Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N+:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[S:12][C:11]=1[CH3:19])[CH3:9].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[Cl:31][C:32]([C:35]1[N:40]=[C:39](C(Cl)(Cl)Cl)[N:38]=[C:37]([C:45]([Cl:48])([Cl:47])[Cl:46])[N:36]=1)([Cl:34])[Cl:33]>C1(C)C=CC=CC=1>[CH2:8]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[S:12][C:11]1=[CH:19][C:39]1[N:40]=[C:35]([C:32]([Cl:31])([Cl:34])[Cl:33])[N:36]=[C:37]([C:45]([Cl:47])([Cl:48])[Cl:46])[N:38]=1)[CH3:9]
Reactant: ClC(Cl)(Cl)c1nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n1
Reactant: CC[n+]1c(C)sc2ccccc21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCN1C(=Cc2nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n2)Sc2ccccc21

Procedure:
Within a period of half an hour, 10 g (0.1 mol) of triethylamine was added dropwise to a suspension of 35 g (0.1 mol) of 3-ethyl-2-methyl-benzothiazolium-p-toluene-sulfonate and 43 g (0.1 mol) of tris-trichloromethyl-s-triazine in 300 ml of toluene. After completion of the addition the reaction mixture was stirred for half an hour, until the exothermic reaction ceased; the product which had precipitated was filtered off and dried. Compound 2 was obtained in nearly pure form in a quantity of 40 g. By evaporating the toluene in vacuo and treating the solid residue with ethanol, another 9 g of the product resulted. After recrystallization from 2-methoxy-ethanol 40 g (82%) of yellow needles of melting point 238° to 241° C. were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.Cl[CH2:14][CH2:15][CH2:16][O:17][CH3:18]>[OH-].[Na+].O>[CH3:18][O:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([C:9](=[O:11])[CH3:10])=[C:6]([CH3:8])[CH:7]=1
Reactant: CC(=O)c1c(C)cc(O)cc1C
Reactant: COCCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCCCOc1cc(C)c(C(C)=O)c(C)c1
Temperature: 140 °C
Reaction time: 16 h
Yield: 85.7 %

Procedure:
A pressure glass vessel charged with 1-(4-hydroxy-2,6-dimethylphenyl)ethanone (800 mg, 4.9 mmol, 1.0 equiv) and 1-chloro-3-methoxypropane (528.97 mg, 4.9 mmol, 1.0 equiv) in 50% aqueous NaOH solution (10.0 mL) was stirred at 140° C. for 16 h. The residue was diluted with H2O (20 mL) and extracted with EtOAc (3×30 mL). The organic layer was separated, dried over MgSO4(s), and concentrated under reduced pressure to give 1-(4-(3-methoxypropoxy)-2,6-dimethylphenyl)ethanone (987.8 mg, 4.2 mmol) as yellow oil in 86% yield: 1H NMR (DMSO-d6, 500 MHz) δ 6.56 (s, 2 H), 4.02-4.04 (m, 2 H), 3.53-3.55 (m, 2 H), 3.36 (s, 3 H), 2.45 (s, 3 H), 2.23 (s, 6 H), 2.02-2.04 (m, 3H); ESI-MS: m/z 237.7 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[N:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]2[C:6](=[N:7][C:8](=[O:19])[C:9](=[O:18])[N:10]=2)[CH:5]=1)([O-:3])=[O:2].[C:20]1([N:26]=[C:27]=[S:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C=O)C>[C:20]1([NH:26][C:27]([N:14]2[CH2:15][CH2:16][C:17]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]4[NH:7][C:8](=[O:19])[C:9](=[O:18])[NH:10][C:11]=4[C:12]=3[CH2:13]2)=[S:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1N=c2cc([N+](=O)[O-])c3ncccc3c2=NC1=O
Reactant: S=C=Nc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=c1[nH]c2cc([N+](=O)[O-])c3c(c2[nH]c1=O)CN(C(=S)Nc1ccccc1)CC3
Temperature: 60 °C
Reaction time: 24 h

Procedure:
A mixture of the 6-nitropyridoquinoxalinedione (0.1 g, 0.38 mmol), phenylisothiocyanate (70 μL), triethylamine (70 μL) in DMF (5 mL) was stirred at 60° C. for 24 hours. The mixture was poured onto water and allowed to stand. The precipitate was collected by filtration, washed with water and ether, and dried in vacuo to give product (130 mg) as a beige solid; mp 270-274° C., nmR, IR.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](=O)[CH3:4].BrBr.[CH3:9][CH:10]([CH3:17])[CH2:11][CH2:12][NH:13][C:14]([NH2:16])=[S:15].C([O-])(=O)C.[Na+]>CO>[CH:2]([C:3]1[N:16]=[C:14]([NH:13][CH2:12][CH2:11][CH:10]([CH3:17])[CH3:9])[S:15][CH:4]=1)([CH3:6])[CH3:1]
Reactant: CC(=O)C(C)C
Reactant: CC(C)CCNC(N)=S
Agent: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CCNc1nc(C(C)C)cs1
Temperature: 25 °C
Yield: 21.2 %

Procedure:
A solution of 3-methyl-2-butanone (2.64 g) in methanol (30 ml) was cooled to −30° C. bromine (4.8 g) was added, and heated to room temperature with stirring. To the obtained colorless solution were added N-(3-methylbutyl)thiourea (2.92 g) and sodium acetate (2.40 g) and the mixture was stirred with heating under reflux for 2 hrs. The reaction mixture was concentrated, diluted with ethyl acetate and washed with water. The ethyl acetate layer was concentrated, and the residue was purified by silica gel column chromatography with ethyl acetate-hexane (gradient of 1:9 to 2:1 by volume ratio) to give the title compound (0.90 g, yield 21%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[C:14]([CH2:5][N:10]([CH3:14])[CH3:11])=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Solvent: CN(C)C=O
Product: Cc1ncn(-c2ccc(Br)cc2C#N)c1CN(C)C

Procedure:
A solution of 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile (11.0 g, 42.0 mmol) and N,N-dimethylmethyleneiminium chloride (5.0 g, 53.4 mmol) in DMF (75 mL) was stirred at 90° C. for 16 h. The solvent was evaporated, and the oily residue was partitioned between saturated aqueous sodium bicarbonate solution and Ethyl acetate. The organic phase was dried over sodium sulfate, concentrated and purified by chromatography (SiO2, gradient CH2Cl2 to 35% (CH2Cl2/MeOH=9/1) to afford the tide compound as an oil that solidifies on standing (10.62 g, 79%). MS: m/e=319.2/321.3 [M+H]+.
Reaction SMILES: [NH:1]([C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=1)[NH2:2].C(N(CC)CC)C.C(O[CH:22]=[N:23][C:24]#[N:25])C>C(O)C>[NH2:25][C:24]1[N:1]([C:3]2[NH:4][C:5]3[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=3[N:7]=2)[N:2]=[CH:22][N:23]=1
Reactant: NNc1nc2ccccc2[nH]1
Reactant: CCOC=NC#N
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1ncnn1-c1nc2ccccc2[nH]1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 2-hydrazino-1H-benzimidazole (5.0 g, 33.7 mmol) in ethanol (30 ml) is added sequentially triethylamine (5 ml, 33.7 mmol) and N-cyanoformimidic acid ethyl ester (3.3 g, 33.7 mmol) with cooling. After stirring for 2 hours at 0° C. the resulting precipitate is filtered with suction and dried to give 3-amino-2-(1H-benzimidazol-2-yl)-1,2,4-triazole. 1H-NMR (400 MHz, d6-DMSO): 13.0 (s, 1H); 7.77 (s,1H); 7.70 (m, 2H); 7.50 (m, 2H); 7.20 (s, 2H).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][N:17]([C:21]([NH:23][C:24]5[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=5)[C:27]([OH:29])=O)=[O:22])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=CC=1.[NH:35]1[CH:39]=[CH:38][C:37]([NH2:40])=[N:36]1>>[NH:35]1[CH:39]=[CH:38][C:37]([NH:40][C:27]([C:26]2[CH:25]=[C:24]([NH:23][C:21]([N:17]3[CH2:16][C:15]4[CH:14]=[N:13][C:12]5[NH:8][N:9]=[CH:10][C:11]=5[C:20]=4[CH2:19][CH2:18]3)=[O:22])[CH:32]=[CH:31][CH:30]=2)=[O:29])=[N:36]1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CN(C(=O)Nc2cccc(C(=O)O)c2)CC4)cc1
Reactant: Nc1cc[nH]n1
Product: O=C(Nc1cc[nH]n1)c1cccc(NC(=O)N2CCc3c(cnc4[nH]ncc34)C2)c1

Procedure:
The compound N-[3-(1H-pyrazol-3-ylcarbamoyl)phenyl]-3,6,8,9-tetrahydro-7H-pyrazolo[3,4-c][2,7]naphthyridine-7-carboxamide was prepared using 3-(3-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7-carboxamido)benzoic acid and 1H-pyrazol-3-amine as described in general procedure J. The compound was obtained as a solid. LCMS [M+H]: 403.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][C:12]([O:13][CH2:14][CH2:15]Br)=[CH:11][C:10]=1[CH3:19])C1C=CC=CC=1.[ClH:20].[CH2:21]([C:23]1[CH:36]=[CH:35][C:26]([CH2:27][C:28]2([OH:34])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:25][CH:24]=1)C.C(=O)([O-])[O-].[K+].[K+]>>[ClH:20].[OH:8][C:9]1[CH:18]=[CH:17][C:12]([O:13][CH2:14][CH2:15][N:31]2[CH2:32][CH2:33][C:28]([OH:34])([CH2:27][C:26]3[CH:35]=[CH:36][C:23]([CH3:21])=[CH:24][CH:25]=3)[CH2:29][CH2:30]2)=[CH:11][C:10]=1[CH3:19]
Reactant: Cc1cc(OCCBr)ccc1OCc1ccccc1
Reactant: CCc1ccc(CC2(O)CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(CC2(O)CCN(CCOc3ccc(O)c(C)c3)CC2)cc1

Procedure:
The title compound was prepared from 2-(4-benzyloxy-3-methylphenoxy)ethyl bromide (385 mg, 1.2 mmol), 4-(4-ethylbenzyl)-4-hydroxypiperidine hydrochloride (290 g, 1.2 mmol) and potassium carbonate (414 mg, 3 mmol) in two steps as white solid (200 mg): mp 90-94° C. (dec.). 1H NMR (CD3OD) 1.641 (m, 2 H), 1.859 (m, 2 H), 2.083 (5, 3 H), 2.224 (s, 3 H), 2.718 (s, 2 H), 3.260-3.423 (m, 6 H), 4.133 (m, 2 H), 6.585 (s, 2 H), 6.668 (s, 1 H), 7.035 (m, 4 H).
Reaction SMILES: [CH:1]1([C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[NH2:8])[CH2:5][CH2:4][CH:3]=[CH:2]1.C(=O)(O)[O-].[Na+].[Cl:18][CH2:19][C:20](Cl)=[O:21]>C(Cl)Cl.O>[CH:1]1([C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[NH:8][C:20](=[O:21])[CH2:19][Cl:18])[CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: Nc1ccccc1C1C=CCC1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(CCl)Nc1ccccc1C1C=CCC1
Temperature: 0 °C
Yield: 77 %

Procedure:
A solution of 10.00 g (62.8 mmol) of 2-(cyclopent-2-enyl)aniline from Example 1 in 150 mL of methylene chloride and 5.28 g (62.8 mmol) of sodium bicarbonate in 15 mL of water were combined with rapid stirring and cooled 0° C. with the aid of an ice bath. A solution of 7.099 (62.8 mmol) of chloroacetyl chloride in 25 mL of methylene chloride was then added dropwise through the course of 20 min. After an additional hour of vigorous stirring. the layers were separated and the organic layer was dried over anhydrous magnesium sulfate. Evaporation of the solvent in the organic layer and recrystallization of the precipitate with ether afforded 11.41 g (77% yield) of N-[2-(cyclopent-2-enyl)phenyl]-2-chloroacetamide: mp 101°-102° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:23]([CH:25]1[O:27][CH2:26]1)Br>C(#N)C>[O:27]1[CH2:26][CH:25]1[CH2:23][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Nc1ccccc1O)c1ccccc1
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=C(Nc1ccccc1OCC1CO1)c1ccccc1

Procedure:
To a strred solution of N-(2-hydroxy-phenyl)-benzamide (0.81 g, 3.80 mmol), and cesium carbonate (1.61 g, 4.94 mmol) in acetonitrile was added epibromohydrin (0.63 ml, 7.60 mmol). After 4 hours the reaction mixture was partitioned between dichloromethane and water. After evaporation of the organic solvent, the residue was crystallized from petroleum ether and diethyl ether yielding the title compound (0.741 g, 73%).
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:9]=3[N:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:18][C:19]1[CH:20]=[C:21]([N:25]=[C:26]=[O:27])[CH:22]=[CH:23][CH:24]=1>ClCCl>[Cl:18][C:19]1[CH:20]=[C:21]([NH:25][C:26]([CH:2]2[CH2:3][NH:4][CH2:5][CH2:6][N:1]2[C:7]2[C:8]3[N:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:9]=3[N:10]=[CH:11][N:12]=2)=[O:27])[CH:22]=[CH:23][CH:24]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: Clc1cnc2c(N3CCNCC3)ncnc2c1
Solvent: ClCCl
Product: O=C(Nc1cccc(Cl)c1)C1CNCCN1c1ncnc2cc(Cl)cnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a solution of 4-(piperazin-1-yl)-7-chloro-pyrido[3,2-d]pyrimidine (1.0 g, 4 mmole) in dichloromethane (40 ml), was added 3-chlorophenyl isocyanate (615 mg, 4 mmole). The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, resulting in the pure title compound (1.6 g, yield 99%) as a white solid which was characterized by its mass spectrum as follows: MS (m/z): 403.1 ([M+H]+, 100).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=C(C(F)(F)F)[O:10][N:9]=2)=[CH:4][CH:3]=1.Cl.NO.[C:20](=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:20][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:9][OH:10])[NH2:12])=[CH:4][CH:3]=1
Reactant: Oc1ccc(-c2noc(C(F)(F)F)n2)cc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: NO
Agent: [K+]
Solvent: CCO
Product: COc1ccc(C(N)=NO)cc1
Yield: 20 %

Procedure:
3-(4-hydroxyphenyl)-5-trifluoromethyl-1,2,4-oxadiazole 13.32 g (0.1 mol) 4-methoxybenzonitrile, 20.85 g (0.3 mol) of hydroxylamine hydrochloride and 41.40 g (0.3 mol) potassium carbonate was added to 400 mL absolute ethanol and refluxed 21 hours. The product was filtered and recrystallized from methanol to give 3.12 g (0.02 mol) of 4-methoxybenzamide oxime.
Reaction SMILES: [O-]CC.[Na+].[CH:5]1([N:10]2[C:14]3[CH:15]=[CH:16][C:17]([C:19](=[O:28])[CH2:20][C:21]4[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=4)=[CH:18][C:13]=3[N:12]([CH3:29])[C:11]2=[O:30])[CH2:9][CH2:8][CH2:7][CH2:6]1.[N:31](OCCCC)=[O:32]>C(O)C.O>[CH:5]1([N:10]2[C:14]3[CH:15]=[CH:16][C:17]([C:19](=[O:28])[C:20]([C:21]4[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=4)=[N:31][OH:32])=[CH:18][C:13]=3[N:12]([CH3:29])[C:11]2=[O:30])[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: CCCCON=O
Reactant: Cc1cccc(CC(=O)c2ccc3c(c2)n(C)c(=O)n3C2CCCC2)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cccc(C(=NO)C(=O)c2ccc3c(c2)n(C)c(=O)n3C2CCCC2)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sodium ethoxide (9.27 mL of a 21% solution in ethanol, 28.6 mmol) was added to ethanol (12 mL) at 0 deg C. After 5 minutes, 1-cyclopentyl-3-methyl-5-m-tolylacetyl-1,3-dihydro-benzoimidazol-2-one (prepared as described in the general procedure, 5 gm, 14.3 mmol) was added. n-Butyl nitrite (3.34 mL, 28.6 mmol) was then added dropwise over 5 minutes. When the addition was complete, the flask was covered with a septum and allowed to stand in the refrigerator overnight, after which time LCMS of an aliquot showed essentially complete reaction. The reaction mixture was diluted with 300 mL of water and allowed to stir at room temperature overnight. The resulting precipitate was filtered and dried in vacuo. The yellow solid was slurried with benzene for 2 hours and filtered to afford 4.0 gm of a pale tan solid. The title oxime is formed a ca. 10:1 mixture of isomers.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][SiH:12]([CH3:14])[CH3:13].[C:15]([Mg]Br)#[CH:16]>>[CH2:11]([Si:12]([CH3:14])([CH3:13])[C:15]#[CH:16])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH3:2]
Reactant: C[SiH](C)CCCCCCCCCCCl
Reactant: C#C[Mg]Br
Product: C#C[Si](C)(C)CCCCCCCCCC
Temperature: 0 °C

Procedure:
A round bottom flask was charged with chlorodecyldimethylsilane (12.362 g; 50.00 mmol) and the flask was cooled with an ice-water bath to 0° C. Ethynylmagnesium bromide (0.5M in THF, 125.0 cm3, 62.50 mmol) was added into the flask over 30 min. The cooling bath was removed and the mixture was stirred at 50° C. for an additional hour.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([NH:16][C@:17]1([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:19][C@H:18]1[CH:20]=[CH2:21])=[O:15])=O)(C)(C)C.[ClH:27].O1CCOCC1>>[ClH:27].[OH:13][C@H:11]1[CH2:12][NH:8][C@H:9]([C:14]([NH:16][C@:17]2([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:19][C@H:18]2[CH:20]=[CH2:21])=[O:15])[CH2:10]1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C)C(=O)OCC
Agent: Cl
Solvent: C1COCCO1
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](O)CN1)C(=O)OCC
Yield: 97 %

Procedure:
A stirred slurry of ethyl 1(R)-[1-tert-butoxycarbonyl-4(R)-hydroxypyrrolidine-2(S)-carboxamido]-2(S)-vinylcyclopropanecarboxylate (5.0 g, 13.6 mmol) was treated with 4N HCl/dioxane (20 mL) for 3 h. The reaction mixture was concentrated in vacuo to give 4.5 g (97%) of ethyl 1(R)-[4(R)-hydroxypyrrolidine-2(S)-carboxamido]-2(S)-vinylcyclopropanecarboxylate hydrochloride as a white solid: 1H NMR (300 MHz, CD3OD) δ 1.26 (t, J=7.14 Hz, 3 H), 1.46 (dd, J=9.70, 5.31 Hz, 1H), 1.80 (dd, J=8.23, 5.31 Hz, 1H), 2.00-2.15 (m, 1 H), 2.18-2.30 (m, 1H), 2.45 (dd, J=13.36, 7.50 Hz, 1H), 3.36-3.48 (m, 1H), 4.11-4.24 (m, 2H), 4.44 (dd, J=10.25, 7.68 Hz, 1H), 4.58-4.65 (m, 1H), 4.84-4.94 (m, 1H), 5.17 (d, J=1.83 Hz, 1H), 5.27-5.42 (m, 1H), 5.67-5.89 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:26][CH2:27][CH2:28][N:29]=[C:30]=[O:31]>C(O)C.ClCCl>[Cl:26][CH2:27][CH2:28][NH:29][C:30]([NH:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:15])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1)=[O:31]
Reactant: O=C=NCCCl
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Solvent: ClCCl
Solvent: CCO
Product: O=C(NCCCl)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 30 %

Procedure:
To a stirred solution of [4-(6-aminopyridazin-3-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone (0.070 g, 0.200 mmol) in a mixture of ethanol and dichloromethane (1:1, 15 mL) was added 2-chloroethylisocyanate (80.0 μL, 0.79 mmol) in one portion. The mixture was then stirred for 10 minutes at room temperature and then concentrated in vacuo. The residue was washed with 5% HCl solution, water and dried. The residue was purified by column chromatography to afford the title compound in 30% yield (0.028 g). 1H NMR (300 MHz, CDCl3) δ 7.98 (b., s, 1H), 7.75 (d, J=7.0 Hz, 1H), 7.64 (t, J=7.0 Hz, 1H), 7.56 (t, J=7.0 Hz, 1H), 7.37 (d, J=7.0 Hz, 1H), 7.12 (d, J=10.0 Hz, 1H), 4.99 (m, 1H), 4.06-3.89 (m, 2H), 3.69-3.59 (m, 6H), 3.56-3.53 (m, 2H), 3.47-3.44 (m, 2H), 3.35-3.33 (m, 2H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[CH:4]([C:5](=[O:22])[CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([C:36](O)=[O:37])[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([C:36]([O:1][C@H:2]2[CH2:19][CH2:18][C@@:17]3([CH3:20])[CH:4]([C:5](=[O:22])[CH2:6][C@@H:7]4[C@@H:16]3[CH2:15][CH2:14][C@@:12]3([CH3:13])[C@H:8]4[CH2:9][CH2:10][C:11]3=[O:21])[CH2:3]2)=[O:37])[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: C[C@]12CC[C@H](O)CC1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)O[C@H]2CC[C@@]3(C)C(C2)C(=O)C[C@@H]2[C@@H]3CC[C@]3(C)C(=O)CC[C@@H]23)CC1
Yield: 62 %

Procedure:
Prepared in 62% yield from 3β-hydroxyandrostane-6,17-dione and 1-(tert-butoxycarbonyl)-4-piperidinecarboxylic acid by the procedure described in Prepn. 43. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 4.65 (1H, m), 3.60-1.20 (29H, m), 1.35 (9H, s), 0.78 (3H, s), 0.69 (3H, s).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[N:5][N:4]=[N:3]1.[CH2:14]([N:16](CC)[CH2:17][CH3:18])[CH3:15].ClC(OCC(C)C)=O.C(NCC)C>CN(C)C=O>[CH2:14]([N:16]([CH2:17][CH3:18])[C:11](=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1[N:2]([CH3:1])[N:3]=[N:4][N:5]=1)[CH3:15]
Reactant: CCN(CC)CC
Reactant: Cn1nnnc1CCCCC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)CCCCc1nnnn1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.9 %

Procedure:
(5-(1-Methyl-1,2,3,4-tetrazol-5-yl)valeric acid (1.8 g) is dissolved in dimethylformamide (50 ml), and thereto is added triethylamine (1.1 g). To the mixture is added dropwise with stirring isobutyl chloroformate (1.5 g) under ice-cooling, and the mixture is stirred at room temperature for 30 minutes. To the mixture is added dropwise with stirring diethylamine (0.9 g) at rood temperature, and the mixture is stirred for 2 hours. Dimethylformamide is distilled off under reduced pressure, and the residue is purified by column chromatography (Wakogel C-200). After eluting with benzene-chloroform (1:1), the eluate is distilled under reduced pressure to give N,N-diethyl-5-(1-methyl-1,2,3,4-tetrazol-5-yl)valeramide (0.7 g), colorless liquid, b.p. 190°-200° C. (bath temperature)/0.07 mmHg, nD25 =1.4907.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[S:8][C:7]2[C:9]([CH3:16])([CH3:15])[CH2:10][CH2:11][C:12]([CH3:14])([CH3:13])[C:6]=2[CH:5]=1)O.[Br-:17].[C:18]1([PH+:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[Br-:17].[CH3:13][C:12]1([CH3:14])[C:6]2[CH:5]=[C:4]([CH:2]([P+:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH3:1])[S:8][C:7]=2[C:9]([CH3:16])([CH3:15])[CH2:10][CH2:11]1
Reactant: CC(O)c1cc2c(s1)C(C)(C)CCC2(C)C
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CC#N
Product: CC(c1cc2c(s1)C(C)(C)CCC2(C)C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 103.4 %

Procedure:
20.2 g of 4,5,6,7-tetrahydro-α,4,4,7,7-pentamethylbenzo[b]thiophene-methanol are dissolved in 260 ml of acetonitrile and the solution is treated with 29.2 g of triphenylphosphonium bromide. After stirring at 50° C. for 3 hours, the mixture is evaporated to dryness, the residue is taken up with 80% aqueous ethanol and extracted twice with hexane. The ethanol phase is evaporated, the residue is dissolved in methylene chloride, the solution is dried over sodium sulphate and evaporated. There are obtained 49.4 g of [1-(4,5,6,7-tetrahydro-4,4,7,7-tetramethylbenzo-[b]thien-2-yl)ethyl]triphenylphosphonium bromide as an amorphous white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][N:5]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C[O-].[Na+].[CH3:26][C:27](=[CH:29][CH2:30][CH2:31]/[C:32](=[CH:34]/CO)/[CH3:33])[CH3:28].CO>C1(C)C=CC=CC=1>[CH2:1]([O:2][C:3](=[O:22])[CH2:4][N:5]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])/[CH:26]=[C:27](/[CH2:29][CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33])\[CH3:28]
Reactant: CC(C)=CCC/C(C)=C/CO
Reactant: CCCCCCCCN(CCCCCCCC)CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CCCCCCCCN(CCCCCCCC)CC(=O)OC/C=C(\C)CCC=C(C)C
Reaction time: 1 h

Procedure:
To a mixture of N,N-dioctylglycine methyl ester (47.02 g, 150 mmol, 1 eq) in toluene (250 ml) under argon was slowly added some sodium methoxide (1.01 g, 0.019 mol, 0.125 eq) and geraniol (27.3 ml, 158 mmol, 1.05 eq). The mixture was heated under vacuum (10 mm Hg) and the methanol produced by the transesterification reaction is distilled with toluene over one hour after which the reaction appeared completed by 1H NMR. Any remaining toluene is evaporated under vacuum. Diethyl ether was added (200 ml) and the mixture stored at 4° C. for one hour prior to filtration. The filtrate was then concentrated under vacuum yielding to the expected N,N-dioctylglycine geranyl ester as a light yellow oil (quantitative yield).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]([NH2:17])=[S:16])=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:19][C:20](=O)[CH2:21][O:22][C:23](=[O:25])[CH3:24]>CN(C=O)C>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]2[S:16][CH:19]=[C:20]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[N:17]=2)=[N:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=S)Nc1ccc(Oc2ccccc2)cn1
Reactant: CC(=O)OCC(=O)CCl
Solvent: CN(C)C=O
Product: CC(=O)OCc1csc(Nc2ccc(Oc3ccccc3)cn2)n1
Temperature: 70 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
(5-Phenoxy-pyridine-2-yl)-thiourea (0.86 mmol) is dissolved in DMF (1 ml) and acetic acid 3-chloro-2-oxo-propyl ester (1.1 eq.) in 1 ml DMF is added and stirred 2 h at 70° C. After cooling to RT the precipitate is filtered, washed with water and dried 16 h in vacuo at 40° C. “A9” is obtained after column chromatography (heptan/ethyl acetate) as colourless powder in a yield of 69%; mp. 158.5-160.5° C.; HPLC (method C): 1.89 min; LC-MS (method A): 1.938 min, 342.15 (M+H+); 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] 11.375 (s, 1H), 8.105 (d, 1H, J=2.8 Hz), 7.519 (dd, 1H, J=8.9 Hz, J=2.8 Hz), 7.389-7.347 (m, 2H), 7.120-7.088 (m, 2H), 6.995-6.978 (m, 2H), 6.918 (s, 1H), 5.007 (s, 2H), 2.064 (s, 3H).