Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)(S)=[S:8])C=CC=CC=1.[CH2:16]([O:18][C:19](=[O:24])[CH:20]([C:22]#[N:23])[CH3:21])[CH3:17]>C(O)(C)C>[NH2:23][C:22](=[S:8])[CH:20]([CH3:21])[C:19]([O:18][CH2:16][CH3:17])=[O:24]
Reactant: CCOC(=O)C(C)C#N
Reactant: S=P(S)(c1ccccc1)c1ccccc1
Solvent: CC(C)O
Product: CCOC(=O)C(C)C(N)=S
Reaction time: 8 h

Procedure:
A mixture of diphenylphosphinodithioic acid (Alfa-Aesar) (7.48 g, 29.9 mmol) and 2-cyanopropionic acid ethyl ester (ABCR, 1.980 mL, 14.94 mmol) in isopropanol (80 mL) was heated under reflux for 8 h then stood at rt overnight. Reaction mixture was filtered and filtrate was diluted with EtOAc and washed with 1N NaOH, brine, and dried over Na2SO4. Crude was purified by chromatography on silica gel using a Hex/EtOAc gradient. Appropriate fractions were combined and evaporated to yield title compound as a yellow oily solid. 1H NMR (300 MHz, DMSO-d6) δ ppm: 9.60 (s, 1H), 9.40 (s, 1H), 4.05 (q, 2H), 3.74 (q, 1H), 1.29 (d, 3H), 1.15 (t, 3H). [ES+MS] m/z 162 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:25]([OH:27])=O)[CH2:10][CH2:11][CH2:12][CH:13]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:29]([O:36][C:37](=[O:43])[C@@H:38]1[CH2:42][CH2:41][CH2:40][NH:39]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH2:29]([O:36][C:37](=[O:43])[C@@H:38]1[CH2:42][CH2:41][CH2:40][N:39]1[C:25](=[O:27])[C@H:9]([CH2:10][CH2:11][CH2:12][CH:13]([C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[NH2:14])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCC(N)C(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCCC(N)C(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 8 h

Procedure:
All the obtained oily t-butyloxycarbonyl-ε-carbobenzoxy-L-lysine and L-proline benzylester hydrochloride (4.3 g, 17.8 m mole) were dissolved in methylene dichloride and WSC (3.3 ml, 17.8 m mole) was added thereto while cooling to -15° C. The mixture was stirred overnight and the methylene dichloride was distilled off under reduced pressure. The residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with 1N hydrochloric acid, 5% sodium bicarbonate and water in order, and dried with anhydrous sodium sulfate. The ethyl acetate was distilled off under reduced pressure to obtain an oily t-butyloxycarbonyl-ε-carbobenzoxy-L-lysyl-L-proline benzylester.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[CH2:20][CH2:19][C:14]2(OCC[O:15]2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.CC1C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[CH2:12][CH2:13][C:14](=[O:15])[CH2:19][CH2:20]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COCCC2CCC3(CC2)OCCO3)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: O=C1CCC(CCOCc2ccccc2)CC1
Yield: 97 %

Procedure:
8-(2-Benzyloxy-ethyl)-1,4-dioxa-spiro[4.5]decane (Intermediate R1, 1.02 g, 3.70 mmol) (obtainable as described in the publication by Ciufolini et. al. J. Amer. Chem. Soc. 1991, 113, 8016, incorporated herein by reference) was dissolved in acetone (100 mL):H2O (5 mL) and reacted with TsOH (140 mg, 0.74 mmol) at 45 EC for 5 h. After a standard aqueous work-up the material was purified by chromatography on SiO2 to give 4-(2-benzyloxy-ethyl)-cyclohexanone as a colorless oil (97%).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[O:3]1.[H-].[Na+].[CH3:19][O:20][CH2:21][CH2:22]Br>CN(C=O)C>[CH3:19][O:20][CH2:21][CH2:22][O:15][C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1
Reactant: COCCBr
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (150 mg, 0.682 mmol) in DMF (5 mL) was added 60% NaH (136 mg, 3.41 mmol) and 2-bromoethyl methyl ether (0.13 mL, 1.363 mmol). The resulting solution was stirred at 50° C. overnight, cooled to ambient temperature, quenched with water, and extracted with EtOAc. The combined extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography to give the title compound (114 mg, 60% yield).
Reaction SMILES: CC(C)=[O:3].[CH2:5]1[O:15][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].S(=O)(=O)(O)O>>[CH2:5]([OH:15])[CH:6]([OH:3])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CC(C)=O
Reactant: CCCCCCCCC1CO1
Agent: O=S(=O)(O)O
Product: CCCCCCCCC(O)CO

Procedure:
A homogeneous clear solution is prepared by adding 3 moles of acetone to 1 mole of 1-decene oxide at room temperature. After adding 50 grams of 5% aqueous sulfuric acid to the solution, the acetone is evaporated off and the resulting solution is neutralized by adding an aqueous sodium hydroxide. The neutralized solution is extracted with pet ether and the extract dried over anhydrous magnesium sulfate. The pet ether is stripped off and 1,2-decanediol is obtained by distilling under vacuo.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C:13]([OH:15])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:17][NH:18][O:19][CH3:20].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:20][O:19][N:18]([CH3:17])[C:13]([C@H:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)=[O:15]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C(=O)O)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (S)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (430 mg, 2.0 mmol) in CH2Cl2 (20 mL) was added CDl (356 mg, 2.2 mmol). The mixture was stirred at room temperature for 20 minutes, N,O-dimethylhydroxylamine hydrochloride (234 mg, 2.4 mmol) and DIPEA (258 mg, 2.6 mmol) were then added subsequently at 0° C. The mixture was stirred at 0° C. for 0.5 hour, then warmed up and stirred at ambient temperature overnight. The mixture was washed with HCl (1 N), saturated aqueous NaHCO3 and water, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound for the next step.
Reaction SMILES: [CH:1]1([C:4]2[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.Br[C:13]1C=CC(C2CCCC2)=C[CH:14]=1.[Li]CCCC.CCCCCC.CN(C=O)C>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([CH:8]=[O:9])=[CH:10][CH:11]=2)[CH2:3][CH2:2][CH2:14][CH2:13]1
Reactant: Brc1ccc(C2CCCC2)cc1
Reactant: O=Cc1ccc(C2CC2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=Cc1ccc(C2CCCC2)cc1

Procedure:
The title compound was synthesized in analogy to 4-cyclopropyl benzaldehyde (described in example S1-A) using 2.07 g of 1-bromo-4-cyclopentyl-benzene (9.2 mmol), 6.32 ml of a 1.6 molar solution of n-BuLi in hexane (10.11 mmol) and 1.422 ml of DMF (18.4 mmol). 4-Cyclopentyl-benzaldehyde was isolated by flash column chromatography (5:95 EtOAc/c-hexane) as a colorless liquid (1146 mg, 72%). 1H NMR (CDCl3, 300 MHz): δ 1.53-1.91 (m, 6H), 2.11 (m, 2H), 3.07 (quint, J=8.5 Hz, 1H), 7.40 (d, J=8 Hz, 2H), 7.80 (d, J=8 Hz, 2H), 9.97 (s, 1H).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=CC=C[CH:5]=1.N[C@H](C(O)=O)CCCCN>>[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH:4]([CH3:9])[CH3:5]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: NCCCC[C@H](N)C(=O)O
Product: CC(C)C[C@H](N)C(=O)O

Procedure:
* 6.00 (6); Phe. 3.49 (4); Lys. 3.04 (3)
Reaction SMILES: [OH:1]CC1C=C(O)C=CC=1.C(N(CC)CC)C.[C:17]([O:20][C:21]1[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:23](Cl)=[O:24])(=[O:19])[CH3:18]>C1(C)C=CC=CC=1.O>[C:17]([O:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([OH:1])=[O:24])(=[O:19])[CH3:18]
Reactant: OCc1cccc(O)c1
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)Oc1ccccc1C(=O)O
Yield: 200 %

Procedure:
3-hydroxymethylphenol (10 g, 0.08 moles) is dissolved in toluene (50 ml) containing triethylamine (9.8 g, 0.1 moles). To the so obtained solution an acetylsalicylic acid chloride solution (16 g, 0.08 moles) in toluene (50 ml) is added at a temperature of 5°-10° C. under stirring. The mixture is maintained at a temperature in the above mentioned range, under stirring for 2 hours, then poured in water and then extracted with dichloromethane (2×100 ml). The organic phase is separated, washed in sequence with a 25% w/v potassium carbonate solution, with water, with a 3% hydrochloric acid solution and lastly with water again, then anhydrified with sodium sulphate and the solvent evaporated under vacuum. The residue is crystallized from isopropanol. 3-hydroxymethylphenyl ester of the 2-acetoxybenzoic acid (45.8 g, 0.16 moles, yield 80%) is obtained.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([OH:28])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].S=[C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:31]1[C:32]([O-:34])=[O:33].COC1C=CC([Te](C2C=CC(OC)=CC=2)=O)=CC=1>>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([OH:28])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1].[C:32]([O-:34])(=[O:33])[C:31]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:30]=1
Reactant: O=C([O-])C1C=CC=CC1=S
Agent: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: COc1ccc([Te](=O)c2ccc(OC)cc2)cc1
Product: O=C([O-])c1ccccc1

Procedure:
5-Cholesten-3β-ol-thionobenzoate (253 mg, 0.50 mmol) was reacted with bis-(p-methoxyphenyl)-telluroxide for 1.5 h. 5-Cholesten-3β-ol-benzoate (162 mg, 66%) m.p. 143°-145° was obtained after p.l.c. (petroleum ether-ethyl acetate 9:1). The product obtained was recrystallized from ethyl acetate (130 mg, 53%), m.p. 144.5 (lit., 150°-151°), νmax (CCl4) 1722 cm-1.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[CH3:9][C:10]([CH3:12])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:9][C:10]1([CH3:12])[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2]1
Reactant: CC(C)=O
Reactant: Oc1ccccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC1(C)Oc2ccccc2O1
Reaction time: 24 h

Procedure:
A mixture of catechol (55 g, 0.5 moles), acetone (150 ml), benzene (150 ml) and p-toluenesulfonic acid (15 mg) was refluxed in a Soxlet extractor containing 140 g of baked 4Å molecular sieves for 24 hours, as described in E. R. Cole, et al., Aust. J. Chem. 33, 675 (1980). The sieves were replaced with fresh sieves and refluxing continued for another 24 hours. The solvents were removed in vacuo and the residue was triturated with 1 liter of hexane. The light yellow solution was decanted and washed with 10% NaOH until the washes were colorless. The organic layer was dried (Na2SO4) and evaporated to 32.4 g (43%) of title compound as an oil which was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:10]=CC(S(C)(=O)=O)=C[C:3]=1C(O)=O.[Cl:15][C:16]1[CH:24]=[CH:23][C:22]([S:25]([OH:27])=[O:26])=[CH:21][C:17]=1[C:18]([OH:20])=[O:19].IC(C)C>C(O)(C)C>[Cl:15][C:16]1[CH:24]=[CH:23][C:22]([S:25]([CH:2]([CH3:10])[CH3:3])(=[O:27])=[O:26])=[CH:21][C:17]=1[C:18]([OH:20])=[O:19]
Reactant: O=C(O)c1cc(S(=O)O)ccc1Cl
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Solvent: CC(C)O
Solvent: CC(C)I
Product: CC(C)S(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Yield: 42 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 2-Chloro-5-methanesulfonyl-benzoic acid from 2-Chloro-5-sulfino-benzoic acid and 2-iodopropane in 20 ml isopropanol/20 ml water and obtained in 42% yield. MS (m/e): 261.1 (MH−, 100%).
Reaction SMILES: [NH:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[C:2]1=O.P(Cl)(Cl)([Cl:16])=O>[OH-].[NH4+]>[Cl:16][C:2]1[N:3]2[C:12]3[C:7]([CH2:6][CH2:5][CH2:4]2)=[CH:8][CH:9]=[CH:10][C:11]=3[N:1]=1
Reactant: O=c1[nH]c2cccc3c2n1CCC3
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: Clc1nc2cccc3c2n1CCC3
Reaction time: 1.5 h
Yield: 65.8 %

Procedure:
A slurry of 13.60 g of 5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one and phosphorus oxychloride (35 ml) was heated under reflux, with stirring, for 1.5 hrs and stirred at ambient temperature overnight. 10% Ammonium hydroxide (100 ml) and ice were added. The mixture was filtered, and the filtrate was extracted with dichloromethane. The organic extracts were washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated. The residue was purified by flash chromatography (silica; 10:1 dichloromethane-ethyl acetate). The appropriate fractions were collected and evaporated to give 9.90 g (65.8%) of product, mp 78° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:29]=[N:30][C:31](F)=[CH:32][CH:33]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>CN1C(=O)CCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:29]=[N:30][C:31]([N:35]6[CH2:39][CH2:38][CH2:37][CH2:36]6)=[CH:32][CH:33]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(-c4ccc(F)nc4)ccc2OCC3)c(F)c1
Reactant: C1CCNC1
Solvent: CN1CCCC1=O
Product: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(-c4ccc(N5CCCC5)nc4)ccc2OCC3)c(F)c1
Temperature: 150 °C
Yield: 5.9 %

Procedure:
2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-fluoro-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene, from the procedure for 249, (470 mg, 1.0 mmol) Pyrrolidine (85 mg, 1.2 mmol) DIPEA (340 mg, 3 mmol) and NMP (4 mL) were added in a 10 mL of sealed tube, and the mixture was heated by microwave at 150° C. for 120 min under N2. The reaction mixture was filtered to gather the solution and water was added. The mixture was extracted by DCM (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by preparative HPLC to give 294 (31.3 mg, yield: 5.9%). 1HNMR (DMSO-d6, 400 MHz): δ8.81 (s, 1H), 8.38 (s, 1H), 8.12 (d, J=8.8 Hz, 1H), 7.98-7.97 (m, 1H), 7.78-7.77 (m, 1H), 7.76-7.78 (m, 2H), 7.46-7.40 (m, 1H), 7.38 (d, J=8.4 Hz, 1H), 7.51 (t, J=8.8 Hz, 1H), 7.48 (t, J=4.4 Hz, 1H), 7.26 (s, 1H), 6.60 (d, J=8.8 Hz, 1H), 4.38 (s, 2H), 3.54 (s, 3H), 3.22 (s, 2H), 2.07 (s, 4H). ESI-MS: m/z=529 [M+H+]
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[C:3]=1[N+:12]([O-])=O>C(O)(=O)C.O.[Zn]>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[C:3]=1[NH2:12]
Reactant: COC(=O)c1cccc(C)c1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cccc(C)c1N
Yield: 81.7 %

Procedure:
In this example 0.02 mole of 2-methyl-6-methoxycarbonyl-nitrobenzene in 25 ml of acetic acid was added dropwise to a slurry containing 6.5 g of zinc dust suspended in 25 ml of water at 30°-35° C. The resulting exothermic reaction is controlled by maintaining the mixture at about room temperature (about 20°-25° C.) through external cooling. The reaction product mixture was filtered to remove the zinc dust and the filtrate, then washed sequentially with methylene chloride and water, and then extracted with methylene chloride. The extract was washed with an aqueous ammonium hydroxide, then with water and filtered through diatomaceous earth. The filtrate was then dried and evaporated affording 2.7 g of the title product as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:21][C:22]1[CH:35]=[CH:34][C:25]([C:26]([N:28]2[CH2:32][CH2:31][C@@H:30]([NH2:33])[CH2:29]2)=[O:27])=[CH:24][CH:23]=1>O1CCOCC1.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1>[Cl:21][C:22]1[CH:35]=[CH:34][C:25]([C:26]([N:28]2[CH2:32][CH2:31][C@@H:30]([NH:33][C:2]3[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=3)[CH2:29]2)=[O:27])=[CH:24][CH:23]=1
Reactant: CCOC(=O)/C=C/c1ccc(Cl)nc1
Reactant: N[C@@H]1CCN(C(=O)c2ccc(Cl)cc2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)/C=C/c1ccc(N[C@@H]2CCN(C(=O)c3ccc(Cl)cc3)C2)nc1
Temperature: 90 °C
Yield: 32.7 %

Procedure:
To a solution of ethyl (2E)-3-(6-chloro-3-pyridyl)acrylate (3.5 g) in dioxane (70 mL) was added palladium(II) acetate (371 mg) and 2′-(dicyclohexylphosphino)-N,N-dimethyl-2-biphenylamine (110 mg) and cesium carbonate (583 mg), and (3R)-1-(4-chlorobenzoyl)-3-pyrrolidinamine (4.09 g). The mixture was heated at 90° C. for 3 hours. The resulting mixture was diluted with AcOEt, and the precipitate was removed by filtration. The filtrate was concentrated and residual brown oil was purified by purified by silica gel column chromatography eluted with AcOEt and hexane (1:4)-AcOEt to give ethyl (2E)-3-(6-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate (2.16 g) as dark yellow form.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:14][CH2:13][CH2:12][CH2:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(CCCCO)cc1
Reactant: BrCCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CCCCOCCCCCCBr)cc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 20.1 %

Procedure:
A stirred mixture of 4-(4-nitrophenyl)butan-1-ol (2.0 g, 10 mmol), tetra-n-butylammonium hydrogen sulfate (0.17 g, 0.5 mmol), and 1,6-dibromohexane (3.2 mL, 20 mmol) in dichloromethane (10 mL) was treated with aqueous sodium hydroxide solution (10 M, 1 mL). The reaction mixture was stirred for 6 days at room temperature. The organic and aqueous phases were separated. The aqueous phase was extracted thrice with dichloromethane. The combined organics were washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified via automated flash silica gel chromatography, using a 40 g SiliSep flash column (hexanes/ethyl acetate). Concentration of the desired fractions under reduced pressure provided the title compound as a pale straw-colored oil (0.72 g, 20%). ES/MS calcd. for C16H25BrNO3+ 358.1. found m/z=358.2 (M+H)+.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16](OS(C)(=O)=O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][NH2:24]>CO>[CH:1]([N:14]1[CH2:17][CH:16]([NH:24][CH3:23])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CO
Product: CNC1CN(C(c2ccccc2)c2ccccc2)C1
Yield: 67.9 %

Procedure:
1-Benzhydryl-3-(methylamino)azetidine was prepared under the conditions of Example 9, but starting with 50 g of 1-benzhydryl-3-(methanesulphonyloxy)-azetidine and 48.9 g of methylamine in 250 cm3 of methanol. 27 g of 1-benzhydryl-3-(methylamino)azetidine are obtained in the form of a colorless solid, melting point 75° C.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1>[Pd].C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:11][CH:12]=1
Reactant: O=C(O)C=Cc1ccc(F)cc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)CCc1ccc(F)cc1
Reaction time: 4.5 h
Yield: 90.9 %

Procedure:
A mixture of 4-fluorocinnamic acid (300.0 g, 1.8 mol, Aldrich) and 5% palladium on carbon (9.0 g) in ethanol (3 L) was hydrogenated at atmospheric pressure and room temperature for 4.5 h. The mixture was filtered through Celite (diatomaceous earth) and the filtrate was concentrated in vacuo to give 275.1 g (91%) of 3-(4-fluorophenyl)propionic acid as a white solid, m.p., 86°-88° C.; NMR (DMSO-d6): d12.15 (br s, 1H, COOH), 7.07-7.29 (m,4H, Ar), 2.81(t, 2H, CH2CO), 2.52 (t,2H, ArCH2).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:19])=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=O)[CH2:8]1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[S:3][C:4]([Cl:19])=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=[N:24][NH:23][C:20]([NH2:22])=[NH:21])[CH2:8]1
Reactant: N=C(N)NN
Reactant: Cc1ccnc2c1C(=O)CC(c1cc(Cl)sc1Cl)C2
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1cc(Cl)sc1Cl)C2
Yield: 207.2 %

Procedure:
In ethanol (10 ml) was dissolved (−)-7-(2,5-dichlorothiophen-3-yl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.35 g), and to the mixture were added aminoguanidine hydrochloride (0.15 g), concentrated hydrochloric acid (0.28 ml) and water (0.28 ml). The mixture was refluxed for 4 hours, and under reduced pressure, the solvent was evaporated. The residue was dissolved in water, and the mixture was washed with ethyl acetate and concentrated under reduced pressure. The residue was heated in a little amount of ethanol, and the solution was cooled. Precipitated crystals were filtered off, and the mother liquor was concentrated to give crystals, which were recrystallized from water to give (−)-7-(2,5-dichlorothiophen-3-yl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 109) (0.47 g) as colorless crystals.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])=[O:2].C(=O)([O-])[O-].[K+].[K+].I[CH:21]([CH3:23])[CH3:22]>CN(C)C=O>[CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH:21]([CH3:23])[CH3:22])[C:6]([O:8][CH3:9])=[O:7])=[O:2]
Reactant: COC(=O)c1ccc(O)c(C=O)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(C)C)c(C=O)c1
Temperature: 60 °C
Yield: 98 %

Procedure:
To methyl 3-formyl-4-hydroxy-benzoate (10.0 g, 55.5 mmol), potassium carbonate (30.7 g, 222 mmol) and N,N-dimethylformamide (63 mL) was added 2-iodopropane (11.1 mL, 111 mmol). The mixture was heated at 60° C. for 18 hours. The mixture was filtered using ethyl acetate (200 mL) and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (150 mL) and was washed with water (3×75 mL) and a saturated aqueous solution of sodium chloride (1×75 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to yield methyl 3-formyl-4-isopropoxy-benzoate (98%) as a yellow viscous liquid. ESI-MS m/z calc. 222.2. found 223.3 (M+1)+; Retention time: 1.51 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 10.35 (s, 1H), 8.23 (d, J=2.3 Hz, 1H), 8.17 (dd, J=8.8, 2.3 Hz, 1H), 7.39 (d, J=8.9 Hz, 1H), 4.98-4.83 (m, 1H), 3.85 (s, 3H), 1.38 (d, J=6.0 Hz, 6H).