Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:26])[O:11][C@H:12]([C@H:22]([OH:25])[CH2:23][OH:24])[C:13]=1[O:14]CC1C=CC=CC=1)C1C=CC=CC=1.[OH-].[Na+].[N:29]1[N:30]([C:38]2[CH:43]=[C:42]([CH2:44]Br)[CH:41]=[CH:40][C:39]=2[OH:46])[N:31]=[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=12>C1COCC1.[Pd]>[N:29]1[N:30]([C:38]2[CH:43]=[C:42]([CH:41]=[CH:40][C:39]=2[OH:46])[CH2:44][O:24][CH2:23][C@H:22]([C@H:12]2[O:11][C:10](=[O:26])[C:9]([OH:8])=[C:13]2[OH:14])[OH:25])[N:31]=[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=12
Reactant: O=C1O[C@H]([C@H](O)CO)C(OCc2ccccc2)=C1OCc1ccccc1
Reactant: Oc1ccc(CBr)cc1-n1nc2ccccc2n1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C1O[C@H]([C@H](O)COCc2ccc(O)c(-n3nc4ccccc4n3)c2)C(O)=C1O
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
35 g of (R)-3,4-bisbenzyloxy-5-((R)-1,2-dihydroxyethyl)-5H-furan-2-one (98.2 mmol; 1 eq.) are dissolved in 250 ml of THF under a protective-gas atmosphere, and 3.93 g of sodium hydroxide (98.2 mmol; 1 eq.) are added at 0° C. After 30 min, the 2-benzotriazol-2-yl-4-bromomethylphenol (35.8 g; 117.9 mmol; 1.2 eq.) dissolved in 100 ml of THF is added dropwise, the mixture is stirred at 0° C. for 60 min and at 70° C. for 7 hours. After the reaction solution has been cooled to room temperature, 2 g of Pd/C are added, and the mixture is hydrogenated for 5 hours under a hydrogen atmosphere at 3 bar and 50° C. After filtration through a Celite pad, the solution is neutralised using 2 N HCl solution. The extraction is carried out twice with 250 ml of sat. NaHCO3 solution and 100 ml of sat. NaCl solution. The product is precipitated from the org. phase using 370 ml of heptane.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([OH:18])(=[O:17])[CH:14]([CH3:16])[CH3:15].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH3:15][C:14]([CH3:16])([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:13]([OH:18])=[O:17]
Reactant: CC(C)C(=O)O
Reactant: BrCc1ccccc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(Cc1ccccc1)C(=O)O
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of diisopropylamine (12.6 g, 125 mmol) in tetrahydrofuran (100 ml) under anhydrous conditions at 0° C. was added n-butyllithium (80.6 ml, 1.55M in hexane, 125 mmol). The reaction mixture was stirred for 30 minutes at 5° C. and then isobutyric acid (4.4 g, 50 mmol) was added. The reaction mixture was stirred at 0° C. for 30 minutes and then benzyl bromide (17.1 g, 100 mmol) was added dropwise. The reaction mixture was stirred for 2 hours at ambient temperature, quenched with saturated aqueous ammonium chloride (60 ml) and then acidified with 6N hydrochloric acid with cooling. The aqueous phase was saturated with sodium chloride and extracted with diethyl ether (2×100 ml). The combined organic phase was washed with saturated aqueous sodium chloride (2×25 ml) and then dried over magnesium sulfate and concentrated in vacuo to give viscous oil. The oil was distilled at 0.2 mmHg and the product was collected at 160°-170° C. The product was purified by chromatography on a 5×15 cm column of silica gel eluted with 10 percent diethyl ether/hexane (1 L) and 50 percent diethyl ether/hexane (1 L) to afford the desired product as a colorless solid. m.p. 58°-9° C.
Reaction SMILES: [BH4-].[Na+].[CH3:3][CH:4]([CH3:20])[CH2:5][CH:6]([C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8].Cl>C(O)C.O>[OH:19][CH:12]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]([CH2:5][CH:4]([CH3:3])[CH3:20])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(=O)C(CC(C)C)C(=O)OCC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CC(O)C(CC(C)C)C(=O)OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
Sodium borohydride (1.1 g, 29 mmol) was added to an ice-cold solution of diethyl 2-(2-methylpropyl)-3-oxopentanedioate (7.5 g, 29 mmol) in ethanol (75 ml). The mixture was stirred at 5°-10° C. for 2 h, then 2 N hydrochloric acid (18 ml) was added slowly at 0° C., and the mixture was stirred at room temperature for 45 min. The mixture was diluted with water (400 ml), then was extracted with ethyl acetate (4×100 ml). The extracts were washed with water (2×100 ml) and brine (100 ml), then were dried (Na2SO4) and evaporated in vacuo to leave the title compound as an oil (7.5 g, 100%).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:22]=[N:21][CH:20]=[C:19]([CH3:23])[N:18]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)[CH:5]=[C:4]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]2)[C:3]1=[O:38]>C(O)(C(F)(F)F)=O.ClCCl>[NH2:30][C@H:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:4]2[C:3](=[O:38])[N:2]([CH3:1])[CH:7]=[C:6]([N:8]3[C:16]4[CH:15]=[C:14]([C:17]5[CH:22]=[N:21][CH:20]=[C:19]([CH3:23])[N:18]=5)[N:13]=[CH:12][C:11]=4[CH:10]=[N:9]3)[CH:5]=2)[CH2:25]1
Reactant: Cc1cncc(-c2cc3c(cn2)cnn3-c2cc(N3CCC[C@H](NC(=O)OC(C)(C)C)C3)c(=O)n(C)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2cc(N3CCC[C@H](N)C3)c(=O)n(C)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
A mixture of tert-butyl N-[(3S)-1-[1-methyl-5-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-oxo-3-pyridyl]-3-piperidyl]carbamate (0.2245 mmol; 116.0 mg) in TFA (1 mL) and dichloromethane (4 mL) was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 233 as an off-white solid (51.6 mg, 54%). 1H NMR (400 MHz, DMSO) δ 9.47-9.40 (s, 1H), 9.36-9.30 (s, 1H), 8.66-8.57 (s, 2H), 8.48-8.40 (s, 1H), 7.96-7.90 (d, J=2.5 Hz, 1H), 6.96-6.90 (d, J=2.5 Hz, 1H), 3.69-3.61 (d, J=6.6 Hz, 2H), 3.58-3.52 (s, 3H), 2.83-2.72 (t, J=9.7 Hz, 1H), 2.63-2.58 (s, 3H), 2.30-2.23 (m, 1H), 1.88-1.81 (d, J=9.0 Hz, 1H), 1.74-1.68 (d, J=13.3 Hz, 1H), 1.63-1.53 (d, J=12.8 Hz, 1H), 1.18-1.06 (m, 1H); MS (ESI) m/z: 417.2 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:3]=1[C:12](NN)=O.[C:16](=O)(O)[O-:17].[Na+]>Cl>[CH2:12]1[C:3]2=[C:4]3[C:9](=[CH:10][CH:11]=[C:2]2[NH:1][C:16]1=[O:17])[N:8]=[CH:7][CH:6]=[CH:5]3
Reactant: O=C([O-])O
Reactant: NNC(=O)c1c(N)ccc2ncccc12
Agent: Cl
Agent: [Na+]
Product: O=C1Cc2c(ccc3ncccc23)N1
Yield: 45 %

Procedure:
6-Aminoquinoline-5-carboxylic acid hydrazide was dissolved in 10 mL of 2 M hydrochloric acid and heated briefly on a hot plate. The reaction was neutralized by gradual addition of solid sodium bicarbonate and filtered. The collected product was dried under vacuum at 55° C. to give 416 mg (45%) of 1,3-dihydro-pyrrolo[3,2-f]quinoline-2-one as a brown solid. Mass spectrum (negative ion chemical ionization): m/z=183 (60%). 1H NMR (DMSO-d6): δ3.80 (s, 2H), 7.35 (d, J=8.8 Hz, 1H), 7.44 (dd, J=8.4, 4.2 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H), 8.08 (d, J=8.4 Hz, 1H), 8.70 (dd, J=4.2, 1.6 Hz, 1H), 10.57 (br s, 1H).
Reaction SMILES: [H-].[Na+].[I-].[Cl:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][N:9]1[C:17]([CH2:18][N+](C)(C)C)=[C:16]([CH3:23])[N:15]=[C:10]12.[CH2:24]([OH:27])[C:25]#[CH:26]>>[Cl:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][N:9]1[C:17]([CH2:18][O:27][CH2:24][C:25]#[CH:26])=[C:16]([CH3:23])[N:15]=[C:10]12
Reactant: Cc1nc2c3cccc(Cl)c3ccn2c1C[N+](C)(C)C
Reactant: C#CCO
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Product: C#CCOCc1c(C)nc2c3cccc(Cl)c3ccn12
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 60% sodium hydride (0.235 g) in propargyl alcohol (9.36 ml) was added 7-chloro-2-methyl-3-trimethylammoniomethylimidazo[2,1-a]isoquinoline iodide (2.08 g) and the mixture was heated at 100° C. with stirring for 2 hours. After being cooled, the mixture was evaporated in vacuo and the residue was dissolved in chloroform. The solution was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (20 g) with a mixture of chloroform and methanol (100:1) as an eluent to give 7-chloro-2-methyl-3-propargyloxymethylimidazo[2,1-a]isoquinoline. This compound was treated with a solution of hydrogen chloride in ethanol to give 7-chloro-2-methyl-3-propargyloxymethylimidazo[2,1-a]isoquinoline hydrochloride (1 g).
Reaction SMILES: Cl.[CH:2]1([CH2:5][N:6]2[CH2:23][CH2:22][C@@:13]34[C:14]5[CH:15]=[C:16](O)[CH:17]=[CH:18][C:19]=5[CH2:20][C@@H:7]2[C@@H:8]3[CH2:9][C:10]([CH3:25])([CH3:24])[O:11][CH2:12]4)[CH2:4][CH2:3]1.Cl.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1.N1C=CC=CC=1>C(Cl)Cl>[CH:2]1([CH2:5][N:6]2[CH2:23][CH2:22][C@@:13]34[C:14]5[CH:15]=[C:16]([C:27](=[O:34])[C:28]6[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=6)[CH:17]=[CH:18][C:19]=5[CH2:20][C@@H:7]2[C@@H:8]3[CH2:9][C:10]([CH3:25])([CH3:24])[O:11][CH2:12]4)[CH2:4][CH2:3]1
Reactant: CC1(C)C[C@H]2[C@H]3Cc4ccc(O)cc4[C@@]2(CCN3CC2CC2)CO1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)C[C@H]2[C@H]3Cc4ccc(C(=O)c5cccnc5)cc4[C@@]2(CCN3CC2CC2)CO1

Procedure:
Equimolar amounts of 17-cyclopropylmethyl-7,7-dimethyl-3-hydroxy-6-oxamorphinan (XIV, prepared in Example 5), nicotinoyl chloride hydrochloride and pyridine are mixed together in dry methylene chloride and heated at reflux temperature for 3 hours to produce the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[NH:10][CH2:11][CH2:12]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]1([C:21]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:25][CH2:24][NH:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>C1COCC1>[CH2:1]([O:8][C:9](=[O:14])[NH:10][CH2:11][CH2:12][N:23]1[CH2:24][CH2:25][C:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:22]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCBr)OCc1ccccc1
Reactant: c1ccc(C2(c3ccccc3)CCNC2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCN1CCC(c2ccccc2)(c2ccccc2)C1)OCc1ccccc1
Reaction time: 15 h

Procedure:
(2-Bromo-ethyl)-carbamic acid benzyl ester (1.10 g, 4.26 mmol), 3,3-diphenyl-pyrrolidine (Example A18, 836 mg, 3.75 mmol) and DIPEA (1.0 mL 5.7 mmol) are dissolved in THF (20 mL) and stirred for 15 h at reflux. The mixture is quenched with Na2CO3 (50 mL) and extracted with CH2Cl2 (3×50 mL). The organic extracts are washed with sat. aq. Na2CO3 (30 mL), dried (Na2SO4), filtered and evaporated. The residue is purified by FC (SiO2, EtOAc-heptane) to provide the title compound.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[C:12]([O:16][C:17]([NH:19][OH:20])=[O:18])([CH3:15])([CH3:14])[CH3:13].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28]>C(Cl)Cl>[C:12]([O:16][C:17]([NH:19][O:20][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: OCCCCCCBr
Reactant: CC(C)(C)OC(=O)NO
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NOCCCCCCO
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.2 %

Procedure:
To a solution of 179 μL (183 mg, 1.2 mmol) of DBU in 1 mL of CH2Cl2 was added 133 mg (1.0 mmol) of N-(tert-butyloxycarbonyl)hydroxylamine (Aldrich Chemical Co.) and 157 μL (217 mg, 1.2 mmol) of 6-bromohexan-1-ol (Aldrich Chemical Co.), and the mixture was stirred for 18 hours at room temperature. The mixture was concentrated to give a yellow oil. Purification by silica gel chromatography (35/5/65 EtOAc/MeOH/hexanes) gave 180 mg (77%) of compound 27 as a colorless oil: 1H NMR (CDCl3) δ 1.39 (m, 4H), 1.48 (s, 9H), 1.59 (m, 4H), 3.63 (t, 2H), 3.85 (t, 2H), 7.42 (s, 1H); 13C NMR (CDCl3) δ 25.6, 25.8, 28.1, 28.4, 62.8, 76.8, 81.7, 157.2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:15]=[CH:16][C:17]4[O:21][CH2:20][CH2:19][C:18]=4[CH:22]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:4]([CH3:23])[C:3]=1[CH3:24].[CH3:25][O:26][C:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[CH:29][N:28]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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>[O:21]1[C:17]2[CH:16]=[CH:15][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:31]5[CH:30]=[CH:29][N:28]=[C:27]([O:26][CH3:25])[CH:32]=5)[C:3]([CH3:24])=[C:4]([CH3:23])[CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:22][C:18]=2[CH2:19][CH2:20]1
Reactant: COc1cc(B(O)O)ccn1
Reactant: Cc1cc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)nc(Cl)c1C
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: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1cc(-c2nc(NC(=O)C3(c4ccc5c(c4)CCO5)CC3)cc(C)c2C)ccn1
Temperature: 80 °C
Yield: 88.8 %

Procedure:
To N-(6-chloro-4,5-dimethylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxamide (100 mg, 0.29 mmol), 2-methoxypyridin-4-ylboronic acid (67 mg, 0.44 mmol) and tetrakis(triphenylphosphine)palladium (0) (34 mg, 0.029 mmol) in 1,2-dimethoxyethane (3.0 mL), 2 M Na2CO3 (438 μL, 0.87 mmol) was added. The reaction mixture was stirred and heated at 80° C. for 16 hours under N2 atmosphere. Product and starting material were observed. 0.5 Equivalents of 2-methoxypyridin-4-ylboronic acid and 0.05 equivalents of tetrakis(triphenylphosphine)palladium (0) were added and continued heating for 40 hours. The reaction mixture was diluted with ethyl acetate (5 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-30% ethyl acetate in hexane) to yield 1-(2,3-dihydrobenzofuran-5-yl)-N-(2′-methoxy-3,4-dimethyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide as a yellow solid (107 mg, 88%). ESI-MS m/z calc. 415.5. found 416.7 (M+1)+. Retention time 1.74 minutes.
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:17][C:16]=2[CH2:31][S:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:7]=1)C.[OH-].[Li+].O>CO>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([C:22]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][C:8]3[CH:7]=[C:6]([CH2:5][C:4]([OH:39])=[O:3])[CH:11]=[CH:10][C:9]=3[O:12][CH3:13])=[C:16]([CH2:31][S:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:17]=2)=[O:30])=[CH:28][CH:27]=1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)c3ccc(Cl)cc3)cc2CSc2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(CC(=O)O)cc1Oc1ccc(NC(=O)c2ccc(Cl)cc2)cc1CSc1ccccc1
Temperature: 60 °C

Procedure:
To {3-[4-(4-chloro-benzoylamino)-2-phenylsulfanylmethyl-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester (0.9 mmol) was added lithium hydroxide (0.3 g), H2O (5 mL), and MeOH (20 mL). The reaction was stirred at 60° C., and then worked up and purified by preparative HPLC to give the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@@H:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:23](=[O:46])/[CH:24]=[CH:25]/[C:26]3[CH:45]=[CH:44][C:29]([O:30][CH2:31][CH2:32][N:33]4C(=O)C5C(=CC=CC=5)C4=O)=[CH:28][CH:27]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.C1COCC1.NN>CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@@H:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:23](=[O:46])/[CH:24]=[CH:25]/[C:26]3[CH:27]=[CH:28][C:29]([O:30][CH2:31][CH2:32][NH2:33])=[CH:44][CH:45]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCOc1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)[C@H]2c2ccc3c(c2)CCO3)cc1
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Product: NCCOc1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)[C@H]2c2ccc3c(c2)CCO3)cc1
Temperature: 45 °C
Reaction time: 4 h
Yield: 25.3 %

Procedure:
To a solution of (E)-(R)-2-[2-(4-{3-[1-(2,3-dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-oxo-propenyl}-phenoxy)ethyl]isoindole-1,3-dione (0.85 g, 1.4 mmol) in 50 mL of MeOH:THF was added hydrazine (0.38 mL, 3 equiv., 35% in water). The resulting mixture was stirred at 45° C. for 4 hours. Evaporation in vacuo and flash chromatography with DCM:MeOH (80.20) as eluting solvent gave the title compound (0.17 g, 26%) as yellow powder. MP: 186° C. Analysis for C30H29N3O3. 0.3CH2Cl2 : Calculated: C,72.06; H,5.91; N,8.32; Found C,72.12; H,6.08; N,8.6%. [α]D20 =-285 (c=0.29, MeOH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.[N:9]([O-])=O.[Na+].O.O.Cl[Sn]Cl>Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][NH2:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1cccc(Br)c1
Reaction time: 1 h

Procedure:
To a solution of 3-bromo-phenylamine (17 g, 0.1 mol) in concentrated HCl (200 mL) was added an aqueous solution (20 mL) of NaNO2 (7 g, 0.1 mol) at 0° C. and the resulting mixture was stirred for 1 h. A solution of SnCl2.2H2O (45 g, 0.2 mmol) in concentrated HCl (500 mL) was then added at 0° C. The reaction solution was stirred for an additional 2 h at RT. The precipitate was filtered and washed with ethanol and ether to give (3-bromo-phenyl)-hydrazine as a white solid, which was used for the next reaction without further purification
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:7]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19].[CH3:28][C:29]1[NH:33][N:32]=[N:31][N:30]=1>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH:8]2[N:7]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)(=[O:20])=[O:19])[CH:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:30]3[C:29]([CH3:28])=[N:33][N:32]=[N:31]3)[CH2:10][CH2:9]2)=[CH:12][CH:13]=1
Reactant: Cc1nnn[nH]1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCCCl)CCC2c2ccc(F)cc2)cc1
Product: Cc1ccc(S(=O)(=O)N2C(CCCCn3nnnc3C)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e=458.4 (M+H+), was prepared in accordance with the general method of example 82b from (2RS,5RS)-2-(4-chloro-butyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 5-methyl-1H-tetrazole.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:6][CH:7]([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>>[CH3:20][O:19][C:18]1[CH:17]=[CH:16][C:5]([CH2:6][CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:3]=1[CH2:2][O:1][C:30]([NH:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=1)=[O:31]
Reactant: COc1ccc(N=C=O)cc1
Reactant: COC(=O)C(Cc1ccc(OC)c(CO)c1)C(=O)OC
Product: COC(=O)C(Cc1ccc(OC)c(COC(=O)Nc2ccc(OC)cc2)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(hydroxymethyl)-4-methoxybenzyl]malonate and 4-methoxyphenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:12]=[N:13][N:14]([CH3:32])[C:15]=2[C@H:16]2[O:22][CH2:21][C@@H:20]([F:23])[C@H:19]([NH:24]C(=O)OC(C)(C)C)[CH2:18][CH2:17]2)=[O:9])[CH:5]=[CH:4][C:3]=1[F:33].[F:34][C:35]1[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O>>[NH2:24][C@H:19]1[C@H:20]([F:23])[CH2:21][O:22][C@H:16]([C:15]2[N:14]([CH3:32])[N:13]=[CH:12][C:11]=2[NH:10][C:8](=[O:9])[C:6]2[CH:5]=[CH:4][C:3]([F:33])=[C:2]([C:39]3[CH:38]=[CH:37][CH:36]=[C:35]([F:34])[C:40]=3[F:41])[N:7]=2)[CH2:17][CH2:18]1
Reactant: Cn1ncc(NC(=O)c2ccc(F)c(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: OB(O)c1cccc(F)c1F
Product: Cn1ncc(NC(=O)c2ccc(F)c(-c3cccc(F)c3F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(6-bromo-5-fluoropicolinamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 103), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2,3-difluorophenyl)boronic acid gave 223. 1H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.27 (dd, J=8.7, 3.9 Hz, 1H), 8.12 (t, J=9.1 Hz, 1H), 7.90 (s, 1H), 7.69-7.52 (m, 2H), 7.47-7.37 (m, 1H), 4.84 (dd, J=10.3, 3.7 Hz, 1H), 4.39-4.16 (m, 1H), 4.12-3.86 (m, 2H), 3.76 (s, 3H), 3.15-3.02 (m, 1H), 2.12-2.01 (m, 1H), 1.84-1.70 (m, 1H), 1.70-1.56 (m, 4H). LCMS (ES+) m/z 464 (M+1).
Reaction SMILES: [NH2:1]/[C:2](=[N:12]\[O:13][C:14](=O)[CH2:15][O:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:19][CH2:18]1)/[C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[C:9]([O-:11])=[O:10]>N1C=CC=CC=1>[CH2:26]([O:25][C:23]([N:20]1[CH2:21][CH2:22][CH:17]([O:16][CH2:15][C:14]2[O:13][N:12]=[C:2]([C@@H:3]3[CH2:8][CH2:7][CH2:6][CH2:5][N:4]3[C:9]([O:11][C:27]([CH3:32])([CH3:28])[CH3:26])=[O:10])[N:1]=2)[CH2:18][CH2:19]1)=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: N/C(=N\OC(=O)COC1CCN(C(=O)OCc2ccccc2)CC1)[C@@H]1CCCCN1C(=O)[O-]
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1c1noc(COC2CCN(C(=O)OCc3ccccc3)CC2)n1

Procedure:
The title compound was prepared by a similar method to Preparation 13 from (Z)-(2S)-2-[amino([2-(1-[(benzyloxy)carbonyl]-4-piperidyloxy)acetyl]oxyimino)methyl]-1-piperidinecarboxylate [see Preparation 93] and pyridine. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 80:20, changing to 50:50, by volume, hexane:ethyl acetate, in 5% increments, to afford tert-butyl (2S)-2-{5-[(1-[(benzyloxy)carbonyl]-4-piperidyloxy)methyl]-1,2,4-oxadiazol-3-yl}-1-piperidinecarboxylate.
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:12](O)(=[O:22])[C:13]1[CH:21]=[CH:20][C:18]([OH:19])=[C:15]([O:16][CH3:17])[CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:22])[C:13]1[CH:21]=[CH:20][C:18]([OH:19])=[C:15]([O:16][CH3:17])[CH:14]=1
Reactant: COc1cc(C(=O)O)ccc1O
Reactant: CCCCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCCCCCCOC(=O)c1ccc(O)c(OC)c1
Yield: 50 %

Procedure:
The n-decyl vanillate was synthesized by refluxing decyl alcohol with vanillic acid in the presence of p-toluenesulfonic acid. After removal of the unreacted alcohol, purification and recrystallization from n-pentane, the n-decyl vanillate had a melting point of 40°-40.5° C. (Yield: about 50%).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:14]=[C:13]2[C:8]([NH:9][C:10](=[O:17])[C:11](=[O:16])[N:12]2[OH:15])=[CH:7][CH:6]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.[CH3:23]O>>[OH:15][N:12]1[C:13]2[C:8](=[CH:7][CH:6]=[C:5]([CH2:4][C:1]([O:3][CH3:23])=[O:2])[CH:14]=2)[NH:9][C:10](=[O:17])[C:11]1=[O:16]
Reactant: CO
Reactant: O=C(O)Cc1ccc2[nH]c(=O)c(=O)n(O)c2c1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc2[nH]c(=O)c(=O)n(O)c2c1
Temperature: 25 °C
Yield: 76 %

Procedure:
A mixture of 0.5 g (2.1 mmol) 7-carboxymethyl-1-hydroxyquinoxaline-2,3(1H,4H)-dione, 5 dr. sulfuric acid (97%) and 50 ml methanol was refluxed for 1 h. After cooling to 25° C. the precipitate was filtered off and washed with ether to give 0.4 g (76%) of 1-hydroxy-7-methoxycarbonylmethyl-quinoxaline-2,3(1H,4H)-dione. M.p. decomp. 1H-NMR (DMSO-d6): 12.2 (1H, broad s), 7.5-7.1 (3H, m), 3.9 (2H, s), 3.7 (3H,s).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3[CH:15]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[NH:13][C:12](=[O:22])[CH:11]=3)=[CH:4][C:3]=2[O:2]1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(=O)([O-])[O-].[Ag+2].CN(C)C=O>[CH3:34][CH:28]([CH2:27][CH2:26][CH2:25][CH2:24][O:22][C:12]1[CH:11]=[C:10]([C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:1][O:2][C:3]=3[CH:4]=2)[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]=1)[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)C(C)CCCCBr
Reactant: O=c1cc(-c2ccc3c(c2)OCO3)cc(-c2ccccc2)[nH]1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)CCCCOc1cc(-c2ccc3c(c2)OCO3)cc(-c2ccccc2)n1
Temperature: 100 °C

Procedure:
The procedure in Example 5 is followed but using 4-(3,4-methylenedioxyphenyl)-6-phenyl-2-pyridinone (2.5 g), ethyl 6-bromo-2-methylhexanoate (4 g), silver carbonate (1.2 g) and dimethylformamide (100 cc). The reaction mixture is heated at 100° C. for 72 hours. The product is purified by chromatography under pressure on silica gel (30-60 mm; eluent: n-hexane-ethyl acetate 9-1 ). (yellowish oil)