Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH3:8])[CH:3](O)[CH:4]=[CH2:5].C[O:10][C:11](=O)[CH:12](C=O)[CH3:13]>>[CH3:13][CH:12]([CH2:5][CH:4]=[CH:3][CH:2]([CH3:1])[CH2:7][CH3:8])[CH:11]=[O:10]
Reactant: COC(=O)C(C)C=O
Reactant: C=CC(O)C(C)CC
Product: CCC(C)C=CCC(C)C=O
Yield: 75.2 %

Procedure:
57 g (0.5 mole) of 4-methyl-hex-1-en-3-ol and 70 g of α-formylpropionic acid methyl ester (0.6 mole) are heated at from 140° to 200° C whilst stirring; at the same time the methanol liberated is distilled off through a 20 cm column and the carbon dioxide is measured using a gas flow meter. 11.5 liters of carbon dioxide are liberated in the course of three hours. When the elimination of methanol and carbon dioxide has ceased, the mixture is fractionated. 58 g of the above aldehyde (yield: 75% of theory) are obtained. B.p. = 75° - 80° C at 11 mm Hg.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:22])[C:9]3[CH:10]=[C:11]([C:16]4[CH:17]=[N:18][CH:19]=[N:20][CH:21]=4)[CH:12]=[CH:13][C:14]=3[O:15][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH3:23][C:24]([CH3:29])([CH3:28])[CH2:25][CH2:26][OH:27].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:23][C:24]([CH3:29])([CH3:28])[CH2:25][CH2:26][O:27][C:2]1[C:7]2[C:8](=[O:22])[C:9]3[CH:10]=[C:11]([C:16]4[CH:17]=[N:18][CH:19]=[N:20][CH:21]=4)[CH:12]=[CH:13][C:14]=3[O:15][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: O=c1c2cc(-c3cncnc3)ccc2oc2ccnc(Cl)c12
Reactant: CC(C)(C)CCO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)CCOc1nccc2oc3ccc(-c4cncnc4)cc3c(=O)c12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A resealable tube was charged with 1-chloro-8-(pyrimidin-5-yl)-10H-chromeno[3,2-c]pyridin-10-one (0.320 g, 1.033 mmol), 3,3-dimethyl-1-butanol (0.260 mL, 2.066 mmol), cesium carbonate (0.842 g, 2.58 mmol), and acetonitrile (10.0 mL). The system was flushed with argon, the tube was sealed, and the mixture stirred at 100° C. for 5 h. The material was partitioned between dichloromethane and water. The aqueous phase was separated and extracted with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a brown solid. This solid was purified via column chromatography on silica gel (RediSep 120 g column, gradient elution with 50-100% ethyl acetate-hexane) to afford 1-(3,3-dimethylbutoxy)-8-(pyrimidin-5-yl)-10H-chromeno[3,2-c]pyridin-10-one as a white solid. MS m/z=376.2 [M+H]+. Calcd for C22H21N3O3: 375.4.
Reaction SMILES: [CH3:1][NH2:2].O.[C:4]([C:6]1[CH:7]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:9]=[CH:10][CH:11]=1)#[N:5]>C(Cl)Cl>[C:4]([C:6]1[CH:7]=[C:8]([S:12]([NH:2][CH3:1])(=[O:14])=[O:13])[CH:9]=[CH:10][CH:11]=1)#[N:5]
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Reactant: CN
Solvent: O
Solvent: ClCCl
Product: CNS(=O)(=O)c1cccc(C#N)c1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
A flask containing DCM (90 mL) and methylamine in water (40 wt %, 7.5 mmol) is chilled in an ice water bath with magnetic stirring. 3-Cyano-benzenesulfonyl chloride (5 g, 2.49 mmol) is added along with DCM (10 mL) to wash down the sides of the flask. After 30 min, concentrated HCl in water is added at 0° C., until the reaction is acidic (pH<4). Water (50 mL) is added and DCM is removed in vacuo. The residue is filtered to afford 3-cyano-N-methyl-benzenesulfonamide as a solid (99%). MS: 195 (M+H); 1H NMR (300 MHz, CDCl3): δ 2.76 (d, 3H), 4.48 (broad-s, N—H), 7.7 (t, 1H), 7.9 (d, 1H), 8.13 (d, 1H), 8.19 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8]S(C(F)(F)F)(=O)=O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[CH2:24](O)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:4]1[C:5]([N+:16]([O-:18])=[O:17])=[C:6]([O:8][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c(-c2ccco2)n1
Reactant: OCCc1ccccc1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nc(OCCc2ccccc2)c([N+](=O)[O-])c(-c2ccco2)n1

Procedure:
From trifluoro-methanesulfonic acid 2-amino-6-furan-2-yl-5-nitro-pyrimidin-4-yl ester, phenethylalcohol and DBU in DME. ES-MS m/e (%): 327 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][C@@H:12]([C:14]3[O:18][NH:17][C:16](=[O:19])[CH:15]=3)[CH2:11][CH2:10][N:9]2C(OC)=O)=[C:4]([F:24])[CH:3]=1.Br>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@H:12]([C:14]3[O:18][NH:17][C:16](=[O:19])[CH:15]=3)[CH2:11][CH2:10][NH:9]2)=[C:4]([F:24])[CH:3]=1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@H]1c1ccc(Cl)cc1F
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@@H](c3ccc(Cl)cc3F)C2)o[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.8 %

Procedure:
(2S,4S)-methyl 2-(4-chloro-2-fluorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.45 g, 1.27 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 10.00 mL, 57.08 mmol) and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-(trans-2-(4-chloro-2-fluorophenyl)piperidin-4-yl)isoxazol-3(2H)-one (82 mg, 22%). 1H NMR (400 MHz, dmso) δ 1.66-1.77 (m, 1H), 1.77-1.90 (m, 1H), 1.92-2.00 (m, 1H), 2.02-2.10 (m, 1H), 2.63-2.79 (m, 1H), 2.88-2.97 (m, 1H), 3.03-3.86 (omitted signals), 3.95 (d, 1H), 5.88 (s, 1H), 7.27 (dd, 1H), 7.35 (dd, 1H), 7.56 (t, 1H). HRMS Calcd for [C14H14ClFN2O2+H]+: 297.0806. Found: 297.0806.
Reaction SMILES: O.O.[OH:3][C:4]([C:7]1[N:8]=[C:9]([CH2:52][CH2:53][CH3:54])[N:10]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:11]=1[C:12]([OH:14])=[O:13])([CH3:6])[CH3:5].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:64][C:65]1[O:66][C:67](=[O:71])[O:68][C:69]=1[CH3:70]>CC(C)=O>[CH3:54][CH2:53][CH2:52][C:9]1[N:10]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:32][N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:11]([C:12]([O:14][CH2:70][C:69]2[O:68][C:67](=[O:71])[O:66][C:65]=2[CH3:64])=[O:13])=[C:7]([C:4]([OH:3])([CH3:6])[CH3:5])[N:8]=1
Reactant: Cc1oc(=O)oc1CCl
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCc2oc(=O)oc2C)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: -12.5 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
4-(1-hydroxy-1-Methylethyl)-2-propyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methyl imidazole-5-carboxylic acid dihydrate (250 g) in acetone (4000 ml) was added to suspension of potassium carbonate (50 g), potassium iodide (15 g) & 4-chloromethyl-5-methyl-1,3-dioxol-2-one (75 g) in acetone (1500 ml) at reflux temperature. Reaction mass was refluxed for 2-6 hrs. Progress of reaction was monitor by HPLC. After completion of reaction mass was filtered, distilled the acetone from filtrate & dissolved the residue obtained in toluene (2500 ml). Toluene layer was washed with brine & dried (Na2SO4). Toluene layer was filtered & cooled to −5 to −20° C. Conc hydrochloric acid (600 ml) was added slowly to above reaction mass at −5 to −20° C. & Stir for 1 hr at −5 to −20° C. Separated the two layers. Ethyl acetate (3000 ml) was added to aqueous layer. The pH of combined layers was adjusted to 5.0-6.5 by slowly adding potassium carbonate solution. Both the layers were separated (Store the ethyl acetate layer containing compound). Aqueous layer was extracted with ethyl acetate (3×2000 ml). The combined organic layer was washed with brine. Ethyl acetate was partially distilled (about 85% of original volume) from organic layer containing compound under reduced pressure. Reaction mass was cooled, filtered, washed with ethyl acetate (3×200 ml) & dried to get Olmesartan Medoxomil (150 g).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C@@H:9]([C:11]([OH:13])=[O:12])[NH2:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[ClH:16].[CH3:17]O>>[ClH:16].[NH2:10][CH:9]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:15][CH:14]=1)[C:11]([O:13][CH3:17])=[O:12]
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)C(N)Cc1ccc([N+](=O)[O-])cc1

Procedure:
A solution of p-nitro-L-phenylalanine (12.6 g) and c.HCl (7.5 g) in methanol (150 ml) was refluxed for 1.5 hours and the solvent then evaporated in vacuo. The residue was triturated with ether and recrystallised from SVM to give the desired product as a off-white solid, [α]25 +15.3° (c=0.55, MeOH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[N:29]1([CH2:34][CH2:35][NH2:36])[CH2:33][CH2:32][CH2:31][CH2:30]1>C(Cl)Cl>[N:29]1([CH2:34][CH2:35][NH:36][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)=[O:10])[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: NCCN1CCCC1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(NCCN1CCCC1)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Bromo-pyridine-2-carboxylic acid (0.81 g, 4 mmol) was combined with 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (0.85 g, 4.8 mmol) and diluted with DCM (20 mL). This was immediately treated with 4-methyl morpholine (0.81 g, 8 mmol) and allowed to stir at ambient temperature for 1 h. 2-Pyrrolidin-1-yl-ethylamine (0.46 g, 4 mmol) was then added in one portion. Stirring was continued overnight. Reaction solvents were removed and residue was taken up in ethyl acetate and washed once with water. Aqueous phase was back extracted once with fresh ethyl acetate. Organic phases were combined, washed once with brine and dried over sodium sulfate. Filtration followed by rotary evaporation provided product as yellow oil which solidified upon standing. Yellowish solids (0.5 g, 42%)
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:24](=[O:25])[NH:23][N:22]=[CH:21][C:10]3=[C:11]([C:15]4[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=4)[NH:12][C:13]([CH:14]=1)=[C:9]23)=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C>[CH2:32]([NH:39][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:24](=[O:25])[NH:23][N:22]=[CH:21][C:10]3=[C:11]([C:15]4[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=4)[NH:12][C:13]([CH:14]=1)=[C:9]23)=[O:4])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Cn1cc(-c2[nH]c3cc(NC(=O)CCl)cc4c3c2C=NNC4=O)cn1
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2[nH]c3cc(NC(=O)CNCc4ccccc4)cc4c3c2C=NNC4=O)cn1
Temperature: 50 °C
Yield: 12.5 %

Procedure:
To a solution of 2-Chloro-N-[2-(1-methyl-1H-pyrazol-4-yl)-6-oxo-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-yl]-acetamide 270(a) (100 mg, 0.28 mmol) in DMF (1.5 mL) was added Cs2CO3 (˜5 eq.) followed by benzyl amine (33 mg, 0.3 mmol.). The resulting mixture was heated at 50° C. overnight. Excess Cs2CO3 was filtered and the clear dark solution was purified by reverse phase HPLC to afford 15 mg of desired product as yellow solids.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:26][CH2:27]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:25])[C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:34]1([C:40]2([C:46]([NH2:48])=[O:47])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:26][CH2:27][N:43]3[CH2:42][CH2:41][C:40]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)([C:46]([NH2:48])=[O:47])[CH2:45][CH2:44]3)[CH2:13][CH2:12][N:11]([C:14](=[O:25])[C:15]3[CH:16]=[CH:17][C:18]([C:21]([CH3:22])([CH3:23])[CH3:24])=[CH:19][CH:20]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: CC(C)(C)c1ccc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc1
Agent: Cl
Product: CC(C)(C)c1ccc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc1

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3,4-dichloro-phenyl)-1-(4-tert-butyl-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (0.6 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (0.72 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [Cl-].[C:2]([C:4]1[C:16]([N+:17]([O-])=O)=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][NH2+:9]1)#[N:3].[CH2:20]([N:23]=[C:24]=[O:25])[CH2:21][CH3:22]>>[NH2:17][C:16]1[C:4]([C:2]#[N:3])=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:24]([NH:23][CH2:20][CH2:21][CH3:22])=[O:25]
Reactant: CCCN=C=O
Reactant: N#Cc1c(OC[C@@H]2CCC[NH2+]2)cccc1[N+](=O)[O-]
Agent: [Cl-]
Product: CCCNC(=O)N1CCC[C@H]1COc1cccc(N)c1C#N
Yield: 100 %

Procedure:
Prepared as in Example 209a from (S)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride (Example 209b) and propyl isocyanate in 100% yield as a white solid. MS 303 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10]N=N[C:7]=2[CH:11]=1.[C:12]1([N:18]=[C:19]=[S:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:19](=[N:18][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[S:20][C:7]=2[CH:11]=1
Reactant: COc1ccc2snnc2c1
Reactant: S=C=Nc1ccccc1
Product: COc1ccc2sc(=Nc3ccccc3)sc2c1

Procedure:
A solution of 5-methoxy-1,2,3-benzothiadiazole (5 g) in 50 ml of phenyl isothiocyanate is heated at 220° C under an inert atmosphere until the evolution of nitrogen ceases (about two hours). The excess phenyl isothiocyanate is removed in vacuo. The resultant residue is chromatographed on silica gel (500 ml) eluting with pentane/dichloromethane (4:1). Fractions containing the desired product (Rf =0.2, silica gel, benzene) are combined and concentrated in vacuo. The resultant solid is recrystallized from pentane to yield 2.8 g of the title compound, melting point 58°-60° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[NH2:8].[C:23](O)(=O)[CH3:24].C(=O)C=O>C(#N)C>[C:17]1([C:15]([N:12]2[CH2:11][CH2:10][N:9]([C:4]3[CH:3]=[C:2]4[C:7](=[CH:6][CH:5]=3)[N:8]=[CH:24][CH:23]=[N:1]4)[CH2:14][CH2:13]2)=[O:16])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1N
Reactant: CC(=O)O
Agent: O=CC=O
Solvent: CC#N
Product: O=C(c1ccccc1)N1CCN(c2ccc3nccnc3c2)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 28.1 %

Procedure:
A suspension of (4-(3-amino-4-nitrophenyl)piperazin-1-yl)(phenyl)methanone (2.0 g, 9.0 mmol), 5 ml acetic acid and palladium on carbon (100 mg, 5%) in 50 ml ethanol was stirred at room temperature under hydrogen atmosphere overnight. The mixture was filtered with the aid of celite. Crude (4-(3,4-diaminophenyl)piperazin-1-yl)(phenyl)methanone (1.2 g, 41%) was obtained after removing of solvents. A suspension of (4-(3,4-diaminophenyl)piperazin-1-yl)(phenyl)methanone (0.2 g, 0.67 mmol), acetic acid (0.23 ml, 4.0 mmol) and 40% oxalaldehyde (0.14 ml, 1.0 mmol) in 40 ml acetonitrile was stirred at 50° C. under argon atmosphere overnight. The reaction was quenched with the 5 ml water and extracted with ethyl acetate (3×40 ml). The extraction was concentrated after drying over anhydrous sodium sulfate. Phenyl(4-(quinoxalin-6-yl)piperazin-1-yl)methanone (0.060 g, 28%) was obtained by flash column chromatograph (10% acetone in ethyl acetate). 1H NMR (500 MHz, CDCl3) δ (ppm) 3.37 (d, br, 4H), 3.69 (s, br, 2H), 4.01 (s, br, 2H), 7.30 (d, J=2.7 Hz, 1H), 7.48 (m, 5H), 7.50 (dd, J=9.3, 2.7 Hz, 1H), 7.56 (d, J=9.3 Hz, 1H), 8.65 (d, J=1.9 Hz, 1H), 8.73 (d, J=1.9 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ (ppm) 49.1, 49.3, 110.8, 123.0, 127.6, 29.0, 130.4, 130.5, 1135.7, 139.0, 142.6, 144.9, 151.9, 145.6, 170.9.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1([C:12]([C@@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)=O)[CH2:11][CH2:10][CH2:9][CH2:8]1.O.[OH-].[Na+]>O1CCCC1>[N:7]1([CH2:12][C@@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C([C@@H]1CCCN1)N1CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C1CN[C@H](CN2CCCC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
A 1.0 M solution of lithium aluminium hydride in tetrahydrofuran (87 ml, 87 mmol) was added dropwise to a solution of the crude (pyrrolidin-1-yl)-((S)-pyrrolidin-2-yl)methanone (4.89 g, 29 mmol) in tetrahydrofuran (90 ml). The reaction mixture was heated to reflux for 6 h. It was cooled to room temperature. Water (3.6 ml) was added carefully. A 1 N solution of sodium hydroxide (3.6 ml, 3.6 mmol) was added carefully. Water (10.7 ml) was added. The mixture was stirred for 1 h at room temperature. The precipitation was filtered off. The solvent was removed in vacuo to give 2.67 g of (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=O.[CH2:11]([NH2:14])[CH2:12][NH2:13].[BH4-].[Na+].C(NCCN)C1C=CC=CC=1>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][NH:13][CH2:12][CH2:11][NH2:14]
Reactant: NCCN
Reactant: O=Cc1cc(F)cc(F)c1
Agent: NCCNCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NCCNCc1cc(F)cc(F)c1
Yield: 55 %

Procedure:
At 16.77 g (0.118 mol) quantity of 3,5-difluorobenzaldehyde was treated with 50 ml ethylenediamine and 4.47 g (0.118 mol) sodium borohydride in 500 ml methanol by the method prescribed for N-benzylethylenediamine (Example 1) to give 12.0 g (55% yield) of desired product, b.p. 90°-92° C. at 199.98-226.65 Nm-2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH:12]1(O)[CH2:23][CH2:22]C[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4].CO>[CH:1]1([O:2][C:3](=[O:11])[C:4]2[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=2)[CH2:22][CH2:23][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: OC1CCCCCCCCCCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CO
Product: O=C(OC1CCCCCCCCCCC1)c1ccc(O)cc1
Temperature: 160 °C
Reaction time: 5 h

Procedure:
22.82 g (0.15 mol) p-hydroxybenzoic acid methyl ester, 55.30 g (0.30 mol) cyclododecanol and 28 mg (0.1 mmol) tetraisopropyl orthotitanate are placed under argon in a round-bottom flask with distillation bridge. The mixture is stirred and heated to 160° C. within one hour. On reaching this temperature the pressure is reduced to 900 mbar and during the further course of the reaction to 800 mbar, during which time methanol is removed by distillation. Stirring is continued for 5 hours at this temperature. A further 0.05 ml tetraisopropyl orthotitanate are added and the reaction mixture is stirred for a further 20 hours at 170° C. under normal pressure. The residue undergoes column chromatography (silica gel 60, 0040-0.063 mm, Merck). An n-hexane/acetone mixture (5:1) is used as eluent. The product obtained in this way is freed from adhering cyclododecanol under high vacuum at 140° C. The residue is recrystallised in acetone. 5.9 g (13%) in the form of colourless crystals are obtained:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[N:31]([CH3:32])[C:11]2[CH:12]=[C:13]([C:26](OCC)=[O:27])[C:14]3[CH2:15][CH2:16][CH:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[NH:18][C:19]=3[C:10]=2[N:9]=1.[OH-].[K+].S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1.O>[OH:27][CH2:26][C:13]1[C:14]2[CH2:15][CH2:16][CH:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:18][C:19]=2[C:10]2[N:9]=[C:8]([CH3:7])[N:31]([CH3:32])[C:11]=2[CH:12]=1
Reactant: CCOC(=O)c1cc2c(nc(C)n2C)c2c1CCC(c1ccccc1)N2
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2c3c(c(CO)cc2n1C)CCC(c1ccccc1)N3
Reaction time: 2 h
Yield: 31.4 %

Procedure:
To a suspension of 0.2 g (5.3 mmol) lithium aluminium hydride in 15 ml tetrahydrofuran was slowly added a solution of 1.0 g (2.9 mmol) ethyl 2,3-dimethyl-8-phenyl-6,7,8,9-tetrahydro-3H-imidazo[4,5-h]quinoline-5-carboxylate in 5 ml tetrahydrofuran. After 2 h, the reaction mixture was carefully hydrolyzed with 0.1 ml water, 0.2 ml 6N aqueous potassium hydroxide and 0.1 ml water. Anhydrous magnesium sulfate was added and the mixture was stirred 1 h. After filtration through celite, the filtrate was evaporated and the residue purified by column chromatography on silica gel (dichloromethane/methanol=13:1). Crystallization from acetone yielded 0.28 g (32%) of the title compound as a colourness solid. m.p. 253-254° C.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH3:28][S:29]([C:32]1[S:36][C:35]([C:37](O)=[O:38])=[CH:34][CH:33]=1)(=[O:31])=[O:30]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:37]([C:35]5[S:36][C:32]([S:29]([CH3:28])(=[O:31])=[O:30])=[CH:33][CH:34]=5)=[O:38])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)s1
Agent: Cl
Product: CS(=O)(=O)c1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCN(c4nccc5c4CCO5)CC3)CC2)s1

Procedure:
The title compound, off-white solid (98 mg, 76%), MS (ISP) m/z=519.2 [(M+H)+], mp 229° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 5-methanesulfonyl-thiophene-2-carboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH:10]1[CH2:25][C:26]([O:28]CC)=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)C.[OH-].[Na+].Cl>O1CCCC1>[CH2:18]([O:17][C:15]([N:11]1[CH2:12][CH2:13][CH2:14][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH:10]1[CH2:25][C:26]([OH:28])=[O:27])=[O:16])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)CC1C(NC(=O)OC(C)(C)C)CCCN1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCCN(C(=O)OCc2ccccc2)C1CC(=O)O
Yield: 104.4 %

Procedure:
Benzyl (2RS,3SR)-3-[(tert-butoxycarbonyl)amino]-2-(2-ethoxy-2-oxoethyl)piperidine-1-carboxylate (3.08 g), ethanol (30 mL), tetrahydrofuran (8 mL) and aqueous 2N sodium hydroxide solution (4.4 mL) were stirred at room temperature for 4 hours. The reaction solution was neutralized with aqueous 2N hydrochloric acid solution and then concentrated. The residue was added water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, concentrated and obtained the title compound (3.00 g) having the following physical properties.