Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:21][NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]3[CH3:20])=[C:4]([O:31][CH3:32])[CH:3]=1.C(=O)([O-])O.[Na+].[CH:38]1[C:50]2[CH:49]([CH2:51][O:52][C:53](Cl)=[O:54])[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:42]=2[CH:41]=[CH:40][CH:39]=1>O1CCOCC1.O.C(OCC)(=O)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:21][N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])[C:53]([O:52][CH2:51][CH:49]3[C:48]4[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=4[C:42]4[C:50]3=[CH:38][CH:39]=[CH:40][CH:41]=4)=[O:54])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]3[CH3:20])=[C:4]([O:31][CH3:32])[CH:3]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: COc1ccccc1NCc1c(-c2ccc(O)cc2OC)ccc2c1C(C)=CC(C)(C)N2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cc(O)ccc1-c1ccc2c(c1CN(C(=O)OCC1c3ccccc3-c3ccccc31)c1ccccc1OC)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 34 %

Procedure:
6-(4-Hydroxy-2-methoxyphenyl)-5-(2-methoxyphenylaminomethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 4-1, 37.7 mg, 0.0876 mmol) and sodium hydrogen carbonate (9.5 mg, 0.113 mmol) were dissolved in 1,4-dioxane (0.5 mL)-water (0.5 mL), and then 9-fluorenylmethoxycarbonyl chloride (25.6 mg, 0.0990 mmol) was added thereto under ice cooling. After the reaction mixture was stirred at room temperature for 3 hours, it was diluted with ethyl acetate (10 mL). The mixture was washed with 1N aqueous HCl solution (10 mL), water (10 mL) and saturated brine (10 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (19.7 mg) as a colorless amorphous product. (Yield 34%)
Reaction SMILES: C(OC([O:6][C@H:7]1[C@@H:12]2[C@@H:13]([CH3:16])[CH2:14][CH2:15][C@@H:11]2[C:10]([C:17]([O:19][CH3:20])=[O:18])=[CH:9][O:8]1)C)C.B.[Na]>C(O)C.[Ni](Cl)Cl>[OH:6][CH:7]1[C@@H:12]2[C@@H:13]([CH3:16])[CH2:14][CH2:15][C@@H:11]2[CH:10]([C:17]([O:19][CH3:20])=[O:18])[CH2:9][O:8]1
Reactant: CCOC(C)O[C@@H]1OC=C(C(=O)OC)[C@H]2CC[C@H](C)[C@@H]12
Agent: Cl[Ni]Cl
Agent: B
Agent: [Na]
Solvent: CCO
Product: COC(=O)C1COC(O)[C@H]2[C@@H]1CC[C@@H]2C
Temperature: 80 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
Methyl (1S, 4aS, 7S, 7aR)-1-[1-(ethoxy)ethoxy]-7-methyl-1, 4a, 5, 6, 7, 7a-hexahydrocyclopenta[c]pyran-4-carboxylate (1.0 g, 0.0035 mol) obtained in Example 4 was dissolved in 20 mι of ethanol suspending nickel chloride (1.14 g), and 10 mι of an ethanol solution of sodium boron hydride (830 mg, 0.021 mol) was added. Thereafter, the reaction solution was stirred at 80° C. for 3 hours under heat-reflux. The reaction mixture solution was filtered by a celite, and was once concentrated under a reduced pressure. The residual matter was dissolved in 100 mι of ethyl acetate, washed with water (50 mι×3) and dried by the addition of magnesium sulfate. The residual matter was further filtered, and the solvent was distilled off under a reduced pressure. The residual matter was dissolved in 30 mι of tetrahydrofuran without purification and was stirred at room temperature for 2 hours after the addition of 10 mι of 2N hydrochloric acid solution. After the reaction solution was neutralized by adding 50 mι of saturated sodium bicarbonate solution, it was extracted by ethyl acetate (50 mι×3). After the organic layer was Joined, it was dried by the addition of magnesium sulfate, filtered, and then concentrated under a reduced pressure. The residual matter was purified by chromatography using silica gel, and the solvent of the fraction obtained from hexane:ether=7:3 eluent was distilled off. A colorless oily substance was thus obtained, i.e., methyl (4aS, 7S, 7aR)-1, 3, 4, 4a, 5, 6, 7, 7a-octahydro-1-hydroxy-7-methylcyclopenta[c]pyran-4-carboxylate (480 mg, yield=63.7%). This methyl (4aS, 7S, 7aR)-1, 3, 4, 4a, 5, 6, 7, 7a-octahydro-1-hydroxy-7-methylcyclopenta[c]pyran-4-carboxylate had the following physicochemical properties:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=4[C:33]#[N:34])=[CH:22][CH:23]=3)[CH:18]=[N:17]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1C1C=CC=CN=1.[BH4-].[Na+]>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=4[CH2:33][NH2:34])=[CH:22][CH:23]=3)[CH:18]=[N:17]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(CCn2ncc3cc(Oc4ccc(F)cc4C#N)ccc32)CC1
Agent: [BH4-]
Agent: [Na+]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(CCn2ncc3cc(Oc4ccc(F)cc4CN)ccc32)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
To a solution of 4-{2-[5-(2-cyano-4-fluorophenoxy)-indazol-1-yl]-ethyl}-piperazine-1-carboxylic acid tert-butyl ester (0.160 g, 0.344 mmol), CoBr2 (0.008 g, 0.034 mmol), [2,2′]bipyridinyl (0.016 g, 0.010 mmol) in EtOH (6 mL) was added NaBH4 (0.039 g, 1.0 mmol). The mixture was stirred for 3 hours at room temperature. The reaction was quenched with MeOH (3 mL) and acetic acid (10 drops). The solution was concentrated under reduced pressure and diluted with ethyl acetate. The mixture was washed with aqueous NaHCO3, brine, dried over MgSO4, and concentrated under reduced pressure. The crude oil was chromatographed eluting with 1% triethylamine in ethyl acetate, MeOH/CH2Cl2/hexanes (1:15:15, 1% triethylamine), then MeOH/CH2Cl2/hexanes (1:10:10, 1% triethylamine). The pure product was obtained in 86% yield.
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[NH:19][CH:20]1[CH2:24][CH2:23][NH:22][CH2:21]1.C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:32][C:33]#[N:34]>CN(C)C=O>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[NH:19][CH:20]1[CH2:24][CH2:23][N:22]([CH2:32][C:33]#[N:34])[CH2:21]1
Reactant: c1ccc(Cn2c(NC3CCNC3)nc3ccccc32)nc1
Reactant: N#CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCN1CCC(Nc2nc3ccccc3n2Cc2ccccn2)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
To a stirred and heated (60° C.) suspension of 14 parts of 1-(2-pyridinylmethyl)-N-(3-pyrrolidinyl)-1H-benzimidazol-2-amine dihydrochloride and 9.5 parts of sodium carbonate in 113 parts of N,N-dimethylformamide were added dropwise 3.2 parts of 2-chloroacetonitrile. Upon completion, stirring was continued for 3 hours at 60° C. After cooling, the mixture was poured into ice water and the product was extracted six times with methylbenzene. The combined organic layers were washed with water, dried, filtered and evaporated, yielding 11 parts (87%) of 3-[[1-(2-pyridinylmethyl)-1H-benzimidazol-2-yl]amino]-1-pyrrolidineacetonitrile as a residue (compound 133).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[O:13])=[CH:5][CH:4]=1.C(O[CH:17](OCC)[N:18]([CH3:20])[CH3:19])C>>[CH3:17][N:18]([CH:20]=[C:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:10]1=[O:13])[CH3:19]
Reactant: COc1ccc2c(c1)C(=O)CCC2
Reactant: CCOC(OCC)N(C)C
Product: COc1ccc2c(c1)C(=O)C(=CN(C)C)CC2

Procedure:
The 3,4-dihydro-2-(dimethylaminomethylene)-7-methoxy-1(2H)-naphthalenone starting material was prepared from 7-methoxy-1-tetralone (5.0 g, 28.4 mmol) and N,N-dimethylformamide diethyl acetal (10 ml, 58.3 mmol) ito give the desired product as a yellow solid (1.28 g). m.p. 95.1 °. MS (ES+) 232 (MH+, 100%).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N+:8]([O-:18])[CH2:9][C:10]3[N:11]([N:12]=[C:13]([C:15]([OH:17])=O)[N:14]=3)[C:5]=2[S:4][C:3]=1[CH3:25].C(N(CC)CC)C.C(Cl)(=O)OCC.[NH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>O.O1CCCC1>[CH3:1][C:2]1[C:6]2[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N+:8]([O-:18])[CH2:9][C:10]3[N:11]([N:12]=[C:13]([C:15]([N:39]4[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]4)=[O:17])[N:14]=3)[C:5]=2[S:4][C:3]=1[CH3:25]
Reactant: Cc1sc2c(c1C)C(c1ccccc1)=[N+]([O-])Cc1nc(C(=O)O)nn1-2
Reactant: C1CCNCC1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1sc2c(c1C)C(c1ccccc1)=[N+]([O-])Cc1nc(C(=O)N3CCCCC3)nn1-2
Reaction time: 0.08 h

Procedure:
To a mixture of 178 mg. of 7,8-dimethyl-6-phenyl-4H-thieno[3,2-f]-s-triazolo[1,5-a][1,4]diazepine-2-carboxylic acid 5-oxide, 0.1 ml. of triethylamine and 5 ml. of tetrahydrofuran is added 0.07 ml. of ethyl chlorocarbonate under stirring and cooling on an ice-sodium chloride bath, and the mixture is stirred for 5 minutes. Then, to the mixture is added 0.07 ml. of piperidine, followed by stirring for 30 minutes, and water is added to the resulting mixture. Then, the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried over sodium sulfate and then the solvent is evaporated. Thereafter, addition of ether to the residue gives 7,8-dimethyl-6-phenyl-2-piperidinocarbonyl-4H-thieno[3,2-f]-s-triazolo[1,5-a][1,4]diazepine-5-oxide as crystals. Recrystallization from ethyl acetate gives colorless prisms melting at 213° to 214° C.
Reaction SMILES: [CH:1]1([CH2:4][CH:5]([NH2:18])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH2:33][C:34](O)=[O:35])[CH:25]=[CH:26][C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:20]>>[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH2:33][C:34]([NH:18][CH:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:35])[CH:25]=[CH:26][C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:20]
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1OCC
Reactant: NC(CC1CC1)c1ccccc1N1CCCCC1
Product: CCOC(=O)c1ccc(CC(=O)NC(CC2CC2)c2ccccc2N2CCCCC2)cc1OCC

Procedure:
Prepared analogously to Example 47 from α-cyclopropylmethyl-2-piperidino-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.
Reaction SMILES: C([CH:3]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[NH:10][CH:9]=1)[C:4]([OH:6])=[O:5])C.[H-].[Na+].[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C1COCC1.CN(C=O)C>[CH3:18][O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([S:27]([C:24]1[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=1)(=[O:29])=[O:28])[CH:9]=[C:8]2[CH2:7][CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCC(Cc1c[nH]c2ccc(OC)cc12)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(CCC(=O)O)cn2S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32926.4 %

Procedure:
In THF(640 ml)-DMF(130 ml) was dissolved ethyl 3-(5-methoxy-1H-indol-3-yl)propionic acid (99.3 g, 0.4 mol). To the solution was added in limited amounts, under ice-cooling, a suspension of 60% sodium hydride in oil (18.4 g, 0.46 mol) in THF(50 ml)-DMF(10 ml). The mixture was stirred at room temperature for one hour, and the mixture was again cooled with ice. To the mixture was gradually added p-toluenesulfonyl chloride (83.9 g, 0.44 mmol), followed by stirring for a further 3 hours at room temperature. The reaction mixture was poured into an ice-saturated NH4Cl solution (180 ml). The upper layer was subjected to extraction with ethyl acetate (100 ml+500 ml). The extract solution was washed with a saturated aqueous saline solution (300 ml×2), followed by drying over Na2SO4. The residue was purified by means of silica gel chromatography (eluent: hexane-ethyl acetate (2:1)) and then were added hydrochloric acid (100 ml) and acetic acid (400 ml), and was refluxed for 1 hour. The reaction mixture was concentrated and the resulting crystals were washed with water, dried under reduced pressure and washed with methanol-isopropyl ether (1:3) to obtain the title compound (54.1 g: m.p. 172°-174° C.)
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].C(=O)(O)[O-].[Na+].Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>O.C(OCC)(=O)C>[C:1]([NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: CC(=O)NC1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCC(NC(C)=O)CC1
Temperature: 25 °C
Yield: 103.2 %

Procedure:
A solution of 4-acetamidopiperidine (20.7 g), sodium bicarbonate (10.6 g) and water (300 ml) was cooled to 0° C., and 17.7 g of ethyl chloroformate was added dropwise, with stirring. Upon completion of the addition, the reaction mixture was allowed to warm to ambient temperature and was diluted with water and ethyl acetate. The layers were separated, and the organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated to give 32.2 g (100%) of product.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([OH:17])(=[O:16])[CH2:11][CH2:12][C:13]([CH3:15])=[O:14].N1CCCCC1.C1(C)C=CC=CC=1>O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:15][C:13]([CH2:12][CH2:11][C:10]([OH:17])=[O:16])=[O:14])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)CCC(=O)O
Solvent: O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: O=C(O)CCC(=O)C=Cc1ccc(Cl)cc1
Yield: 44 %

Procedure:
To a dry 250 ml flask equipped with a magnetic stirrer, Dean-Stark trap, and reflux condenser was charged 15 g of 4-chlorobenzaldehyde, 12.4 g levulenic acid, 5.7 ml of piperidine, and 100 ml of toluene. The reaction was refluxed for 3 hours, after which no water was observed to azeotrope from the solution. The reaction was cooled and stripped to yield a reddish-brown liquid which was triturated with hexane to yield 11.2 g of product as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[N+:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])#[C-:13].C(N(CC)CC)C>O1CCCC1>[CH3:18][O:17][C:15]([C:14]1[N:12]=[CH:13][O:5][C:4]=1[C:3]1[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:2]=1[F:1])=[O:16]
Reactant: [C-]#[N+]CC(=O)OC
Reactant: O=C(Cl)c1ccc(F)cc1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ncoc1-c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a 500 ml three neck flask fitted with mechanical stirrer under nitrogen is added 2,4-difluorobenzoyl chloride (141 mmol, 25 g), methyl isocyanoacetate (143 mmol, 13 mL), triethylamine (424 mmol, 60 mL) and tetrahydrofuran (200 mL). The mixture is stirred for 72 hours at room temperature. The reaction is concentrated to a thick slurry and then transferred to a separatory funnel using 500 mls of distilled water. The aqueous mixture is extracted with ethyl acetate (4×250 mL). The ethyl acetate washes are combined and washed with brine. The organics are dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue is disolved in hot ethanol (400 mL) and treated with decolorizing carbon and magnesium sulfate. After 15 minutes, the mixture is filtered to remove the insolubles. To the filtrate is added to one liter of distilled water. A precipitate forms and the resultant mixture is allowed to stand. The resulting solid is collected by filtration and is washed with copious amounts of water. The resulting solid is dried under vacuum to give the title compound.
Reaction SMILES: [C:1]([NH:24][CH:25]([CH3:35])[CH2:26][NH:27]C(=O)OC(C)(C)C)(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22].C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[NH2:27][CH2:26][CH:25]([NH:24][C:1](=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22])[CH3:35]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NC(C)CNC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NC(C)CN
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
To a solution of tert-butyl 2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidopropylcarbamate (2.10 g, 4.34 mmol) in DCM (100 mL) at 0° C. was slowly added TFA (30 mL). The mixture was stirred (0° C., 2 h), warmed to RT and stirred (16 h). The mixture was basified to pH=10 with saturated aqueous Na2CO3 and extracted with EA (2×200 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to afford (4Z,7Z,10Z,13Z,16Z,19Z)-N-(1-aminopropan-2-yl)docosa-4,7,10,13,16,19-hexaenamide (1.60 g, 98%) as a light yellow oil. Mass calculated for C25H40N2O=384.6. found: [M+H]+=385.2.
Reaction SMILES: COC1C=CC(N2C[C@H](C[N:15]3[CH2:20][CH2:19][CH:18]([O:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)OC2=O)=CC=1>CS(C)=O>[N+:28]([C:25]1[CH:26]=[CH:27][C:22]([O:21][CH:18]2[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]2)=[CH:23][CH:24]=1)([O-:30])=[O:29]
Reactant: COc1ccc(N2C[C@H](CN3CCC(Oc4ccc([N+](=O)[O-])cc4)CC3)OC2=O)cc1
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(OC2CCNCC2)cc1

Procedure:
3-p-methoxyphenyl-5(S)-[(4-p-nitrophenoxypiperidino)methyl]-2-oxazolidinone (hydrochloride), m.p. 250°-253°; [α]D =-32.7° (DMSO).
Reaction SMILES: [Mg].[F:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Br.[CH:11]1([C:15](Cl)=[O:16])[CH2:14][CH2:13][CH2:12]1.O>C(OCC)C.O1CCCC1.CCCCCC.C1(C)C=CC=CC=1>[F:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][C:15]([CH:11]1[CH2:14][CH2:13][CH2:12]1)=[O:16]
Reactant: O=C(Cl)C1CCC1
Reactant: Fc1ccccc1CBr
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C(Cc1ccccc1F)C1CCC1
Yield: 38.6 %

Procedure:
20 ml of anhydrous diethyl ether were added to 1.06 g (44 mmole) of metallic magnesium, and then a solution of 7.56 g (40 mmole) of 2-fluorobenzyl bromide in 10 ml of diethyl ether was slowly added dropwise to the resulting mixture, whilst stirring; the mixture was then stirred at room temperature for 1 hour. The resulting solution was slowly added dropwise to a solution of 4.74 g (40 mmole) of cyclobutanecarbonyl chloride in 30 ml of tetrahydrofuran, whilst cooling in a methanol-dry ice bath, over a period of 2 hours, and then the mixture was allowed to return to room temperature, whilst stirring, over a period of 2 hours. At the end of this time, 100 ml of water and 150 ml of diethyl ether were added to the reaction mixture, and the organic layer was separated, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography, using a 9:1 by volume mixture of toluene and hexane as the eluent, to give 2.97 g of the title compound as a pale yellow oil.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][CH2:6][NH:7][C:8]([NH:10][C:11]1[S:12][C:13]([C:17]2[CH:22]=[CH:21][C:20]([S:23](=[O:28])(=[O:27])[N:24]([CH3:26])[CH3:25])=[CH:19][CH:18]=2)=[C:14]([CH3:16])[N:15]=1)=[O:9])C.[OH-].[Na+].Cl>CO>[CH3:26][N:24]([CH3:25])[S:23]([C:20]1[CH:21]=[CH:22][C:17]([C:13]2[S:12][C:11]([NH:10][C:8](=[O:9])[NH:7][CH2:6][CH2:5][C:4]([OH:29])=[O:3])=[N:15][C:14]=2[CH3:16])=[CH:18][CH:19]=1)(=[O:27])=[O:28]
Reactant: CCOC(=O)CCNC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)N(C)C)cc2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc(NC(=O)NCCC(=O)O)sc1-c1ccc(S(=O)(=O)N(C)C)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 3-{3-[5-(4-dimethylsulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-propionic acid ethyl ester (Example 24) in methanol (5 ml) is added dropwise sodium hydroxide (2M, 3 ml) over 2 minutes. The reaction mixture is heated at reflux overnight and then allowed to cool to room temperature. The mixture is neutralised with hydrochloric acid (2M, 3 ml) and the resulting precipitate is filtered, washed with water (20 ml) and dried in vacuo to yield the titled compound.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]3[CH:21]=[C:20]([C:22]4[CH:27]([CH2:28][CH3:29])[CH2:26][C:25](=[O:30])[NH:24][N:23]=4)[CH:19]=[CH:18][C:16]=3[N:17]=2)=[CH:9][CH:8]=1)(=O)=O.[CH2:33]=[CH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[CH2:28]([CH:27]1[C:22]([C:20]2[CH:19]=[CH:18][C:16]3[N:17]=[C:13]([C:10]4[CH:9]=[CH:8][C:7]([CH:33]=[CH:34][C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[CH:12][CH:11]=4)[O:14][C:15]=3[CH:21]=2)=[N:23][NH:24][C:25](=[O:30])[CH2:26]1)[CH3:29]
Reactant: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(OS(=O)(=O)C(F)(F)F)cc3)oc2c1
Reactant: C=Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(C=Cc4ccccc4)cc3)oc2c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
60 mg (128 μmol) 4-[6-(4-ethyl-6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-benzoxazol-2-yl]-phenyl trifluoro-methanesulphonate, 14.7 μl (128 μmol) styrene, 2.9 mg (13 μmol) palladium-(II)-acetate, 4.1 mg (13 μmol) tri-o-tolylphosphine, 72 μl (513 μmol) triethylamine and 2 ml acetonitrile are combined and stirred overnight at 80° C. Then a further 7.5 μl styrene, 2.9 mg palladium-(II)-acetate and 4 mg tri-o-tolyphosphine are added and the mixture is stirred for 5 days at 80° C. Then it is diluted with DCM and extracted successively with 10% sodium carbonate solution and sat. saline solution. The org. phase is evaporated down completely i.V. and the residue is purified through silica gel (eluant: DCM/methanol). The residue obtained is crystallised from cyclohexane/EA.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[CH:7]=[CH:6][N+:5]([O-])=[CH:4][CH:3]=1.C[Si]([C:16]#[N:17])(C)C.CN(C)C(Cl)=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[C:16]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][N:5]=1)[C:1]([O:10][CH3:11])=[O:9])#[N:17]
Reactant: C[Si](C)(C)C#N
Reactant: COC(=O)c1cc[n+]([O-])cc1
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)c1ccnc(C#N)c1
Reaction time: 8 h

Procedure:
To a solution of methyl isonicotinate N-oxide (20.0 g, 0.26 mol) in 200 mL of methylene chloride was added trimethylsilyl cyanide (16.1 g, 0.32 mol), followed by a solution of dimethylcarbamyl chloride (17.82 g, 0.32 mol) in 50 mL of methylene chloride at room temperature. The reaction mixture was stirred overnight (about eighteen hours) and then treated with 500 mL of 10% potassium carbonate solution. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated to 15.2 g of crude product as a brown solid, which was used without further purification.