Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([F:15])=[CH:13][C:12](OB(O)O)=[CH:11][C:10]=1[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:22]1[N:23]=[C:24]([N:32]2[CH2:37][CH2:36][N:35]([CH2:38][CH3:39])[CH2:34][CH2:33]2)[C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH2:38]([N:35]1[CH2:34][CH2:33][N:32]([C:24]2[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:31]=[C:22]([C:12]3[CH:13]=[C:14]([F:15])[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[C:10]([F:20])[CH:11]=3)[N:23]=2)[CH2:37][CH2:36]1)[CH3:39]
Reactant: OB(O)Oc1cc(F)c(OCc2ccccc2)c(F)c1
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
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: Cc1ccccc1
Product: CCN1CCN(c2nc(-c3cc(F)c(OCc4ccccc4)c(F)c3)cc3ccccc23)CC1
Yield: 199.2 %

Procedure:
4-Benzyloxy-3,5-difluorophenylboric acid (1.97 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (5.20 g) were heated under reflux in the presence of tetrakistriphenylphosphinepalladium(0) (0.50 g) in toluene (250 ml) and a 10% aqueous solution of sodium carbonate (150 ml) in nitrogen atmosphere for 1 hr. 4-Benzyloxy-3,5-difluorophenylboric acid (1.15 g) was additionally added thereto, and the mixture was heated under reflux for 1 hr. 4-Benzyloxy-3,5-difluorophenylboric acid (1.15 g) was additionally added to the resulting mixture, and then heated under reflux overnight. The organic layer was separated and extracted with 2N hydrochloric acid twice. The resulting aqueous layer was washed with ethyl acetate, adjusted to pH 10 by a 8N aqueous solution of sodium hydroxide, extracted with ethyl acetate, washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 1-(4-ethylpiperazin-1-yl)-3-(4-benzyloxy-3,5-difluorophenyl)isoquinoline (6.44 g) as a brown viscous oil.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]([O:27][C:28](=[O:43])[CH2:29][NH:30][C:31]([C:33]1[N:41]=[C:40]2[N:35]([N:36]=[C:37](Cl)[CH:38]=[CH:39]2)[N:34]=1)=[O:32])[CH3:26].C(N(C(C)C)C(C)C)C.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:25]([O:27][C:28](=[O:43])[CH2:29][NH:30][C:31]([C:33]1[N:41]=[C:40]2[N:35]([N:36]=[C:37]([NH:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][CH:9]([O:8][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:10][CH2:11]3)[CH:38]=[CH:39]2)[N:34]=1)=[O:32])[CH3:26]
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: CCOC(=O)CNC(=O)c1nc2ccc(Cl)nn2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNC(=O)c1nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2n1
Temperature: 25 °C
Reaction time: 28 h
Yield: 39.8 %

Procedure:
1.41 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 1.23 g of N-(6-chloro[1,2,4]triazolo[1,5-b]pyridazine-2-carbonyl)glycine ethyl ester were dissolved in 17 ml of N,N-dimethylformamide; 1.50 ml of N-ethyldiisopropylamine was added, followed by stirring at room temperature for 28 hours, then at 60° C. for 19 hours. After cooling, aqueous sodium bicarbonate was added, followed by extraction with ethyl acetate-tetrahydrofuran (1:1); the extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (50:5:1). The desired fraction was collected, concentrated, recrystallized by the addition of tetrahydrofuran, collected by filtration, washed with ethyl ether and dried to yield 987 mg of the title compound.
Reaction SMILES: [O:1]1[C:5]([C:6](OCC)=[O:7])=[CH:4][C:3]2[CH:11]=[CH:12][C:13]3[CH:14]=[CH:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[C:22]=3[C:2]1=2>C(Cl)Cl.CCCCCC>[O:1]1[C:5]([CH2:6][OH:7])=[CH:4][C:3]2[CH:11]=[CH:12][C:13]3[CH:14]=[CH:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[C:22]=3[C:2]1=2
Reactant: CCOC(=O)c1cc2ccc3ccc4ccccc4c3c2o1
Solvent: CCCCCC
Solvent: ClCCl
Product: OCc1cc2ccc3ccc4ccccc4c3c2o1
Yield: 91 %

Procedure:
Using the procedure outlined in Example 14A, ethyl phenanthro[4,3-b]-furan-2-carboxylate (H. G. Pars Pharmaceutical Laboratories, Inc.) gave a 91% yield of phenanthro[4,3-b]furan-2-methanol, mp 125°-126°, (C,H), (CH2Cl2 /hexane).
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-])=O)=[C:10]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.S([O-])([O-])(=O)=O.[Mg+2]>>[Cl:1][C:2]1[C:11]([NH2:12])=[C:10]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1NCC1CCOCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: Nc1c(Cl)nc2ccccc2c1NCC1CCOCC1
Reaction time: 4 h
Yield: 85.7 %

Procedure:
The method of Part B of Example 1 was used to hydrogenate 2-chloro-3-nitro-N-(tetrahydro-2H-pyran-4-ylmethyl)quinolin-4-amine (7 g, 20 mmol) with the modifications that the reaction was stopped after four hours, and magnesium sulfate was added to the mixture before filtration. 2-Chloro-N4-(tetrahydro-2H-pyran-4-ylmethyl)quinoline-3,4-diamine (5 g) was isolated as a sticky, amber solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]([CH:16]([CH3:18])[CH3:17])[C:8](=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[OH:19][C:20]1[C:25]2[N:26]=[C:27]([NH:29][C:30](=[O:32])[CH3:31])[S:28][C:24]=2[CH:23]=[CH:22][CH:21]=1>>[C:30]([NH:29][C:27]1[S:28][C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([O:19][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]([CH:16]([CH3:18])[CH3:17])[C:8](=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:25]=2[N:26]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)Nc1nc2c(O)cccc2s1
Reactant: CCCCCCC(=O)N(CCCCCBr)C(C)C
Product: CCCCCCC(=O)N(CCCCCOc1cccc2sc(NC(C)=O)nc12)C(C)C
Yield: 41.8 %

Procedure:
N-(5-Bromopentyl)-N-isopropylheptanamide (75 mg, 0.23 mmol) was alkylated with commercial N-(4-hydroxybenzo[d]thiazol-2-yl)acetamide (54 mg, 0.26 mmol) as described above to give analog 30 (43 mg, 42%) as a sticky solid. TLC: EtOAc/hexanes (1:4), Rf˜0.30; 1H NMR (300 MHz, 45/55 mixture of rotamers) δ 11.50 (br s, —NH, 1H), 7.37-7.42 (m, 1H), 7.18-7.26 (m, 1H), 6.84-6.88 (m, 1H), 4.58-4.78 and 4.00-4.10 (m, 1H for two rotamers), 4.02 (t, J=6.3 Hz, 2H), 3.12 (t, J=7.3 Hz, 2H), 2.22-2.45 (m, 5H), 1.82-1.92 (m, 2H), 1.44-1.70 (m, 4H), 1.20-1.40 (m, 8H), 1.11-1.19 (m, 6H), 0.82-0.95 (m, 3H); 13C NMR (75 MHz) δ 173.94, 172.78, 169.40, 169.36, 157.89, 151.62, 138.43, 138.32, 133.91, 133.87, 124.92, 124.85, 114.02, 113.87, 109.66, 108.35, 69.46, 69.08, 48.53, 48.33, 45.94, 43.61, 41.20, 34.26, 34.09, 31.91, 31.88, 31.39, 29.55, 29.45, 29.37, 29.30, 25.88, 25.77, 25.71, 24.43, 24.16, 23.55, 22.77, 21.59, 20.80, 14.28. HRMS (ESI-neg) calcd for C24H36N3O3S [M−1]− 446.2477. found 446.2434.
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[CH:15]=[CH:14][C:8]2[NH:9][C:10](=[O:13])[CH2:11][S:12][C:7]=2[CH:6]=1.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([CH:25]=O)=[CH:17]1.O>CN(C=O)C>[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([CH:25]=[C:11]2[C:10](=[O:13])[NH:9][C:8]3[CH:14]=[CH:15][C:5]([CH3:4])=[CH:6][C:7]=3[S:12]2)=[CH:17]1
Reactant: Cc1ccc2c(c1)SCC(=O)N2
Reactant: O=Cc1c[nH]c2ccccc12
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)SC(=Cc1c[nH]c3ccccc13)C(=O)N2
Temperature: 140 °C

Procedure:
Sodium methoxide (0.28 g, 5.2 mmol) was added in one portion to a solution of 7-methyl-2H-1,4-benzothiazin-3(4H)-one (0.72 g, 4.0 mmol) and indole-3-carboxaldehyde (0.88 g, 6.0 mmol) in dry DMF (4 mL). The mixture was heated for 48 h at 140° C., allowed to cool, then poured into water (60 ml). The precipitate was collected by filtration and washed with water. The precipitate was then refluxed with toluene (100 ml) and filtered hot to give a yellow solid which was purified by silica gel chromatography using a gradient of (100:1) to (100:20) toluene:ethanol as the mobile phase.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14][CH:15]2[C:18]([N:20]([CH2:29][CH2:30][CH3:31])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=O)=[CH:11][CH:10]=1>CCOCC>[CH3:7][O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14][CH:15]2[CH2:18][N:20]([CH2:29][CH2:30][CH3:31])[CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:11][CH:10]=1
Reactant: CCCN(CCc1ccccc1)C(=O)C1CCc2ccc(OC)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCCN(CCc1ccccc1)CC1CCc2ccc(OC)cc21
Reaction time: 5 h

Procedure:
To a suspension of 1 g of lithium aluminum hydride in 15 milliliters of anhydrous ether was added a solution of 5 g of the residue of 6-methoxy-N-propyl-N-(2-phenylethyl)-1-indanamide in 15 milliliters of anhydrous ether at a rate which maintained gentle reflux of the reaction mixture. Reflux and stirring were continued for 5 hours. The reaction mixture was then stirred overnight without heating. Destruction of the excess lithium aluminium hydride was completed by cautious dropwise addition of 1 milliliter of water followed by dropwise addition of 1 milliliter of 14% sodium hydroxide solution and subsequent addition of 5 milliliters of water. Stirring was continued for 30 minutes. Filtration yielded a clear ether solution which was dried (MgSO4) and evaporated, yielding 4 grams of an oil, which was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8](=[O:10])[CH3:9])[C:5](O)=[O:6].C(Cl)(=O)C([Cl:14])=O>CN(C)C=O.C(OCC)C>[CH3:1][O:2][N:3]=[C:4]([C:8](=[O:10])[CH3:9])[C:5]([Cl:14])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CON=C(C(C)=O)C(=O)O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CON=C(C(C)=O)C(=O)Cl
Temperature: 20 °C
Reaction time: 1 h

Procedure:
Dimethylformamide (2 drops) is added to a solution, at 20° C., of 2-methoxyimino-3-oxo-butyric acid, syn isomer (4.08 g) in diethyl ether (50 cc), after which oxalyl chloride (2 cc) dissolved in diethyl ether (5 cc) is added dropwise in the course of 15 minutes. The mixture is stirred for 1 hour at 20° C., dimethylformamide (1 drop) is added again and the reaction is continued for 15 minutes. The mixture is concentrated to dryness at 20° C. under 20 mm Hg (2.7 kPa) and the residue is taken up in petroleum ether (2×30 cc), the solvent being evaporated each time at 20° C. under 20 mm Hg (2.7 kPa). The 2-methoxyimino-3-oxo-butanoyl chloride, syn isomer, thus obtained is dissolved in methylene chloride (50 cc) and a 5.4 N solution of hydrogen chloride in ether (0.2 cc), and bromine (1.14 cc), are added to this solution at 20° C. The mixture is stirred for 20 hours at 20° C. and then concentrated to dryness at 20° C. under 20 mm Hg (2.7 kPa), and a brown oil (5.42 g) consisting principally of 4-bromo-2-methoxyimino-3-oxo-butyryl chloride, syn isomer, is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH:33][O:34][CH3:35])=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:32][N:33]([O:34][CH3:35])[C:22]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:20])[CH3:21])=[O:23])=[CH:30][CH:31]=1
Reactant: CONCc1ccc(F)cc1
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Product: CON(Cc1ccc(F)cc1)C(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and (4-fluorophenyl)-N-methoxymethanamine. White crystals; mp 141° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.66 (6H, s, 2×CH3), 3.59 (3H, s, OCH3), 4.07 (4H, m, 2×CH2), 4.90 (2H, s, NCH2), 5.20 (2H, s, OCH2), 6.81 (2H, m, aromatics), 7.26-7.30 (3H, m, aromatics), 7.36 (2H, m, aromatics), 7.44 (2H, m, aromatics). HRMS (ESI+) calculated for C25H27FN3O5 [M+H+]: 468.1935: found: 468.1916.
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:23]=1[C:24](Cl)=[O:25]>ClCCl>[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:23]=1[C:24]([N:6]1[CH:7]=[C:2]([F:1])[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]1=[O:8])=[O:25]
Reactant: CN(C)C=Nc1nc(O)ncc1F
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C=Nc1nc(=O)n(C(=O)c2c(Cl)cccc2Cl)cc1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To an 8 mL screw-cap vial were added dichloromethane (CH2Cl2; 4 mL), N′-(5-fluoro-2-hydroxy-pyrimidin-4-yl)-N,N-dimethylformamidine (100 mg, 0.54 mmol), and triethylamine (Et3N; 120 mg, 1.2 mmol). To this mixture was added 2,6-dichlorobenzoyl chloride (113 mg, 0.54 mmol), and the resulting mixture was shaken at room temperature for 24 h. After evaporation to dryness, the residue was taken up in N,N-dimethylformamide (DMF; 2 mL), filtered, and placed directly onto a reverse phase chromatography column. After elution, the title compound was isolated as a pale yellow solid (75 mg, 39%): mp 185-187° C.; 1H NMR (300 MHz, CDCl3) δ 8.80 (s, 1H), 8.20 (d, J=5.6 Hz, 1H), 7.31-7.20 (m, 3H), 3.23 (s, 3H), 3.21 (s, 3H); ESIMS m/z 357 ([M+H]+).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([NH2:10])=[O:9].[CH3:12][O:13]C(OC)N(C)C>C(O)(=O)C>[CH:12]([NH:10][C:8](=[O:9])[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:11])=[O:13]
Reactant: Cc1ccccc1CC(N)=O
Reactant: COC(OC)N(C)C
Solvent: CC(=O)O
Product: Cc1ccccc1CC(=O)NC=O
Temperature: 120 °C
Reaction time: 0.92 h

Procedure:
A mixture of 2-o-tolylacetamide (Lee, Dong-Ung; Mayer, Klaus K.; Wiegrebe, Wolfgang; Lauber, Rolf; Schlunegger, Urs P.; Arch. Pharm. 1988, 321; 265-272) (320 mg, 2.15 mmol) and N,N,-dimethylformamide dimethylacetal (1.1 mL, 8.59 mmol) was stirred under N2 for 55 min at 120° C. The excess of N,N,-dimethylformamide dimethylacetal was eliminated under reduced pressure. The residue was dissolved in 3 mL of 70% aqueous acetic acid and stirred at 0° C. for 30 min. The precipitate was filtered, washed with water and dried to afford the title compound as a white solid. MS (DCI/NH3) m/z 195 (M+NH4)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:10]1[CH2:12][CH2:11]1)[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH:10]1[CH2:11][CH2:12]1)[NH:9][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N(N)C1CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N(Nc1ccccc1)C1CC1
Temperature: 50 °C
Yield: 45.3 %

Procedure:
A mixture of N-cyclopropyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 28; 0.111 g, 0.64 mmol), phenylboronic acid (Aldrich; 156 mg, 1.3 mmol), copper(II) acetate (116 mg, 0.64 mmol) and triethylamine (180 μL, 1.3 mmol) in 1,2-dichloroethane (3 mL) was heated in an oil bath at 50° C. for 16 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 5-40% ethyl acetate/hexanes, to give N-cyclopropyl-N′-phenyl-hydrazinecarboxylic acid tert-butyl ester (72 mg, 45%) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4]([CH3:10])([CH3:9])[CH:3]2[NH:11][CH2:12][C:13]([N:15]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>ClC1C=CC=CC=1>[CH3:1][C:2]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4]([CH3:10])([CH3:9])[CH:3]2[NH:11][CH2:12][C:13]([N:15]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[S:37]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC12CCC(C1)C(C)(C)C2NCC(=O)N(c1ccccc1)C1CCCCC1
Solvent: Clc1ccccc1
Product: CC12CCC(C1)C(C)(C)C2NCC(=S)N(c1ccccc1)C1CCCCC1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-[(1,3,3-trimethylbicyclo[2.2.1]hept-2-yl)amino]-N-cyclohexyl-N-phenylacetamide (110 mg, 0.272 mmol) in chlorobenzene (3 mL) was added Lawesson's reagent (70 mg, 0.17 mmol). The solution was stirred at 120° C. for 2 hours. The solvent was removed under reduced pressure, and the residue purified on preparatory plate using 15% ethyl acetate/hexanes to furnish 2-[(1,3,3-trimethylbicyclo[2.2.1]hept-2-yl)amino]-N-cyclohexyl-N-phenylthioacetamide as a yellow solid. (M+1)=385.0].
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C1COCC1>[O:16]1[CH2:17][CH2:18][N:13]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=2)[CH2:14][CH2:15]1
Reactant: N#Cc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: N#Cc1ccc(N2CCOCC2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a stirred solution of 4-chloro-2-nitrobenzonitrile (2.0 g, 11 mmol) in THF (40 mL) was added morpholine (1.0 g, 11 mmol). The reaction was heated at reflux overnight. After this time the reaction was cooled to rt and then it was partitioned between EtOAc (150 mL) and NaHCO3 (50 mL, satd aq. solution). The separated organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo. Column chromatography (hexanes:EtOAc, 1:0 to 1:1) gave 4-morpholino-2-nitrobenzonitrile.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])C(O)=O)=[CH:4][CH:3]=1.C(=O)=O>O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:12])=[CH:4][CH:3]=1
Reactant: O=C(O)C(O)c1ccc(O)cc1
Agent: O=C=O
Solvent: O
Product: O=Cc1ccc(O)cc1
Reaction time: 0.5 h

Procedure:
9.3 g of 4-hydroxyphenylglycolic acid in the form of the monohydrate (molecular weight 186) are dissolved in 50 g of water, and 82 g of an aqueous 20% FeCl3 solution are added over a period of 20 to 30 minutes at 75° to 80° C., initiating a vigorous evolution of carbon dioxide which stops after another 30 minutes at 100° C. The reaction takes place at a pH-value of from 2 to 0.8. Most of the 4-hydroxybenzaldehyde formed crystallises out of the acid oxidation solution on cooling to 0° C. and is filtered off under suction. The residual 4-hydroxy benzaldehyde is removed from the cold aqueous mother liquor by repeated extraction with benzene. Most of the p-hydroxybenzaldehyde is added to the benzene solution thus obtained, most of the benzene evaporated off and pure 4-hydroxybenzaldehyde precipitated in crystalline form either with light petrol or with cyclohexane.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([NH:11][C:12](=[O:14])[CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[O-]CC.[Na+].Br[CH:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22]>C(O)C>[CH2:9]([O:8][C:6](=[O:7])[C:5]([NH:11][C:12](=[O:14])[CH3:13])([CH:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH3:10]
Reactant: CC(Br)c1cccc2ccccc12
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(NC(C)=O)(C(=O)OCC)C(C)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-Acetylaminopropanedioic acid diethyl ester (20.8 g) was added to a solution of sodium ethoxide in ethanol (prepared from sodium (2.2 g) and ethanol (100 ml)). After the mixture was stirred for 10 minutes at ambient temperature, 1-(1-bromoethyl)naphthalene was added. The reaction mixture was stirred for 18 hours at room temperature. The precipitated solid was collected by filtration and dissolved in chloroform. The chloroform solution was dried over magnesium sulfate and evaporated to give 2-acetylamino-2-[1-(1-naphthyl)ethyl]propanedioic acid diethyl ester (21.59 g).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].CN1CCCC1=O.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][SH:30])=[CH:27][CH:26]=1.[H-].[Na+]>O>[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][S:30][C:2]2[CH:3]=[C:4]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])=[CH:27][CH:26]=1
Reactant: COc1ccc(CS)cc1
Reactant: COC(=O)Cc1ccc([N+](=O)[O-])c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)Cc1ccc([N+](=O)[O-])c(SCc2ccc(OC)cc2)c1

Procedure:
A mixture of methyl 3-fluoro4-nitrophenylacetate(1.05 g), N-methylpyrrolidinone(10 mL) and 4-methoxybenzyl mercaptan was stirred under argon and treated with sodium hydride(0.22 g of a 60% dispersion in mineral oil) and the resulting mixture was stirred at ambient temperature for 0.5 h. Water was added and the mixture was extracted with ether, and the extract was washed with brine, dried and evaporated to dryness. The residue was purified by flash chromatography eluting with increasingly polar mixtures of ethyl acetate and hexane to give the product (1.35 g), [m/e365, (M+NH4)+].
Reaction SMILES: [F:1][C:2]1[C:3]([N:14]2[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15]2)=[C:4]([C:7]([F:13])=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH2:5][OH:6].[C:20](OC(=O)C)(=[O:22])[CH3:21]>O>[C:20]([NH:19][CH:16]1[CH2:17][CH2:18][N:14]([C:3]2[C:2]([F:1])=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[C:7]([F:13])[C:4]=2[CH2:5][OH:6])[CH2:15]1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: NC1CCN(c2c(F)cc([N+](=O)[O-])c(F)c2CO)C1
Solvent: O
Product: CC(=O)NC1CCN(c2c(F)cc([N+](=O)[O-])c(F)c2CO)C1
Reaction time: 0.17 h

Procedure:
To 3,6-difluoro-2-(3-amino-1-pyrrolidinyl)-5-nitrobenzyl alcohol (43 mg) is added acetic anhydride (0.5 ml) at room temperature. The mixture is stirred at the same temperature for 10 minutes, and the reaction mixture is diluted with water and extracted with dichloromethane. The organic layer is washed with water and aqueous saturated sodium chloride in this order and dried over anhydrous magnesium sulfate, and then solvent is distilled off. The resulting residue is purified by silica gel column chromatography (solvent, dichloromethane→methanol:dichloromethane=1:12) and then recrystallized from dichloromethane to give 2-(3-acetylamino-1-pyrrolidinyl)-3,6-difluoro-5-nitrobenzyl alcohol (40 mg), as yellow prisms, m.p. 142.5°-143.5° C.