Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16](=O)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[CH:9]2[OH:18])=[N:6][CH:7]=1.[CH2:19]([O:21][C:22]([CH:24]=[PH3])=[O:23])[CH3:20]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:9](=[O:18])[C:10]3[C:15](=[N:14][CH:13]=[CH:12][N:11]=3)[CH:16]2[CH2:24][C:22]([O:21][CH2:19][CH3:20])=[O:23])=[N:6][CH:7]=1
Reactant: CCOC(=O)C=[PH3]
Reactant: O=C1c2nccnc2C(O)N1c1ccc(Cl)cn1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1c2nccnc2C(=O)N1c1ccc(Cl)cn1
Yield: 90.2 %

Procedure:
6-(5-Chloro-2-pyridyl)-6,7-dihydro-7-hydroxy-5H-pyrrolo[3,4-b]pyrazin-5-one (1.05 g) and ethoxycarbonylmethylenephosphorane (1.39 g) were dissolved in dry toluene (30 ml) and the solution was refluxed for 6 hours. After cooling, the solvent was distilled off and the residue was purified by silica gel column chromatography. Fractions eluted with dichloromethaneethyl acetate (2:1) were collected and the solvent was distilled off to give crude crystals. Recrystallization from ether-dichloromethane (5:1) gave 1.2 g of 6(5-chloro pyridyl)-6,7-dihydro-7-ethoxycarbonylmethyl-5H-pyrrolo[3,4-b]pyrazin-5-one
Reaction SMILES: C(Cl)CCl.[Br:5][C:6]1[CH:7]=[C:8]([NH2:13])[CH:9]=[N:10][C:11]=1[CH3:12].[C:14]([C:16]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][N:27]=1)[C:22](O)=[O:23])([CH3:18])[CH3:17])#[N:15].C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.O>[Br:5][C:6]1[CH:7]=[C:8]([NH:13][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][N:27]=[C:19]([C:16]([C:14]#[N:15])([CH3:17])[CH3:18])[CH:20]=2)[CH:9]=[N:10][C:11]=1[CH3:12]
Reactant: Cc1ncc(N)cc1Br
Reactant: CC(C)(C#N)c1cc(C(=O)O)ccn1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncc(NC(=O)c2ccnc(C(C)(C)C#N)c2)cc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
EDC (1.3 equiv.) was added to a solution of 5-bromo-6-methylpyridin-3-amine (1.05 equiv), 2-(2-cyanopropan-2-yl)isonicotinic acid (1.0 equiv), HOAt (1.3 equiv) in DMF (0.17 M). The mixture was stirred at ambient temperature 3 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed sequentially with 1M aqueous sodium hydroxide and brine, dried over sodium sulfate, filtered, and concentrated. The crude was purified by ISCO(50% EtOAc/Heptane). Combined fractions still contained 17% 5-bromo-6-methylpyridin-3-amine. Add 2-(2-cyanopropan-2-yl)isonicotinic acid (0.3 equiv), EDC (0.3 equiv), HOAt (0.3 equiv) in DMF (0.17 M). After stirred at rt overnight, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed sequentially with 1M aqueous sodium hydroxide and brine, dried over sodium sulfate, filtered, and concentrated to yield N-(5-bromo-6-methylpyridin-3-yl)-2-(2-cyanopropan-2-yl)isonicotinamide in 71% over three steps. LCMS (m/z) (M+H)=359.0, Rt=0.73 min.
Reaction SMILES: [Li]CCCC.CCCCCC.Br[C:13]1[CH:14]=[CH:15][C:16]2[S:20][C:19]3[CH:21]=[CH:22][C:23]([N:25]4[C:37]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=5[C:31]5[C:26]4=[CH:27][CH:28]=[CH:29][CH:30]=5)=[CH:24][C:18]=3[C:17]=2[CH:38]=1.C[O:40][B:41](OC)[O:42]C.Cl>O1CCCC1>[CH:36]1[C:37]2[N:25]([C:23]3[CH:22]=[CH:21][C:19]4[S:20][C:16]5[CH:15]=[CH:14][C:13]([B:41]([OH:42])[OH:40])=[CH:38][C:17]=5[C:18]=4[CH:24]=3)[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:32]=2[CH:33]=[CH:34][CH:35]=1
Reactant: COB(OC)OC
Reactant: Brc1ccc2sc3ccc(-n4c5ccccc5c5ccccc54)cc3c2c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc2sc3ccc(-n4c5ccccc5c5ccccc54)cc3c2c1
Temperature: 0 °C
Reaction time: 24 h
Yield: 69.7 %

Procedure:
An excess of 1.6M n-BuLi in hexane (30 mL, 48 mmol) was added to a solution of 9-(8-bromodibenzo[b,d]thiophen-2-yl)-9H-carbazole (18.6 g, 43.4 mmol) in 500 ml dry tetrahydrofuran at −78° C. under N2. The reaction mixture was then maintained at 0° C. for 1 h before cooling to −78° C. Trimethylborate (5.9 g, 56 mmol) was added dropwise, the solution was then warmed slowly to room temperature and stirred for 24 h. 2N HCl (100 ml) was added and then the mixture was stirred for a further 1 h. The reaction mixture was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was evaporated in vacuum, and the residue was crystallized from n-hexane to give 8-(9H-carbazol-9-yl)dibenzo[b,d]thiophen-2-ylboronic acid 11.9 g (63%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[N:24][NH:23][C:22]4=[O:26])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Br[CH:28]([CH2:32][CH3:33])[C:29](=[O:31])[CH3:30].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.C1(C)C=CC=CC=1>[CH2:32]([CH:28]([N:23]1[C:22](=[O:26])[N:21]([C:18]2[CH:19]=[CH:20][C:15]([N:12]3[CH2:11][CH2:10][N:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH2:14][CH2:13]3)=[CH:16][CH:17]=2)[CH:25]=[N:24]1)[C:29](=[O:31])[CH3:30])[CH3:33]
Reactant: CCC(Br)C(C)=O
Reactant: COc1ccc(N2CCN(c3ccc(-n4cn[nH]c4=O)cc3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(C(C)=O)n1ncn(-c2ccc(N3CCN(c4ccc(OC)cc4)CC3)cc2)c1=O
Yield: 21.1 %

Procedure:
A mixture of 2,4-dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-3H-1,2,4-triazol-3-one (0.05 mol) prepared as described in Eβ-A-0,006,711, 3-bromo-2-pentanone (0.073 mol) and K2CO3 (10 g) in DMF (200 ml) and toluene (200 ml) was stirred and refluxed overnight using a water separator. The solvent was evaporated. The residue was dissolved in CH2Cl2. The organic solution was washed, dried, filtered and the solvent was evaporated. The residue was crystallized from 2-propanol. The precipitate was filtered off and the filtrate was evaporated. The residue was triturated in DIPE, filtered off and dried, yielding 4.6 g of (±)-2-(1-ethyl-2-oxopropyl)-2,4-dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-3H-1,2,4-triazol-3-one (intermn.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[N:5][C:6]2[C:7]=1[NH:8][C:9]([CH:12]1[CH2:17][CH:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:15][CH2:14][CH2:13]1)=[N:10][CH:11]=2.[Li+].[CH3:25][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[CH3:25][CH:17]1[CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:15][CH2:14][CH2:13][CH:12]1[C:9]1[NH:8][C:7]2=[C:3]([CH3:2])[CH:4]=[N:5][C:6]2=[CH:11][N:10]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Cc1cnc2cnc(C3CCNC(c4ccccc4)C3)[nH]c1-2
Agent: Cl
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cnc2cnc(C3CCNC(c4ccccc4)C3C)[nH]c1-2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
To a 0° C. solution of 7-methyl-6-phenyl-4-piperidylpyrrolo[3,2-d]pyrimidine (Example 89) (177.3 mg, 0.61 mmol) in THF (10 mL) under a nitrogen atmosphere was added LiHMDS (1.0 M soln from Aldrich Chemical Company) (1.3 mL, 1.27 mmol). This mixture was stirred at 0° C. for 0.5 h then CH3I (Aldrich Chemical Comapny) (41 mL, 0.67 mmol) was added. The 0° C. bath was removed and the solution stirred at room temperature for 2.5 h. The reaction mixture was poured into a separatory funnel containing EtOAc (35 mL) and H2O (50 mL). The organic solution was collected washed with H2O (3×40 mL), saturated NaCl (70 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified via flash chromatography on silica gel 95:5 CHCl3/MeOH as eluant to give 164 mg (86%) of the title compound as a beige colored solid. Mp: 123.0-125.0° C. 1H NMR (DMSO-d6; 400 MHz): δ 1.68 (m, 2), 1.78 (m, 4), 2.30 (s, 3), 3.42 (br s, 4), 3.66 (s, 3), 7.44-7.54 (m, 5), 8.61 (s, 1) MS m/z: 307 (M+1).
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][N:4]([C:6]2[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3]1.[Cl:17][C:18]1[N:19]=[C:20]([C:25](O)=[O:26])[NH:21][C:22]=1[CH2:23][CH3:24].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>>[Cl:17][C:18]1[N:19]=[C:20]([C:25]([NH:1][CH:2]2[CH2:3][N:4]([C:6]3[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=3)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5]2)=[O:26])[NH:21][C:22]=1[CH2:23][CH3:24]
Reactant: CCOC(=O)c1cccc(N2CC(N)C2)c1
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CCOC(=O)c1cccc(N2CC(NC(=O)c3nc(Cl)c(CC)[nH]3)C2)c1
Yield: 44.4 %

Procedure:
The same operation as in Example (217c) was performed using ethyl 3-(3-aminoazetidin-1-yl)benzoate obtained in Example (223b) (114 mg, 0.52 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (90 mg, 0.52 mmol), WSC hydrochloride (298 mg, 1.55 mmol), 1-hydroxybenzotriazole (70 mg, 0.52 mmol) and N-methylmorpholine (0.11 mL, 1.04 mmol), to obtain 87 mg of the title compound as a gray white solid (45%).
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:26])[C@H:12]([CH2:21][CH2:22][CH2:23][CH2:24][NH2:25])[NH:13]C(OC(C)(C)C)=O)C.C([O:30][C:31](=[O:42])[C:32](=O)[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)C>>[C:31]([CH:32]([NH:13][C@H:12]([C:11]([N:7]1[CH2:8][CH2:9][CH2:10][C@H:6]1[CH2:5][C:4]([OH:27])=[O:3])=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][NH2:25])[CH2:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)([OH:30])=[O:42]
Reactant: CCOC(=O)C[C@@H]1CCCN1C(=O)[C@H](CCCCN)NC(=O)OC(C)(C)C
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Product: NCCCC[C@H](NC(CCc1ccccc1)C(=O)O)C(=O)N1CCC[C@H]1CC(=O)O

Procedure:
The product of Step A above is condensed with 2-oxo-4-phenylbutyric acid ethyl ester by the procedure of Example 1, Step E. The diastereomers are separated by silica gel chromatography. The individual diastereomers are converted into the corresponding diacids by saponification as in Example 2 and the -BOC group is removed in hydrogen chloride in ethyl acetate by the procedure of Example 1, Step D. The resulting hydrochloride salt is converted to the free base by absorbing on a strong acid ion exchange resin (Dowex 50W; H+ cycle) and eluting with 3% pyridine in water. Freeze drying affords the desired product, and the S,S,S and R,S,S, diastereomers are separated using reverse phase HPLC.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH:9](Cl)[CH:10]=[C:11]([Cl:13])[Cl:12])[CH2:3][C:4]([O:6]CC)=[O:5].CC(C)(C(Cl)C=C(Cl)Cl)CC(OC)=O>>[CH3:1][C:2]1([CH3:15])[CH:9]([CH:10]=[C:11]([Cl:13])[Cl:12])[O:6][C:4](=[O:5])[CH2:3]1
Reactant: CCOC(=O)CC(C)(C)C(Cl)C=C(Cl)Cl
Agent: COC(=O)CC(C)(C)C(Cl)C=C(Cl)Cl
Product: CC1(C)CC(=O)OC1C=C(Cl)Cl
Yield: 95 %

Procedure:
The above procedure was repeated except that 27.4 parts of ethyl 3,3-dimethyl-4,6,6-trichloro-5-hexenoate was used in lieu of methyl 3,3-dimethyl-4,6,6-trichloro-5-hexenoate. In this case, 19.8 parts of 3,3-dimethyl-4-(2',2'-dichlorovinyl)-4-butanolide was obtained (yield 95%).
Reaction SMILES: Cl[CH2:2][N:3]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[F:14])[C:4](Cl)=[O:5].[F:15][C:16]([F:35])([F:34])[O:17][C:18]1[CH:33]=[CH:32][C:21]([CH2:22][NH:23][C:24]([NH:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[S:25])=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[F:29][C:28]([F:30])([F:31])[CH2:27][N:26]=[C:24]1[N:23]([CH2:22][C:21]2[CH:20]=[CH:19][C:18]([O:17][C:16]([F:35])([F:15])[F:34])=[CH:33][CH:32]=2)[C:4](=[O:5])[N:3]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[F:14])[CH2:2][S:25]1
Reactant: FC(F)(F)CNC(=S)NCc1ccc(OC(F)(F)F)cc1
Reactant: Cc1ccc(N(CCl)C(=O)Cl)c(F)c1
Solvent: Cc1ccccc1
Product: Cc1ccc(N2CSC(=NCC(F)(F)F)N(Cc3ccc(OC(F)(F)F)cc3)C2=O)c(F)c1
Yield: 54.3 %

Procedure:
0.60 g of N-chloromethyl-N-(2-fluoro-4-methylphenyl)carbamoyl chloride and 0.84 g of 1-(4-trifluoromethoxybenzyl)-3-(2,2,2-trifluoroethyl)thiourea were dissolved in 50 ml of toluene, and the solution was heated under reflux for 5 hours. After the reaction, toluene was evaporated under reduced pressure. The resulting oily product was purified by column chromatography silica gel; developing solvent hexane/ethyl acetate (9:1)) to give 0.68 g of the captioned compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:5]([NH:7][CH2:8][C:9]1[C:14]([Cl:15])=[CH:13][C:12]([O:16][CH3:17])=[CH:11][C:10]=1[Cl:18])=[O:6].C(N(C(C)C)CC)(C)C>C1COCC1.C(OC(=O)C)C>[CH:19]1([CH:4]2[CH2:3][CH2:2][N:7]([CH2:8][C:9]3[C:14]([Cl:15])=[CH:13][C:12]([O:16][CH3:17])=[CH:11][C:10]=3[Cl:18])[C:5]2=[O:6])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COc1cc(Cl)c(CNC(=O)C(CCBr)C2CCCCC2)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(Cl)c(CN2CCC(C3CCCCC3)C2=O)c(Cl)c1
Yield: 79.3 %

Procedure:
Treat a solution of 4-bromo-2-cyclohexyl-N-(2,6-dichloro-4-methoxy-benzyl)-butyramide (2.0 g, 4.6 mmol) in THF (30 mL) with diisopropyl ethyl amine (1.19 g, 9.19 mmol) at 40° C. for 12 hours and at reflux for 6 hours. Cool the reaction, dilute with ethylacetate and wash with HCl (1N) and water. After drying the organic layer over sodium sulfate, filtrate and concentrate under vacuum. Purify the residue by silica gel chromatography with 1:4 ethyl acetate:hexane to afford 1.3 g (80%) of the title compound. MS (m/z): 356 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH2:10][CH2:9][CH:8]([NH:11][C:12]3[CH:13]=[CH:14][C:15]([F:29])=[C:16]([C@:18]4([CH3:28])[C:24]([F:26])([F:25])[CH2:23][O:22][CH2:21][C:20](=O)[NH:19]4)[CH:17]=3)[C:5]2=[N:6][CH:7]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:39]2)=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[N:6][C:5]2[CH:8]([NH:11][C:12]3[CH:13]=[CH:14][C:15]([F:29])=[C:16]([C@:18]4([CH3:28])[C:24]([F:26])([F:25])[CH2:23][O:22][CH2:21][C:20](=[S:39])[NH:19]4)[CH:17]=3)[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: C[C@]1(c2cc(NC3CCc4cc(Cl)cnc43)ccc2F)NC(=O)COCC1(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@]1(c2cc(NC3CCc4cc(Cl)cnc43)ccc2F)NC(=S)COCC1(F)F
Temperature: 80 °C
Reaction time: 3 h
Yield: 129 %

Procedure:
To a solution of (5R)-5-(5-(3-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylamino)-2-fluorophenyl)-6,6-difluoro-5-methyl-1,4-oxazepan-3-one (intermediate A22A) (62 mg, 146 μmmol) in dioxane (2.2 ml) at 23° C. was added 2,4-bis-(4-methoxy-phenyl)-[1,3,2,4]dithiadiphosphetane 2,4-disulfide (Lawesson's reagent) (38.3 mg, 94.6 μmmol) and the mixture was stirred at 80° C. for 3 h. The reaction mixture was poured onto sat. NaHCO3-solution and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated to give a yellow solid, which was purified by silica gel column chromatography with n-heptane/ethyl acetate to give the (R)-5-[5-(3-chloro-6,7-dihydro-5H-[1]pyrindin-7-ylamino)-2-fluoro-phenyl]-6,6-difluoro-5-methyl-[1,4]oxazepane-3-thione (54 mg, 84%) as a white solid. MS (ISP): m/z=443.0 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[CH:5]2.C(N1C=CN=C1)(N1C=CN=C1)=O.C1CCN2C(=NCCC2)CC1.[C:37](O)([CH3:40])([CH3:39])[CH3:38]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:12])=[CH:5]2
Reactant: CC(C)(C)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 40 °C
Reaction time: 3 h
Yield: 6.3 %

Procedure:
5.52 g of 5-chloro-2-indolecarboxylic acid are dissolved in 40 ml of DMF, 4.57 g of carbonyldiimidazole are added at RT, under nitrogen, the mixture is then heated to 40° C and 4.3 g of DBU and 4.17 g of tertbutanol are added. Heating is continued at 40° C. for 3 hours, the precipitate formed is then filtered off and the filtrate is concentrated under vacuum. The residue is taken up in EtOAc, washed with 10% Na2CO3 solution, with saturated aqueous NaCl, with sulphate buffer and then dried over Na2SO4 and concentrated. The residue is chromatographed on silica, eluting with DCM, to give 0.45 g of the expected compound: m.p.=140-142° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(#N)C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][Cl:25]>C(OC(=O)C)C>[Cl:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: ClCCCCCBr
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#Cc1ccc(OCCCCCCl)cc1
Reaction time: 8 h
Yield: 90 %

Procedure:
While 70 g of 4-hydroxybenzonitrile (7) were added to 500 ml of acetonitrile and stirred, 85.3 g of potassium carbonate and 77.4 ml of 1-bromo-5-chloropentane were added. Subsequently, the temperature was gradually increased and stirring under reflux was continued for 8 hr, and then stirring was further continued at room temperature for 18 hr. After the reaction was completed, the resultant reaction mixture was added with 500 ml of ethylacetate and then washed with water. Thereafter, the ethylacetate layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrated compound was dissolved in 280 ml of methanol, stirred at 0° C. for 2 hr, and then filtered, thus obtaining 118 g (yield: 90%) of a title compound as a white solid.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH2:31]([O:33][C:34]1[CH:35]=[C:36]([CH:42]=[CH:43][C:44]=1[O:45][CH2:46][CH3:47])/[C:37](=[N:40]/[H])/[NH:38]O)[CH3:32].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:31]([O:33][C:34]1[CH:35]=[C:36]([C:37]2[N:40]=[C:1]([C:2]3[CH:3]=[CH:4][N:5]=[CH:6][CH:7]=3)[O:9][N:38]=2)[CH:42]=[CH:43][C:44]=1[O:45][CH2:46][CH3:47])[CH3:32]
Reactant: [H]/N=C(\NO)c1ccc(OCC)c(OCC)c1
Reactant: O=C(O)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2noc(-c3ccncc3)n2)cc1OCC
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 26 %

Procedure:
In a microwave vial, a stirring solution of isonicotinic acid (200 mg, 1.62 mmol) in DMF was treated with HOBt (319 mg, 2.43 mmol) and EDCI (467 mg, 2.43 mmol) at room temperature. The reaction was stirred for 20 min followed by addition, in a single portion, of (Z)-3,4-diethoxy-N-hydroxybenzimidamide (436 mg, 1.94 mmol). The reaction was stirred for additional 30 min at room temperature and then heated to 130° C. for 35 min in the initiator. The reaction was diluted using a saturated solution of NaHCO3 and extracted with EtOAc (80 ml×3). The organic phase was dried over Na2SO4 anhydrous and concentrated under reduced pressure. The product was purified by column chromatography using CH2Cl2:MeOH (95:5) to offer the product in 26% yield (131 mg) as pale brown solid. 1H NMR (300 MHz, CDCl3): δ 8.85 (d, J=5.4 Hz, 2H), 8.02 (d, J=6.0 Hz, 2H), 7.71 (dd, J1=1.8 Hz, J2=8.1 Hz, 1H), 7.62 (d, J=2.1 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 4.19 (q, J=6.9 Hz, 2H), 4.14 (q, J=6.9 Hz, 2H), 1.50 (t, J=3.0 Hz, 3H), 1.46 (t, J=3.3 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 173.54, 16928, 151.64, 151.07, 148.91, 131.37, 121.48, 121.15, 118.75, 112.74, 111.82, 64.78, 64.59, 14.87, 14.81. MS (EI) m/z: 312 (M+), HRMS (EI) for C17H17N3O3 (M+): calcd 312.1343. found 312.1348.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:11][C:12]([O:14][CH2:15][C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[OH-].[Na+]>O1CCCC1>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[CH2:15][O:14][C:12]([NH:11][C:5]1([C:3]([OH:4])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:13]
Reactant: COC(=O)C1(NC(=O)OCc2ccco2)CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(NC1(C(=O)O)CCCCC1)OCc1ccco1
Reaction time: 18 h
Yield: 74.4 %

Procedure:
28.13 g (0.1 mol) of 1-[[(2-furanylmethoxy)carbonyl]amino]cyclohexanecarboxylic acid methyl ester was added to a mixture solution of 150 ml of 2N aqueous sodium hydroxide solution and 200 ml of tetrahydrofuran, and the mixture was heated under reflux for 18 hours. After the solvent was distilled off, water was added to the residue, and the mixture was washed with diethyl ether. After potassium hydrogensulfate was added to the aqueous layer to acidify it, it was extracted with ethyl acetate twice. After the organic layer was washed with saturated brine and it was dried with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the residue, and the mixture was stirred for 18 hours. The obtained crystal was collected by filtration to obtain 19.89 g (74%) of the title compound.
Reaction SMILES: [OH:1][C@:2]12[C@@H:15]3[NH:16][CH2:17][CH2:18][C@:7]1([C:8]1[C:9]([O:19][CH3:20])=[CH:10][CH:11]=[CH:12][C:13]=1[CH2:14]3)[CH2:6][C:5](=[O:21])[CH2:4][CH2:3]2.C([O-])([O-])=O.[K+].[K+].[CH:28]1([C:31](Cl)=[O:32])[CH2:30][CH2:29]1>CN(C=O)C>[CH:28]1([C:31]([N:16]2[CH2:17][CH2:18][C@@:7]34[C:8]5[C:9]([O:19][CH3:20])=[CH:10][CH:11]=[CH:12][C:13]=5[CH2:14][C@@H:15]2[C@:2]3([OH:1])[CH2:3][CH2:4][C:5](=[O:21])[CH2:6]4)=[O:32])[CH2:30][CH2:29]1
Reactant: O=C(Cl)C1CC1
Reactant: COc1cccc2c1[C@]13CCN[C@H](C2)[C@]1(O)CCC(=O)C3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc2c1[C@]13CCN(C(=O)C4CC4)[C@H](C2)[C@]1(O)CCC(=O)C3
Temperature: 0 °C
Yield: 85.6 %

Procedure:
To an ice-cooled mixture of 330 mg (1.15 mmol) 14-hydroxy-4-methoxymorphinan-6-one, 400 mg (2.89 mmol) anhydrous K2CO3 in 10 ml dry DMF was dropped a solution of 0.11 ml (1.21 mmol) cyclopropanecarboxylic acid chloride in 3 ml dry DMF during 10 min. while stirring. This mixture was stirred at 0° C. for an additional 50 min., then filtered, washed with CHCl3 and the filtrate evaporated. The residue was partitioned between water and CH2Cl2, the organic layer separated, washed with brine, dried and evaporated. The resulting solid residue was crystallized with ethanol to give 350 mg (86%) N-cyclopropylcarbonyl-14-hydroxy-4-methoxymorphinan-6-one, m.p. 223°-225°, [α]D26 --167.2° (C 0.97, CHCl3).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11](I)=[C:10]([F:15])[CH:9]=1.[F:16][C:17]1[C:22]([F:23])=[C:21]([Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:20]=[CH:19][C:18]=1B1OCC(C)(C)CO1>O.O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:18]2[CH:19]=[CH:20][C:21]([Si:24]([CH3:25])([CH3:27])[CH3:26])=[C:22]([F:23])[C:17]=2[F:16])=[C:10]([F:15])[CH:9]=1
Reactant: CC1(C)COB(c2ccc([Si](C)(C)C)c(F)c2F)OC1
Reactant: Fc1cc(Br)ccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[Si](C)(C)c1ccc(-c2ccc(Br)cc2F)c(F)c1F
Yield: 88 %

Procedure:
A solution of 16.6 g (120 mmol) of K2CO3 in 50 ml of water is added to a solution of 15 g (50 mmol) of 4-bromo-2-fluoro-1-iodobenzene, 14.9 g (50 mmol) of 6 and 2.31 g (2 mmol) of [Pd(PPh3)4] in 100 ml of dioxane, and the mixture is refluxed overnight. The organic phase is washed with water and sat. NaCl, dried over MgSO4 and filtered through SiO2. The solvent is removed under-reduced pressure, petroleum ether is added to the oily residue, and the product is recrystallised at −25° C. (yield: 88%, m.p. 78.0° C.).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].CCS[C:8]([C:10]([F:13])([F:12])[F:11])=[O:9]>CO>[F:11][C:10]([F:13])([F:12])[C:8]([NH:4][CH2:3][CH2:1][OH:2])=[O:9]
Reactant: NCCO
Reactant: CCSC(=O)C(F)(F)F
Solvent: CO
Product: O=C(NCCO)C(F)(F)F
Reaction time: 8 h

Procedure:
Ethanolamine (12 g) is dissolved in methanol (50 ml) and S-ethylthiotrifluoroacetate (35 g) is added dropwise. The reaction is permitted to stand overnight irrigated with a stream of argon to remove ethanethiol. The excess solvent is removed in vacuo to leave the title product.