Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][CH:3]=1.CS(Cl)(=O)=O.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[N:32]1C2C(=CC=CC=2)[CH:35]=[CH:34][CH:33]=1>[P].N1C=CC=CC=1>[NH2:32][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:33]([NH2:32])[CH2:34][CH3:35]
Reactant: c1ccc2ncccc2c1
Reactant: Oc1ccnc2cccnc12
Agent: CS(=O)(=O)Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [P]
Solvent: c1ccncc1
Product: CCCN
Product: Nc1ccnc2cccnc12

Procedure:
4-Hydroxy-1,5-naphthyridines can be prepared from 3-aminopyridine derivatives by reaction with diethyl ethoxymethylene malonate to produce the 4-hydroxy-3-carboxylic acid ester derivative with subsequent hydrolysis to the acid, followed by thermal decarboxylation in quinoline (as for example described for 4-Hydroxy-[1,5]naphthyridine-3-carboxylic acid, J. T. Adams et al., J. Amer. Chem. Soc., 1946, 68, 1317). A 4-hydroxy-[1,5]naphthyridine can be converted to the 4-chloro derivative by heating in phosphorus oxychlo'ride, or to the 4-methanesulphonyloxy or 4-trifluoromethanesulphonyloxy derivative by reaction with methanesulphonyl chloride or trifluoromethanesulphonic anhydride, respectively, in the presence of an organic base. A 4-amino 1,5-naphthyridine can be obtained from the 4-chloro derivative by reaction with n-propylamine in pyridine.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH2:13]1[C@@H:22]2[C@H:17]([CH2:18][CH2:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=32)[NH:16][CH2:15][CH2:14]1.C(Cl)Cl.CO>O>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:16]3[C@@H:17]4[C@H:22]([C:21]5[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=5[CH2:19][CH2:18]4)[CH2:13][CH2:14][CH2:15]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@@H]21
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: O=C(c1ccc2[nH]cnc2c1)N1CCC[C@H]2c3ccccc3CC[C@@H]21
Yield: 31 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and trans-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 31% of theory; TLC: rf=0.40 (silica gel, CH2Cl2/MeOH/32% aqueous NH3 90:10:1); Mass spectrum (ESI+): m/z=332 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 1.32-1.46 (m, 1H), 1.53-1.76 (m, 2H), 2.14-2.24 (m, 1H), 2.30-2.43 (m, 1H), ca. 2.49-2.56 superimposed by D3CSOCHD2 signal (m, 1H), 2.77-2.93 (m, 2H), 3.03-3.13 (m, 1H), ca. 3.25-3.34 superimposed by H2O signal (m, 1H), 3.34-3.43 (m, 1H), 3.67-3.76 (m, 1H), 7.07-7.19 (m, 3H), 7.26-7.32 (m, 2H), 7.59-7.70 (m, 2H), 8.30 (s, 1H), 12.60 (broad s, 1H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH2:13][CH2:12]1)=[O:10])(C)(C)C.Cl>CO.CCOCC>[NH2:7][CH:8]([CH2:32][C:33]1[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH2:13][CH2:12]1)=[O:10]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2OCCN2CCOCC2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2OCCN2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
To a solution of (1-(4-chloro-benzyl)-2-{4-[2-(2-morpholin-4-yl-ethoxy)-phenyl]-piperazine-1-yl}-2-oxo-ethyl)-carbamic acid tert-butyl ester (23.57 g, 41.1 mmol) in MeOH (225 mL) was added 1.0 M HCl in Et2O. The mixture is stirred at r.t. overnight. The solid was filtered, washed with Et2O and dried under vacuum overnight to afford 2-amino-3-(4-chloro-phenyl)-1-{4-[2-(2-morpholin-4-yl-ethoxy)-phenyl]-piperazine-1-yl}-propan-1-one (19.6 g, 36 mmol, 88%).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:24][CH2:25][CH3:26])=[CH:14][C:13]2=[O:27])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:29]N(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.Cl.[OH:60][C@@H:61]([CH2:91]O)[CH2:62][N:63]1[CH:67]=[CH:66][C:65]([NH:68]C(=O)[C@@H](N2CC(OC3C=CC=C(Cl)C=3Cl)=CC2=O)CC(C)C)=[N:64]1>ClCCl.C(OCC)(=O)C>[CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:24][CH2:25][CH3:26])=[CH:14][C:13]2=[O:27])[C:9]([NH:68][C:65]2[CH:66]=[CH:67][N:63]([CH2:62][C:61]([OH:60])([CH3:91])[CH3:29])[N:64]=2)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Reactant: CCCc1ccccc1OC1=CC(=O)N([C@@H](CC2CCCCC2)C(=O)O)C1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCCc1ccccc1OC1=CC(=O)N([C@@H](CC2CCCCC2)C(=O)Nc2ccn(CC(C)(C)O)n2)C1
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 29.2 %

Procedure:
To a stirred solution of (S)-3-cyclohexyl-2-[2-oxo-4-(2-propyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionic acid (160 mg, 0.43 mmol) in dichloromethane (12 mL) was gradually added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (230 mg, 1.2 mmol) and N,N-diisopropylethyl amine (260 mg, 2.0 mmol) at room temperature, under nitrogen. After 15 min, 1-hydroxybenzotriazole (184 mg, 1.2 mmol) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 63 mg, 0.39 mmol) were added to the reaction mixture. The reaction mixture was then stirred at 23° C. for 48 h. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous ammonium chloride solution followed by a saturated aqueous sodium bicarbonate solution. The organic layer was then washed with a saturated aqueous sodium chloride solution, separated, dried over sodium sulfate and concentrated in vacuo to afford the crude product, which was purified by flash column chromatography (silica gel (100-200 mesh)) which afforded (S)-3-cyclohexyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[2-oxo-4-(2-propyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionamide (58 mg, 26%) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ ppm 0.90 (t, J=7.3 Hz, 3H), 0.94-1.08 (m, 2H), 1.14 (br. s., 3H), 1.15 (br. s., 3H), 1.17-1.33 (m, 4H), 1.51-1.58 (m, 2H), 1.61-1.79 (m, 5H), 1.83 (d, J=12.7 Hz, 1H), 1.87-1.97 (m, 1H), 2.39-2.63 (m, 2H), 3.61 (br. s., 1H), 3.93 (s, 2H), 4.07 (d, J=17.9 Hz, 1H), 4.26 (d, J=17.9 Hz, 1H), 4.85 (s, 1H), 4.85-4.90 (m, 1H), 6.68 (d, J=2.0 Hz, 1H), 7.09 (d, J=7.8 Hz, 1 H), 7.15-7.23 (m, 3H), 7.29 (d, J=2.0 Hz, 1H), 8.57 (br. s., 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CCOCC>[N:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)[CH:2]=1
Reactant: Brc1ccccn1
Reactant: c1ccc2[nH]ccc2c1
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: c1cncc(-n2ccc3ccccc32)c1
Temperature: 100 °C
Yield: 14.6 %

Procedure:
Under an argon atmosphere, a solution of bromopyridine (1.7 mL, 17.6 mmol) in toluene (15 mL) is added to indole (2.0 g, 17.1 mmol), tris(dibenzylideneacetone)palladium (480 mg, 0.52 mmol), 2-(di-tert-butylphosphino)biphenyl (5.52 mg, 0.76 mmol), sodium tert-butoxide and toluene (25 mL) and the stirred mixture is heated at 100° C. for 48 hr. After cooling to room temperature, ether is added and the reaction mixture is filtered through Hi-Flo and concentrated. The residue is purified by chromatography eluting with pentane-25% ethyl acetate. Product containing fractions are combined and concentrated to afford 1-(pyridin-3-yl)-1H-indole (485 mg, 15%) as a yellow-brown oil.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1>CN(C)C=O>[CH3:1][NH:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[CH:10][CH:11]=1)=[O:4]
Reactant: Nc1ccc(N2CCN(c3ccncc3)CC2)cc1
Reactant: CN=C=O
Solvent: CN(C)C=O
Product: CNC(=O)Nc1ccc(N2CCN(c3ccncc3)CC2)cc1
Reaction time: 3 h
Yield: 52.9 %

Procedure:
Methyl isocyanate (0.18 g) was added to a stirred solution of 1-(4-aminophenyl)-4-(4-pyridyl)piperazine (0.51 g) in dry N,N-dimethylformamide (5 ml). The resulting mixture was stirred for 3 hours, diluted with a few ml. of ethanol and filtered. The solid was crystallised from methanol to give the title compound (0.33 g), m.p. 258°-260° C. Found: C,65.46; H,6.83; N,22.25. C17H21N5O requires: C,65.57; H,6.80; N,22.49%.
Reaction SMILES: [F:1][CH:2]([O:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4].Cl.[O-:16][C:17]#[N:18].[K+]>O>[F:1][CH:2]([O:7][C:8]1[CH:14]=[CH:13][C:11]([NH:12][C:17]([NH2:18])=[O:16])=[CH:10][CH:9]=1)[C:3]([F:4])([F:5])[F:6]
Reactant: N#C[O-]
Reactant: Nc1ccc(OC(F)C(F)(F)F)cc1
Agent: Cl
Agent: [K+]
Solvent: O
Product: NC(=O)Nc1ccc(OC(F)C(F)(F)F)cc1
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
10 g of 4-tetrafluoroethoxyaniline, prepared as in Example 1, in 40 ml of water, and 10 ml of 1:1 HCl, were reacted with 3.9 g of potassium cyanate. The mixture was stirred for 30 minutes and the formed solid was filtered out, rinsed with cool water, and dried to give 10.5 g of the desired compound, having a melting point of 167°-168° C.
Reaction SMILES: C([O:3][P:4]([CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([C:19]2[NH:23][C:22]3[CH:24]=[C:25]([C:28]4[O:29][C:30]([C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=5)=[N:31][N:32]=4)[CH:26]=[CH:27][C:21]=3[N:20]=2)=[C:14]([CH3:40])[CH:13]=1)(=[O:8])[O:5]CC)C.C[Si](Br)(C)C>C(Cl)Cl>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C:30]2[O:29][C:28]([C:25]3[CH:26]=[CH:27][C:21]4[N:20]=[C:19]([C:15]5[C:16]([CH3:18])=[CH:17][C:12]([CH2:11][CH2:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5])=[CH:13][C:14]=5[CH3:40])[NH:23][C:22]=4[CH:24]=3)=[N:32][N:31]=2)=[CH:34][CH:35]=1
Reactant: CCOP(=O)(C/C=C/c1cc(C)c(-c2nc3ccc(-c4nnc(-c5ccc(Cl)cc5)o4)cc3[nH]2)c(C)c1)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: Cc1cc(CCCP(=O)(O)O)cc(C)c1-c1nc2ccc(-c3nnc(-c4ccc(Cl)cc4)o3)cc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of [(E)-3-(4-{6-[5-(4-chlorophenyl)-[1,3,4]oxadiazol-2-yl]-1H-benzoimidazol-2-yl}-3,5-dimethylphenyl)-allyl]-phosphonic acid diethyl ester (1.44 g, 2.5 mmol) in CH2Cl2 (15 mL) was added trimethylsilylbromide (1.62 mL, 12.5 mmol) and the mixture was stirred at RT for 18 h. The solvent was removed under reduced pressure and the residue was purified by reverse phase HPLC using a gradient of 0-80% MeCN/water containing 0.7% NH4OH to give the title compound. MS: m/z 523.1 (M+1). H1-NMR (DMSO-d6): δ ppm 8.46 (s, 0.6H), 8.19 (d, J=8.59 Hz, 2H), 8.0 (d, J=8.21 Hz, 1H), 7.88 (s broad, 0.4H), 7.72 (d, J=8.59 Hz, 2H), 7.05 (s, 2H), 2.64 (t, 2H), 2.11 (s, 6H), 1.78 (m, 2H), 1.41 (m, 2H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C@H:19]([O:23][CH2:24][CH3:25])[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.C(=O)([O-])O.[Na+].Cl[C:32]([O:34][CH:35]1[CH2:40][CH2:39][CH:38]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:37][CH2:36]1)=[O:33].CO.ClCCl>O1CCCC1>[CH2:24]([O:23][C@@H:19]([CH2:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([NH:2][C:32]([O:34][CH:35]3[CH2:40][CH2:39][CH:38]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:37][CH2:36]3)=[O:33])=[CH:8][CH:7]=2)=[CH:13][CH:14]=1)[C:20]([OH:22])=[O:21])[CH3:25]
Reactant: CCO[C@@H](Cc1ccc(OCCc2ccc(N)cc2)cc1)C(=O)O
Reactant: CC(C)(C)C1CCC(OC(=O)Cl)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: CCO[C@@H](Cc1ccc(OCCc2ccc(NC(=O)OC3CCC(C(C)(C)C)CC3)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
3-{4-[2-(4-Aminophenyl)ethoxy]phenyl}-(S)-2-ethoxypropanoic acid hydro chloride (0.2 g, 0.547 mmole) and sodium hydrogen carbonate (0.05 g, 0.595 mmole) were mixed in tetrahydrofurane (5 ml), stirred at room temperature for 20 minutes and then 4-tert-butylcyclohexyl chloroformate (0.131 g, 0.599 mmole) was added. The reaction mixture was stirred at room temperature overnight and then a little more 4-tert-butylcyclohexyl chloroformate was added since the reaction was not complete according to HPLC. The reaction mixture was stirred for 2 more hours and then evaporated to dryness. Ethyl acetate and water were added to the residue and the phases were separated. The organic phase was dried with magnesium sulfate and the solvent was evaporated. Chromatography on silica gel (Isolute, SI ) using dichloromethane:heptane (1:1), followed by dichloromethane, and then methanol: dichloromethane (1:99) as eluants gave 0.28 g (93% yield) (S)-2-ethoxy-3[4-(2-[4-([{4-(tert-butyl)cyclohexyl}oxy]carbonylamino)phenyl]ethoxy)phenyl]propanoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([CH3:10])[CH:3]=1.C[C:12]([CH3:15])([O-:14])C.[K+].C1C[O:20][CH2:19][CH2:18]1>>[Br:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:18]/[C:19]([O:14][CH2:12][CH3:15])=[O:20])=[C:4]([CH3:10])[CH:3]=1
Reactant: C1CCOC1
Reactant: CC(C)(C)[O-]
Reactant: Cc1cc(Br)ccc1C=O
Agent: [K+]
Product: CCOC(=O)/C=C/c1ccc(Br)cc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-bromo-2-methylbenzaldehyde (1 eq) and triethylphosphonoacetate (1.1 eq) in THF (0.3M) at rt was added dropwise potassium t-butoxide (1.1 eq, 1M, THF). The mixture was stirred at rt 3 h, quenched with HCl 10%, diluted with ether, washed with a NaHCO3 Solution, brine, dried over MgSO4, filtered and concentrated. Flash chromatography (Hexane:EtOAc; 90:10 to 70:30) afforded the title compound.
Reaction SMILES: C[N:2](/[CH:4]=[C:5](\[CH2:11][CH3:12])/[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[NH:13]([C:15]1[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][N:16]=1)N>>[C:21]([C:19]1[CH:18]=[CH:17][N:16]=[C:15]([NH:13][NH:2]/[CH:4]=[C:5](\[CH2:11][CH3:12])/[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:20]=1)#[N:22]
Reactant: CCOC(=O)/C(=C/N(C)C)CC
Reactant: N#Cc1ccnc(NN)c1
Product: CCOC(=O)/C(=C/NNc1cc(C#N)ccn1)CC

Procedure:
The title compound was prepared from ethyl (2E)-2-(dimethylaminomethylidene)butanoate and 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) according to the procedure for the preparation of Example 84, part B. [M+H] Calc'd for C13H16N4O2, 261; Found, 261.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C@@H:10]3[CH2:12][C@H:11]3[CH:13]=O)[C:4]=2[CH2:3][CH2:2]1.Cl.[NH2:16]O.[OH-].[Na+].C(O)C.O>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C@@H:10]3[CH2:12][C@H:11]3[CH2:13][NH2:16])[C:4]=2[CH2:3][CH2:2]1
Reactant: NO
Reactant: O=C[C@@H]1C[C@H]1c1cccc2c1CCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: NC[C@@H]1C[C@H]1c1cccc2c1CCO2
Reaction time: 18 h
Yield: 70.5 %

Procedure:
A mixture of (-)-(trans)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropanecarboxaldehyde (1.98 g, 10.5 mmol), hydroxylamine hydrochloride (2.29 g, 33 mmol), and 30% NaOH (3.5 mL, 35 mmol), in 5:1 ethanol/water (50 mL) was heated on a steam bath for 2 h. The solution was concentrated in vacuo, and the residue mixed with water. The mixture was extracted with CH2Cl2. The organic extracts were dried and concentrated in vacuo to give a solid which NMR analysis showed to be a mixture of the cis and trans oximes. This material was dissolved in THF (20 mL) and added to solution of alane in THF [prepared from LAH (1.14 g, 30 mmol) and H2SO4 (1.47 g, 15 mmol) at 0° C.]. The reaction was stirred for 18 h, and quenched successively with water (1.15 mL), 15% NaOH (1.15 mL), and then water (3.45 mL). The mixture was filtered and the filtrate was concentrated in vacuo. The residue was mixed with ether and washed with water and then 1N HCl. The acid washes were made basic and extracted with CH2Cl2. The extracts were dried and concentrated in vacuo to give the amine product (1.4 g, 70.5%). The amine was converted to the fumarate salt in ethanol (mp: 197°-198° C.). Anal. Calc'd for C12H15NO.C4H4O4 : C, 62.94; H, 6.27; N, 4.59; Found: C, 62.87; H, 6.31; N, 4.52.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]([CH3:9])[CH:7]=[N:8][C:4]=2[C:3]=1[CH3:12].C([N:15]=[C:16](S)[N:17](C(OCC1C=CC=CC=1)=O)[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])C.[C:39]([O:42][CH2:43][CH3:44])(=[O:41])C>CO>[CH2:43]([O:42][C:39]([N:15]=[C:16]([NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[NH:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]([CH3:9])[CH:7]=[N:8][C:4]=2[C:3]=1[CH3:12])=[O:41])[C:44]1[CH:10]=[CH:11][CH:2]=[CH:3][CH:4]=1
Reactant: CCOC(C)=O
Reactant: CCN=C(S)N(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: Cc1c(N)ccc2c1ncn2C
Solvent: CO
Product: Cc1c(NC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)ccc2c1ncn2C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 250 mg of 5-amino-1,4-dimethylbenzimidazole in 75 mL of ethyl acetate and 10 mL of methanol are added 789 mg of ethyl N,N-bis(benzyloxycarbonyl)pseudothiourea and 665 mg of mercuric acetate and the mixture is stirred at room temperature for 15 hours. The mixture is filtered on Celite and rotary evaporated. The residue is purified by flash column chromatography on silica gel, eluting with 5% methanol/ethyl acetate to provide 590 mg of 5-[N2,N3-bis(benzyloxycarbonyl)guanidino]-1,4-dimethybenzimidazole as a white solid.
Reaction SMILES: [CH2:1]([N:6]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:9](=O)[C:7]1=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:19][CH:20]([CH3:26])[CH2:21][C:22]([NH:24][NH2:25])=[O:23]>>[CH3:18][O:17][C:14]1[CH:15]=[C:16]2[C:11](/[C:9](=[N:25]/[NH:24][C:22](=[O:23])[CH2:21][CH:20]([CH3:26])[CH3:19])/[C:7](=[O:8])[N:6]2[CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:12][CH:13]=1
Reactant: CC(C)CC(=O)NN
Reactant: CCCCCN1C(=O)C(=O)c2ccc(OC)cc21
Product: CCCCCN1C(=O)/C(=N\NC(=O)CC(C)C)c2ccc(OC)cc21

Procedure:
The title compound was prepared as a yellow solid, using 1-pentyl-6-methoxy-isatin obtained in Example 39(A) and 3-methylbutanohydrazide according to the synthetic method E. NMR (CDCl3): δ 0.92 (t, 3H), 1.05 (d, 6H), 1.36 to 1.39 (m, 4H), 1.69-1.75 (m, 2H), 2.30 (m, 2H), 2.72 (d, 1H), 3.72 (t, 2H), 3.89 (s, 3H), 6.44 (d, 1H), 6.64 (dd, 1H), 7.54 and 7.77 (d for isomers, 1H), 12.41 and 13.03 (br s for isomers, 1H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)N.[CH3:12][C:13]([CH:15]=[CH2:16])=O.ClC(Cl)=O.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([NH:35][C:36]([NH2:38])=[S:37])[CH:26]=[CH:27][C:28]=1[N:29]1[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]1>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([NH:35][C:36]2[S:37][C:13]([CH2:12][C:5]3[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:11])([F:10])[F:1])[CH:4]=3)=[C:15]([CH3:16])[N:38]=2)[CH:26]=[CH:27][C:28]=1[N:29]1[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]1
Reactant: C=CC(C)=O
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Agent: O=C(Cl)Cl
Product: COc1cc(Nc2nc(C)c(Cc3cccc(C(F)(F)F)c3)s2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 7 without purification of the intermediate from 161 mg (1 mmol) 3-trifluoromethylaniline and 421 mg (6 mmol) methyl vinylketone. The crude chloroketone was used without further purification in the next step with 53 mg (0.2 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea. The crude product was purified on silica gel with methylene chloride/methanol 19/1 yielding 50 mg (55%) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-[4-methyl-5-(3-trifluoromethyl-benzyl)-thiazol-2-yl]-amine as a brown solid. MS ISP (m/e): 459.1 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.18 (s, 1H), 7.66-7.53 (m, 7H), 7.23 (s, 1H), 7.01 (s, 1H), 4.11 (s, 2H), 3.77 (s, 3H), 2.25 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]1[CH2:12][O:11][C:10](=[O:13])[O:9]1)(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:14](O)(=O)[CH:15]=[CH2:16].[CH2:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[C:27]([O:32][CH3:33])(=[O:31])[C:28]([CH3:30])=[CH2:29].[C:34]([O:39][CH2:40][CH2:41][OH:42])(=[O:38])[C:35]([CH3:37])=[CH2:36]>>[C:1]([O:6][CH2:7][CH:8]1[CH2:12][O:11][C:10](=[O:13])[O:9]1)(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:27]([O:32][CH2:33][CH2:14][CH2:15][CH2:16][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:21][CH2:20][CH3:19])(=[O:31])[C:28]([CH3:30])=[CH2:29].[C:34]([O:39][CH2:40][CH2:41][O:42][CH2:1][CH3:2])(=[O:38])[C:35]([CH3:37])=[CH2:36].[CH2:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C=CC(=O)O
Reactant: C=C(C)C(=O)OCCO
Reactant: C=C(C)C(=O)OC
Agent: C=C(C)C(=O)OCC1COC(=O)O1
Solvent: C=Cc1ccccc1
Product: C=C(C)C(=O)OCCCCCCCCCCCC
Product: C=C(C)C(=O)OCCOCC

Procedure:
(2-oxo-1,3-dioxolan-4-yl)-methyl methacrylate/reaction product of Cadura E 10 and acrylic acid/styrene/methyl methacrylate/Hydroxyethyl methacrylate;
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])([OH:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.[C:19]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1)(=[O:21])[CH3:20]>>[C:19]([NH:22][C:23]1[CH:24]=[CH:25][C:26]([S:29]([NH:1][CH2:2][C:3]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])([OH:10])[CH2:4][N:5]2[CH:9]=[N:8][CH:7]=[N:6]2)(=[O:31])=[O:30])=[CH:27][CH:28]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Product: CC(=O)Nc1ccc(S(=O)(=O)NCC(O)(Cn2cncn2)c2ccc(Cl)cc2Cl)cc1

Procedure:
Following the procedure described in the preceeding examples but using 3-amino-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol and 4-acetamidobenzenesulfonylchloride, the title compound was obtained in a similar yield:
Reaction SMILES: [CH:1]([C:5]1[C:10]([OH:11])=[C:9]([CH:12]([CH2:14][CH3:15])[CH3:13])[CH:8]=[C:7]([CH2:16]OC)[CH:6]=1)([CH2:3][CH3:4])[CH3:2].[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=1[OH:27].S(=O)(=O)(O)O.C1(C)C(O)=CC=CC=1>C(Cl)Cl>[OH:11][C:10]1[C:9]([CH:12]([CH3:13])[CH2:14][CH3:15])=[CH:8][C:7]([CH2:16][C:24]2[CH:23]=[C:22]([CH3:26])[C:21]([OH:27])=[C:20]([CH3:19])[CH:25]=2)=[CH:6][C:5]=1[CH:1]([CH3:2])[CH2:3][CH3:4]
Reactant: CCC(C)c1cc(COC)cc(C(C)CC)c1O
Reactant: Cc1cccc(C)c1O
Agent: Cc1ccccc1O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCC(C)c1cc(Cc2cc(C)c(O)c(C)c2)cc(C(C)CC)c1O
Yield: 90 %

Procedure:
The procedure of Example 2 was followed using 50.45 grams (0.202 mol) of 2,6-di-sec-butyl-α-methoxy-p-cresol in 30 mL methylene chloride and 39.0 grams (0.320 mol) 2,6-dimethylphenol with 42 grams 78% sulfuric acid. The reaction was carried out at about 8° C. with mechanical stirring. The 2,6-di-sec-butylephenol used to prepare the cresol according to the procedure of Example 3 was of only 85.7 percent purity. Accordingly, the yield of the cresol was only 67% (86.9 area % by gas chromatography). The product of the invention: [4-[[4-hydroxy-3,5-bis(1-methylpropyl)phenyl]methyl]-2,6-dimethylphenol, was obtained as a viscous oil (liquid) at room temperature in 90 percent yield (61.77 grams) (84.4 area percent by gas chromatography). The compound has a pour point of 22° C. (as measured by ASTM test D-97).