Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]#[N:10])[CH2:4][CH2:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:10][CH2:9][CH2:8][N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1
Reactant: N#CCN1CCC(O)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCN1CCC(O)CC1
Yield: 43.6 %

Procedure:
The method follows that of S6 using 4-hydroxy-piperidin-1-yl-acetonitrile (18.97 g, 0.136 mol), LiAlH4 (15.48 g, 0.408 mol) and dry THF (150 mL). The title compound (8.56 g, 44%) was afforded as a straw-coloured oil after kugelrohr distillation (178° C., 0.05 mbar). δH(250 MHz; CDCl3); 1.55 (m, 2H, 1×CHCH2CH2 and 1×CH2CH2CH), 1.85 (m, 2H, 1×CHCH2CH2 and 1×CH2CH2CH), 2-2.25 (m, 5H, NCH2CH2, NCH2CH2 and OH), 2.38 (t, 2H, H2NCH2CH2N), 2.72 (t, 4H, H2NCH2CH2N, NH2) and 3.65 (m, 1H, CH2CHOH); δC(62.9 MHz; CDCl3); 34.56, 38.98, 51.35, 60.84 and 67.64; FAB MS, m/z(M+H)+ 145; IR υmax/cm−1; 3375 (broad), 1600, 1460, 1370, 1290 and 1070.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[C:9]([NH:10][CH:11]([CH2:14]OS(C)(=O)=O)[CH2:12][CH3:13])=[CH:8][C:7]([CH3:20])=[N:6][C:5]=1[O:21][C:22]1[C:27]([CH3:28])=[CH:26][C:25]([Cl:29])=[CH:24][C:23]=1[CH3:30].[I-].[Na+].[CH2:34]([NH2:36])[CH3:35].C(N(CC)CC)C>C(#N)C>[CH3:1][O:2][C:3](=[O:31])[C:4]1[C:9]([NH:10][CH:11]([CH2:14][NH:36][CH2:34][CH3:35])[CH2:12][CH3:13])=[CH:8][C:7]([CH3:20])=[N:6][C:5]=1[O:21][C:22]1[C:27]([CH3:28])=[CH:26][C:25]([Cl:29])=[CH:24][C:23]=1[CH3:30]
Reactant: CCC(COS(C)(=O)=O)Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC
Reactant: CCN
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCNCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC
Temperature: 70 °C
Reaction time: 6 h

Procedure:
A solution of 2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-methanesulfonyloxymethyl-propylamino)-6-methyl-nicotinic acid methyl ester in acetonitrile was treated with sodium iodide, ethylamine and triethylamine. The resulting mixture was heated to 70° C. overnight, then 85° C. for 6 hrs, then 100° C. overnight until tic showed no starting material. The resulting mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried, concentrated, and purified to give the title compound as an oil. 1H NMR(CDCl3) d 8.06(d, 1H), 7.02(s, 2H), 6.31(s, 1H), 3.88(s, 3H), 3.86(m,1H), 2.85(m, 4H), 2.12(s,3H), 2.07(s, 6H), 1.64(m, 1H), 1.60(m, 1H), 1.27(m, 3H), .99(t, 3H)
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([NH2:10])[CH:4]=1.[OH-].[Na+].[CH:13](O)=O>>[F:2][C:3]1[CH:8]=[CH:7][C:6]2[N:9]=[CH:13][NH:10][C:5]=2[CH:4]=1
Reactant: O=CO
Reactant: Nc1ccc(F)cc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Fc1ccc2nc[nH]c2c1
Yield: 86.9 %

Procedure:
Under ice cooling, 4 mol/L hydrochloric acid (200 mL) and formic acid (38.3 g) were sequentially added to 4-fluoro-1,2-phenylenediamine (21.0 g), and the mixture was heated to reflux for 90 minutes while being stirred. Under ice cooling, the reaction mixture was basified with a 10% aqueous solution of sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was washed with diisopropyl ether, and 5-fluorobenzimidazole (19.7 g) was obtained. 5-Fluorobenzimidazole (19.7 g) thus obtained was dissolved in toluene (500 mL), and methyl orthoformate (38.7 g) and benzenesulfonic acid monohydrate (1.0 g) were sequentially added thereto. The mixture was heated to reflux for 40 hours while being stirred. After distilling off the solvent and methyl orthoformate under reduced pressure, the residue was diluted with toluene. Diisopropylamine (1 mL) and a saturated aqueous solution of sodium hydrogen carbonate were sequentially added thereto under ice cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by basic silica gel chromatography (20% to 100% ethyl acetate/hexane), and thus the title compound (25.2 g) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C@:15]34[CH2:17][CH2:18][NH:19][C@@H:9]([C@@H:10]3[CH:11]=[CH:12][C:13](=[O:20])[CH2:14]4)[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.O.C([O-])([O-])=O.[K+].[K+].[CH:28]1([C:31](Cl)=[O:32])[CH2:30][CH2:29]1>CN(C=O)C>[CH:28]1([C:31]([N:19]2[CH2:18][CH2:17][C@@:15]34[C:16]5[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=5[CH2:8][C@@H:9]2[C@@H:10]3[CH2:11][CH2:12][C:13](=[O:20])[CH2:14]4)=[O:32])[CH2:30][CH2:29]1
Reactant: COc1cccc2c1[C@]13CCN[C@H](C2)[C@@H]1C=CC(=O)C3
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc2c1[C@]13CCN(C(=O)C4CC4)[C@H](C2)[C@@H]1CCC(=O)C3
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
To a mixture of 1.5 g (5.18 mmol) 4-methoxymorphinen-6-one.1 H2O, 1.3 g (9.41 mmol) anhydrous K2CO3 and 10 ml dry DMF were added dropwise a solution of 0.29 ml (5.31 mmol) cyclopropanecarboxylic acid chloride in 5 ml dry DMF during 10 min. at room temperature. This mixture was stirred at room temperature for 1 h, then poured on 50 ml ice water and extracted with ether. The organic layer was extracted with 2 N HCl, water and brine, dried and evaporated to give an oil, which was crystallized with ether/n-hexane. To 1.5 g (85%) N-cyclopropylcarbonyl-4-methoxymorphinan-6-one, m.p. 144°-147°, [α]D26 -210.0° (c 1.04, CHCl3), were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[NH:7][C:8]([S:10][CH2:11][C:12]3[C:17]([CH3:18])=[C:16]([O:19][CH3:20])[C:15]([CH3:21])=[CH:14][N:13]=3)=[N:9][C:5]=2[CH:4]=1.CC1C([O:42]CC(F)(F)F)=CC=NC=1CSC1NC2C=CC=CC=2N=1>>[CH3:21][C:15]1[CH:14]=[N:13][C:12]([CH2:11][S+:10]([O-:42])[C:8]2[NH:7][C:6]3[CH:22]=[CH:23][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[N:9]=2)=[C:17]([CH3:18])[C:16]=1[O:19][CH3:20]
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Reactant: COc1ccc2[nH]c(SCc3ncc(C)c(OC)c3C)nc2c1
Product: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Yield: 80 %

Procedure:
The experiment described in example 2 was repeated using 46.8 g of 5-methoxy-2-[[(4-methoxy-3,5 dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazole as substrate instead of Lansoprazole sulfide. 39.2 g of crystallized Omeprazole are isolated after crystallization and drying (yield 80%).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[C:22]([C:30]([NH:32][NH2:33])=[O:31])=[CH:23][N:24]([CH3:29])[C:25](=[O:28])[C:26]=2[CH3:27])=[C:16]([F:34])[CH:15]=1>CN(C=O)C.C(OCC)(=O)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[C:22]([C:30]3[O:31][C:1](=[O:2])[NH:33][N:32]=3)=[CH:23][N:24]([CH3:29])[C:25](=[O:28])[C:26]=2[CH3:27])=[C:16]([F:34])[CH:15]=1
Reactant: Cc1c(Nc2ccc(Br)cc2F)c(C(=O)NN)cn(C)c1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(Nc2ccc(Br)cc2F)c(-c2n[nH]c(=O)o2)cn(C)c1=O
Reaction time: 1 h

Procedure:
1,1′-Carbonyldiimidazole (275 mg, 1.70 mmol) was added to a stirred solution or 4-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid hydrazide (728 mg, 1.62 mmol (82% pure material)) in DMF (2 mL). After 1 hour, the reaction mixture was diluted with ethyl acetate and washed with brine. Some of the product precipitated and was collected by filtration. The filtrate was diluted with 1 N HCl and The layers separated. The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated under reduced pressure. The resulting residue was triturated with diethyl ether to give the desired product which was combined with the earlier obtained product. The combined yield of clean desired product was 482 mg (75%); MS APCI (−) m/z 393, 395 (M−, Br pattern) detected; 1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.88 (s, 1H), 7.50 (dd, 1H), 7.21, (d, 1H), 6.59 (t, 1H), 3.52 (s, 3H), 1.76 (s, 3H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[OH:7].[C:8](Cl)(=[O:10])[CH3:9]>>[OH:7][C@H:3]1[CH2:4][CH2:5][CH2:6][C@@H:2]1[NH:1][C:8](=[O:10])[CH3:9]
Reactant: CC(=O)Cl
Reactant: N[C@H]1CCC[C@@H]1O
Product: CC(=O)N[C@H]1CCC[C@@H]1O

Procedure:
Following the procedure of Example 2A, 74.7 g of (S,S)-(+)-2-aminocyclopentanol were reacted with acetyl chloride to provide 107.9 g of the title intermediate as an oil which crystallized upon cooling. NMR.
Reaction SMILES: C(=O)(O)[O-].[Na+].[C:6]1([CH2:12][CH2:13][CH2:14][N:15]2[C:20](=[O:21])[CH2:19][N:18]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:17][C:16]2=[O:29])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[BH4-].[Na+]>C(O)C>[C:6]1([CH2:12][CH2:13][CH2:14][N:15]2[C:16](=[O:29])[CH2:17][N:18]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19][CH:20]2[OH:21])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C1CN(Cc2ccccc2)CC(=O)N1CCCc1ccccc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C1CN(Cc2ccccc2)CC(O)N1CCCc1ccccc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
Saturated aqueous sodium bicarbonate solution (20 ml) was added to a solution of 1-(3-phenylpropyl)-4-benzyl-2,6-piperazinedione (5.35 g) in ethanol (170 ml) at 5° C. and sodium borohydride (1.23 g) added portionwise to the resulting mixture at 5° C. over a period of 2 h. The mixture was stirred for a further 1 h at 5° C. and the solvent removed in vacuo. Water (50 ml) was added, and the mixture extracted with dichloromethane (3×50 ml), the extracts washed with brine and dried (MgSO4). Evaporation of the solvent gave the title compound as a white solid (4.36 g, 81%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][N:5]1[CH:9]=[C:8]([N:10]2[C:22]3[C:21]4[CH:20]=[C:19]([Br:23])[CH:18]=[CH:17][C:16]=4[N:15]=[CH:14][C:13]=3[NH:12][C:11]2=[O:24])[C:7]([CH3:25])=[N:6]1.I[CH3:28]>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][N:5]1[CH:9]=[C:8]([N:10]2[C:22]3[C:21]4[CH:20]=[C:19]([Br:23])[CH:18]=[CH:17][C:16]=4[N:15]=[CH:14][C:13]=3[N:12]([CH3:28])[C:11]2=[O:24])[C:7]([CH3:25])=[N:6]1
Reactant: COC(=O)Cn1cc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)c(C)n1
Reactant: CI
Product: COC(=O)Cn1cc(-n2c(=O)n(C)c3cnc4ccc(Br)cc4c32)c(C)n1

Procedure:
The title compound was synthesized in a similar manner as described for Stage 245.1.1 using [4-(8-bromo-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-3-methyl-pyrazol-1-yl]-acetic acid methyl ester (Stage 101.1.3, 3.43 mmol) and iodomethane to give the title compound as brown solid. (HPLC: tR 2.42 min (Method A); M+H=430, 432 MS-ES)
Reaction SMILES: [C:1]([NH:4][C:5]1[C:15]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:14][C:8]2[C:9](=[O:13])[CH:10]=[CH:11][O:12][C:7]=2[CH:6]=1)(=[O:3])[CH3:2].[H-].[Na+].[H][H].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>CN(C)C=O.C(OCC)(=O)C.O>[C:1]([N:4]([C:5]1[C:15]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:14][C:8]2[C:9](=[O:13])[CH:10]=[CH:11][O:12][C:7]=2[CH:6]=1)[S:28]([CH3:27])(=[O:30])=[O:29])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc2occc(=O)c2cc1Oc1ccccc1
Reactant: CS(=O)(=O)Cl
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N(c1cc2occc(=O)c2cc1Oc1ccccc1)S(C)(=O)=O
Reaction time: 1 h
Yield: 86.3 %

Procedure:
2.95 g of 7-acetylamino-6-phenoxy-4H-1-benzopyran-4-one was dissolved in 30 ml of N,N-dimethylformamide. 440 mg of sodium hydride (purity: 60%) was added thereto with ice-cooling. The mixture was stirred at the same temperature until the generation of hydrogen gas stopped. Then, 1.26 g of methanesulfonyl chloride was added thereto dropwise. The mixture was stirred for 1 hour at 20°-25° C. 200 ml of water and 200 ml of ethyl acetate were added thereto. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The resulting crystal was recrystallized from ethanol to obtain 3.22 g (yield: 86.1%) of 7-(N-acetyl-N-methylsulfonylamino)-6-phenoxy-4H-1-benzopyran-4-one having a melting point of 166°-169° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:35]2[CH2:37][CH2:36]2)[C:5]2[N:6]([C:8]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.C([O-])=O.[Na+]>[Pd].CN(C=O)C.O.CO>[C:29]1([C:8]2[N:6]3[N:7]=[CH:2][CH:3]=[C:4]([CH2:35][CH2:36][CH3:37])[C:5]3=[N:10][C:9]=2[C:11]2[CH:12]=[CH:13][C:14]([C:17]3([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][CH2:18]3)=[CH:15][CH:16]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(C5CC5)cc(Cl)nn4c3-c3ccccc3)cc2)CCC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: CCCc1ccnn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc12
Temperature: 80 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
To a mixture of tert-butyl {1-[4-(6-chloro-8-cyclopropyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-14.6 (0.136 g, 0.26 mmol) and 5% palladium on carbon (0.026 g) in DMF (1 mL) was added a solution of sodium formate (0.18 g, 2.6 mmol, 10.0 eq) in water (0.4 mL). The resulting mixture was stirred at 80° C. for 3 h, diluted with MeOH (10 mL) and stirred at room temperature for 1 h. The resulting solution was filtered through a membrane filter and concentrated under reduced pressure. The resulting material was purified using MPLC (Biotage Isolera; Snap 10 g cartridge, 100% hexane 2.0 min, gradient to 80% hexane/20% EtOAc 4.0 min, 80% hexane/20% EtOAc 2.5 min, gradient to 70% hexane/30% EtOAc 2.5 min, 70% hexane/30% EtOAc 9.6 min) to give tert-butyl {1-[4-(3-phenyl-8-propylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate (0.12 g, 93%):
Reaction SMILES: [CH2:1]=[CH:2][CH:3]([OH:14])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].ClC1C=CC=C(C(OO)=[O:23])C=1.C1C=CC=CC=1>CCCCCC>[O:23]1[CH:2]([CH:3]([OH:14])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:1]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CC(O)CCCCCCCCCC
Solvent: c1ccccc1
Solvent: CCCCCC
Product: CCCCCCCCCCC(O)C1CO1
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.9 %

Procedure:
A 500-ml flask equipped with a stirrer was charged with 23.8 g (0.12 mol) of 1-tridecen-3-ol, 25.0 g (0.145 mol) of m-chloroperbenzoic acid and 250 ml of benzene, and the contents were stirred at room temperature for 48 hours. After completion of the reaction, 200 ml of hexane. Solids deposited were separated by filtration, and the solvent was distilled off under reduced pressure. The resultant residue was purified by column chromatography on silica gel, thereby obtaining 19.0 g (yield: 74%) of 1,2-epoxy-3-tridecanol.
Reaction SMILES: ClCCl.[CH2:4]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[OH:13])[CH:5]=[CH2:6].[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(N(CC)CC)C>[CH3:14][S:15]([O:13][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]1[CH2:4][CH:5]=[CH2:6])(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCC1CCCCC1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCC1CCCCC1OS(C)(=O)=O

Procedure:
To a mixture of 250 ml. of dichloromethane, 25 g. 2-allylcyclohexanol and 16.7 g. of triethylamine cooled in an ice-salt bath to -10° C. is added dropwise, over 15 minutes, 18.9 g. of methanesulfonyl chloride. The mixture is cooled at -10° C. to -15° C. for 30 minutes and then washed with 300 ml. each of cold water, 10% hydrochloric acid, sodium carbonate solution and with saturated sodium chloride solution. The organic layer is dried with magnesium sulfate and concentrated in vacuo to give a pale yellow oil.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[CH3:6][O:7][CH2:8][CH:9]=O.C1CCCCC1>O>[CH3:6][O:7][CH2:8][CH:9]1[O:5][CH2:1][CH2:2][CH2:3][O:4]1
Reactant: OCCCO
Reactant: COCC=O
Solvent: C1CCCCC1
Solvent: O
Product: COCC1OCCCO1
Yield: 89 %

Procedure:
A mixture of 380 g (5 moles) of 1,3-propanediol, 479 g (5.5 moles) of 85% strength methoxyacetaldehyde and 250 ml of cyclohexane was heated with 5 g of the ion exchanger Lewasorb® AC 10 (Bayer Aktiengesellschaft) under a water separator until water no longer separated off. The ion exchanger was filtered off, the solvent was stripped off under reduced pressure and the residue was subjected to fractional distillation under reduced pressure. 587 g (89% yield) of 2-methoxymethyl-1,3-dioxane having a boiling range of 104° to 115° C./150 mbar were obtained.
Reaction SMILES: [CH3:1][C:2](=[O:22])[C:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C:10](=[CH:11][CH2:12][CH:13]=[CH:14]2)[CH2:9][CH2:8]3)[CH2:5][CH:4]=1.[CH3:23][Al](C)C.O>O1CCOCC1.C1(C)C=CC=CC=1>[CH3:23][C@@H:4]1[CH2:5][C@@H:6]2[C@:20]([CH3:21])([CH2:19][CH2:18][C@H:17]3[C@H:7]2[CH2:8][CH2:9][C:10]2[C@:15]3([CH3:16])[CH:14]=[CH:13][CH2:12][CH:11]=2)[C@H:3]1[C:2](=[O:22])[CH3:1]
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CCC4=CCC=C[C@]4(C)[C@H]3CC[C@]12C
Reactant: C[Al](C)C
Solvent: C1COCCO1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3CCC4=CCC=C[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3.1 g (10 mmol) of pregna-1,4,16-trien-20-one is mixed in 25 ml of dioxane with 143.4 mg of CuBr. 9.4 ml (11 mmol) of a 10% solution of trimethyl aluminum in toluene is added to the reaction under nitrogen and stirred for 30 minutes at 20-30° C. For hydrolysis, 0.54 ml of water dissolved in 5 ml of dioxane is added to the reaction. It is stirred for 10 minutes more and the precipitate is filtered off. The precipitate is washed again with a little dioxane. The dioxane solution is concentrated by evaporation on a rotary evaporator and the residue is chromatographed on silica gel with ethyl acetate/hexane as eluent. After concentration by evaporation of the fractions, 2.6 g of 16α-methyl-pregna-1,4-dien-20-one (80% of theory) of a melting point of 175° C. is obtained.
Reaction SMILES: [C:1]1([CH:7]([CH2:10][CH2:11][CH3:12])C=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([NH:17][OH:18])([CH3:16])([CH3:15])[CH3:14].[CH3:19]O>Cl>[C:13]([N+:17]([O-:18])=[CH:19][CH2:12][CH2:11][CH2:10][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CCCC(C=O)c1ccccc1
Reactant: CC(C)(C)NO
Reactant: CO
Agent: Cl
Product: CC(C)(C)[N+]([O-])=CCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39 %

Procedure:
To a mixture of 5-[phenyl-pentanal (1.62 g, 10 mmol, 1.0 equiv) and methanol (50 ml) was added N-tert-butylhydroxylamine (0.93 g, 10.43 mmol, 1.25 equiv) followed by 10 drops of conc. HCl. The mixture was stirred at rt for 18 h. The mixture was concentrated under vacuum to yield a light colored oil. The residue oil was purified by column chromatography (hexane:EtOAc 1:1) followed by EtOAc to give the title compound as a lightly colored oil: Yield: 39%: 1H NMR (CDCl3) δ 7.20 (m, 5H), 6.94 (d, 1H), 2.50 (m, 4H), 1.60 (m, 4H), 1.46 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(C(C)C)CC)C.[CH2:28]([O:30][C:31]1[CH:39]=[C:38]([N+:40]([O-:42])=[O:41])[CH:37]=[CH:36][C:32]=1[C:33](O)=[O:34])[CH3:29].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([C:33]([C:32]3[CH:36]=[CH:37][C:38]([N+:40]([O-:42])=[O:41])=[CH:39][C:31]=3[O:30][CH2:28][CH3:29])=[O:34])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: COc1ccc(-c2c[nH]c3ncccc23)cc1OC
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CCN(CC)C(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCOc1cc([N+](=O)[O-])ccc1C(=O)n1cc(-c2ccc(OC)c(OC)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.5 %

Procedure:
3-(3,4-Dimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine 1(250 mg, 0.98 mmole) was dissolved in 50 mL of CH2Cl2. N,N-diethylisopropylamine (205 uL, 1.2 mmol), 2-ethoxy-4-nitro-benzoic acid (228 mg, 1.1 mmol) and bromotris(pyrolodino)phoshonium hexafluorophosphate (550 mg, 1.1 mmol) were added to the stirring reaction mixture. The mixture was stirred at ambient temperature for 4 h and washed consecutively with saturated sodium bicarbonate and saturated potassium bisulfate solution. The resulting solution was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (30% ethyl acetate in hexanes) to yield 340 mg (77%) of the titled compound as a yellow solid. MS(ESI) [M+H+]+=448.2.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH2:4].[CH:10](=O)/[CH:11]=[CH:12]/[CH3:13]>Cl>[CH3:13][C:12]1[CH:11]=[CH:10][C:5]2[C:3](=[C:2]([CH3:1])[CH:8]=[CH:7][C:6]=2[CH3:9])[N:4]=1
Reactant: C/C=C/C=O
Reactant: Cc1ccc(C)c(N)c1
Agent: Cl
Product: Cc1ccc2c(C)ccc(C)c2n1
Temperature: 25 °C

Procedure:
In 50 ml of 6N hydrochloric acid, 10.0 g of 2,5-dimethylaniline were dissolved. To the resulting solution, 6.8 ml of crotonaldehyde were added dropwise under reflux. After the completion of the dropwise addition, the reaction mixture was heated under reflux for further one hour and the reaction was terminated. After the reaction mixture was allowed to cool down to room temperature, 5N sodium hydroxide was added to neutralize the reaction mixture, followed by extraction with ethyl acetate (200 ml×2). The combined organic layers were washed with saturated saline and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated and the product so obtained was purified by chromatography on a silica gel column, whereby 5.8 g of 2,5,8-trimethylquinoline were obtained. In 30 ml of ethanol were dissolved 3.6 g of 2,5,8-trimethylquinoline and 2.8 g of selenium dioxide, followed by heating under reflux for 6 hours. The residue obtained by distilling off ethanol was subjected to chromatography on a silica gel column, whereby 2.3 g of the product were obtained. Since the product was proved to be a mixture of the raw material, aldehyde and a diethylacetal derivative of the aldehyde from the result of 1H-NMR, it was treated with 6N-hydrochloric acid (10 ml)-THF (20 ml) and then, extracted with ethyl acetate (100 ml×2). The combined organic layers were washed with a saturated aqueous solution of sodium bicarbonate and dried over anhydrous magnesium sulfate, followed by filtration. The filtrate so obtained was concentrated and the residue was purified by chromatography on a silica gel column, whereby 1.9 g of the title compound were obtained.
Reaction SMILES: [CH3:1][C:2]1C=C(C=[C:8](C)[C:9]=1O)C#N.[CH3:12][O:13][C:14]1[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[CH:17]=[CH:16][C:15]=1[C:23]1[N:27]=[C:26]([CH3:28])[O:25][N:24]=1>>[C:2]([CH2:9][CH2:8][CH2:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)=[C:14]([OH:13])[C:19]=1[CH3:20])#[CH:1].[C:2]([CH2:9][CH2:8][CH2:12][O:13][C:14]1[C:19]([CH3:20])=[C:18]([OH:21])[CH:17]=[CH:16][C:15]=1[C:23]1[N:27]=[C:26]([CH3:28])[O:25][N:24]=1)#[CH:1]
Reactant: Cc1cc(C#N)cc(C)c1O
Reactant: COc1ccc(-c2noc(C)n2)c(OC)c1C
Product: C#CCCCOc1c(-c2noc(C)n2)ccc(O)c1C
Product: C#CCCCOc1ccc(-c2noc(C)n2)c(O)c1C

Procedure:
By following a procedure similar to that described in Example 1(a) but substituting for the 3,5-dimethyl-4-hydroxybenzonitrile an equimolar amount of the compound from Example 8, part (d), there can be obtained 3-[4-(3-ethinylpropoxy)-2-hydroxy-3-methylphenyl]-5-methyl-1,2,4-oxadiazole and its positional isomer 3-[2-(3-ethinylpropoxy)-4-hydroxy-3-methylphenyl]-5-methyl-1,2,4-oxadiazole which can be separated by conventional procedures.