Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([O:14][C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[C:21]([C:25](Cl)=[O:26])=[CH:20][CH:19]=[CH:18]4)[CH:5]=[CH:4][C:3]1=2.[NH3:29]>>[CH3:1][C:2]1([CH3:28])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([O:14][C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[C:21]([C:25]([NH2:29])=[O:26])=[CH:20][CH:19]=[CH:18]4)[CH:5]=[CH:4][C:3]1=2
Reactant: N
Reactant: CC1(C)CCC(C)(C)c2cc(Oc3ccc4c(C(=O)Cl)cccc4c3)ccc21
Product: CC1(C)CCC(C)(C)c2cc(Oc3ccc4c(C(N)=O)cccc4c3)ccc21
Yield: 88 %

Procedure:
Utilizing a procedure analogous to that of Example 16(b), 671 mg (1.7 mmol) of 6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyloxy)naphthoyl chloride were reacted with 10 ml of aqueous ammonia (32%) to provide 560 mg (88%) of the expected amide, having a melting point of 175°-6° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.C(O)(=O)C(O)=O.[NH:27]1[C:30]2([CH2:33][O:32][CH2:31]2)[CH2:29][CH2:28]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:27]3[C:30]4([CH2:33][O:32][CH2:31]4)[CH2:29][CH2:28]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: C1CC2(COC2)N1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C(O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1CCC12COC2

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 6-oxa-1-azaspiro[3.3]heptane oxalate (CAN 1359655-43-8) in the presence of TBTU and DIEA to give the title compound as colorless oil; MS (EI): m/e=366.4 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([OH:13])=O.[Cl:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:28]=1[C:22]1([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH2:21][CH:20]2[CH2:29][C:30]([O:32]CC)=[O:31]>>[Cl:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:28]=1[C:22]1([CH2:23][CH2:24][N:25]([C:11](=[O:13])[CH2:10][CH2:9][C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[CH2:26][CH2:27]1)[CH2:21][CH:20]2[CH2:29][C:30]([OH:32])=[O:31]
Reactant: CCOC(=O)CC1CC2(CCNCC2)c2c(Cl)cccc21
Reactant: O=C(O)CCc1ccc(Cl)cc1Cl
Product: O=C(O)CC1CC2(CCN(C(=O)CCc3ccc(Cl)cc3Cl)CC2)c2c(Cl)cccc21

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 1 using 3-(2,4-dichlorophenyl)propanoic acid and ethyl 2-(7-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate followed by a procedure analogous to that in Example 2. LC-MS Method 1 tR=2.03, min, m/z=484, 482, 480
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@:11]([OH:25])([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([O:23][CH3:24])[CH:15]=2)[C@@H:10]([OH:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([O:23][CH3:24])[CH:15]=2)([OH:25])[C@@H:10]([OH:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc([C@@]2(O)CCN(C(=O)OC(C)(C)C)C[C@@H]2O)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1cc([C@@]2(O)CCN(C(=O)OC(C)(C)C)C[C@@H]2O)ccc1N
Reaction time: 5 h

Procedure:
To a solution of (±)-(3S,4S)-3,4-dihydroxy-4-(3-methoxy-4-nitro-phenyl)-piperidine-1-carboxylicacid tert-butyl ester (540 mg) in ethanol (30 mL) was added palladium on carbon 10% (78.00 mg). The mixture was shaken in a Parr apparatus under an atmosphere of hydrogen (˜max 25-30 PSI) for 5 h. Filtration through Celite and evaporation of the solvent provided (±)-(3S,4S)-4-(4-amino-3-methoxy-phenyl)-3,4-dihydroxy-piperidine-1-carboxylic acid tert-butyl ester in quantitative yield.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[Cl:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([S:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)(=[O:31])=[O:30])[CH:23]=[CH:22]2>>[ClH:18].[Cl:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([S:29]([N:32]1[CH2:33][CH2:34][N:35]([C:4](=[O:6])[C:3]3[CH:7]=[CH:8][C:9]([C:11]4[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=4)=[CH:10][C:2]=3[OH:1])[CH2:36][CH2:37]1)(=[O:30])=[O:31])[CH:23]=[CH:22]2
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1O
Agent: Cl
Product: O=C(c1ccc(-c2ccncc2)cc1O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1

Procedure:
In the same manner as in Example A-4, a reaction was conducted using 2-(hydroxy-4-(4-pyridyl)benzoic acid and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as starting materials, whereby the title compound was obtained.
Reaction SMILES: COC([C:5]1[S:13][C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[C:6]=1[NH2:14])=O.N1CCNCC1.CN1CCCC1=O>O>[S:13]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[C:6]([NH2:14])=[CH:5]1
Reactant: COC(=O)c1sc2ncccc2c1N
Agent: C1CNCCN1
Solvent: O
Solvent: CN1CCCC1=O
Product: Nc1csc2ncccc12
Temperature: 145 °C
Yield: 85.6 %

Procedure:
A mixture of 3-aminothieno[2,3-b]pyridine-2-carboxylic acid methyl ester (8.00 g), piperazine (6.70 g), and N-methyl-2-pyrrolidinone (80 ml) was heated to 145° C. for 3 hr, under a nitrogen atmosphere. The solution was allowed to cool, diluted with water (400 ml), and extracted with ethyl acetate. The combined extracts were washed with water and brine dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 4.94 g (86.0%) of residual thieno[2,3-b]pyridine-3-amine.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH:3]([CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[CH2:10]1)[CH2:4][C:5](O)=[O:6].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl:60][C:61]1[CH:70]=[CH:69][C:64]([C:65](=[N:67][OH:68])[NH2:66])=[CH:63][CH:62]=1.[Na+].[Cl-].O>CN(C=O)C>[Cl:60][C:61]1[CH:62]=[CH:63][C:64]([C:65](=[N:67][OH:68])[NH:66][C:5](=[O:6])[CH2:4][CH:3]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:22])[F:24])[CH:16]=3)[CH2:10]2)[C:2]([F:26])([F:1])[F:25])=[CH:69][CH:70]=1
Reactant: O=C(O)CC(CN1CCCC(c2cccc(C(F)(F)F)c2)C1)C(F)(F)F
Reactant: NC(=NO)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(CC(CN1CCCC(c2cccc(C(F)(F)F)c2)C1)C(F)(F)F)NC(=NO)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In a 10 mL round-bottomed flask, 4,4,4-trifluoro-3-((3-(3-(trifluoromethyl)phenyl)piperidin-1-yl)methyl)butanoic acid (27 mg, 70.4 μmol) and HATU (26.8 mg, 70.4 μmol) were combined with DMF (1 ml) to give a colorless solution. DIEA (27.3 mg, 36.9 μl, 211 μmol) was added and the resulting mixture was stirred at room temperature for 10 min. 4-Chloro-N′-hydroxybenzimidamide (12.0 mg, 70.4 μmol) was added and the resulting mixture was stirred at room temperature for 4 hr. The reaction mixture was poured into 50 mL saturated NaCl/H2O (1:1) and extracted with ethyl acetate (2×25 mL). The organic layers were combined, washed with saturated NaCl (1×20 mL), H2O (2×50 mL), dried over MgSO4, filtered and concentrated in vacuo to give N-((4-chlorophenyl)-(hydroxyimino)methyl)-4,4,4-trifluoro-3-((3-(3-(trifluoromethyl)phenyl)piperidin-1-yl)methyl)butanamide as an oil, which was used as is for the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)[NH2:5].[Br:12]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:12][C:8]1[CH:7]=[C:6]([N+:9]([O-:11])=[O:10])[C:4]([NH2:5])=[CH:3][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(F)c(Br)cc1[N+](=O)[O-]
Reaction time: 48 h

Procedure:
4-Bromo-3-fluoro-6-nitroaniline was prepared using an adaptation of the method of Mitchell et al. (Mitchell, R. H. et al., J. Org. Chem. 44:4733 (1979)). To a solution of 3-fluoro-6-nitroaniline (500 mg, 3.2 mmol) in dry DMF (15 mL) under N2 was added dropwise a solution of N-bromosuccinimide (626 mg, 3.2 mmol) in dry DMF. The reaction was allowed to stir 48 h. The solution was then poured into 100 mL H2O. The cloudy yellow suspension which formed was then extracted with 4×25 mL of methylene chloride. The combined organic extracts were washed with 4×25 mL of H2O and 25 mL sat'd NaCl solution. The organic phase was dried (MgSO4) and the drying agent removed by vacuum filtration. The solvent was rotary evaporated to yield a yellow orange oil which crystallized on standing. 1H NMR showed this solid to be a mixture of mono- and dibrominated products in a 3.8:1 ratio. The mixture was separated by flash chromatography (2:1 hexanes:ethyl acetate) to yield 324 mg of a yellow solid (43%). 1H NMR (CDCl3) δ6.19(br s, 2H, NH2); 6.58(d, 1H, JHF =9.6, ArH); 8.39(d, 1H, JHF =6.9, ArH).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([N:15]([CH3:28])[C:16](=[O:27])[CH:17]([NH:25][CH3:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10]([O:12]CC)=O.[NH4+].[OH-]>C1COCC1>[CH2:18]([CH:17]1[N:25]([CH3:26])[C:10](=[O:12])[CH:9]([CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[I:1])[N:15]([CH3:28])[C:16]1=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(Cc1ccccc1I)N(C)C(=O)C(Cc1ccccc1)NC
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1C(=O)C(Cc2ccccc2I)N(C)C(=O)C1Cc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Ethyl 3-(2-iodophenyl)-2-[methyl-(2-methylamino-3-phenylpropionyl)amino]propionate (2.1 g, 4.2 mmol) was taken up in THF (30 ml), and NH4OH (25% (w/v) in H2O, 20 ml) was added. The mixture was stirred at room temperature for 12 h and then concentrated on a rotary evaporator. The residue obtained in this manner was purified by column chromatography (SiO2, hexane/ethyl acetate). This gave 0.4 g (21%) of a non-polar isomer and 0.6 g (31%) of a polar isomer.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[N:5][CH2:4][CH:3]1[CH2:20][NH2:21].Cl[C:23]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:24].CN1CCOCC1>C(Cl)Cl>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[N:5][CH2:4][CH:3]1[CH2:20][NH:21][C:23]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:24]
Reactant: CN1c2ccccc2C(c2ccccc2F)=NCC1CN
Reactant: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)COC(=O)NCC1CN=C(c2ccccc2F)c2ccccc2N1C
Temperature: 25 °C
Yield: 68.2 %

Procedure:
According to the method of Example 1, 1-methyl-2-aminomethyl-5-(2'-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine (250 mg, 0.88 mmole) and isobutyl chloroformate (114 μl, 0.88 mmole) were combined with 4 ml of dry methylene chloride, and 97 μl of N-methylmorpholine (0.88 mmole) at -5° C. was added to the mixture. The resulting reaction mixture was allowed to warm to room temperature over 2 hours, and after dilution and washing, rotoevaporation of the dried extracts of the reaction afforded 230 mg of an oil which was purified by silica gel chromatography (ethyl acetate-hexane elution, 7:3 v/v) to give the analytical sample (120 mg) which was 98% pure by HPLC.
Reaction SMILES: [OH:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[N:3]1.[CH3:15][N:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17](Cl)=[O:18]>CCOC(C)=O.CCCCCCC>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[CH:5]=[CH:6][N:2]([O:1][C:17](=[O:18])[N:16]([CH3:15])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:3]=2)=[CH:8][CH:9]=1
Reactant: COc1ccc(-c2ccn(O)n2)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccn(OC(=O)N(C)c3ccccc3)n2)cc1

Procedure:
The title compound was prepared from 1-hydroxy-3-(4-methoxyphenyl)pyrazole and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to flash chromatography (Quad flash 25, EtOAc-heptane) (93%, oil). HPLC-MS m/z=346.1 (M+Na), Rt: 4.21 min.
Reaction SMILES: C=C([O:4][C:5](=O)[NH:6][C:7]1[CH:12]=[C:11]([C:13]2[C:14]([CH3:25])=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][N:19]=[C:18]([NH:23][CH3:24])[CH:17]=3)[C:10]([CH3:26])=[CH:9][C:8]=1[F:27])C.C(O)(=O)C.C(O)(=O)C.[F:37][C:38]([CH3:43])([CH3:42])[CH2:39][CH2:40][NH2:41].CN1CCCC1>C1COCC1>[F:37][C:38]([CH3:43])([CH3:42])[CH2:39][CH2:40][NH:41][C:5]([NH:6][C:7]1[CH:12]=[C:11]([C:13]2[C:14]([CH3:25])=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][N:19]=[C:18]([NH:23][CH3:24])[CH:17]=3)[C:10]([CH3:26])=[CH:9][C:8]=1[F:27])=[O:4]
Reactant: CC(C)(F)CCN
Reactant: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(NC)cc3nc2C)c(C)cc1F
Agent: CN1CCCC1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNc1cc2nc(C)c(-c3cc(NC(=O)NCCC(C)(C)F)c(F)cc3C)cc2cn1
Yield: 70.9 %

Procedure:
Combine prop-1-en-2-yl(2-fluoro-4-methyl-5-(2-methyl-7-(methylamino)-1,6-naphthyridin-3-yl)phenyl)carbamate (2.5 g, 6.6 mmol), 3-fluoro-3-methylbutan-1-amine diacetate (1.8 g, 7.9 mmol), and N-methylpyrrolidine (2.7 mL, 26.0 mmole) in THF (50 mL) and heat at 50° C. overnight. Evaporate under reduced pressure and partition between NaHCO3 and EtOAc. Wash the organic layer with brine, dry over Na2SO4, concentrate in vacuo, and purify by silica gel chromatography (50-100% EtOAc/DCM) to obtain the title compound (2.0 g, 71%). 1H NMR (400 MHz, DMSO-d6): δ 8.82 (s, 1H), 8.33 (s, 1H), 7.93 (d, J=8 Hz, 1H), 7.83 (s, 1H), 7.16 (d, J=8 Hz, 1H), 6.73 (m, 1H), 6.56 (m, 1H), 6.52 (s, 1H), 3.15 (m, 2H), 2.82 (d, J=5 Hz, 3H), 2.27 (s, 3H), 1.94 (s, 3H), 1.73 (m, 2H), 1.30 (d, J=21.6 Hz, 6H); MS (ESI) m/z: 428.2 (M+H+).
Reaction SMILES: [C:1]1([OH:14])[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[OH:15][CH:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.C1(O)C=CC=CC=1>>[OH:14][C:1]1[CH:2]=[CH:3][C:4]([C:7]2([C:19]3[CH:20]=[CH:21][C:16]([OH:15])=[CH:17][CH:18]=3)[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)=[CH:5][CH:6]=1
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Reactant: O=C1CCC(O)CC1
Solvent: Oc1ccccc1
Product: Oc1ccc(C2(c3ccc(O)cc3)CCC(O)CC2)cc1

Procedure:
A process for the preparation of 4,4'-biphenol which comprises reacting 4-hydroxycyclohexanone with phenol in the presence of an acid catalyst to give 4,4-bis(4-hydroxyphenyl)cyclohexanol of the formula (I) ##STR5## and successively subjecting 4,4-bis(4-hydroxyphenyl)cyclohexanol to decomposition and dehydrogenation reactions in the presence of a dehydrogenation catalyst.
Reaction SMILES: N[C@H:2]([C:5]([OH:7])=O)[CH2:3][SeH].[CH2:8]([C:10]1[CH:15]=C[CH:13]=[CH:12][C:11]=1O)[CH3:9]>>[CH2:8]([C:10]1[C:15]2[O:7][CH:5]=[CH:2][C:3]=2[CH:13]=[CH:12][CH:11]=1)[CH3:9]
Reactant: CCc1ccccc1O
Reactant: N[C@@H](C[SeH])C(=O)O
Product: CCc1cccc2ccoc12

Procedure:
2h. 7-Ethyl-benzofuran is prepared by the method described in J.Chem.Sec. 1920, 1534, but using o-ethylphenol instead of o-cresol. The MS. of the product thus obtained shows the following ion peaks with the relative intensities given within brackets: 131 (100%), 146 (38%) and 77 (10%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[C:19]([NH2:20])=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:9][CH:8]=1)=[O:6])[CH3:2].[CH:22](OCC)(OCC)OCC>>[CH2:1]([O:3][C:4](=[O:21])[C:5]([C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:19]3[N:20]=[CH:22]2)=[CH:11][CH:12]=1)=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)c1ccc(Nc2ncccc2N)cc1
Reactant: CCOC(OCC)OCC
Product: CCOC(=O)C(=O)c1ccc(-n2cnc3cccnc32)cc1

Procedure:
A solution of [4-(3-amino-pyridin-2-ylamino)-phenyl]oxo-acetic acid ethyl ester (195 mg, 0.547 mmol) in triethyl orthoformate (5 mL) is heated at 144° C. for 5 h. The reaction mixture is left in the fridge over night and then refluxed for additional 5 h. The solvent is removed and the product is purified by reverse phase MPLC with ACN/water to afford (4-imidazo[4,5-b]pyridine-3-yl-phenyl)-oxo-acetic acid ethyl ester. ES-MS: 296.10 [M+H]+; tR=1.4 min (System 2).
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[NH:6][C:5](=[O:15])[CH:4]=1.[CH:16]1([C:21]2([CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[O:26][C:25](=[O:27])[CH2:24][C:23](=[O:28])[CH2:22]2)[CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([C:21]2([CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[O:26][C:25](=[O:27])[C:24]([CH2:2][C:3]3[N:8]=[C:7]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=4)[NH:6][C:5](=[O:15])[CH:4]=3)=[C:23]([OH:28])[CH2:22]2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=c1cc(CCl)nc(-c2ccccn2)[nH]1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Cc3cc(=O)[nH]c(-c4ccccn4)n3)C(=O)O2)cc1
Yield: 11 %

Procedure:
The title compound was prepared as described in Example B(53), using 6-(chloromethyl)-2-pyridin-2-ylpyrimidin-4(3H)-one in place of 5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole, and using 6-cyclopentyl-6-[2-(4-methoxyphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione in place of 6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione. Yield: 11%. 1H NMR (300 MHz, DMSO-d6) δ 1.32-1.67 (m, 8H), 1.92 (m, 2H), 2.38 (m, 1H), 2.45-2.52 (m, 2H, overlap with DMSO-d5), 2.60 (d, J=17.7 Hz, 1H), 2.80 (d, J=17.7 Hz, 1H), 3.52 (m, 2H, overlap with H2O), 3.66 (s, 3H, overlap with H2O), 6.07 (s, 3H), 6.68 (d, J=8.4 Hz, 2H), 6.95 (d, J=8.4 Hz, 2H), 7.60 (dd, J=7.5, 4.8 Hz, 1H), 7.93 (td, J=8 Hz, 1.5 Hz, 1H), 8.18 (d, J=8 Hz, 1H), 8.70 (d, J=4.8 Hz, 1H), 10.98 (br s, 1H). LC-MS (APCI) calcd for C29H31N3O5: 501.23; found (M+H+) 502.1 m/z.
Reaction SMILES: [OH:1][NH:2][C:3]([N:5]1[CH2:9][CH2:8][C:7](=[CH:10][C:11]2[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:14]([OH:21])=[C:13]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:12]=2)[C:6]1=[O:26])=[O:4].[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[C:27]([O:1][NH:2][C:3]([N:5]1[CH2:9][CH2:8][C:7](=[CH:10][C:11]2[CH:16]=[C:15]([C:17]([CH3:18])([CH3:19])[CH3:20])[C:14]([OH:21])=[C:13]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:12]=2)[C:6]1=[O:26])=[O:4])(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)c1cc(C=C2CCN(C(=O)NO)C2=O)cc(C(C)(C)C)c1O
Solvent: c1ccncc1
Product: CC(=O)ONC(=O)N1CCC(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Yield: 0.1 %

Procedure:
N-(N-Hydroxycarbamoyl)-3-(3,5-di-tert-butyl-4-hydroxybenzylidene)pyrrolidin-2-one (Ia-4) (2 g, 5.55 mmole), acetic anhydride (680 mg, 6.66 mmole), and pyridine (10 ml) were reacted according to the same method as in Example 22, whereby 1.35 mg of the objective compound (Ia-17) was obtained in 60.5% yield. Mp.: 165°-166° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH:12]=O)=[CH:6]2.[Br-].[Cl:15][C:16]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:17]=1[CH2:18][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li+].CC([N-]C(C)C)C>>[Cl:15][C:16]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:17]=1/[CH:18]=[CH:12]/[C:7]1[NH:8][C:9]2[C:5]([CH:6]=1)=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2
Reactant: Clc1cccc(Cl)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc2[nH]c(C=O)cc2c1
Agent: CC(C)[N-]C(C)C
Agent: [Br-]
Agent: [Li+]
Product: COc1ccc2[nH]c(/C=C/c3c(Cl)cccc3Cl)cc2c1
Reaction time: 5 h

Procedure:
The 5-methoxy-1H-indole-2-carbaldehyde (O) was reacted with (2,6-dichlorobenzyl)(triphenyl)phosphonium bromide (511) prepared as described in example 102 using the procedure described in example 37, except that the LDA and aldehyde were (sequentially) added at 0° C., the ratio of LDA aldehyde was 1.37:1 and the reaction time was 5 h, to give (after crystallisation from CH2Cl2/hexane) the diene (512) as a yellow solid (the pure E isomer) (97%), mp 144–147° C. 1H NMR (CDCl3) δ 8.20 (br s, 1H), 7.36 (d, J=8.1 Hz, 1H), 7.27 (m, 1H), 7.25 (d, J=16.8 Hz, 1H), 7.11 (t, J=8.0 Hz, 1H), 7.03 (d, J=2.4 Hz, 1H), 6.93 (d, J=16.8 Hz, 1H), 6.88 (dd, J=8.7, 2.5 Hz, 1H), 6.61 (d, J=1.8 Hz, 1H), 3.86 (s, 3H). Found: C, 64.04; H, 4.13; N, 4.39. C17H13Cl2NO requires C, 64.17; H, 4.12; N, 4.40.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][N:16]2[C:24](=[O:25])[NH:23][C:22]3[C:17]2=[N:18][C:19]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[N:20][C:21]=3[NH2:26])=[CH:7][CH:6]=1.C(OC([N:40]1[CH2:45][CH2:44][N:43]([CH2:46][CH2:47][C:48](O)=[O:49])[CH2:42][CH2:41]1)=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:13][CH2:14][CH2:15][N:16]2[C:24](=[O:25])[NH:23][C:22]3[C:17]2=[N:18][C:19]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[N:20][C:21]=3[NH2:26])[C:48](=[O:49])[CH2:47][CH2:46][N:43]2[CH2:44][CH2:45][NH:40][CH2:41][CH2:42]2)=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCC(=O)O)CC1
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCNCc3ccc(CC(=O)OC)cc3)c2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(Cc3ccc(CC(=O)OC)cc3)C(=O)CCN3CCNCC3)c2n1

Procedure:
The product of example 1, step (ix) (0.27 g) was dissolved in DCM (10 ml) and treated with 4-(2-carboxy-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (0.16 g) and HATU (0.23 g). The reaction was stirred at rt for 16 h, before 2 mls of TFA added. The mixture was purified by RPHPLC, to give the title compound. Yield 3 mg.
Reaction SMILES: [CH2:1]([C@@:4]1([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:9][CH2:8][N:7]([C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)[CH3:11])[C:6](=[O:19])[N:5]1[CH3:20])[CH:2]=[CH2:3].C([C@@]1(C2C=CC(F)=CC=2)CCN([C@H](C2C=CC(Br)=CC=2)C)C(=[O:46])N1)C=C>>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([C@@H:10]([N:7]2[CH2:8][CH2:9][C@:4]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)([CH2:1][CH2:2][CH2:3][OH:46])[N:5]([CH3:20])[C:6]2=[O:19])[CH3:11])=[CH:13][CH:14]=1.[CH2:1]([C@@:4]1([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[CH2:9][CH2:8][N:7]([C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)[CH3:11])[C:6](=[O:19])[N:5]1[CH3:20])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)N1
Agent: C=CC[C@@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)N1C
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@@](CCCO)(c2ccc(F)cc2)N(C)C1=O

Procedure:
(S)-1-((S)-1-(4-bromophenyl)ethyl)-4-(4-fluorophenyl)-4-(3-hydroxypropyl)-3-methyltetrahydropyrimidin-2(1H)-one was prepared from (S)-4-allyl-1-((S)-1-(4-bromophenyl)ethyl)-4-(4-fluorophenyl)-3-methyltetrahydropyrimidin-2(1H)-one following a procedure analogous to that described in Example 10. (S)-4-allyl-1-((S)-1-(4-bromophenyl)ethyl)-4-(4-fluorophenyl)-3-methyltetrahydropyrimidin-2(1H)-one was prepared from (S)-4-allyl-1-((S)-1-(4-bromophenyl)ethyl)-4-(4-fluorophenyl)tetrahydropyrimidin-2(1H)-one following a procedure analogous to that described in Example 3. LC-MS Method 1 tR=1.383 min, m/z=449.1; 1H NMR (CDCl3) δ=1.20 (m, 1H), 1.35 (m, 3H), 1.60 (m, 2H), 1.71 (m, 1H), 1.98 (m, 2H), 2.12 (m, 1H), 2.49 (m, 1H), 2.64 (m, 1H), 2.83 (m, 3H), 3.70 (m, 2H), 5.85 (m, 1H), 7.01 (m, 2H), 7.13 (m, 4H), 7.39 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([CH:8]=[N:9][OH:10])=[CH:6][CH:5]=1.[Cl:15]N1C(=O)CCC1=O>CN(C)C=O>[OH:10][N:9]=[C:8]([Cl:15])[C:7]1[CH:11]=[CH:12][C:4]([O:3][C:2]([F:13])([F:14])[F:1])=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=Cc1ccc(OC(F)(F)F)cc1
Solvent: CN(C)C=O
Product: ON=C(Cl)c1ccc(OC(F)(F)F)cc1
Yield: 90.3 %

Procedure:
In a similar manner as described in Preparation Example 9, by using dimethylformamide (240 mL), 4-(trifluoromethoxy)benzaldehydeoxime (20.0 g, 97.51 mmol) and N-chlorosuccinimide (14.31 g, 107.26 mmol), a pale yellow solid required compound (21.10 g, 88.04 mmol, 90%) was obtained.