Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(N(C)[C@@H](C)C(N[C@@H](C(C)(C)C)C(N1C[C@@H](C2C=C3C(C[C@@H](C(=O)N[C@H]4C5C(=CC=CC=5)CCC4)N(C(=O)[C@@H](NC(=O)[C@@H](N(C(OC(C)(C)C)=O)C)C)C(C)(C)C)C3)=CC=2)C[C@H]1C(N[C@@H](CC1C=CC=CC=1)C(O)=O)=O)=O)=O)=O)(C)(C)C.FC(F)(F)S(O[C:91]1[CH2:95][N:94]([C:96]([O:98][C:99]([CH3:102])([CH3:101])[CH3:100])=[O:97])[C@H:93]([C:103]([O:105][CH3:106])=[O:104])[CH:92]=1)(=O)=O.CC1(C)C(C)(C)OB([C:117]2[CH:126]=[C:125]3[C:120]([CH2:121][C@@H:122]([C:134]([O:136][CH3:137])=[O:135])[N:123]([C:127]([O:129][C:130]([CH3:133])([CH3:132])[CH3:131])=[O:128])[CH2:124]3)=[CH:119][CH:118]=2)O1>>[C:99]([O:98][C:96]([N:94]1[C@H:93]([C:103]([O:105][CH3:106])=[O:104])[CH:92]=[C:91]([C:117]2[CH:126]=[C:125]3[C:120]([CH2:121][C@@H:122]([C:134]([O:136][CH3:137])=[O:135])[N:123]([C:127]([O:129][C:130]([CH3:131])([CH3:132])[CH3:133])=[O:128])[CH2:124]3)=[CH:119][CH:118]=2)[CH2:95]1)=[O:97])([CH3:102])([CH3:101])[CH3:100]
Reactant: COC(=O)[C@@H]1C=C(OS(=O)(=O)C(F)(F)F)CN1C(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H]1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2CN1C(=O)OC(C)(C)C
Agent: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](c2ccc3c(c2)CN(C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)(C)C)[C@H](C(=O)N[C@@H]2CCCc4ccccc42)C3)C[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)O)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Product: COC(=O)[C@@H]1C=C(c2ccc3c(c2)CN(C(=O)OC(C)(C)C)[C@H](C(=O)OC)C3)CN1C(=O)OC(C)(C)C
Yield: 69.9 %

Procedure:
Following a procedure analogous to that for the synthesis of Compound D of Example 22, (S)-1-tert-butyl 2-methyl 4-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrrole-1,2(2H,5H)-dicarboxylate (585 mg, 1.56 mmol) and (S)-2-tert-butyl 3-methyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate (650 mg, 1.56 mmol) were converted to the title compound (563 mg, 70%). MS (ESI+) m/z 517.4 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[Cl:13].[NH:14]1[CH2:19][CH2:18][CH:17]([N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[NH:22][C:21]2=[O:29])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[Cl:13][C:7]1[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:6]=1[O:5][CH2:4][CH2:3][CH2:2][N:14]1[CH2:15][CH2:16][CH:17]([N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[NH:22][C:21]2=[O:29])[CH2:18][CH2:19]1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: Fc1ccc(OCCCCl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccccc2n1C1CCN(CCCOc2ccc(F)cc2Cl)CC1

Procedure:
A mixture of 3.3 g of 2-(3-chloropropoxy)-5-fluorochlorobenzene, 3.3 g of 1-(4-piperidinyl)-2-oxobenzimidazoline, 0.9 g of sodium carbonate and 80 ml of dimethylformamide was heated at 80° - 90° C for 15 hours. After cooling, the reaction mixture was poured into water and extracted with benzene. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was triturated with ether, cooled and filtered to give 1-{3-(2-chloro-4-fluorophenoxy)propyl}-4-(2-oxo-1-benzimidazolinyl)piperidine, m.p. 130° - 132° C; recrystallized from benzenecyclohexane, m.p. 149° - 149.5° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1)=[O:5].Cl[C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].O>C(Cl)Cl>[Cl:12][C:8]1[CH:7]=[C:6]([C:4](=[O:5])[CH2:3][NH:2][C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: NCC(=O)c1cccc(Cl)c1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(=O)NCC(=O)c1cccc(Cl)c1
Temperature: 25 °C
Yield: 73.1 %

Procedure:
A mixture of 2-amino-1-(3-chlorophenyl)ethanone hydrochloride from Step 79a (2.83 g, 13.7 mmol, 1 eq), ethyl chlorooxoacetate (1.87 g, 13.7 mmol, 1 eq), and CH2Cl2 (40 mL) is cooled in an ice-H2O bath. The mixture is treated with a solution of TEA (4.0 mL, 29 mmol, 2.1 eq) in CH2Cl2 (20 mL), and the reaction is warmed to room temperature overnight. Water is added and the organic layer is separated, dried over MgSO4, filtered., and evaporated. The resulting solid is triturated with hexane/2-propanol and dried in vacuo to provide the title compound (2.70 g, 72%). MS (ESI) for C12H12ClNO4 m/z 270 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[H-].[Na+].[CH:11]1(I)[CH2:15][CH2:14][CH2:13][CH2:12]1.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][N:3]=1
Reactant: Oc1ccc(Br)nc1
Reactant: IC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(OC2CCCC2)cn1
Temperature: 120 °C
Reaction time: 72 h
Yield: 45 %

Procedure:
2-Bromo-5-hydroxypyridine (3 mmol) is dissolved in DMF (10 ml) and NaH (1.4 eq., 60% suspension in liquid paraffin) is added. After 30 min cyclopentyl iodide (2.2 eq.) is added and the reaction solution is stirred 3 days at 120° C. The reaction solution is pored into water and extracted with methyl-tert.-butyl ether. The combined organic layers are dried over MgSO4 and the solvent is removed in vacuo. 2-Bromo-5-cyclopentyloxy-pyridine is obtained after column chromatography (heptane/ethylacetate) as yellow oil in a yield of 45%; HPLC (method C): 2.08 min; LC-MS (method A): 2.05 min, 241.95 (M+H+).
Reaction SMILES: [NH2-:1].[Na+].[CH2:3]([N:5]1[CH2:9][CH:8](O)[CH2:7][N:6]1[CH2:11][CH3:12])[CH3:4].[C:13]1(C)[CH:18]=[CH:17][C:16](S(Cl)(=O)=O)=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[NH:1]([CH:8]1[CH2:9][N:5]([CH2:3][CH3:4])[N:6]([CH2:11][CH3:12])[CH2:7]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCN1CC(O)CN1CC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCN1CC(Nc2ccccc2)CN1CC
Reaction time: 2 h

Procedure:
To a stirred suspension of 7.9 g. (0.2 mole) of sodamide in 100 ml. of dry toluene was added 28.8 g. (0.2 mole) of 1,2-diethyl-4-pyrazolidinol at a rate so that a pot temperature of 30°-35° C. was maintained. After stirring 2.0 hrs. at room temperature, the solution was added dropwise to a solution of 38.0 g. (0.2 mole) of p-toluenesulfonyl chloride in 200 ml. of dry toluene with the pot temperature maintained below 30° C. After stirring for about one hr. at room temperature, the reaction mixture was washed twice with water and dried over sodium sulfate. The dried filtered solution was concentrated to a volume of about 100 ml., aniline (100 ml.) was added, the solution refluxed for 3.0 hrs. and then concentrated. The residue was partitioned between chloroform and dilute sodium hydroxide. The dried chloroform layer was concentrated and the residue distilled at 120° C./0.1 mm. to give 4.0 g. of product.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[C:10](=O)[C:11](=[O:13])[NH:12][C:7]=3[CH:6]=[CH:5][C:4]=2[NH:3][N:2]=1.[CH:15]1[C:20]([NH:21][NH2:22])=[CH:19][CH:18]=[C:17]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:16]=1.Cl>CCOC(C)=O>[O:13]=[C:11]1[NH:12][C:7]2[CH:6]=[CH:5][C:4]3[NH:3][N:2]=[CH:1][C:9]=3[C:8]=2[C:10]1=[N:22][NH:21][C:20]1[CH:19]=[CH:18][C:17]([S:23]([NH2:26])(=[O:24])=[O:25])=[CH:16][CH:15]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: O=C1Nc2ccc3[nH]ncc3c2C1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc4[nH]ncc4c32)cc1
Yield: 8 %

Procedure:
The title compound was prepared from 3,6-dihydro-pyrrolo[3,2-e]indazole-7,8-dione (Cuny, et al., Chemie Berichte 1981, 114,1624–35) and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G in 8% yield: 1H NMR (DMSO-d6): δ 7.02 (d, J=8.7 Hz, 1H), 7.28 Z (s, 2H), 7.51 (d, J=8.6 Hz, 2H), 7.68 (d, J=8.8 Hz, 1H), 7.82 (d, J=8.7 Hz, 2H), 8.34 (s, 1H), 10.98 (s, 1H), 12.90 (s, 1H), 13.20 (s, 1H); APCI-MS m/z 356 (M)−. Anal. Calcd for C15H12N6O3S.1.46H2O.0.2 EtOAc: C, 47.41, H, 4.16; N, 20.99; S, 8.01. Found C, 47.40, H, 3.70; N, 21.00; S, 7.85.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:7](O)([CH3:9])[CH3:8]>O>[CH2:2]=[CH:1][CH3:6].[C:1]1([CH:7]([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccccc1
Reactant: CC(C)O
Solvent: O
Product: C=CC
Product: CC(C)c1ccccc1

Procedure:
alkylation of benzene with isopropanol, or a blend of isopropanol and propylene, to give cumene and water, comprising effecting said alkylation reaction completely in gaseous phase and in the presence of a catalytic system containing a zeolite belonging to the MTW family; 2) oxidation of the cumene thus obtained to cumyl hydroperoxide; 3) treatment of the cumyl hydroperoxide with acids in order to obtain a mixture of phenol and acetone; 4) hydrogenation of the acetone to isopropanol which is recycled to step (1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[CH2:17][NH:16][CH2:15][CH2:14][C:13]=3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:25](C)=O.[Na+].C(O)(=O)C.[OH-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[CH2:17][N:16]([CH3:25])[CH2:15][CH2:14][C:13]=3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cn1cc(Br)cc(Nc2ccc3c(n2)CCNC3)c1=O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CCc2nc(Nc3cc(Br)cn(C)c3=O)ccc2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.4 %

Procedure:
A mixture of 205a (2.75 g, 7.5 mmol), formaldehyde (37 percent in water, 30 ml, 375 mmol), NaBH(OAc)3 (4.75 g, 22.5 mmol) and acetic acid (25 ml, 150 mmol) in methanol (125 ml) was stirred for 4 hours at room temperature. The mixture was then brought to basic condition with saturated NaOH solution and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by column chromatography eluting with 4:1 ethyle acetate/methanol to give 205b (2.0 g, 77%). LC/MS: m/z 349 (M+H)+
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H][H].Cl[CH2:15][CH2:16][CH2:17][C:18]#[CH:19]>CS(C)=O.O>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:19][CH2:18][CH2:17][C:16]#[CH:15])=[CH:7][CH:6]=1
Reactant: COc1ccc(O)cc1
Reactant: C#CCCCCl
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C#CCCCOc1ccc(OC)cc1
Reaction time: 16.5 h
Yield: 93.3 %

Procedure:
To a suspension of 960 mg (40 mmol) of sodium hydride in 25 mL of dimethyl sulfoxide is added 4.97 g (40 mmol) of 4-methoxyphenol. After the evolution of hydrogen has ceased, 4.10 g (40 mmol, 4.24 mL) of 5-chloro-1-pentyne is added. The mixture is maintained with stirring for 16.5 hours, is diluted with water and is extracted with ethyl ether. The ethereal extract is dried over magnesium sulfate, filtered and rotoevaporated to give 7.1 g (93%) of title compound.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Cl[C:26]1[O:27][C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=1>>[O:27]1[C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=[C:26]1[NH:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:20]=[CH:21][CH:22]=[CH:23][N:24]=1)=[O:11]
Reactant: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Clc1nc2ccccc2o1
Product: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3ccccc3o2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A2 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(pyrimidin-2-yl)phenyl)methanone and 2-chlorobenzoxazole. MS (ESI) 442 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH:4]([OH:7])[CH2:5][OH:6].C[C:10]([CH3:13])([O-])[CH3:11].[K+].C1(C)C=CC(S(O[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]/[CH:33]=[CH:34]\[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])(=O)=O)=CC=1>>[CH2:42]([O:7][CH:4]([CH2:5][O:6][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]/[CH:31]=[CH:30]\[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:11][CH2:10][CH3:13])[CH2:3][N:2]([CH3:8])[CH3:1])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]/[CH:34]=[CH:33]\[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH3:25]
Reactant: CCCCCCCC/C=C\CCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CN(C)CC(O)CO
Reactant: CC(C)(C)[O-]
Agent: [K+]
Product: CCCCCCCC/C=C\CCCCCCCCOCC(CN(C)C)OCCCCCCCC/C=C\CCCCCCCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
DOTMA (N-(1-(2,3-Dioleyloxy)propyl)-N,N,N-trimethylammoniun chloride) was prepared as outlined in FIG. 1. A mixture of 3-(dimethylamino)-1,2-propanediol (Aldrich Chemical Co., 1.19 g, 10 mmol), potassium tert-butoxide (3.36 g, 30 mmol) and oleyl p-toluenesulfonate (12.7 g, 30 mmol) in xylenes (50 ) was stirred at room temperature and reduced pressure (30 Torr) for 30 min, and was then heated to 50° C. with stirring for an additional 15 min. The reaction vessel was purged with nitrogen, and the mixture was heated to reflux (approximately 140° C.) for 3 hrs. After cooling, the reaction mixture was diluted with hexane (100 ml), and the resulting solution was extracted with water (2×50 ml). The organic layer was concentrated, and the residue was chromatographed over silica gel by elution with a mixture of hexanes and ether (1:2) to afford the intermediate 2,3-dioleyloxy-1-(dimethylamino)-propane as a colorless oil. Quaternization was carried out by condensation of methyl chloride (50 ml) into a Parr pressure apparatus cooled to -78° C. containing this compound (10 g). The sealed vessel was heated behind a safety shield at 70° C. for 48 h. After cooling to 0° C., the reaction vessel was opened, and the excess methyl chloride was allowed to evaporate under a stream of nitrogen in a well-ventilated hood. The crude residue was recrystallized from acetonitrile to afford DOTMA as an off-white solid, mp. 35°-38° C. Full details of the synthesis of of DOTMA and analogs will be published elsewhere (Gadek and Felgner, in preparation).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][CH:17]=3)[CH2:12][CH2:11][C:10]2=[O:26])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][CH:35]1[CH2:37][CH2:36]1>CN(C)C=O.O>[CH:35]1([CH2:34][N:23]2[CH2:22][CH2:21][CH:20]([O:19][C:15]3[CH:14]=[C:13]4[C:18](=[CH:17][CH:16]=3)[N:9]([C:6]3[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=3)[C:10](=[O:26])[CH2:11][CH2:12]4)[CH2:25][CH2:24]2)[CH2:37][CH2:36]1
Reactant: O=C1CCc2cc(OC3CCNCC3)ccc2N1c1ccc(F)cc1
Reactant: BrCC1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCc2cc(OC3CCN(CC4CC4)CC3)ccc2N1c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 35 %

Procedure:
A suspension of 1-(4-fluorophenyl)-6-(piperidin-4-yloxy)-3,4-dihydroquinolin-2(1H)-one hydrochloride prepared in Example 7-(3) (0.30 g), potassium carbonate (0.55 g) and (bromomethyl)cyclopropane (0.32 g) in N,N-dimethylformamide (10 mL) was stirred at 100° C. for 6 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: chloroform→chloroform/methanol=4/1) and preparative TLC (on a single plate of 2 mm thickness, developing solvent: chloroform/methanol=9/1) to give the titled compound (0.11 g, 35%) as a colorless amorphous substance.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1>>[C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([NH:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[O:15])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)[C@@H]2CCCN2C(=O)OCc2ccccc2)CC1

Procedure:
Working analogously to Example 1, starting from N-[(phenyl-methoxy)carbonyl]-L-proline and 4-(aminomethyl)-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester, the expected product is obtained in the form of a creamy white solid (Yield=99%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1.[H-].[Na+].Cl[CH2:20][N:21]1[C:25]([Cl:26])=[C:24]([Cl:27])[N:23]=[CH:22]1.C(OCC)(=O)C>CN(C)C=O>[CH3:1][C:2]1[C:3]([O:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:20][N:21]3[C:25]([Cl:26])=[C:24]([Cl:27])[N:23]=[CH:22]3)=[CH:12][CH:11]=2)=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1
Reactant: ClCn1cnc(Cl)c1Cl
Reactant: Cc1cnc(C)c(Oc2ccc(O)cc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cnc(C)c(Oc2ccc(OCn3cnc(Cl)c3Cl)cc2)n1
Temperature: 70 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
At room temperature (about 20° C.), 7.8 g of 4-(3,6-dimethyl-2-pyrazinyloxy)-phenol in 20 ml of anhydrous dimethylformamide is dripped into 1.3 g of 80% strength sodium hydride in 30 ml of anhydrous dimethylformamide. The mixture is stirred for one hour at 70° C., and then 6.68 g of 1-chloromethyl- 4,5-dichloroimidazole in 30 ml of anhydrous dimethylformamide is dripped in. The mixture is stirred for 8 hours at 70° C. and overnight at room temperature. It is then stirred into 200 ml of ethyl acetate, and this mixture is washed twice with water, four times with 5% strength sodium hydroxide solution and twice with saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and the solvent is evaporated off under reduced pressure. The crude product obtained is crystallized with n-hexane. There is obtained 8.9 g of 1-[4-(3,6-dimethyl-2-pyrazinyloxy)-phenoxymethyl]-4,5-dichloroimidazole: m.p.: 84°-85° C.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:22])[C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1)#[N:2].N.NCCCCCCCN[C:33](=[O:45])[C:34]1[CH:39]=[CH:38][C:37](OC(F)(F)F)=[CH:36][CH:35]=1.Cl.[CH2:47]([OH:49])C>[Ni]>[CH3:47][O:49][CH:5]([CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:22])[C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]([F:21])([F:19])[F:20])=[CH:15][CH:16]=1)[CH2:4][CH2:3][CH2:1][NH:2][C:33](=[O:45])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: N#CCCCCCCNC(=O)c1ccc(OC(F)(F)F)cc1
Reactant: CCO
Reactant: NCCCCCCCNC(=O)c1ccc(OC(F)(F)F)cc1
Agent: [Ni]
Agent: Cl
Agent: N
Product: COC(CCCNC(=O)c1ccccc1)CCCNC(=O)c1ccc(OC(F)(F)F)cc1

Procedure:
A mixture containing 12 g. of N-(6-cyanohexyl)-4-trifluoromethoxybenzamide in 100 ml. of ethanol, 8 g. of ammonia and 4 g. of Raney nickel was hydrogenated at approximately 30° C. for a period of 5 hours. The reaction mixture was filtered and the solvent and excess ammonia were removed by heating in vacuo. The residual material was dissolved in 150 ml. of isopropyl alcohol acidified with ethanolic hydrogen chloride and the solution was concentrated in vacuo to about 100 ml. The solution was cooled in an ice bath and the solid that separated was collected, washed with cold isopropyl alcohol and ether, and dried at 60° C. in vacuo to yield 9 g. of N-(7-aminoheptyl)-4-trifluoromethoxybenzamide as its hydrochloride, m.p. 178°-181° C.
Reaction SMILES: [CH2:1]([C:3]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH2:6][O:5][CH2:4]1)[CH3:2].C1COCC1.CCO.[Cl-].[NH4+]>[Fe].O>[CH2:1]([C:3]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=2)[CH2:4][O:5][CH2:6]1)[CH3:2]
Reactant: CCC1(COc2ccc([N+](=O)[O-])cc2)COC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CCC1(COc2ccc(N)cc2)COC1
Temperature: 90 °C
Yield: 98.4 %

Procedure:
To a solution of 3-ethyl-3-((4-nitrophenoxy)methyl)oxetane (8.28 g, 34.9 mmol) in a 3:3:1 mixture of THF:EtOH:water (140 mL) at room temperature was added ammonium chloride (2.80 g, 52.3 mmol) followed by iron powder (9.74 g, 174 mmol). The mixture was heated to 90° C. for 1 hour, then it was filtered hot through diatomaceous earth with a THF wash to complete the transfer. The filtrate was concentrated under reduced pressure, and the residue was taken up in ethyl acetate then washed with brine, dried (Na2SO4), and concentrated to provide the title compound (7.12 g, 98% yield) without further purification.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[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.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1C=CC=CC=1>[CH2:25]([O:24][C:22]([CH:21]=[P:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:23])[CH3:26]
Reactant: CCOC(=O)CBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 16 h
Yield: 80.4 %

Procedure:
To a solution of triphenylphosphine (26.20 g, 100 mmol) in benzene (150 ml) was added ethyl bromoacetate (16.70 g, 100 mmol) at 0-5° C. The mixture was kept at room temperature for 16 h. The resulting phosphonium salt was filtered, washed with benzene (100 ml), and dried. To a solution of the solid in water (200 ml) was added benzene (200 ml), followed by 10% NaOH solution (100 ml). The organic layer was separated, and the aqueous layer was extracted with benzene (200 ml). The combined organic layers were washed with water (100 ml) and brine (100 ml), concentrated to 50 ml in vacuo, and poured onto hexane (200 ml). The precipitate was filtered and dried to afford the desired phosphorane (28.00 g, 80%) as a colorless solid. mp 128-130° C.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.CC(=NOC[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39](=[N:44][O:45][CH3:46])[C:40](OC)=[O:41])C1C=CC=C(C(F)(F)F)C=1.ClCCl>CO>[CH3:46][O:45][N:44]=[C:39]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:33]=1)[CH:40]=[O:41]
Reactant: CON=C(C(=O)OC)c1ccccc1CON=C(C)c1cccc(C(F)(F)F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CO
Product: CON=C(C=O)c1ccccc1
Reaction time: 3 h
Yield: 109.6 %

Procedure:
1M diisobutylaluminum hydride/toluene solution (11 ml, 16.5 mmol) was added dropwise to a mixture of methyl 2-[(α-methyl-3-trifluoromethylbenzylidene)aminooxymethyl]-α-methoxyiminophenylacetate (4.83 g, 11.8 mmol) and dichloromethane (47 ml) at −65° C. or lower over 4 minutes, and the mixture was stirred at −78° C. to room temperature for 3 hours. Methanol (7 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The precipitated insoluble materials were removed, and the remaining mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-[(α-methyl-3-trifluoromethylbenzylidene)aminooxymethyl]-(α-methoxyiminophenylacetaldehyde (2.11 g, 47.3%) as a colorless oil.