Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[O:7][N:6]=[C:5]([NH2:8])[CH:4]=1)[CH3:2].[C:9]([O:12][CH2:13][C:14]1[C:15]([N:29]2[CH2:40][CH2:39][N:38]3[C:31](=[CH:32][C:33]4[CH2:34][C:35]([CH3:42])([CH3:41])[CH2:36][C:37]=43)[C:30]2=[O:43])=[N:16][CH:17]=[CH:18][C:19]=1[C:20]1[CH:25]=[C:24](Br)[C:23](=[O:27])[N:22]([CH3:28])[CH:21]=1)(=[O:11])[CH3:10].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:9]([O:12][CH2:13][C:14]1[C:15]([N:29]2[CH2:40][CH2:39][N:38]3[C:31](=[CH:32][C:33]4[CH2:34][C:35]([CH3:42])([CH3:41])[CH2:36][C:37]=43)[C:30]2=[O:43])=[N:16][CH:17]=[CH:18][C:19]=1[C:20]1[CH:25]=[C:24]([NH:8][C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[O:7][N:6]=2)[C:23](=[O:27])[N:22]([CH3:28])[CH:21]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)OCc1c(-c2cc(Br)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: CCc1cc(N)no1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCc1cc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CC(C)(C)C6)C4=O)c3COC(C)=O)cn(C)c2=O)no1
Temperature: 100 °C
Yield: 49.3 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 295a (24.8 mg, 0.222 mmol), [4-(5-bromo-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-{4,4-dimethyl-9-oxo-1,10-diazatri-cyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-3-yl]methyl acetate 273a (100 mg, 0.185 mmol), Pd2(dba)3 (8.5 mg, 0.0093 mmol), Xantphos (10.7 mg, 0.019 mmol), Cs2CO3 (120.6 mg, 0.37 mmol), and dioxane (10 mL). The system was subjected to three cycles of vacuum/nitrogen flush and heated at 100° C. under N2 protection for 3 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. It was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was washed with acetonitrile (0.5 mL) to afford 295b as white solid (52 mg, 49.5%), which was used in the next step without further purification. MS-ESI: [M+H]+ 570.8
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][N:7]=1.C(O)(=O)CC(O)=O.C([K])C.[CH2:21]([O:23][C:24](=[O:35])[CH2:25]C(C1C(F)=CC=CN=1)=O)[CH3:22]>>[CH2:21]([O:23][C:24](=[O:35])[CH2:25][C:8]([C:3]1[C:2]([Cl:1])=[N:7][CH:6]=[CH:5][N:4]=1)=[O:10])[CH3:22]
Reactant: CCOC(=O)CC(=O)c1ncccc1F
Reactant: O=C(O)c1nccnc1Cl
Agent: CC[K]
Agent: O=C(O)CC(=O)O
Product: CCOC(=O)CC(=O)c1nccnc1Cl
Yield: 39.54 %

Procedure:
3-(3-Chloro-pyrazin-2-yl)-3-oxo-propionic acid ethyl ester (12) (2 g, 39.54%) was synthesized as a yellow liquid from 3.5 g of 3-chloro-pyrazine-2-carboxylic acid (11) and 5.64 g of ethyl potassium malonate (2) following the procedure described for 3-(3-fluoro-pyridin-2-yl)-3-oxo-propionic acid ethyl ester (3).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([Br:17])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=O)[CH3:6])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([Br:17])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[S:29])[CH3:6])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C(C)N1C(=O)COc2ccc(Br)cc21
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)N1C(=S)COc2ccc(Br)cc21
Temperature: 25 °C
Yield: 81.4 %

Procedure:
A solution of 2-(6-bromo-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (32.5 g, 100 mmol) and Lawesson reagent (80.1 g, 200 mmol) in toluene (200 mL) was heated at 120° C. for 3 h then cooled at ambient temperature. The solvent was removed in vacuo to give the crude product, which was purified by chromatography on silica gel (eluting with 1% EtOAc in petroleum ether) to give 2-(6-bromo-3-thioxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (28 g, 81.4 mmol, 82%) as a yellow liquid. 1H NMR (CDCl3, 400 MHz): δ 7.18 (dd, J=8.8 Hz, J=2.0 Hz, 1H), 7.01 (d, J=2.0 Hz, 1H), 6.91 (s, J=8.8 Hz, 1H), 6.54 (s, 1H), 4.90 (q, J=15.2 Hz, 2H), 4.22 (m, 2H), 1.68 (d, J=7.2 Hz, 3H), 1.16 (t, J=7.2 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([O:13]CC)=[O:12])=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:16]1([S:26](Cl)(=[O:28])=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.N1C=CC=CC=1.[Li+].[OH-]>C(Cl)Cl>[C:16]1([S:26]([NH:1][C:2]2[C:10]([C:11]([OH:13])=[O:12])=[C:9]3[C:5]([CH:6]=[CH:7][NH:8]3)=[CH:4][CH:3]=2)(=[O:28])=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: CCOC(=O)c1c(N)ccc2cc[nH]c12
Agent: [Li+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(O)c1c(NS(=O)(=O)c2cccc3ccccc23)ccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of ethyl 6-amino-1H-indole-7-carboxylate (prepared as described in Showalter, H. D. et al., J. Org. Chem., 1996, 61, 1155-1158, 0.05 g, 0.25 mmol) in CH2Cl2 (5 mL) was treated with 1-naphthalenesulfonyl chloride (0.066 g, 0.29 mmol) and pyridine (0.040 mL, 0.50 mmol), shaken for 16 hours at ambient temperature, filtered, and concentrated. The concentrate was dissolved in 9:1 methanol/water (1 mL), treated with LiOH (25 mg, 0.6 mmol), and heated to 60° C. for 16 hours. The mixture was concentrated and the concentrate was purified by C18 reverse-phase HPLC using acetonitrile/water/0.1% TFA to provide the desired product. MS (DCI) m/e 384 (M+NH4)+; 1H NMR (500 MHz, DMSO-d6) δ 12.43 (br s, 1H), 10.77 (s, 1H), 8.62 (d, 1H), 8.30 (dd, 1H), 8.18 (d, 1H), 8.03 (d, 1H), 7.69 (m, 1H), 7.64-7.60 (m, 3H), 7.20 (d, 1H), 7.17 (t, 1H), 6.35 (dd, 1H).
Reaction SMILES: [BH4-].[Na+].[S:3]1[C:12]2[C:11](=[O:13])[CH2:10][CH2:9][CH2:8][S:7][C:6]=2[CH:5]=[CH:4]1>C(O)C>[OH:13][CH:11]1[CH2:10][CH2:9][CH2:8][S:7][C:6]2[CH:5]=[CH:4][S:3][C:12]1=2
Reactant: O=C1CCCSc2ccsc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC1CCCSc2ccsc21
Temperature: 70 °C

Procedure:
A solution of sodium borohydride (0.83 g, 0.022 mol) in absolute ethanol (55 ml) was added over thirty minutes to a stirred solution of 5,6,7,8-tetrahydrothieno[3,2-b]thiepin-8-one (3.65 g, 0.020 mole) in absolute ethanol (115 ml) under nitrogen at ambient temperature. After the addition, the mixture was heated at 70° C. for 1.5 hours and then concentrated under reduced pressure. Water (150 ml) was added to the residue and the mixture was extracted with ethyl acetate (3×150 ml). After drying over sodium sulfate, the solvent was evaporated under reduced pressure to yield a solid product weighing 3.63 g (97%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([N:25]=[C:26]=[O:27])[CH:22]=[CH:23][CH:24]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:26]([NH:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([O:18][CH3:17])[CH:20]=2)=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1cccc(N=C=O)c1
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Solvent: ClCCl
Product: COc1cccc(NC(=O)Nc2ccc(OC)c(-c3c(Br)cnn3C)c2)c1
Yield: 91.7 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.032 g, 0.12 mmol) was treated with 3-methoxyphenyl isocyanate (0.018 g, 16.0 μL, 0.14 mmol, 1.05 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.10 to afford Compound 72 (0.047 g, 0.11 mmol, 94%) as a solid film. LCMS m/z (%)=431 (M+H79Br, 100), 433 (M+H81Br, 93). 1H NMR (400 MHz, acetone-d6) δ: 8.13 (s, 2H), 7.68 (d, J=8.9 Hz, 1H), 7.49 (s, 1H), 7.43 (s, 1H), 7.30 (s, 1H), 7.16 (d, J=8.1 Hz, 1H), 7.12 (d, J=7.3 Hz, 1H), 6.98 (d, J=8.0 Hz, 1H), 3.81 (s, 3H), 3.76 (s, 3H). 3.68 (s, 3H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[C:29]([C:31]1([C:34](O)=[O:35])[CH2:33][CH2:32]1)#[N:30]>>[C:29]([C:31]1([C:34]([N:20]2[CH2:21][CH2:22][C:16]3[C:15]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[N:14][C:13]([C:10]4[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=4)=[N:18][C:17]=3[CH2:19]2)=[O:35])[CH2:33][CH2:32]1)#[N:30]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Reactant: N#CC1(C(=O)O)CC1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C(=O)C2(C#N)CC2)C3)cc1

Procedure:
Compound fe was prepared according to the procedure described in Example 213 by reacting 1-ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with 1-cyanocyclopropanecarboxylic acid. LC-MS: m/z=+476 (M+H)−.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH3:36].CN(C)C(=O)C>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH3:36])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(Br)c1ccccc1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(C(C)c2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 130 °C
Reaction time: 16 h
Yield: 19 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), cesium carbonate (2.73 g), (1-bromoethyl)benzene (1.15 mL) and N,N-dimethylacetamide (10 mL) was stirred at 130° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.24 g, 19%).
Reaction SMILES: [CH2:1]([CH:6]1[CH2:11][CH2:10][CH:9]([C:12]23CCC(CCC)(CC2)C[CH2:13]3)[CH2:8][C:7]1=[O:23])[CH2:2]CCC.C(C1COC(=O)C1)(=O)C.[BrH:33]>>[C:7]([CH:6]([CH2:11][CH2:10][CH2:9][CH2:12][CH3:13])[CH2:1][CH2:2][Br:33])(=[O:23])[CH3:8]
Reactant: CCCCCC1CCC(C23CCC(CCC)(CC2)CC3)CC1=O
Reactant: Br
Agent: CC(=O)C1COC(=O)C1
Product: CCCCCC(CCBr)C(C)=O

Procedure:
A mixture of 33 g of 2-n-pentyl-5-(4-n-propylbicyclo[2.2.2]octyl)-cyclohexanone [obtainable by the method of P. Place et al., Tetrahedron 34, 1931 (1978) by reacting 3-acetylbutyrolactone with n-pentyl halide/NaH, subsequently reacting the product with hydrogen bromide to give 3-acetyl-1-bromo-n-octane, converting the latter into the corresponding ethylene ketal, reacting the corresponding Grignard compound with 4-cyano-1-n-propylbicyclo[2.2.2]octane and subsequently subjecting the product to an aldol condensation and catalytically hydrogenating the cyclohex-2-enone to give the target product], 20 ml of 80% hydrazine hydrate and 20 g of KOH in 240 ml of diethylene glycol is boiled under reflux for 2 hours. The reflux condenser is then replaced by a distillation column, the temperature is increased slowly to 200° C. and the mixture is kept at this temperature for 6 hours. After cooling, it is diluted with 300 ml of water, acidified and extracted with toluene. Customary working up of the organic phase gives 1-n-propyl-4-(trans-4-n-pentylcyclohexyl)-bicyclo[2.2.2]octane.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=3)=[N:9][CH2:10][C:11](=S)[NH:12][C:6]=2[C:5]([Cl:23])=[CH:4][CH:3]=1.[C:24]([NH:27][NH2:28])(=O)[CH3:25]>C(O)C>[Cl:1][C:2]1[C:7]2[C:8]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=3)=[N:9][CH2:10][C:11]3[N:12]([C:24]([CH3:25])=[N:27][N:28]=3)[C:6]=2[C:5]([Cl:23])=[CH:4][CH:3]=1
Reactant: CC(=O)NN
Reactant: CC(C)c1ccc(C2=NCC(=S)Nc3c(Cl)ccc(Cl)c32)cc1
Solvent: CCO
Product: Cc1nnc2n1-c1c(Cl)ccc(Cl)c1C(c1ccc(C(C)C)cc1)=NC2
Temperature: 250 °C

Procedure:
In the manner given in Example 2, 6,9-dichloro-1,3-dihydro-5-(p-isopropylphenyl)-2H-1,4-benzodiazepine-2-thione is heated in ethanol with acetic acid hydrazide and the resulting product heated to 250° C. to give 7,10-dichloro-1-methyl-6-(p-isopropylphenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=[O:18])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CC#N>[OH:8][CH2:9][C@@H:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=[O:18]
Reactant: CC(C)(C)OC(=O)N[C@H](CO[Si](C)(C)C(C)(C)C)CN1CCCCC1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@H](CO)CN1CCCCC1=O
Temperature: 55 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a suspension of (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)-3-(2-oxopiperidin-1-yl)propan-2-ylcarbamate (370 mg, 0.96 mmol) in CH3CN (3 mL) was added TBAF (750 mg, 2.88 mmol). The reaction mixture was stirred for 1 h at 50-60° C. The reaction mixture was concentrated in vacuo and then EA was added. This solution was washed with brine, water and concentrated again to afford crude (S)-tert-butyl 1-hydroxy-3-(2-oxopiperidin-1-yl)propan-2-ylcarbamate (260 mg 100%), which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=O.N1C=CC=CC=1.Cl.[NH2:25][OH:26]>C(O)C>[F:1][C:2]([F:17])([F:16])/[C:3](/[C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:25]/[OH:26]
Reactant: NO
Reactant: CCOC(=O)c1cccc(C(=O)C(F)(F)F)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)c1cccc(/C(=N\O)C(F)(F)F)c1
Temperature: 57 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
To a solution of ethyl 3-(2,2,2-trifluoroacetyl)benzoate (500 mg, 2.15 mmol) in ethanol was added pyridine (5 mL) and hydroxylamine hydrochloride (500 mg, 7.2 mmol) and the resulting mixture stirred at 57° C. for 3 hours. The reaction mixture was cooled and passed through an ion exchange column eluting with methanol (30 mL). The methanol solution was evaporated in vacuo to give (E)-ethyl 3-(2,2,2-trifluoro-1-(hydroxyimino)ethyl)benzoate as an oil in 71% yield, 401 mg which was used in the next step without further purification. To a stirred solution of (E)-ethyl 3-(2,2,2-trifluoro-1-(hydroxyimino)ethyl)benzoate (401 mg, 1.54 mmol) in dichloromethane (10 mL) was added DMAP (17 mg, 0.14 mmol) and the mixture cooled to 0° C. 4-methylbenzene-1-sulfonyl chloride (331 mg, 1.74 mmol) was added portion-wise as a solution in dichloromethane (5 mL). The reaction mixture was then left to stand at room temperature for 18 hours. The mixture was diluted with water (10 mL) and the organic layer separated, dried over magnesium sulfate and evaporated in vacuo to afford (E)-ethyl 3-(2,2,2-trifluoro-1-((tosyloxy)imino)ethyl)benzoate as an oil in 78% yield, 500 mg. This material was used in the next step without further purification. A mixture of (E)-ethyl 3-(2,2,2-trifluoro-1-((tosyloxy)imino)ethyl)benzoate (500 mg, 1.2 mmol) in diethylether (5 mL) in a 3-necked flask equipped with an internal thermometer and condenser was cooled to −78° C. Ammonia gas was introduced for 5 min and then stirring continued for 45 min. The reaction mixture was warmed to −33° C. and stirred for 2 hours after which it was allowed to warm to room temperature overnight with stirring.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[C:41]([C:42]([F:45])([F:44])[F:43])=[CH:40][C:7]([CH2:8][C:9]([CH2:20][C:21](=[O:39])[N:22]2[CH2:27][CH2:26][CH:25]([N:28]3[CH2:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:38])[CH2:24][CH2:23]2)(C(OCC)=O)[C:10]([O:12]CC)=[O:11])=[CH:6][C:5]=1[Cl:46]>O.CCO>[NH2:3][C:4]1[C:41]([C:42]([F:44])([F:43])[F:45])=[CH:40][C:7]([CH2:8][CH:9]([CH2:20][C:21](=[O:39])[N:22]2[CH2:27][CH2:26][CH:25]([N:28]3[CH2:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:38])[CH2:24][CH2:23]2)[C:10]([OH:12])=[O:11])=[CH:6][C:5]=1[Cl:46]
Reactant: CCOC(=O)C(CC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1)(Cc1cc(Cl)c(N)c(C(F)(F)F)c1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1c(Cl)cc(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F

Procedure:
3.13 g (78.25 mmol) of NaOH, dissolved in 300 mL water, were added to a solution of 10.00 g (15.65 mmol) of diethyl 2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-malonate in 600 mL EtOH and the mixture was refluxed for 4 h. EtOH was evaporated off i. vac., the reaction mixture was acidified to pH 1 with conc. HCl and 1 hour at RT. The precipitate formed was filtered off, washed with water and dried i. vac.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[C:11](#[N:13])C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[C:11]#[N:13])[CH:8]=[CH:9][CH:10]=1
Reactant: CC#N
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: Cc1ccccc1
Product: N#CC(=O)c1cccc(Cl)c1
Temperature: 25 °C
Yield: 68 %

Procedure:
Metachlorobenzoyl chloride (43.8 g, 0.1 mol), cuprous cyanide (29.1 g, 0.13 mol), and acetonitrile (20 mL) in toluene (37 mL) were refluxed for 3 hours, and were cooled to room temperature. Then, insoluble substances were removed through filtration, and the residue was washed with toluene. Solvent in the resulting filtrate was evaporated under reduced pressure, and the residue was distilled to give metachlorophenyloxoacetonitrile (28 g, 68% yield).
Reaction SMILES: [CH3:1][CH2:2][C:3]([O-])(C)[CH3:4].[K+].O.[CH3:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1COCC1>[CH:11]1[C:10]2[C:1](=[CH:2][CH:3]=[CH:4][CH:9]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CCCCCC
Reactant: CCC(C)(C)[O-]
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To the suspension of ethyl triphenyl phosphonium bromide (5.69 g, 15.3 mmol) in anhydrous THF (30 ml), a solution is added by drops of potassium tert-amylate (8.7 ml, 14.7 mmol, 1.7 M solution in toluene) using a syringe at room temperature. After 1 hour, the reaction mixture is cooled to a temperature of 0° C., the solution of crude aldehyde previously obtained is added (3.32 g, 11.79 mmol) in THF (10 ml), and mixing is continued for hours at room temperature. Then, water (1 ml) is added, and dilution takes place with n-hexane (30 ml). The sediment created is filtered, and the residue is chromatographed on silica gel (cyclohexane), obtaining naphthalene derivative with formula 25 in the form of a yellow oil (3.12 g, 90%).
Reaction SMILES: [CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]4[O:21][C@H:6]5[C:7]([CH:9]=[CH:10][C@:11]2([OH:22])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].BrC[CH:33]1[CH2:36][CH2:35][CH2:34]1>CC(N(C)C)=O>[CH2:33]1[CH2:36][CH:35]([CH2:1][N:2]2[C@@H:12]3[CH2:13][C:14]4[CH:19]=[CH:18][C:17]([OH:20])=[C:16]5[O:21][C@H:6]6[C:7]([CH2:9][CH2:10][C@:11]3([OH:22])[C@:5]6([C:15]=45)[CH2:4][CH2:3]2)=[O:8])[CH2:34]1
Reactant: BrCC1CCC1
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)C=C[C@@]3(O)[C@H]1C5
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CCC2)[C@H]1O5
Temperature: 25 °C
Reaction time: 168 h
Yield: 73.2 %

Procedure:
Noroxymorphone (1.59 g, 5.5 mmol), potassium carbonate (0.61 g, 6.1 mmol), potassium iodide (0.46 g, 2.8 mmol), and dimethyl acetamide (10 mL) were added into a round bottom flask. Bromomethylcyclobutane (0.82 g, 5.5 mmol, 0.62 mL) was added. The reaction was stirred for 7 days at room temperature. At that time, bromomethylcyclobutane (0.82 g, 5.5 mmol, 0.62 mL) was added. The reaction was stirred for an additional 7 days. HPLC analysis indicated that the noroxymorphone was consumed. Distilled water (50 mL) was added and stirred at room temperature for 6 hours. An off-white precipitate formed, which was removed by filtration. The solid was washed with distilled water (25 mL), then slurried for 24 hours in acetonitrile (25 mL). Filtration, washing the solid with acetonitrile (10 mL), and drying at room temperature under vacuum for 24 hours yielded N-(cyclobutylmethyl)-noroxymorphone (1.43 g, 73% yield) as a tan solid.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[CH2:13])[CH:11]=[O:12])=[CH:6][CH:5]=1)[CH3:3].[CH3:14][Li]>C(OCC)C>[CH3:3][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10](=[CH2:13])[CH:11]([OH:12])[CH3:14])=[CH:8][CH:9]=1)[CH3:1]
Reactant: [Li]C
Reactant: C=C(C=O)c1ccc(C(C)C)cc1
Solvent: CCOCC
Product: C=C(c1ccc(C(C)C)cc1)C(C)O
Temperature: -78 °C

Procedure:
6.1 g of aldehyde 44 is dissolved in 250 ml of diethyl ether and cooled under nitrogen to −78° C. 35.8 ml of a methllithium solution (1.6 M in diethyl ether) is now added in drops. After 1.5 hours at this temperature, it is quenched with saturated ammonium chloride solution, extracted with ethyl acetate, washed with sodium chloride solution, dried on sodium sulfate, and the solvent is removed. The residue is purified by chromatography on silica gel with ethyl acetate/hexane, whereby 2.8 g of title compound 45 accumulates as a colorless oil.
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:6]([CH3:7])[O:5][C:4]([C:8]2[NH:12][C:11]([C:13]3[CH:14]=[C:15]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:35])[CH2:32][O:33]C)[CH:29]=3)[O:16][C:17]3[CH:18]=[CH:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[N:21][CH:22]=3)=[CH:10][CH:9]=2)=[N:3]1.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:1][C@@H:2]1[C@H:6]([CH3:7])[O:5][C:4]([C:8]2[NH:12][C:11]([C:13]3[CH:29]=[C:28]([CH:27]=[C:15]([O:16][C:17]4[CH:22]=[N:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=4)[CH:14]=3)[O:30][C@@H:31]([CH3:35])[CH2:32][OH:33])=[CH:10][CH:9]=2)=[N:3]1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C3=N[C@H](C)[C@H](C)O3)[nH]2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1OC(c2ccc(-c3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(O[C@@H](C)CO)c3)[nH]2)=N[C@@H]1C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
5-(3-{5-[(4R,5S)-4,5-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[(1S)-2-methoxy-1-methylethoxy]phenoxy)-2-(methylsulfonyl)pyridine (0.95 g, 1.96 mmol) synthesized in Example (88c) was dissolved in methylene chloride (20 mL) and cooled to −78° C., and boron tribromide (1.0 mol/L methylene chloride solution, 2.15 mL, 2.15 mmol) was added under nitrogen atmosphere. After the temperature was raised naturally and the solution was stirred at room temperature for 30 minutes, a saturated aqueous sodium hydrogencarbonate solution was added to neutralize the reaction solution, followed by extraction with methylene chloride (80 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=70%-100%) to afford the desired compound (617 mg, 67%) as a white solid.