of water and the mixture was extracted with DCM (3×), washed with water, brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (0 to 30% EtOAc/hexanes) to obtain 180 mg (66.2%) mg. Reference: Cammidge, A. N.; Crepy, K. V. L. Tetrahedron, 2004, 60, 4377-4386.
Reaction SMILES: Cl[CH2:2][S:3][C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][N:8]=1.Cl.[Cl:11][C:12]1[CH:13]=[N:14][C:15](=[O:18])[NH:16][CH:17]=1.CC(C)([O-])C.[K+]>CN(C=O)C>[CH3:9][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[S:3][CH2:2][N:16]1[CH:17]=[C:12]([Cl:11])[CH:13]=[N:14][C:15]1=[O:18]
Reactant: Cn1ccnc1SCCl
Reactant: O=c1ncc(Cl)c[nH]1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1ccnc1SCn1cc(Cl)cnc1=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
2-Chloromethylsulfenyl-1-methylimidazole [see Preparation 10] (10 mmol) in DMF (12 ml) was added to a mixture of 5-chloropyrimidin-2-one hydrochloride (10 mmol) and potassium tert-butoxide (20 mmol) in DMF (72 ml). The mixture was stirred at 60° C. for 51/2 hours before the product was distilled off and the residue washed with water and ether. The product was oily. 1H HMR (DMSO d6, δ): 3.57 (CH3), 5.27 (--CH2 --), 6.95-7.22 (imidazole), 8.19 (H-4, d, j 4 Hz), 8.54 (H-6, d, J 4 Hz).