Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:20](=[O:22])[CH2:19][CH:18]([CH2:23][CH2:24][CH3:25])[CH2:17][C:16]=3[NH:15][C:14]([CH3:26])=[C:13]2[C:27]#[N:28])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8].C(N(CC)C(C)C)(C)C.[CH3:38][O:39][C:40]1[CH:48]=[CH:47][CH:46]=[CH:45][C:41]=1[C:42](Cl)=[O:43]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:20](=[O:22])[CH2:19][CH:18]([CH2:23][CH2:24][CH3:25])[CH2:17][C:16]=3[NH:15][C:14]([CH3:26])=[C:13]2[C:27]#[N:28])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[O:8][C:42](=[O:43])[C:41]1[CH:45]=[CH:46][CH:47]=[CH:48][C:40]=1[O:39][CH3:38]
Reactant: COc1ccccc1C(=O)Cl
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(O)c([N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OC(=O)c2ccccc2OC)c([N+](=O)[O-])c1
Reaction time: 4 h

Procedure:
A mixture of 4-(3-bromo-4-hydroxy-5-nitro-phenyl)-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydro-quinoline-3-carbonitrile (200 mg), N,N-diisopropylethylamine (390 μl) and 2-methoxy-benzoyl chloride (53 μl) in dichloromethane (4 ml) was stirred for 4 h. The mixture was diluted with dichloromethane and washed with water. The organic layer was dried (MgSO4), filtered and concentrated in vacuo.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[NH:22][C:21]3[C:20](=[O:23])[N:19]([CH3:24])[C:18](=[O:25])[N:17]([CH3:26])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O)=[O:28].N1C=CC=CC=1>O1CCCC1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:22]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[CH:27]=[O:28])[C:21]3[C:20](=[O:23])[N:19]([CH3:24])[C:18](=[O:25])[N:17]([CH3:26])[C:16]=3[N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(=O)c2[nH]c(N3CCN(C(=O)OC(C)(C)C)CC3)nc2n(C)c1=O
Reactant: O=Cc1ccccc1B(O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cn1c(=O)c2c(nc(N3CCN(C(=O)OC(C)(C)C)CC3)n2-c2ccccc2C=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 120 h
Yield: 17.6 %

Procedure:
4-(1,3-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperazine-1-carboxylic acid tert-butyl ester (226 mg), 2-formylphenyl boronic acid (200 mg), and copper (II) acetate (200 mg) were suspended in anhydrous tetrahydrofuran (5 ml), and pyridine (0.2 ml) was added thereto. The reaction mixture was stirred at room temperature for 5 days, filtered through a short column filled with silica gel, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain 51 mg of the title compound from a fraction eluted with hexane-ethyl acetate (1:1).
Reaction SMILES: [C:1]([O:5][C:6]([N-:8][S:9]([N:12]1[CH:17]=C[C:15](=[N+](C)C)[CH:14]=[CH:13]1)(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].C[NH2+]C1CC[O:26][CH2:25]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:17][N:12]([CH:13]1[CH2:14][CH2:15][O:26][CH2:25]1)[S:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])(=[O:10])=[O:11]
Reactant: C[NH2+]C1CCOC1
Reactant: C[N+](C)=c1ccn(S(=O)(=O)[N-]C(=O)OC(C)(C)C)cc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C1CCOC1)S(=O)(=O)NC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
A flask was charged with N-tert-butoxycarbonyl-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin-1-ylsulfonyl]azanide (2.19 g, 7.27 mmol), N-methyltetrahydrofuran-3-aminium chloride (1.00 g, 7.27 mmol) and triethyl amine (1.01 mL, 7.27 mmol) in 10 mL of CH2Cl2. After 2 h, the solution was concentrated in vacuo and purified by flash column chromatography (10-100% EtOAc/hexanes) to afford tert-butyl {[methyl(tetrahydrofuran-3-yl)amino]sulfonyl}carbamate. tert-butyl {[methyl(tetrahydrofuran-3-yl)amino]sulfonyl}carbamate (1.47 g, 5.23 mmol) was dissolved in 70 mL of CH2Cl2 and 45 mL of trifluoroacetic acid. After 1 h the solution was concentrated in vacuo, diluted in CH2Cl2, washed with saturated aqueous NaHCO3 and brine, then dried over Na2SO4. The solution was concentrated in vacuo to afford the title compound. 1H NMR (600 MHz, DMSO-d6) δ 4.25-4.31 (m, 1H); 3.79-3.84 (m, 1H); 3.58-3.66 (m, 2H); 3.47-3.52 (m, 1H); 2.56 (s, 3H), 2.04-2.10 (m, 1H); 1.81-1.88 (m, 1H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(C)N=NCCO)(OCC)=O.[C:32]([N:35]([CH3:41])[N:36]=[N:37][CH2:38][CH2:39]O)(=[O:34])[CH3:33].C(Cl)(Cl)(Cl)[Cl:43]>CCCCC>[C:32]([N:35]([CH3:41])[N:36]=[N:37][CH2:38][CH2:39][Cl:43])(=[O:34])[CH3:33]
Reactant: CC(=O)N(C)N=NCCO
Reactant: ClC(Cl)(Cl)Cl
Agent: CCOC(=O)N(C)N=NCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCC
Product: CC(=O)N(C)N=NCCCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of triphenylphosphine (5.89 g, 2.25×10-2 mol) and 3-carboethoxy-1-(2 hydroxyethyl)-3-methyltriazene, 5b, (2.9 g, 2.0×10 -2 mol) in 50 mL of carbon tetrachloride (dried over 3A molecular sieves) was refluxed overnight under nitrogen. The reaction mixture was cooled to room temperature and diluted with pentane (250 mL). After standing at 10° C. overnight, the reaction mixture was filtered through a pad of Celite to remove precipitated triphenylphosphine oxide. The filtrate was concentrated on a rotary evaporator at 220° C., the residue (4.2 g) was dissolved in a minimum amount of ether and chromatographed on a column of 35 g of Silica Gel 60 packed in 10% ether in pentane and eluted with 600 mL of this same solvent mixture. Evaporation of the eluent on a rotary evaporator and vacuum transfer (40° C./0.005 mm) of the residue gave 1.94 g 0.0119 mol, 59.6%) of 3-acetyl-1-(2-chloroethyl)-3-methyltriazene, 6b; IR (CCl4) 2970, 1710, 1515, 1145, 990 cm10-1 ; UV (CH3CN) λmax 238 (log ε 4.23); 1H NMR (CDCl3, Me4Si) δ 3.45 (CH3,s), 3.23 (N--CH3, s), 3.90 (Cl--CH2,t,J=5.5 Hz), 4.12 (CH2 -N,t,J=5.5 Hz); proton decoupled 13C NMR (CDCl3, Me4Si) δ 21.85 (CH3 (, 26.92 (N--C H3), 41.78 Cl--CH2), 62.68 (CH2 --N), 63.17 (0--CH2CH3), 173.0 (C=0); exact mass calcd. m/z for C5H10N3OC1 163.0512, found 163.0506 (by EI).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([F:9])[C:6]([N+:10]([O-])=O)=[CH:5][C:4]=1[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:2]>CO.CCOC(C)=O.[Pd]>[NH2:10][C:6]1[C:7]([F:9])=[CH:8][C:3]([C:1]#[N:2])=[C:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=1
Reactant: CCOC(=O)Cc1cc([N+](=O)[O-])c(F)cc1C#N
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)Cc1cc(N)c(F)cc1C#N
Temperature: 25 °C
Reaction time: 72 h
Yield: 81 %

Procedure:
To a solution of ethyl 2-(2-cyano-4-fluoro-5-nitrophenyl)acetate in methanol and EtOAc (1:1, 10 mL) was added 10% Pd/C. The solution was stirred under H2 (1 arm) at RT for 3 days. The solution was filtered and evaporated to obtain ethyl 2-(5-amino-2-cyano-4-fluorophenyl)acetate (0.21 g, 81% yield).
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].C([Li])CCC.C([N-]C(C)C)(C)C.[Li+].[CH:21]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:25][CH:24]=[CH:23][CH2:22]1.ICC>C1COCC1>[CH2:1]([C:21]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:25][CH:24]=[CH:23][CH2:22]1)[CH3:2]
Reactant: CCOC(=O)C1CC=CC1
Reactant: CC(C)NC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCI
Product: CCOC(=O)C1(CC)CC=CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To a solution of diisopropylamine (10 mL, 72 mmol) in anhydrous THF (50 mL) was added n-butyl lithium (29 mL, 72 mmol, 2.5 M solution in hexane) over 20 min at −78° C. The mixture was stirred at 0° C. under nitrogen for 1 h. The freshly prepared lithium diisopropylamide was added to a mixture of ethyl cyclopent-3-enecarboxylate (6.7 g, 47.9 mmol) in anhydrous THF (50 mL) over 20 minutes at −78° C. After another 1 hour at this temperature, iodoethane (11.2 g, 72 mmol) was added over 20 min. Then the mixture was stirred at room temperature for 2 h and quenched with saturated aqueous ammonium chloride solution. The aqueous layer was extracted with ether (3×100 mL). The combined organic layers were washed with diluted hydrochloric acid (1 N), then washed with brine, dried over anhydrous sodium sulfate and filtered. Concentration gave the titled compound (7 g crude) which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 5.60 (s, 2H), 4.21-4.12 (m, 2H), 2.92-2.84 (m, 2H), 2.31-2.25 (m, 2H), 1.75-1.67 (m, 2H), 1.29-1.24 (m, 3H), 0.88-0.82 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[O:12][C:13]3[CH:30]=[CH:29][CH:28]=[CH:27][C:14]=3[C:15]=2[NH:16][C:17](=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]C)=[O:23])=[O:10])=[N:6][CH:7]=1.[OH-].[Na+].Cl>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[O:12][C:13]3[CH:30]=[CH:29][CH:28]=[CH:27][C:14]=3[C:15]=2[NH:16][C:17](=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[O:10])=[N:6][CH:7]=1
Reactant: COC(=O)CCCCC(=O)Nc1c(C(=O)Nc2ccc(Cl)cn2)oc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCCC(=O)Nc1c(C(=O)Nc2ccc(Cl)cn2)oc2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.1 %

Procedure:
Methyl 6-[(2-{[(5-chloropyridin-2-yl)amino]-carbonyl}benzofuran-3-yl)amino]-6-oxohexanoate (4.30 g) obtained in Example 10(1) is suspended in methanol (5 m), and thereto is added at room temperature 2N aqueous sodium hydroxide solution (30 ml). The mixture is stirred at room temperature for 4 hours, and at 50° C. for 2 hours. The reaction solution is diluted with water and acidified by addition of 10% hydrochloric acid under ice-cooling, and the precipitates are collected by filtration and dried to give the title compound (3.54 g). ESI-MS M/Z:414/416[M−H]−
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[N:3]1.[CH2:12]([N:15]([CH2:24][CH2:25][CH3:26])[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1)[CH2:13][CH3:14].O>C1C=CC=CC=1>[CH2:24]([N:15]([CH2:12][CH2:13][CH3:14])[C:16]1[CH:17]=[CH:18][C:19]([CH:20]2[O:21][C:2]([CH3:1])([CH3:11])[N:3]=[C:4]2[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH:22][CH:23]=1)[CH2:25][CH3:26]
Reactant: CCCN(CCC)c1ccc(C=O)cc1
Reactant: CC1(C)N=C1c1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: CCCN(CCC)c1ccc(C2OC(C)(C)N=C2c2ccccc2)cc1

Procedure:
10 g of 2,2-dimethyl-3-phenyl-2H-azirine and 10 g of 4-dipropylaminobenzaldehyde were exposed to light in 2 liters of benzene under an atmosphere of argon for 40 minutes with a mercury high-pressure lamp of 2000 watt in a ring-mantle vessel through an interposed filter fluid. The filter fluid contained 35 g of cupric sulfate pentahydrate per liter of water and had a layer thickness of 1 cm. Not only the reaction solution but also the filter solution were cooled during the exposure to light in that they circulated with aid of pumps through a heat-exchanger positioned outside the photoreactor. During the exposure to light the temperature of the reaction solution amounted to 26° C. measured outside the photoreactor.
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]([C:19]([OH:21])=O)=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:8]=1)=[N+:2]=[N-:3].C[N:23](C(N(C)C)=[N+]1C2C(=NC=CC=2)N=N1)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[Cl-].[NH4+]>CN(C)C=O>[N:1]([C:4]1[S:5][C:6]([C:19]([NH2:23])=[O:21])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:8]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1nc(-c2cccc(C(F)(F)F)c2)c(C(=O)O)s1
Reactant: CN(C)C(N(C)C)=[N+]1N=Nc2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: [N-]=[N+]=Nc1nc(-c2cccc(C(F)(F)F)c2)c(C(N)=O)s1
Reaction time: 2.25 h
Yield: 83.8 %

Procedure:
A solution of 2.20 g (7.01 mmole) of 2-azido-4-(3-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid, 38 mL of dimethylformamide, 3.47 g (8.85 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium, 3-oxide, hexafluorophosphate(1-) (1:1) and 3.75 mL (21.53 mmole) of ethyldiisopropylamine was stirred at room temperature for 23 minutes, then 0.5733 g (10.72 mmole) of ammonium chloride was added. The mixture was stirred for 2.25 hours, then concentrated under reduced pressure and partitioned between 300 mL of ethyl acetate and 75 mL of water. The ethyl acetate layer was washed twice with 60 mL of water, twice with 55 mL of saturated aqueous sodium bicarbonate, once with 50 mL of brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate-hexanes (gradient 10:90-100-:0) to give 1.841 g 2-azido-4-(3-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid amide as a light yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19][CH2:20][C:21](Cl)=[O:22].C(N(CC)CC)C>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:21](=[O:22])[CH2:20][CH2:19][C:15]2[O:14][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C(Cl)CCc1ccco1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCc1ccco1)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 83.3 %

Procedure:
A solution of 1-benzylpiperazine (352 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and 3-(furan-2-yl)propionyl chloride (396.5 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:2). The fractions containing the 1-(4-benzylpiperazin-1-yl)-3-(furan-2-yl)propan-1-one are collected and the solvent is removed in vacuo to give 497 mg of colorless oil.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:44]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH:41]6[CH:42]([OH:43])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:53]([CH3:55])[CH3:54])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH:59]([CH3:61])[CH3:60]>CN(C)C=O>[C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:44]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH:41]6[CH:42]([O:43][CH:59]([CH3:61])[CH3:60])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:53]([CH3:55])[CH3:54])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)Br
Reactant: CC(C)C1=CC2CC3(C=O)C4CCC(C)C4CC2(COC24OC5OC(C(O)C5O2)C4O[Si](C)(C)C(C)(C)C)C13C(=O)OC(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)OC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)OC(c4ccccc4)c4ccccc4)OC2OC1C3O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
50 mg of compound (6) was dissolved in 1.0 ml of dry dimethylformamide under a nitrogen atmosphere and mixed with about 3 mg of sodium hydride under cooling with ice. After 30 minutes, 12.2 μl of 2-bromopropane was added, and the reaction solution was stirred at room temperature. The reaction solution was allowed to react for 63 hours, while about 3 mg of sodium hydride and 12.2 μl of 2-bromopropane were added after 40 hours and further after 46 hours. Then, the reaction solution was charged onto a silica gel column (Kieselgel 60, Merck, 1.0φ×30 cm) and eluted with n-hexane-ethyl acetate (2:1). The fraction containing the desired product was concentrated to dryness to give 13.6 mg of compound (33).
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19].C(N(CC)CC)C.Cl>C(Cl)Cl>[Br:1][CH:2]([CH3:6])[C:3]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:4]
Reactant: CC(Br)C(=O)Cl
Reactant: NCCCCCCCCCCC(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Br)C(=O)NCCCCCCCCCCC(=O)O

Procedure:
30.65 g (178.8 mmol) of α-bromopropionic acid chloride is added in drops at 0° C. to 30 g (149 mmol) of 11-aminoundecanoic acid and 45.24 g (447.1 mmol) of triethylamine in 600 ml of methylene chloride. In this case, the temperature remains between 0° C.-5° C. 800 ml of 5% aqueous hydrochloric acid is added, and the organic phase is separated. The organic phase is extracted once more with 300 ml of 5% aqueous hydrochloric acid, dried on magnesium sulfate and evaporated to dryness in a vacuum. The residue is recrystallized from acetone/diisopropyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[C:6]([F:10])[C:7]=1[CH2:8][OH:9].[CH3:12][O:13][CH2:14][CH2:15][CH2:16]OS(C1C=CC(C)=CC=1)(=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH2:16][CH2:15][CH2:14][O:13][CH3:12])[CH:5]=[C:6]([F:10])[C:7]=1[CH2:8][OH:9]
Reactant: COCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: OCc1c(F)cc(O)cc1Cl
Product: COCCCOc1cc(F)c(CO)c(Cl)c1
Yield: 90 %

Procedure:
This compound was prepared from 3-chloro-5-fluoro-4-hydroxymethyl-phenol and toluene-4-sulfonic acid 3-methoxy-propyl ester according to the procedure described in Example 179 to give the product as a yellowish oil (382 mg, 90%); MS (EI): 248.1 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[CH2:11][CH2:12][CH2:13][OH:14])=[CH:4][CH:3]=1.O.[NH2:18][NH2:19].[Cl-].[NH4+]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][OH:14])[NH:19][N:18]=2)=[CH:4][CH:3]=1
Reactant: O=C(CCCO)CC(=O)c1ccc(F)cc1
Reactant: NN
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: OCCCc1cc(-c2ccc(F)cc2)n[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
To a solution of 1-(4-fluorophenyl)-6-hydroxyhexane-1,3-dione (38 g, 0.17 mol) in 150 mL ethanol and hydrazine hydrate (17.05 g, 0.34 mol) is added slowly over a 30 min period (exothermic up to 35° C.). The resulting solution is stirred for 1 h at RT then the mixture is added to aqueous ammonium chloride. Extraction with ethyl acetate and evaporation of the organic phase results in the crude product. The product is purified by trituration with 2×200 mL n-hexane and the product is obtained as solid (29 g, 77%).
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17](=[O:19])[CH3:18]>CN(C=O)C>[CH2:3]([S:10][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17](=[O:19])[CH3:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)OCCCCBr
Reactant: SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCCCCSCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (0.45 g, 60% in mineral oil, 11.1 mmol) in DMF (5 mL) is added benzylmercaptan (1.43 mL, 11.03 mmol) and the resulting yellow solution is stirred at RT for 30 min. The mixture is cooled to 0° C. then acetic acid 4-bromobutyl ester (2.2 g, 11.2 mmol) is added dropwise (exothermic). The mixture is allowed to warm to RT and is quenched with 1N HCl (35 mL). The mixture is extracted with MTBE and the organic phase is dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue is purified by flash chromatography using EtOAc/hexane (4:1) as eluent to give the title compound as an oil.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH:20]4[CH:15]([CH2:16][CH2:17][NH:18][CH2:19]4)[CH2:14]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[C:37]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:38]([C:43](O)=[O:44])=[CH:39][CH:40]=[CH:41][CH:42]=1.S1C=CC=C1C1C=CC=CC=1C(O)=O>>[C:37]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]([N:18]1[CH2:17][CH2:16][CH:15]2[CH:20]([N:13]([C:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:12]=[CH:11][N:10]=3)[CH2:14]2)[CH2:19]1)=[O:44]
Reactant: c1ccc(-c2ccnc(N3CC4CCNCC43)n2)cc1
Reactant: O=C(O)c1ccccc1-c1ccccc1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Product: O=C(c1ccccc1-c1ccccc1)N1CCC2CN(c3nccc(-c4ccccc4)n3)C2C1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting 8-(4-phenyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane (Intermediate 6) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and biphenyl-2-carboxylic acid for 2-thiophen-2-yl-benzoic acid. MS (ESI) mass calcd. for C29H26N4O, 446.54; m/z found, 447.3 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.44-7.28 (m, 13H), 7.27-6.79 (m, 3H), 4.70-3.66 (m, 4H), 3.59-2.31 (m, 3H), 2.19-0.93 (M, 3H).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[OH:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]2[CH:22]3[CH2:31][CH2:30][CH2:29][CH:23]3[C:24](=[O:28])[NH:25][C:26]=2[CH:27]=1>CN(C=O)C.C(OCC)(=O)C>[Si:1]([O:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]2[CH:22]3[CH2:31][CH2:30][CH2:29][CH:23]3[C:24](=[O:28])[NH:25][C:26]=2[CH:27]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C1Nc2cc(CCCO)ccc2C2CCCC12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCc1ccc2c(c1)NC(=O)C1CCCC21
Reaction time: 3 h
Yield: 105.3 %

Procedure:
At 0° C., 3.65 g (24.5 mmol) of tert-butyldimethylsilyl-chloride and 3.29 g (48.9 mol) of imidazole are added to a solution of 3.0 g (12.2 mmol) of 7-(3-hydroxypropyl)-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one in 50 ml of DMF. After 3 hours, the batch is diluted with ethyl acetate, washed with water, 10% citric acid and saturated NaHCO3, dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography with hexane-ethyl acetate on silica gel yields 4.62 g of product.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:13]1([C:19]2[N:23]=[C:22]([CH2:24][C:25](O)=[O:26])[O:21][N:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1CCCCC1>C(O)C>[CH2:11]([O:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:24]([C:22]3[O:21][N:20]=[C:19]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:23]=3)[C:25](=[O:26])[O:1]2)=[CH:6][CH:7]=1)[CH3:12]
Reactant: CCOc1ccc(C=O)c(O)c1
Reactant: O=C(O)Cc1nc(-c2ccccc2)no1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOc1ccc2cc(-c3nc(-c4ccccc4)no3)c(=O)oc2c1

Procedure:
5 parts of 2-hydroxy-4-ethoxy benzaldehyde and 7 parts of the ethyl ester of 3-phenyl-1,2,4-oxadiazole-5-acetic acid are dissolved in 80 parts of ethanol, then 0.3 part of piperidine is added. The mixture is heated under reflux for one hour, then the precipitate obtained after cooling is filtered. 8 parts of 7-ethoxy-3-(3-phenyl 1,2,4-oxadiazol-5-yl) coumarin are obtained which melts at 229° C. after crystallization in dioxane.