Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([N+:30]([O-])=O)[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]=[N:16][N:17]([CH2:19][CH2:20][N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[CH:18]=3)[S:13][C:6]=12.[Cl-].[NH4+]>CO.O.[Zn]>[F:1][C:2]1[CH:29]=[C:28]([CH:27]=[CH:26][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]=[N:16][N:17]([CH2:19][CH2:20][N:21]4[CH2:22][CH2:23][CH2:24][CH2:25]4)[CH:18]=3)[S:13][C:6]=12)[NH2:30]
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4cn(CCN5CCCC5)nn4)sc23)c(F)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: Nc1ccc(Oc2ccnc3cc(-c4cn(CCN5CCCC5)nn4)sc23)c(F)c1
Temperature: 25 °C
Yield: 70.2 %

Procedure:
To a solution of 360 (150 mg, 0.329 mmol) in MeOH (10 mL) was added ammonium chloride (35.3 mg, 2 eq, 0.660 mmol) in water (1 mL) and zinc powder (86 mg, 4 eq, 1.320 mmol) and the reaction mixture was heated to reflux for 3 hours. The mixture was cooled to RT then filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM and washed with water. The organic phase was collected, dried over anhydrous Na2SO4, filtered and concentrated to afford the title compound 361 (98 mg, 70% yield) that was used in the next step with no additional purification. MS (m/z): 425.5 (M+H)
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22][CH3:23])=[O:21]>CN(C=O)C>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:2]2[O:1][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:4][C:3]=2[CH:6]=1
Reactant: COc1ccc(O)c(C=O)c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc(OC)ccc2o1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-Hydroxy-5-methoxy-benzaldehyde (10 g, 65.8 mmol) was stirred in DMF (90 mL) with potassium carbonate (23 g, 0.17 mol) under nitrogen, then methyl bromoacetate was added dropwise. The mixture was stirred at room temperature for 4 h. The reaction was then heated to 80° C. for 18 h. The reaction was allowed to cool then poured onto ice water (200 mL) and the resulting brown suspension was allowed to stir for 30 min. After this time the solid was collected by filtration and washed with water. The solid was dried to afford (5.22 g, 39%), which was taken through to the next step with no further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:14]2[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][N:10]([CH3:20])[CH2:9]1.[N+:21]([O-])([OH:23])=[O:22]>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:14]2[CH:15]=[C:16]([OH:19])[C:17]([N+:21]([O-:23])=[O:22])=[CH:18][C:13]=2[CH2:12][CH2:11][N:10]([CH3:20])[CH2:9]1
Reactant: O=[N+]([O-])O
Reactant: CN1CCc2ccc(O)cc2C(c2ccccc2F)C1
Solvent: CC(=O)O
Product: CN1CCc2cc([N+](=O)[O-])c(O)cc2C(c2ccccc2F)C1
Temperature: 0 °C

Procedure:
5.0 g 5-(2-fluorophenyl)-7-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine was dissolved in 90 ml of a mixture of acetic acid and cooled in ice-water bath 0° C. Under stirring was added 1,7 ml fuming nitric acid and the mixture was stirred in the cold for 1 h. The reaction mixture was neutralized (pH 7.9) and the precipitate was extracted with ethyl acetate, dried and evaporated. After column chromatography (kieselgel/CH2Cl2 : CH3OH 95: 5) was isolated yellow crystals. M.p. 90°-94° C. (dec). NMR: C5H 4.61d; C6H g 41% 6 s and C9H 7.88 s ppm. respectively.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH:5]=[N:6][CH:7]=1
Reactant: CN(C)C(=O)CCl
Reactant: OCc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C(=O)COCc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
To a solution of (5-Bromo-pyridin-3-yl)-methanol (600 mg, 3.2 mmol) in THF (50 mL) is added 60% NaH (160 mg, 3.9 mmol) at 0° C. under N2 atmosphere. The mixture is stirred at room temperature for 1 hour. Then 2-chloro-N,N-dimethyl-acetamide (420 mg, 3.5 mmol) is added into the mixture at 0° C. After addition, the mixture is stirred at room temperature for 16 hrs. After quenching with saturated NH4Cl aqueous solution, the mixture is extracted with EtOAc for three times. The organic layers are combined, dried over Na2SO4, filtered and concentrated. The crude product is purified by preparative TLC to give 700 mg of 2-(5-bromo-pyridin-3-ylmethoxy)-N,N-dimethyl-acetamide.
Reaction SMILES: [Cl:1][CH2:2][C@@H:3]([OH:21])[CH2:4][C@@H:5]([OH:20])[CH2:6][C:7]([O:9][C:10]([CH3:19])([CH3:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8].CO[C:24](OC)([CH3:26])[CH3:25].CS(O)(=O)=O>CC(C)=O.C(OCC)(=O)C>[Cl:1][CH2:2][C@H:3]1[O:21][C:24]([CH3:26])([CH3:25])[O:20][C@@H:5]([CH2:6][C:7]([O:9][C:10]([CH3:18])([CH3:19])[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:8])[CH2:4]1
Reactant: CC(C)(Cc1ccccc1)OC(=O)C[C@H](O)C[C@H](O)CCl
Reactant: COC(C)(C)OC
Agent: CS(=O)(=O)O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(Cc1ccccc1)OC(=O)C[C@H]1C[C@@H](CCl)OC(C)(C)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The crude compound (3R,5S)-2-methyl-1-phenylpropan-2-yl 6-chloro-3,5-dihydroxy-hexanoate (21.1 g) prepared in Example 3 was dissolved in acetone (210 ml), and 2,2-dimethoxypropane (65.6 ml) and methanesulfonic acid (0.2 ml) were added dropwise thereto, followed by stirring at room temperature for 2 hours. The reaction liquid was diluted with ethyl acetate (320 ml) and washed successively with a saturated sodium bicarbonate aqueous solution (320 ml), a saturated sodium chloride aqueous solution (320 ml) and purified water (320 ml). The separated organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give the crude title compound (23.7 g).
Reaction SMILES: C([SiH](CC)CC)C.O[CH:9]([C:20]1[S:34][C:23]2[C:24]([CH2:30][CH:31]([CH3:33])[CH3:32])=[N:25][N:26]([CH3:29])[C:27](=[O:28])[C:22]=2[CH:21]=1)[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:29][N:26]1[C:27](=[O:28])[C:22]2[CH:21]=[C:20]([CH2:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[CH:12][CH:11]=3)[S:34][C:23]=2[C:24]([CH2:30][CH:31]([CH3:33])[CH3:32])=[N:25]1
Reactant: CC(C)Cc1nn(C)c(=O)c2cc(C(O)c3cccc4ccccc34)sc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Cc1nn(C)c(=O)c2cc(Cc3cccc4ccccc34)sc12
Reaction time: 0.5 h
Yield: 87 %

Procedure:
Triethylsilane (0.3 ml) was added to a solution of 2-[1-hydroxy-1-(1-naphthalenyl)methyl]-5-methyl-7-(2-methylpropyl)thieno[2,3-d]pyridazin-4(5H)-one (0.3 g) prepared as described in Example 6 above and trifluoroacetic acid (2 ml) in dichloromethane (10 ml). After 30 minutes, the reaction mixture was evaporated and the residue remaining was dissolved in ethyl acetate. The ethyl acetate solution was washed twice with saturated sodium hydrogen carbonate solution and once with brine, and then dried and evaporated. Purification by chromatography eluting with iso-hexane/ethyl acetate (4:1 to 2:1), and subsequent HPLC eluting with isohexane:ethyl acetate (2:1) gave the title compound (0.25 g).
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:27])[C:5]([CH3:26])([CH3:25])[CH2:6][O:7][C:8](=[O:24])[C@@H:9]([CH:21]([CH3:23])[CH3:22])[NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].[I-:28].[Na+]>C(#N)C>[I:28][CH2:2][O:3][C:4](=[O:27])[C:5]([CH3:26])([CH3:25])[CH2:6][O:7][C:8](=[O:24])[C@@H:9]([CH:21]([CH3:23])[CH3:22])[NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: CC(C)[C@@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)C(=O)OCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)[C@@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)C(=O)OCI

Procedure:
2,2-Dimethyl-3-(N-CBz-D-valyloxy)-propionic acid chloromethyl ester (2.4 g, 6 mmole) was dissolved in acetonitrile (30 ml). Sodium iodide (1.26 g, 8.4 mmole) was added to the solution. After reaction at 70° C. for 2 hr, the reaction mixture was filtered and the residue was dissolved in methylene chloride (20 ml) and refiltered. The solution was dried and gave the titled product. 2.68 g.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26]>CC(C)=O>[Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26])=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C(C)Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1

Procedure:
The above phenol (1.3 g, 5.08 mm), K2CO3 (1.05 g), methyl α-bromopropionate (0.85 ml, 1.5 eq) and acetone (20 ml) is refluxed for 8 hours. The mixture is then filtered and the filtrate concentrated to give oily methyl 2-[4-(3,5-dichloro-2-pyridyloxy)phenoxy]propionate.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[CH:8][C:9]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:3])[CH3:2].C(Cl)(Cl)[Cl:15].N1C=CC=CC=1.ClCl>C(Cl)(Cl)(Cl)Cl>[C:1]([NH:4][C:5]1[S:6][C:7]([Cl:15])=[CH:8][C:9]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:3])[CH3:2]
Reactant: ClC(Cl)Cl
Reactant: COC(=O)c1ccsc1NC(C)=O
Agent: ClCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1cc(Cl)sc1NC(C)=O
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4 parts of methyl 2-acetamidothiophene-3-carboxylate in a mixture of 80 parts by volume of chloroform and 12 parts by volume of pyridine, 20 parts by volume of a 10% (W/V) solution of chlorine in carbon tetrachloride is added dropwise. After stirring for further 30 minutes, the mixture is washed with an aqueous sodium bicarbonate solution and, then, with water. Evaporation of the solvent, and recrystallization of the residue from methanol gives methyl 2-acetamido-5-chlorothiophene-3-carboxylate as crystals. Colorless needles, melting point: 110°-110.5° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]([N+:14]([O-:16])=[O:15])[N:7]=1.Cl[CH2:18][S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20].[K]>C1COCC1.CN(C=O)C>[C:22]1([S:19]([CH2:18][C:9]2[C:8]([N+:14]([O-:16])=[O:15])=[N:7][C:6]([CH:2]3[O:3][CH2:4][CH2:5][O:1]3)=[C:11]([O:12][CH3:13])[CH:10]=2)(=[O:21])=[O:20])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=S(=O)(CCl)c1ccccc1
Reactant: COc1ccc([N+](=O)[O-])nc1C1OCCO1
Agent: [K]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc(CS(=O)(=O)c2ccccc2)c([N+](=O)[O-])nc1C1OCCO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.3 %

Procedure:
A mixture of 0.6 g (2.6 mmol) 2-[1,3]dioxolan-2-yl-3-methoxy-6-nitro-pyridine, 0.55 g (2.9 mmol) of chloromethylphenylsulfone and 2.9 ml (2.9 mmol) of potassium t-butoxode (1M solution in THF) in 5 ml of DMF were combined at 5° C. and stirred at ambient temperature for 18 hours. The reaction mixture was quenched with 25 ml of water and extracted with ethyl acetate. The ethyl acetate extracts were combined, dried (Na2SO4), and evaporated. The residue was chromatographed on silica using 5:1 chloroform/ethyl acetate as the elutant. Appropriate fractions were combined and evaporated to yield 0.28 g of 3-benzenesulfonylmethyl-6-[1,3]dioxolan-2-yl-5-methoxy-2-nitro-pyridine as an oil. TLC: Rf=0.4 (1:1 chloroform/ethyl acetate). 1H NMR (CDCl3) δ 7.7 (m, 3H), 7.55 (m, 2H), 7.42 (s, 1H), 6.30 (s, 1H), 4.90 (s, 2H), 4.30 (m, 2H), 4.10 (m, 2H), 4.02 (s, 3H).). Mass Spectrum: m/e=381.0 (p+1).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:13].C[C:15]([O:17][C:18](C)=O)=O.C(OC)(OC)OC>CN(C)C=O>[CH3:1][N:2]1[C:11](=[O:12])/[C:10](=[CH:15]/[O:17][CH3:18])/[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:13]
Reactant: CN1C(=O)Cc2ccccc2C1=O
Reactant: CC(=O)OC(C)=O
Solvent: COC(OC)OC
Solvent: CN(C)C=O
Product: CO/C=C1/C(=O)N(C)C(=O)c2ccccc21
Temperature: 125 °C

Procedure:
To a stirred mixture of 0.35 g (2.0 mmol) of (N-methyl)isoquinoline-1,3(2H,4H)-dione, 3.2 ml of Ac2O, and 0.80 ml of N,N-dimethylformamide is added 0.44 ml (4.0 mmol) of (MeO)3CH at 25° C. The mixture is stirred at 125° C. for 30 m, cooled, and concentrated under high vacuum. The residue is recrystallized from Et2O-hexane to give 0.20 g of tan solid, mp 145-150° C. (dec); MS (ES+) m/z 218.2 (M+H)+1: Analysis for C12H11NO3: Calcd: C, 66.35; H, 5.10; N, 6.45. Found: C, 65.98; H, 4.99; N, 6.42.
Reaction SMILES: C([O:4][C@H:5]([CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[N:24]=[C:25]([C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)[O:26][C:27]=2[CH3:28])=[C:17]([O:34][CH3:35])[CH:16]=1)[C:6]([O:8][CH:9](C)C)=[O:7])(=O)C.O>Cl>[O:30]1[CH:31]=[CH:32][CH:33]=[C:29]1[C:25]1[O:26][C:27]([CH3:28])=[C:23]([CH2:22][O:21][C:18]2[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][CH2:12][C@@H:5]([OH:4])[C:6]([O:8][CH3:9])=[O:7])=[CH:16][C:17]=2[O:34][CH3:35])[N:24]=1
Reactant: COc1cc(CCC[C@@H](OC(C)=O)C(=O)OC(C)C)ccc1OCc1nc(-c2ccco2)oc1C
Agent: Cl
Solvent: O
Product: COC(=O)[C@H](O)CCCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 76.8 %

Procedure:
Isopropyl (R)-(+)-2-acetoxy-5-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxyphenyl]pentanoate (4.87 g) was dissolved in methanolic HCl (5%, 100 ml), which was stirred for 12 hours at room temperature. The solution was poured into water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The residue was subjected to column chromatography on silica gel. From the fraction eluted with ethyl acetate-hexane (1:1), was obtained methyl (R)-(-)-5-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxyphenyl]-2-hydroxypentanoate (3.2 g, 77%), which was recrystallized from ethyl acetate-isopropyl ether to give colorless prisms, m.p.83-84° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.I[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18]>>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COc1ccccc1I
Reactant: c1ccc2[nH]ccc2c1
Product: COc1ccccc1-n1ccc2ccccc21
Yield: 99.9 %

Procedure:
Using general procedure A, indole (146 mg, 1.25 mmol)) was coupled with 2-iodoanisole (135 μL, 1.04 mmol). The crude product was purified by flash chromatography on silica gel (2×15 cm; hexane-ether 15:1; 15 mL fractions). Fractions 6-10 provided 232 mg (100% yield) of the product as a colorless oil. The 1H NMR spectrum was in accord with that reported by Maiorana et al. Maiorana, S.; Baldoli, C.; Del Buttero, P.; Di Ciolo, M.; Papagni, A. Synthesis 1998, 735.
Reaction SMILES: Cl.[F:2][CH2:3][CH2:4][NH2:5].[CH:6]1[CH:11]=[CH:10][C:9]([O:12][C:13](OC2C=CC=CC=2)=[N:14][C:15]#[N:16])=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C>CC#N>[F:2][CH2:3][CH2:4][NH:5][C:13](=[N:14][C:15]#[N:16])[O:12][C:9]1[CH:10]=[CH:11][CH:6]=[CH:7][CH:8]=1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: NCCF
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#CN=C(NCCF)Oc1ccccc1
Reaction time: 14 h

Procedure:
Fluoroethyl amine hydrochloride (5.50 g, 90% purity, 49.75 mmol) was added to a solution of diphenyl cyanocarbonimidate (11.84 g, 49.70 mmol) in CH3CN, followed by addition of diisopropylethyl amine (17.30 mL, 99.32 mmol). After stirring for 14 hours, the reaction mixture was concentrated and the residue was taken up in EtOAc. The organic layer was washed sequentially with H2O (3×75 mL) and aq 2N KOH (3×100 mL), then concentrated to give a viscous oil, which was solidified upon standing at room temperature. Recrystallization from ether gave the desired 1-(2-fluoro-ethyl)-2-phenyl-3-cyanoisourea intermediate. A portion of this intermediate was mixed with an appropriate amine in CH3CN. The resulting reaction mixture was refluxed for 14 hours. After cooling to room temperature, the mixture was diluted with EtOAc and the resulting organic phase was washed with H2O (3×75 mL) and then concentrated. The residue was purified by column chromatography using hex:EtOAc (2:3) as eluant to give a semi-pure product. Recrystallization from EtOAc afforded the final pure cyanoguanidine.
Reaction SMILES: [CH:1](OCC)(OCC)OCC.[NH2:11][C:12]1[CH:13]=[N:14][C:15]2[C:20]([C:21]=1[NH:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:19][CH:18]=[CH:17][CH:16]=2>C1(C)C=CC=CC=1>[N:22]1([CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:11]=[CH:1]1
Reactant: CC(C)(C)OC(=O)NCCNc1c(N)cnc2ccccc12
Reactant: CCOC(OCC)OCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCn1cnc2cnc3ccccc3c21
Temperature: 25 °C
Yield: 81.2 %

Procedure:
Triethyl orthoformate (11.3 g, 73.4 mmol) was added to a solution of tert-butyl N-[2-(3-aminoquinolin-4-yl)aminoethyl]carbamate (21 g, 69.4 mmol) in anhydrous toluene (250 mL). The reaction mixture was heated at reflux for 5 hours and then allowed to slowly cool to ambient temperature. The resulting precipitate was isolated by filtration and dried to provide 17.6 g of tert-butyl N-[2-(1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate as a light tan solid, m.p. 154-155° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[OH-].[K+].I[CH2:19][CH2:20][CH3:21]>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCI
Reactant: c1ccc(CNCc2ccccn2)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCN(Cc1ccccn1)Cc1ccccn1
Reaction time: 1 h
Yield: 53.7 %

Procedure:
To a flask were added 1.0 g di-(2-picolyl)amine, 0.85 g of pulverized potassium hydroxide and 15 ml of N,N-dimethylformamide. After stirring for 1 hour under nitrogen, the mixture was cooled to 5 C and 1.7 g of 1-iodopropane were added. The mixture was heated to 35 C and stirred for 16 hours. After quenching with 30 ml water, the product was extracted with ethyl acetate and washed twice with water. Following removal of solvent, the product was purified by silica gel chromatography using ethyl acetate to give 0.65 g of a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[C@@H:7]1[CH2:11][C@@H:10]([N:12]=[N+]=[N-])[CH2:9][N:8]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:22])[C@@H:7]1[CH2:11][C@@H:10]([NH2:12])[CH2:9][N:8]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)[C@@H]1C[C@@H](N)CN1C(=O)OC(C)(C)C

Procedure:
A solution (4R)-1-(tert-butyloxycarbonyl)-4-azido-L-proline tert-butyl ester (191 mg, 0.611 mmol) in 90% ethanol (15 mL) was hydrogenated in the presence of 10% palladium-on-charcoal (40 mg) under a balloon atmosphere of hydrogen gas for one hour. The catalyst was removed by filtration through Celite, the filter washed with methanol, and the combined filtrate and washings evaporated. The title compound was obtained as a colorless oil after drying under high vacuum; yield 177 mg.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[CH:20](=O)[CH:21]=[O:22]>C1COCC1>[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]/[N:10]=[CH:20]/[CH:21]=[O:22])=[CH:5][CH:4]=1
Reactant: NNc1ccc(F)cc1
Reactant: O=CC=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C/C=N/Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
A solution of 4-fluorophenylhydrazine hydrochloride (1 g, 6 mmol) in THF (20 mL) is treated with DIPEA (3 mL, 18 mmol). Then oxalaldehyde (40% in water, 0.89 g, 6.0 mmol) in THF (10 mL) is added dropwise in an ice-bath. After the addition, the mixture is stirred at RT for 30 min, quenched with water, and extracted with EtOAc. The organic phase is washed with saturated aqueous sodium chloride, dried over Na2SO4 and concentrated to afford the crude title compound (0.97 g, 97% yield). MS (m/z): 167 (M+H).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:14]=[C:15]([CH:28]=[CH:29][CH:30]=2)[O:16][CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)=[CH:4]1.Br[CH2:32][C:33]([O:35]CC)=[O:34]>CN(C=O)C>[N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[CH:27][C:18]=1[CH2:17][O:16][C:15]1[CH:14]=[C:13]([CH:30]=[CH:29][CH:28]=1)[CH2:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:3]([CH2:32][C:33]([OH:35])=[O:34])[CH:4]=1
Reactant: c1cc(Cc2c[nH]c3ccccc23)cc(OCc2ccc3ccccc3n2)c1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)Cn1cc(Cc2cccc(OCc3ccc4ccccc4n3)c2)c2ccccc21
Reaction time: 2 h

Procedure:
Sodium hydride (60%, 22 mg, 0.55 mmol) is added to a solution of 2-[3-(1H-indol-3-ylmethyl)-phenoxymethyl]-quinoline (90 mg, 0.25 mmol, example 90) in DMF (2.5 mL). After stirring 5 minutes ethyl bromoacetate (0.1 mL, 0.9 mmol) is added and the reaction is allowed to stir 2 h. The reaction is partitioned between ethyl acetate and ammonium chloride and the organic phase is washed with water. The organic phase is dried over magnesium sulfate, concentrated and then the solid is titurated with ethyl ether and ethyl acetate to provide the title compound as a solid. m.p. 151–159° C.; 1H NMR (300 MHz, CDCl3) δ 8.20 (t, 2H), 7.83–7.80 (m, 1H), 7.77–7.71 (m, 1H), 7.67 (d, 1H), 7.61–7.53 (m, 1H), 7.45–7.42 (m, 1H), 7.29–7.14 (m, 3H), 7.05–6.99 (m, 2H), 6.94 (s, 1H), 6.85 (m, 2H), 5.16 (s, 2H), 4.84(s, 2H), 4.11 (s, 2H); MS (ESI) 423 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[N:20]1([CH2:25][C:26]2([OH:31])[CH2:30][CH2:29][NH:28][CH2:27]2)[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:28]4[CH2:29][CH2:30][C:26]([CH2:25][N:20]5[CH2:24][CH2:23][CH2:22][CH2:21]5)([OH:31])[CH2:27]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: OC1(CN2CCCC2)CCNC1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCC(O)(CN4CCCC4)C3)c(F)cc2c1=O

Procedure:
1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid and 3-(1-pyrrolidinylmethyl)-3-hydroxy-pyrrolidine are reacted according to example 1, yielding 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[3-(1-pyrrolidinylmethyl)-3-hydroxy-1-pyrrolidinyl]3-quinolinecarboxylic acid, melting point: 229°-234° C. (decomposition).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:13]1[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=1)[C:11]#[N:12].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([O:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)[N:14]=1)[C:11]#[N:12]
Reactant: COc1ccc(O)cc1
Reactant: N#CC(c1ccnc(Cl)n1)c1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COc1ccc(Oc2nccc(C(C#N)c3nc4ccccc4s3)n2)cc1
Temperature: 100 °C
Reaction time: 192 h
Yield: 51.4 %

Procedure:
To a solution of 1 (0.300 g, 1.05 mmol) in DMSO (7 ml) were added 4-methoxyphenol (0.261 g, 2.1 mmol) and cesium carbonate (1.7 g, 5.25 mmol) and the suspension was shaken at 100° C. for 8 days. After cooling to r.t., the suspension was poured onto ice/water and the product was extracted with AcOEt. The organic phases were washed with water then brine, dried over MgSO4 and concentrated to dryness. The residue was triturated in hot EtOH then filtered off and dried under vacuum at 50° C. overnight, affording 202 mg (51%) of the title compound.