Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(P(CCCC)CCCC)CCC.CN(C(/N=N/C(N(C)C)=O)=O)C.[CH2:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH:27]1[OH:35].[CH2:36]([O:38][C:39](=[O:52])[CH2:40][CH:41]1[C:50]2[C:45](=[CH:46][C:47](O)=[CH:48][CH:49]=2)[CH2:44][CH2:43][CH2:42]1)[CH3:37]>C1C=CC=CC=1>[CH2:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH:27]1[O:35][C:47]1[CH:46]=[C:45]2[C:50](=[CH:49][CH:48]=1)[CH:41]([CH2:40][C:39]([O:38][CH2:36][CH3:37])=[O:52])[CH2:42][CH2:43][CH2:44]2
Reactant: CCOC(=O)CC1CCCc2cc(O)ccc21
Reactant: OC1Cc2ccccc2C1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)/N=N/C(=O)N(C)C
Solvent: c1ccccc1
Product: CCOC(=O)CC1CCCc2cc(OC3Cc4ccccc4C3)ccc21

Procedure:
Tributyl phosphine (137 mg, 0.68 mmol) and TMAD (122 mg, 0.68 mmol) were added successively to a dry benzene (10 mL) solution of 2-indanol (92 mg, 0.68 mmol) and ethyl 2-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)acetate 52.5 (160 mg, 0.68 mmol) with stirring under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 days. The product was isolated by silica gel column chromatography after filtration and evaporation of the solvent in vacuo. (R/S)-Ethyl 2-(6-(2,3-dihydro-1H-inden-2-yloxy)-1,2,3,4-tetrahydronaphthalen-1-yl)acetate (52) was obtained as a colorless oil (85 mg, 35%). LC-MS ESI (pos.) m/e: 351 (M+H).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([O:22][C:23]3[CH:28]=[C:27]([N:29]4[C:37]5[C:32](=[CH:33][C:34]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:35][CH:36]=5)[CH2:31][CH2:30]4)[N:26]=[CH:25][N:24]=3)[CH2:18][CH2:17]2)=[O:15])[CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[NH:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([O:22][C:23]3[CH:28]=[C:27]([N:29]4[C:37]5[C:32](=[CH:33][C:34]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:35][CH:36]=5)[CH2:31][CH2:30]4)[N:26]=[CH:25][N:24]=3)[CH2:18][CH2:17]2)=[O:15])[CH2:9]1
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCN(C(=O)OC3CCN(Cc4ccccc4)C3)CC2)ncn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCN(C(=O)OC3CCNC3)CC2)ncn1

Procedure:
23a (0.2 mmol) and 30 mg of Pd/C in 3 mL of ethanol were stirred under 60 psi of hydrogen for 12 h. The suspension was filtered on celite with ethanol, evaporated and purified by preparative HPLC to afford 23-1, LCMS 488.1 (MH+). tR=5.21 (Method 5).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][CH:23]=1)[O:7][C:8]1[C:13]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:12]([O:19][CH3:20])[N:11]=[CH:10][N:9]=1)(=[O:3])[CH3:2].[CH2:24](O)[CH2:25][OH:26].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:2][C:1]1([C:4]2[CH:5]=[C:6]([CH:21]=[CH:22][CH:23]=2)[O:7][C:8]2[C:13]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:12]([O:19][CH3:20])[N:11]=[CH:10][N:9]=2)[O:26][CH2:25][CH2:24][O:3]1
Reactant: COC(=O)Cc1c(OC)ncnc1Oc1cccc(C(C)=O)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC(=O)Cc1c(OC)ncnc1Oc1cccc(C2(C)OCCO2)c1
Yield: 95.6 %

Procedure:
A mixture of methyl 4-(3-acetylphenoxy)-6-methoxy-pyrimidin-5-yl-acetate (15.0 g, 47 mmol), ethylene glycol (7.9 ml, 140 mmol) and p-toluene sulfonic acid is refluxed, removing the water azeotropically. After two hours the organic phase is washed with saturated sodium carbonate solution, dried (MgSO4) and evaporated to give the methyl 4-[3-(2-methyldioxolan-2-yl)-phenoxy]-6-methoxy-pyrimidin-5-yl-acetate as a yellow oil (16.2 g).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7].Cl[C:15]([O:17][CH2:18][CH2:19][CH2:20][Cl:21])=[O:16].C(N(CC)C(C)C)(C)C>ClCCl>[Cl:21][CH2:20][CH2:19][CH2:18][O:17][C:15]([N:11]1[CH2:10][CH2:9][N:8]([C:6]([CH:2]2[CH2:3][CH2:4][CH2:5][O:1]2)=[O:7])[CH2:13][CH2:12]1)=[O:16]
Reactant: O=C(Cl)OCCCCl
Reactant: O=C(C1CCCO1)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(OCCCCl)N1CCN(C(=O)C2CCCO2)CC1
Reaction time: 2 h

Procedure:
To a 0° C. solution of 1-(tetrahydrofuran-2-ylcarbonyl)piperazine (202 mg, 1.1 mmol) in dichloromethane (5 mL) was added 3-chloropropyl chloroformate (133 μL, 1.1 mmol) followed by N,N-diisopropylethylamine (192 μL, 1.1 mmol). The reaction was allowed to reach room temperature over 2 h, at which time the reaction was evaporated to yield the title compound as a wheat colored oil that was used without further purification.
Reaction SMILES: [O:1]=[C:2]([CH2:8][C:9](=[O:12])[CH2:10][CH3:11])[C:3]([O:5]CC)=O.[Cl-].C[C:15](=[NH2+:17])C.N>>[OH:1][C:2]1[C:3](=[O:5])[NH:17][CH2:15][C:8]=1[C:9](=[O:12])[CH2:10][CH3:11]
Reactant: CCOC(=O)C(=O)CC(=O)CC
Reactant: CC(C)=[NH2+]
Agent: N
Agent: [Cl-]
Product: CCC(=O)C1=C(O)C(=O)NC1

Procedure:
Reaction of ethyl 2,4-dioxohexanoate with dimethylmethylene ammonium chloride and ammonia, analogous to the procedure in Preparation 8, gave the title compound as an amorphous solid. 1H nmr (250 MHz, DMSO-d6) δ 0.99 (t, J=7.3 Hz, 3H), 2.75 (q, J=7.3 Hz, 2H), 3.81 (s, 2H), 8.84 (s, 1H).
Reaction SMILES: [CH:1]1([C:4]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)(O)[CH2:5][CH2:6][N:7]([CH3:9])[CH3:8])[CH2:3][CH2:2]1.[ClH:19]>CCOCC>[ClH:19].[Cl:19][CH2:3][CH2:2][CH:1]=[C:4]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[CH2:5][CH2:6][N:7]([CH3:9])[CH3:8]
Reactant: COc1ccc(C(O)(CCN(C)C)C2CC2)cc1
Agent: Cl
Solvent: CCOCC
Product: COc1ccc(C(=CCCCl)CCN(C)C)cc1

Procedure:
1-Cyclopropyl-3-di-methylamino-1-(4-methoxyphenyl)- 1-propanol was dissolved in ether and ethereal hydrogen chloride was added to the ether solution. The ether insoluble hydrochloride salt was separated by filtration and recrystallized from isopropanol.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([N+:11]([O-:13])=[O:12])[C:7]([OH:10])=[N:8][CH:9]=1.[CH3:14]I>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([N+:11]([O-:13])=[O:12])[C:7](=[O:10])[N:8]([CH3:14])[CH:9]=1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(Cl)cc([N+](=O)[O-])c1=O
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A mixture of NaH (577 mg, 14.4 mmol) and 5-chloro-2-hydroxy-3-nitropyridine (2.1 g, 12.0 mmol) in DMF (21 mL) was stirred for 1 h at 5° C. Methyl iodide (1.1 mL, 18.0 mmol) was added. The resulting mixture was allowed to warm to rt, stirred overnight, cooled to 0° C., quenched by addition of water, and extracted with EtOAc. The organic layer was dried (Na2SO4), filtered, and concentrated. The residue was used without further purification. tR: 0.61 min (LC-MS 2); ESI-MS: 189.1/191.1 [M+H]+ (LC-MS 2).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:17])[NH:6][CH:7]1[CH2:11][C:10](=[O:12])[O:9][CH:8]1[O:13][CH2:14][CH2:15]Cl)[CH:2]=[CH2:3].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>CN(C=O)C>[CH2:1]([O:4][C:5](=[O:17])[NH:6][CH:7]1[CH2:11][C:10](=[O:12])[O:9][CH:8]1[O:13][CH2:14][CH2:15][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH:2]=[CH2:3]
Reactant: C1COCCN1
Reactant: C=CCOC(=O)NC1CC(=O)OC1OCCCl
Solvent: CN(C)C=O
Product: C=CCOC(=O)NC1CC(=O)OC1OCCN1CCOCC1

Procedure:
Is prepared from [2-(2-chloro-ethoxy)-5-oxo-tetrahydro-furan-3-yl]-carbamic acid allyl ester by reaction with morpholine (2 eq) and KI (1 eq) in DMF.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1I)=[O:4].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:69]([O:71][P:72]([CH2:75][CH2:76][NH2:77])([CH3:74])=[O:73])[CH3:70]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[NH:77][CH2:76][CH2:75][P:72]([O:71][CH2:69][CH3:70])([CH3:74])=[O:73])=[O:4]
Reactant: CCOP(C)(=O)CCN
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOP(C)(=O)CCNc1cc(C#CC(C)(C)C)sc1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
5-(3,3-Dimethyl-but-1-ynyl)-3-iodo-thiophene-2-carboxylic acid methyl ester (669 mg, 1.92 mmol), Pd(OAc)2 (64 mg, 0.288 mmol), BINAP (179 mg, 0.288 mmol), and Cs2CO3 (1.56 g, 4.8 mmol) were combined in a sealed tube. A solution of (2-amino-ethyl)-methyl-phosphinic acid ethyl ester (578 mg, 3.85 mmol) in toluene (14 mL), which had been degassed by bubbling argon through it for 30 minutes, was added. The sealed tube was purged with argon and then sealed. The tube was placed in a 120° C. oil bath. The reaction was stirred overnight, then cooled to room temperature and filtered through filter paper. The residue was stirred vigorously with EtOAc and then the EtOAc was passed through filter paper. The combined filtrates were concentrated and 5-(3,3-Dimethyl-but-1-ynyl)-3-[2-(ethoxy-methyl-phosphinoyl)-ethylamino]-thiophene-2-carboxylic acid methyl ester (466 mg, 66%) was isolated by silica gel column chromatography (MeOH/EtOAc) as a green crystalline solid.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[C:12]2[O:13][CH2:14][CH2:15][O:16][C:11]=2[C:10]([C:17]([O:19][CH3:20])=[O:18])=[CH:9][CH:8]=1.[N+:21]([O-])([O-:23])=[O:22].[K+].C(=O)([O-])[O-].[K+].[K+]>O.C(O)(=O)C>[NH2:6][C:7]1[C:12]2[O:13][CH2:14][CH2:15][O:16][C:11]=2[C:10]([C:17]([O:19][CH3:20])=[O:18])=[CH:9][C:8]=1[N+:21]([O-:23])=[O:22]
Reactant: O=[N+]([O-])[O-]
Reactant: COC(=O)c1ccc(N)c2c1OCCO2
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc([N+](=O)[O-])c(N)c2c1OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.4 %

Procedure:
Concentrated sulphuric acid (6.5 ml) was treated cautiously with stirring at 5°-10° C. with glacial acetic acid (12 ml) and to the resulting solution was added methyl 8-amino-1,4-benzodioxan-5-carboxylate (1.5 g, 0.0072 mole). The mixture was stirred at room temperature for 1 h, then treated portionwise over 45 minutes with potassium nitrate (0.85 g, 0.0084 mole). The mixture was stirred for a further 4 h then poured into water (100 ml) and basified with potassium carbonate. A precipitate was produced and this was filtered off, washed with water and dried to afford methyl 8-amino-7-nitro-1,4-benzodioxan-5-carboxylate as a yellow solid (0.30 g). The filtrate was extracted with ethyl acetate and the extract dried (Na2SO4) and concentrated in vacuo to afford a further 1.1 g of the product as an orange solid. 1H NMR (CDCl3) δ:8.50(s,1 H), 6.0-7.0(v br,2 H), 4.30-4.55(m,4 H), 3.87(s,3 H).
Reaction SMILES: [BH4-].[Na+].Cl.[Cl:4][C:5]1[CH:6]=[C:7]2[C:11]3=[C:12]([CH:27]=1)[C:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[N:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:10]3[CH2:9][CH2:8]2.O>C(O)C.C(Cl)(Cl)Cl>[Cl:4][C:5]1[CH:6]=[C:7]2[C:11]3=[C:12]([CH:27]=1)[CH:13]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:10]3[CH2:9][CH2:8]2
Reactant: Clc1cc2c3c(c1)C(c1ccccc1)=Nc1ccccc1N3CC2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: O
Product: Clc1cc2c3c(c1)C(c1ccccc1)Nc1ccccc1N3CC2
Reaction time: 1.17 h

Procedure:
1.65 g NaBH4 is added portionwise over 6 minutes to rapidly stirred ice cold slurry of 4.0 g 4-chloro-1,2-dihydro-6-phenylindolo[1,7-ab][1,5]benzodiazepine hydrochloride in 50 ml absolute ethanol under N2. After 70 minutes at 0° C., water is added dropwise over 10 minutes and the reaction mixture is concentrated to leave an oil. The resulting oil is dissolved in CHCl3, washed with water, brine, dried over Na2SO4, and concentrated to give 4-chloro-6-phenyl-1,2,6,7-tetrahydroindolo[1,7-ab][1,5]benzodiazepine, m.p. 192.5°-194.5° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[O-]S([O-])(=O)=O.[Mg+2].[NH:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[NH2:16]>C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:16][NH:15][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:4][CH2:3]1
Reactant: CN1CCC(=O)CC1
Reactant: CC(C)(C)OC(=O)NN
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CN1CCC(NNC(=O)OC(C)(C)C)CC1
Yield: 63.4 %

Procedure:
To a solution of 1-methylpiperidin-4-one (3.0 g, 27 mmol) in DCM (60 mL) was added MgSO4 (6.5 g, 54 mmol) and tert-butyl hydrazinecarboxylate (2.9 g, 22 mmol). The reaction mixture was heated to reflux overnight. The solid was filtered off and the filtrate was concentrated. The residue was purified by silica gel chromatography eluting with EtOAc/petroleum ether (1:20) to give tert-butyl 2-(1-methylpiperidin-4-yl)hydrazinecarboxylate (3.2 g, 53% yield) as a colorless oil. LCMS (ESI) m/z: 228.3 [M+H+].
Reaction SMILES: C(OC(C(C[C:11]1[CH:16]=[CH:15][C:14]2[O:17][CH2:18][O:19][C:13]=2[CH:12]=1)C(O)=O)=O)C.N1CCCCC1.[C:26](O)(=[O:28])C>C1C=CC=CC=1>[CH3:26][O:28][C:11]1[CH:16]=[CH:15][C:14]2[O:17][CH2:18][O:19][C:13]=2[CH:12]=1
Reactant: CC(=O)O
Reactant: CCOC(=O)C(Cc1ccc2c(c1)OCO2)C(=O)O
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: COc1ccc2c(c1)OCO2
Reaction time: 18 h

Procedure:
A mixture of the aldehyde of Example 1(p), (1.48 g, 5.25 mmol), 2-ethoxycarbonyl-3-(3,4-methylenedioxyphenyl)propanoic acid (2.34 g. 7.88 mmol), piperidine (223 mg, 0.26 ml, 2.7 mmol) and acetic acid (0. 17 ml) in benzene (50 ml) was stirred at reflux under argon using a Dean-Stark trap. After 18 hours, the benzene was removed in vacuo and the residue partitioned between t-butyl methyl ether and water. The layers were separated, and the aqueous further extracted (×3). The combined organic extracts were washed twice with water, 5% sodium bicarbonate solution, sat'd ammonium chloride, and brine, then dried (MgSO4), filtered and concentrated under reduced pressure. Silica gel chromatography (50% ether/hexanes) afforded the title compound as an oil. (1.048 g, 42%)
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[CH:4][CH:3]=1.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].O>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.C1(C)C=CC=CC=1.O1CCCC1>[CH3:13][O:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([C:27]2[CH:26]=[CH:25][C:24]([C:15]3[CH:16]=[CH:17][C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:14]=3)=[CH:29][CH:28]=2)=[CH:3][CH:4]=1
Reactant: OB(O)c1ccc(-c2ccc3ccccc3c2)cc1
Reactant: COc1ccc(Br)c2ccccc12
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: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2ccc(-c3ccc4ccccc4c3)cc2)c2ccccc12
Temperature: 25 °C
Yield: 68.6 %

Procedure:
1-Bromo-4-methoxynaphthalene (25 g, 0.105 mol), 4-(naphthalen-2-yl)phenylboronic acid (30.4 g, 0.137 mol), potassium carbonate (21.9 g, 0.16 mol), tetrakis(triphenylphosphine)palladium(0) (2.4 g, 0.01 mol), water (25 mL), tetrahydrofuran (75 mL) and toluene (75 mL) were stirred in a 250 mL round-bottom flask for 12 hours under reflux. After completion of the reaction, the reaction mixture was cooled to room temperature and extracted with ethyl acetate (300 mL) and water (1000 mL). The organic layer was dried with magnesium sulfate and concentrated under reduced pressure. The resulting solid was dissolved in hot toluene (400 mL) and filtered. The filtrate was recrystallized in methanol (800 mL). The resultant solid was filtered and washed with hexane (300 mL) to obtain a product (26 g, 0.072 mol, 68.4%).
Reaction SMILES: [ClH:1].C([O:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19]([C@H:21]1[CH2:26][CH2:25][C@H:24]([CH2:27][NH:28][C:29]([NH2:31])=[NH:30])[CH2:23][CH2:22]1)=[O:20])=[O:11])C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[ClH:1].[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19]([C@H:21]1[CH2:22][CH2:23][C@H:24]([CH2:27][NH:28][C:29]([NH2:31])=[NH:30])[CH2:25][CH2:26]1)=[O:20])([OH:11])=[O:9]
Reactant: [H][H]
Reactant: N=C(N)NC[C@H]1CC[C@H](C(=O)Nc2ccccc2C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: N=C(N)NC[C@H]1CC[C@H](C(=O)Nc2ccccc2C(=O)O)CC1

Procedure:
The above N-(o-benzyloxycarbonylphenyl)-trans-4-guanidinomethylcyclohexylcarboxamide hydrochloride (1.09 g, 0.0024 mole) is dissolved in methanol (50 ml), and thereto is added 10% palladium-carbon (0.23 g), and the mixture is stirred with blowing hydrogen gas under atmospheric pressure at 30° C. for one hour. After the completion of the reaction, palladium-carbon is filtered off, and the filtrate is concentrated under reduced pressure. The resulting residue is recrystallized from a mixture of methanol-water to give N-(o-carboxyphenyl)-trans-4-guanidinomethylcyclohexanecarboxamide hydrochloride (0.76 g) as white crystals, melting at around 135°-145° C. and after being solidified, decomposing at 215°-220° C.
Reaction SMILES: [C:1]1([C:7]2[CH:19]=[CH:18][C:10]([O:11][CH2:12][CH2:13][CH2:14][C:15](O)=[O:16])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CCOCC1.Cl.[NH2:28][OH:29].C1COCC1>S(Cl)(Cl)=O.O>[C:1]1([C:7]2[CH:19]=[CH:18][C:10]([O:11][CH2:12][CH2:13][CH2:14][C:15]([NH:28][OH:29])=[O:16])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=C(O)CCCOc1ccc(-c2ccccc2)cc1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCCOc1ccc(-c2ccccc2)cc1)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.6 %

Procedure:
A suspension of 4-(4-phenylphenoxy)butanoic acid (2.42 g, 9.45 mmol) in thionyl chloride (25 mL) was heated at reflux for 90 minutes, during which time the mixture became homogenous. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was taken up in 1:1 methylene chloride/THF. In a separate flask 4-methylmorpholine (3.5 mL, 32 mmol) was added to a solution of hydroxylamine hydrochloride (2.1 g, 30 mmol) in water (10 mL). THF (20 mL) was then added and the hydroxylamine solution was decanted into the acid chloride solution, and the reaction mixture was vigorously stirred for 2 hours. The reaction mixture was partitioned between saturated aqueous NH4Cl and methylene chloride. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to give 4-(4-phenylphenoxy)butanohydroxamic acid (1.45 g) as a white solid. 1H NMR (DMSO-d6) δ 1.94 (m, 2H), 2.14 (t, 2H, J=7 Hz), 4.01 (t, 2H, J=6 Hz), 7.02 (d, 2H, J=8 Hz), 7.29 (t, 1H, J=6 Hz), 7.43 (t, 2H, J=6 Hz), 7.62 (m, 4H), 8.71 (s, 1H), 10.44 (s, 1H). MS (DCI/NH3) 289 (M+NH4+, 100), 272 (M+H+, 35), 255 (30). Anal. Calcd for: C16H17NO3 : C, 70.83; H, 6.32; N, 5.16. Found: C, 64.81; H, 6.65; N, 5.82.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][C@@H:13]3[CH2:15][C@H:10]2[CH2:11][N:12]3[C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.[NH2:53][OH:54]>N1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][C@@H:13]3[CH2:15][C@H:10]2[CH2:11][N:12]3[C:16]2[CH:17]=[CH:18][C:19]([C:20]([NH:53][OH:54])=[O:21])=[CH:23][CH:24]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: NO
Reactant: N#Cc1cccc(N2C[C@@H]3C[C@H]2CN3c2ccc(C(=O)O)cc2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Product: N#Cc1cccc(N2C[C@@H]3C[C@H]2CN3c2ccc(C(=O)NO)cc2)c1
Reaction time: 0.25 h
Yield: 91.2 %

Procedure:
Title compound 248 (0.21 g, 0.590 mmol) and BOP (0.287 g, 0.649 mmol) were combined and pyridine (5.90 ml) was added. The mixture was stirred 15 min. Hydroxylamine hydrochloride (0.045 g, 0.649 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was concentrated, water and 3N HCl were added (to reach pH=5). This aqueous mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was dissolved in THF (3 mL) and MeOH (3 mL), 4M KOH (0.3 ml) was added and the homogenous mixture was concentrated partially. The resulting aq. solution was diluted with water and 3N HCl (0.4 ml) was added. The precipitate was filtered, washed with water and ether and pumped on Hi-Vac overnight to afford title compound 249 (0.18 g, 91%) as a pink solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.81 (s, 1H), 8.70 (d, J=1.8 Hz, 1H), 7.56 (d, J=8.7 Hz, 2H), 7.27 (t, J=7.9 Hz, 1H), 7.01 (s, 1H), 6.95 (d, J=7.6 Hz, 1H), 6.88 (d, J=8.6 Hz, 1H), 6.58 (d, J=8.6 Hz, 2H), 4.73 (d, J=5.1 Hz, 2H), 3.57 (d, J=9.4 Hz, 2H), 3.03 (t, J=10.1 Hz, 2H), 2.06 (s, 2H). LRMS (ESI): (calc.) 334.1. (found) 333.4 (MH)−.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]([CH:9]2[CH2:13][CH2:12][CH2:11][O:10]2)[CH:6]=[CH:7][N:8]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1.CS(C)=O.C([O-])([O-])=O.[K+].[K+]>O>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[O:22][CH2:3][C:4]1[N:5]([CH:9]2[CH2:13][CH2:12][CH2:11][O:10]2)[CH:6]=[CH:7][N:8]=1
Reactant: COc1cccc(O)c1
Reactant: ClCc1nccn1C1CCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cccc(OCc2nccn2C2CCCO2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.6 %

Procedure:
To a mixture of 2-chloromethyl-1-(tetrahydro-furan-2-yl)-1H-imidazole hydrochloride, (5.7 g, 30.6 mmol), 3-methoxyphenol (7.6 g, 61.2 mmol) and DMSO (30 mL) was added K2CO3 (12.7 g, 91.8 mmol). The mixture was stirred at ambient temperature under N2 overnight. Water (100 mL) was added and the mixture was extracted with CH2Cl2 (3×100 mL). The combined CH2Cl2 extracts were washed with 2N NaOH, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 1:2 hexane/EtOAc) to provide the desired 2-(3-methoxy-phenoxymethyl)-1-(tetrahydro-furan-2-yl)-1H-imidazole (3.49 g, 41%) as a colorless oil: ESI MS m/z 275 [C15H18N2O3+H]+.
Reaction SMILES: [H-].[Na+].[CH:3](NC(C)C)(C)C.[CH:10]1[C:23]2[CH:22]([CH2:24][C:25]([OH:27])=[O:26])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[O:15][C:14]=2[CH:13]=[CH:12][CH:11]=1.C([Li])CCC.CI.C(=O)([O-])O.[Na+]>O1CCCC1>[CH:20]1[C:21]2[CH:22]([CH:24]([CH3:3])[C:25]([OH:27])=[O:26])[C:23]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:15][C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)NC(C)C
Reactant: O=C(O)CC1c2ccccc2Oc2ccccc21
Agent: O=C([O-])O
Agent: [H-]
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CC(C(=O)O)C1c2ccccc2Oc2ccccc21
Temperature: -15 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 55 mg (1.26 mmol) of sodium hydride previously washed with n-hexane in 5 ml of tetrahydrofuran were added 316 mg (3.13 mmol) of diisopropylamine, and then a solution of 300 mg (1.25 mmol) of 2-(9H-xanthen-9-yl)acetic acid in 4 ml of tetrahydrofuran was dropwise added thereto. After completion of the addition, the resulting mixture was heated under refluxing for 20 minutes and then cooled to -15° C., after which 1.2 ml (1.9 mmol) of a 1.6M n-butyllithium solution were added thereto followed by stirring at the same temperature for 15 minutes. To the mixture was dropwise added a solution of 531 mg of methyl iodide in 2 ml of tetrahydrofuran over a period of 10 minutes, after which stirring was continued at the same temperature for an hour. With ice-cooling the reaction was stopped by addition of a diluted aqueous solution of sodium hydrogencarbonate and the reaction mixture was washed with dichloromethane. The aqueous layer separated was acidified with concentrated hydrochloric acid and extracted twice with ether. The combined ether extracts were subsequently washed with water and a saturated aqueous solution of sodium chloride and the solvent distilled off to give a mixture of the titled Compound A, B and C. The mixture thus obtained was used in the following reaction without purification.