Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCl.[NH2:4][CH2:5][C:6]1([CH2:10][NH2:11])[CH2:9][O:8][CH2:7]1.[C:12]1([C:18](Cl)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+]>O>[NH2:4][CH2:5][C:6]1([CH2:10][NH:11][C:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:9][O:8][CH2:7]1
Reactant: NCC1(CN)COC1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: NCC1(CNC(c2ccccc2)(c2ccccc2)c2ccccc2)COC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.4 %

Procedure:
A dichloromethane suspension (3.0 ml) of C-(3-aminomethyloxetan-3-yl)methylamine (411 mg, 3.54 mmol) prepared according to the method described in J. Org. Chem., (1985),50(17), 3211; and Japanese Patent Application Kokai Publication No. (JP-A) S61-69784 (unexamined, published Japanese patent application) was cooled to 0° C., and a dichloromethane solution (3.0 ml) of triphenylmethyl chloride (246 mg, 0.88 mmol) was added thereto. The mixture was stirred at 0° C. for 30 minutes, and then at room temperature for one hour. A saturated aqueous sodium bicarbonate solution (1.0 ml) and water (15 ml) were added to the solution. The mixture was extracted three times with dichloromethane (20 ml). The organic layers were combined together, and dried over anhydrous sodium sulfate. After the inorganic salt was removed by filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (developing solvent: dichloromethane:methanol=20:1) to yield (3-aminomethyloxetan-3-ylmethyl)tritylamine (162 mg) as a white amorphous material.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([CH2:9][NH2:10])[CH2:8][CH2:7]1.[CH:11]1[N:16]=[C:15](Cl)[C:14]2[N:18]=[CH:19][N:20]([C@@H:21]3[O:25][C@H:24]([CH2:26][OH:27])[C@@H:23]([OH:28])[C@H:22]3[OH:29])[C:13]=2[N:12]=1.C(N(CC)CC)C>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([CH2:9][NH:10][C:15]2[C:14]3[N:18]=[CH:19][N:20]([C:13]=3[N:12]=[CH:11][N:16]=2)[C@@H:21]2[O:25][C@H:24]([CH2:26][OH:27])[C@@H:23]([OH:28])[C@H:22]2[OH:29])[CH2:8][CH2:7]1
Reactant: NCC1(c2cccs2)CC1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Solvent: CCN(CC)CC
Product: OC[C@H]1O[C@@H](n2cnc3c(NCC4(c5cccs5)CC4)ncnc32)[C@H](O)[C@@H]1O

Procedure:
Reaction of the above amine (1.53 g, 10 mmol) with 6-chloropurine riboside (2.87 g, 10 mmol) and triethylamine (2.02 g, 20 mmol) as described in Example 1 gives, after a second crystallization from ethanol, N6((1-thien-2-ylcyclopropyl)methyl)adenosine (2.90 g, 71%) as a fluffy off-white solid m.p. 136°-138.5° C. Found: C, 53.78; H, 5.45; N, 17.28; S, 7.52%. C18H21N5O4S calculated requires: C, 53.60; H, 5.21; N, 17.37; S, 7.94%.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].C([O:13][C:14]1[CH:19]=[CH:18][C:17]([S+:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)(C)(C)C.FC(F)(F)S(O)(=O)=O>CO>[F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[OH:13][C:14]1[CH:19]=[CH:18][C:17]([S+:20]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][CH:15]=1
Reactant: CC(C)(C)Oc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CO
Product: Oc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Yield: 93 %

Procedure:
A solution of 48.4 g (0.1 mol) of (p-tert-butoxyphenyl)diphenylsulfonium trifluoromethanesulfonate and 1.5 g (0.01 mol) of trifluoromethanesulfonic acid in 500 g of methanol was heated at 60° to 70° C. for 6 hours with stirring. The reaction mixture was evaporated in vacuo. The residual oil was washed two times with 100 g of diethyl ether. The amount of this crude product was 40 g (yield 93%). Without further purification, the crude product was used in subsequent reaction.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[C:14]([NH2:23])[C:13]=2[N:12]=[CH:11]1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[NH2:23][C:14]1[C:13]2[N:12]=[CH:11][N:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: NCCCCCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)c1ccccc1
Product: Nc1nc2ccccc2c2c1ncn2CCCCCCCCNC(=O)c1ccccc1
Yield: 28.1 %

Procedure:
Using the general method of Example 186 1-(8-aminooctyl)-1H-imidazo[4,5-c]quinolin-4-amine (3.85 mmol) was reacted with benzoyl choride (450 μL, 3.85 mmol) to provide 0.45 g of N-[8-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)octyl]benzamide as an off white powder, m.p. 133.1-136.7° C. Analysis: Calculated for C25H29N5O.0.25 H2O: % C, 71.49; % H, 7.08; % N, 16.67. Found: % C, 71.37; % H, 7.05; % N, 16.62.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Na].[CH3:11][O:12][CH2:13][C:14]#[C:15][C:16]1[C:21]2[CH:22]=[CH:23][O:24][C:20]=2[C:19]([NH2:25])=[CH:18][CH:17]=1.Cl[C:27]1[C:36]2[C:31](=[CH:32][C:33]([O:39][CH2:40][CH2:41][CH2:42][N:43]3[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]3)=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]=[CH:29][C:28]=1[C:50]#[N:51]>CN(C=O)C>[C:50]([C:28]1[CH:29]=[N:30][C:31]2[C:36]([C:27]=1[NH:25][C:19]1[C:20]3[O:24][CH:23]=[CH:22][C:21]=3[C:16]([C:15]#[C:14][CH2:13][O:12][CH3:11])=[CH:17][CH:18]=1)=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH2:40][CH2:41][CH2:42][N:43]1[CH2:44][CH2:45][N:46]([CH3:49])[CH2:47][CH2:48]1)[CH:32]=2)#[N:51]
Reactant: COCC#Cc1ccc(N)c2occc12
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCN1CCN(C)CC1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: CN(C)C=O
Product: COCC#Cc1ccc(Nc2c(C#N)cnc3cc(OCCCN4CCN(C)CC4)c(OC)cc23)c2occc12
Temperature: 0 °C

Procedure:
Sodium hexamethyldisilazane (1M solution in THF; 0.63 ml) was added to a mixture of [4-(3-methoxyprop-1-ynyl)benzofuran-7-yl]amine (0.06 g) and 4-chloro-3-cyano-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline (0.106 g) in DMF (5 ml) that was cooled to 0° C. The resultant mixture was stirred and allowed to warm to ambient temperature for 16 hours. The reaction mixture was reduced in vacuo and partitioned between ethylacetate and water. The organics were washed with water, saturated brine and dried with magnesium sulfate. The solvent was removed in vacuo and the residue purified by column chromatography on silica using a gradient of 0–10% methanol/dichloromethane as eluent. The product fractions were combined and reduced in vacuo and the residue dissolved in minimal dichloromethane, diluted with diethyl ether and precipitated as an HCl salt by the addition of 1.0M ethereal HCl. The resultant solid was centrifuged and washed with diethyl ether (X3) and dried to give the title compound as a yellow solid. (0.077 g); NMR Spectrum: (DMSOd6 @ 373K) 2.30 (m, 2H), 2.80 (s, 3H), 3.15–3.20 (m, 2H), 3.36–3.50 (m, 11H), 4.02 (s, 3H), 4.37 (t, 2H), 4.45 (s, 2H), 7.01 (s, 1H), 7.35 (d, 1H), 7.44 (d, 1H), 7.59 (s, 1H), 8.00 (s, 1H), 8.11 (s, 1H), 8.65 (s, 1H); Mass Spectrum: M+H+ 540.14.
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:25]=[C:26]1[O:30][C:28](=[O:29])[CH2:27]1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:28]([O:11][CH2:10][CH2:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:29])[CH2:27][C:26]([CH3:25])=[O:30]
Reactant: C=C1CC(=O)O1
Reactant: OCCCC(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)OCCCC(c1ccccc1)c1ccccc1
Temperature: 80 °C

Procedure:
825 mg (3.65 mmol) of 4,4-diphenylbutane-1-ol, 0.1 ml (0.72 mmol) of triethylamine and 0.40 ml (5.19 mmol) of diketene were stirred in 30 ml of toluene under heating at 80° C. for 4 hours. After the addition of saturated aqueous sodium hydrogencarbonate solution at room temperature followed by the extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[C:8]([CH2:12]Cl)[NH:9][C:10](=[O:11])[C:5]=2[S:4][C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH:20]1[CH2:24][CH2:23][C@@H:22]([OH:25])[CH2:21]1>CO>[Br:1][C:2]1[C:6]2[N:7]=[C:8]([CH2:12][N:20]3[CH2:24][CH2:23][C@@H:22]([OH:25])[CH2:21]3)[NH:9][C:10](=[O:11])[C:5]=2[S:4][C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O[C@@H]1CCNC1
Reactant: O=c1[nH]c(CCl)nc2c(Br)c(-c3ccccc3)sc12
Solvent: CO
Product: O=c1[nH]c(CN2CC[C@@H](O)C2)nc2c(Br)c(-c3ccccc3)sc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of EXAMPLE 10A (90 mg, 0.25 mmol) in methanol (5 mL) was added (R)-pyrrolidin-3-ol (87 mg, 1 mmol) and the mixture stirred at ambient temperature for 2 days. The solvent was removed and residue purified by flash chromatography on silica gel using 1:10:0.5 methanol/ethyl acetate/concentrated ammonium hydroxide to give the title compound. 1H NMR (DMSO-d6) δ 7.75-7.77 (m, 2H), 7.54-7.59 (m, 3H), 4.85 (br, 1H), 4.20 (t, J=6.3 Hz, 1H), 3.69-3.75 (m, 2H), 2.81-2.86 (m, 2H), 2.57-2.58 (m, 2H), 2.01-2.08 (m, 1H), 1.59-1.65 (m, 1H).
Reaction SMILES: [NH2:1][C:2](=[O:40])[C@@H:3]([NH:24][C:25]([C@@H:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:23]=[CH:22][C:14]3[N:15]([CH2:19][CH2:20][OH:21])[C:16](=[O:18])[S:17][C:13]=3[CH:12]=2)=[CH:7][CH:6]=1.[Si:41](Cl)([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42].N1C=CN=C1.O>CN(C=O)C>[NH2:1][C:2](=[O:40])[C@@H:3]([NH:24][C:25]([C@@H:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])=[O:26])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:23]=[CH:22][C:14]3[N:15]([CH2:19][CH2:20][O:21][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[C:16](=[O:18])[S:17][C:13]=3[CH:12]=2)=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc3c(c2)sc(=O)n3CCO)cc1)C(N)=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc3c(c2)sc(=O)n3CCO[Si](C)(C)C(C)(C)C)cc1)C(N)=O
Reaction time: 4 h
Yield: 78.4 %

Procedure:
A solution of (S)-tert-butyl 2-((S)-1-amino-3-(4-(3-(2-hydroxyethyl)-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)phenyl)-1-oxopropan-2-ylcarbamoyl)piperidine-1-carboxylate (138 mg), tert-butyldimethylsilyl chloride (40.2 mg) and imidazole (41.3 mg) in DMF (1 mL) was stirred for 16 h. Further tert-butyldimethylsilyl chloride (40.2 mg) and imidazole (41.3 mg) were added and stirred for 4 h. Water was added and the mixture was extracted thrice with ethyl acetate. The organic layers were washed twice with water, combined, dried over magnesium sulfate, evaporated and purified by flash silica chromatography eluting with 1:2 acetone/isohexane to give the subtitle compound (130 mg) as a colourless gum.
Reaction SMILES: [F:1][C:2]1[C:7]2[NH:8]C(=O)O[C:11](=[O:12])[C:6]=2[CH:5]=[CH:4][CH:3]=1.O1CCOCC1.C(=O)=O.[NH3:23]>>[NH2:8][C:7]1[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=1[C:11]([NH2:23])=[O:12]
Reactant: N
Reactant: O=c1[nH]c2c(F)cccc2c(=O)o1
Agent: O=C=O
Solvent: C1COCCO1
Product: NC(=O)c1cccc(F)c1N

Procedure:
A mixture of 8-Fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (2.00 g, 0.0110 mol) in 1,4-Dioxane (25 mL, 0.32 mol) was treated with ammonia (20 mL, 0.5 M in dioxane) and warmed to 60° C. for 2 h (dry ice cold finger). Additional ammonia (20 mL) was added and after 1 h at 60° C., solvent was evaporated to afford title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][C:33]1[N:34]=[C:35]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:36][C:37]=1[CH3:38])[CH2:6][O:7][C:8]1[C:12](/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])=[CH:11][N:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[N:9]=1.[C:45]([O:51][CH2:52]Cl)(=[O:50])[C:46]([CH3:49])([CH3:48])[CH3:47].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][C:33]1[N:34]=[C:35]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:36][C:37]=1[CH3:38])[CH2:6][O:7][C:8]1[C:12](/[CH:13]=[CH:14]/[C:15]([O:17][CH2:52][O:51][C:45](=[O:50])[C:46]([CH3:49])([CH3:48])[CH3:47])=[O:16])=[CH:11][N:10]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:22][CH:23]=2)[N:9]=1
Reactant: COc1cc(COc2nn(-c3ccc(C(F)(F)F)cc3)cc2/C=C/C(=O)O)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: CC(C)(C)C(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COc2nn(-c3ccc(C(F)(F)F)cc3)cc2/C=C/C(=O)OCOC(=O)C(C)(C)C)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 60 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
A mixture of (2E)-3-{3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-2-propenoic acid (0.303 g), chloromethyl pivalate (0.075 g), potassium carbonate (0.138 g) and N,N-dimethylformamide (5 mL) was stirred at 60° C. for 1 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. Recrystallization of the obtained crystal from hexane-ethyl acetate gave [(2,2-dimethylpropanoyl)oxy]methyl (2E)-3-{3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-2-propenoate as a colorless powder (0.271 g, yield 75%). melting point: 131-132° C.
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][C:4]([C:7]2[O:8][C:9]([CH3:25])=[C:10]([CH2:12][CH2:13][O:14]S(C3C=CC(C)=CC=3)(=O)=O)[N:11]=2)=[CH:3][CH:2]=1.[CH2:32]([O:34][C:35](=[O:47])[C:36]([O:39][C:40]1[CH:45]=[CH:44][C:43](O)=[CH:42][CH:41]=1)([CH3:38])[CH3:37])[CH3:33].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:32]([O:34][C:35](=[O:47])[C:36]([CH3:38])([O:39][C:40]1[CH:45]=[CH:44][C:43]([O:14][CH2:13][CH2:12][C:10]2[N:11]=[C:7]([C:4]3[CH:5]=[CH:6][C:1]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:2][CH:3]=3)[O:8][C:9]=2[CH3:25])=[CH:42][CH:41]=1)[CH3:37])[CH3:33]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1
Yield: 47 %

Procedure:
A mixture of toluene-4-sulfonic acid 2-(2-biphenyl-4-yl—methyl-oxazol-4-yl)ethyl ester (14.9 g, 34.3 mmol), 2-(4-hydroxyphenoxy)-2-methyl propionic acid ethyl ester (American Home Products U.S. Pat. No. 3,795,691 (6.15 g, 27.4 mmol) and Cs2CO3 (12.0 g, 36.8 mmol) was heated at 55° C. in DMF (110 mL) for 18 h. The reaction was partitioned between ethyl acetate (160 mL) and H2O (180 mL), and the aqueous phase extracted with ethyl acetate (150 mL). The combined organic phases were dried (MgSO4) and concentrated under reduced pressure to an oil which was purified by column chromatography (600 mL SiO2, 10% ethyl acetate/hexanes to 20% ethyl acetate/hexanes) to provide 2-methyl-2-{4-[2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethoxy]phenoxy}propionic acid ethyl ester (6.25 g, 47%) as a colorless, viscous oil: Rf=0.48 in 35% ethyl acetate/hexanes; 1H NMR (500 MHz, CDCl3) δ 8.05-8.03 (m, 2H), 7.67-7.64 (m, 4H), 7.46 (m, 2H), 7.38 (m, 1H), 6.83-6.77 (m, 4H), 4.22 (q, J=9.2 Hz, 2H), 4.18 (t, J=8.8 Hz, 2H), 2.97 (t, J=8.8 Hz, 2H), 2.37 (s, 3H), 1.52 (s, 6H), 1.27 (t, J=9.2 Hz, 3H).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=O)[CH:9]=[C:8]([CH3:18])[N:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(OC(=O)[N:25]([CH2:36][CH2:37][NH2:38])[CH2:26][C:27]1[CH:35]=[CH:34][C:30]2[O:31][CH2:32][O:33][C:29]=2[CH:28]=1)(C)(C)C>>[O:31]1[C:30]2[CH:34]=[CH:35][C:27]([CH2:26][NH:25][CH2:36][CH2:37][NH:38][C:13](=[O:15])[C:12]([C:10]3[CH:9]=[C:8]([CH3:18])[N:7]=[C:6]([N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)[N:11]=3)([CH3:17])[CH3:16])=[CH:28][C:29]=2[O:33][CH2:32]1
Reactant: CC(C)(C)OC(=O)N(CCN)Cc1ccc2c(c1)OCO2
Reactant: Cc1cc(C(C)(C)C(=O)O)nc(-n2ccnc2)n1
Product: Cc1cc(C(C)(C)C(=O)NCCNCc2ccc3c(c2)OCO3)nc(-n2ccnc2)n1

Procedure:
N-{2-[(Benzo[1,3]dioxol-5-ylmethyl)-amino]-ethyl}-2-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-isobutyramide was prepared following the procedures described in the preparation of Example 56 using 2-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-2-methyl-propionic acid and (2-amino-ethyl)-benzo[1,3]dioxol-5-ylmethyl-carbamic acid tert-butyl ester. [M+H]+ 423.26; 1H NMR (400 MHz, CD3OD) δ 8.70 (s, 1H), 8.00 (s, 1H), 7.35 (s, 1H), 7.14 (s, 1H), 6.94-6.80 (m, 3H), 5.98 (s, 2H), 4.10 (s, 2H), 3.53 (t, 2H), 3.13 (t, 2H), 2.58 (s, 3H), 1.63 (s, 6H).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:49]=[C:48]([CH3:50])[C:44]4[NH:45][CH:46]=[N:47][C:43]=4[CH:42]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([CH:27]4[CH2:32][CH2:31][N:30](CC5C=CC=CC=5)[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:51]=[CH:52][CH:53]=[CH:54][C:4]=2[NH:3]1.[H][H]>CO.[Pd]>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:49]=[C:48]([CH3:50])[C:44]4[NH:45][CH:46]=[N:47][C:43]=4[CH:42]=3)[C:19]([N:21]3[CH2:22][CH2:23][CH:24]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH2:25][CH2:26]3)=[O:20])=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:51]=[CH:52][CH:53]=[CH:54][C:4]=2[NH:3]1
Reactant: [H][H]
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(Cc4ccccc4)CC3)CC2)cc2nc[nH]c12
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCNCC3)CC2)cc2nc[nH]c12
Reaction time: 2 h

Procedure:
75 mg (0.09 mmol) (R)-2-(1′-benzyl-4,4′-bipiperidinyl-1-yl)-1-(7-methyl-1H-benzimidazol-5-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate were dissolved in 10 mL MeOH and combined with 30 mg 10% Pd/C. The mixture was hydrogenated for 2 h in a Parr apparatus at 50° C. and 50 psi hydrogen pressure. Then the catalyst was filtered off and the filtrate was evaporated down i.vac.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([CH2:13][OH:14])([CH2:11][OH:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].P(=O)(O)(O)O.[CH3:21][C:22]([CH3:24])=O>C1C=CC=CC=1>[CH3:21][C:22]1([CH3:24])[O:12][CH2:11][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:15])([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:13][O:14]1
Reactant: CCOC(=O)C(CO)(CO)C(=O)OCC
Reactant: CC(C)=O
Agent: O=P(O)(O)O
Solvent: c1ccccc1
Product: CCOC(=O)C1(C(=O)OCC)COC(C)(C)OC1
Yield: 87 %

Procedure:
To diethyl-bis-(hydroxymethyl)malonate (50 g) in acetone (50 ml) and benzene (200 ml) is added phosphoric acid (10 g). . The mixture is refluxed while stirring and separating water which distills. When water evolution is complete, the reaction mixture is cooled and the organic layer is separated, stirred with solid sodium carbonate (10 g), filtered and evaporated to give the title product (52 g) (87%) nD26 1.4412.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[Cl-].[NH4+].CO>[Zn].O>[CH3:1][O:2][C:3](=[O:23])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 100.2 %

Procedure:
To a mixture of of N-[(1,1-dimethylethoxy)carbonyl]-4-nitro-L-phenylalanine methyl ester (222 mmol, 72 g), zinc dust (˜325 mesh, 2.2 mol, 145.2 g, 10 equiv) and ammonium chloride (3.3 mol, 178.1 g, 15 equiv) was added methanol (1 L) and water (500 mL) at room temperature. After addition of water, an exothermic reaction ensued and the internal temperature rose to 45 to 50° C. The suspension was stirred for 30 min to 1 h at room temperature, at which time TLC analysis of the mixture indicated the absence of starting material, and the reaction mixture was filtered through a pad of celite and the filtered cake was washed with methanol (1 L) and water (500 mL). Concentration to remove most of the methanol afforded white solid which was collected by filtration and washed with water. After air drying, 65.5 g of a white solid, mp 86-89° C. was obtained. 1H-NMR (DMSO-d6) (400 MHz) δ 6.9 (d, 2H, J=20 Hz), 6.62 (d, 2H, J=20 Hz), 7.39 (d, 1H, J=22 Hz), 4.26-4.28 (m, 1H), 3.68 (s, 3H), 2.96-3.19 (m, 2H), 1.25 (s, 9H). HR MS: Obs. mass, 294.1614. Calcd. mass, 294.1621 (M+).
Reaction SMILES: [Na].C(O)(=O)C.[CH:6]([NH2:8])=[NH:7].[CH3:9][O:10][C:11]1[CH:24]=[CH:23][C:14]([O:15][C:16](=[CH:19]N(C)C)[CH:17]=O)=[CH:13][CH:12]=1.[O-]CC.[Na+]>C(O)C>[CH3:9][O:10][C:11]1[CH:24]=[CH:23][C:14]([O:15][C:16]2[CH:17]=[N:7][CH:6]=[N:8][CH:19]=2)=[CH:13][CH:12]=1
Reactant: N=CN
Reactant: COc1ccc(OC(C=O)=CN(C)C)cc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(Oc2cncnc2)cc1
Reaction time: 40 h
Yield: 64.8 %

Procedure:
Sodium metal (4.1 g) was dissolved in absolute ethanol (90 ml) and formamidine acetate (18.4 g) and 2-(p-methoxyphenoxy)-3-(dimethylamino)acrolein (13.0 g) were added to the ethanolic solution of sodium ethoxide. The mixture was heated under reflux, with stirring, for 40 hr and then the solvent was removed, by distillation under reduced pressure. The residue was treated with water (200 ml) and chloroform (200 ml), the chloroform layer was separated and the chloroform removed by distillation under reduced pressure. The residue was purified by column chromatography over silica gel using chloroform as eluent to give 5-(p-methoxyphenoxy)pyrimidine as an oil (7.7 g) which was characterised by p.m.r. spectroscopy.
Reaction SMILES: [F:1][CH2:2][CH:3]1[CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.[F:14][C:15]([F:20])([F:19])[C:16]([OH:18])=[O:17].C(Cl)Cl>>[F:14][C:15]([F:20])([F:19])[C:16]([OH:18])=[O:17].[F:1][CH2:2][CH:3]1[CH2:6][NH:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CC(CF)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FCC1CNC1

Procedure:
tert-Butyl 3-(fluoromethyl)azetidine-1-carboxylate (0.1 g, 0.53 mmol) and trifluoroacetic acid/DCM (1:1, 5.3 mL) was stir at room temperature for 30 min. Then the reaction mixture was concentrated on a rotary evaporator to afford 3-(fluoromethyl)azetidine 2,2,2-trifluoroacetate as clear oil. 1H NMR (DMSO-d6; TFA salt): δ 8.74 (br, 2H), 4.54 (dd, 2H), 4.08-3.98 (m, 2H), 3.84-3.76 (m, 2H), 3.20-3.06 (m, 1H).