Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:12])[C:9]([CH3:11])=[CH2:10].[OH:14][CH:15]1[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2>C1(C)C=CC=CC=1>[C:8]([O:14][CH:15]1[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:12])[C:9]([CH3:11])=[CH2:10]
Reactant: C=C(C)C(=O)Cl
Reactant: OC1c2ccccc2-c2ccccc21
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC1c2ccccc2-c2ccccc21

Procedure:
With stirring and ice cooling, 111 g of triethylamine was added to a mixture of 120 g of methacrylic acid chloride, 182 g of 9-hydroxyfluorene, and 1500 g of toluene. The mixture was stirred at room temperature for 16 hours. By standard aqueous work-up and solvent distillation, a crude product was obtained. It was purified by column chromatography, yielding the target compound, 9-fluorenyl methacrylate.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:7][CH:6]=1>CO.[OH-].[Na+]>[O:22]=[C:4]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:7][CH:6]=1)[C:3]([OH:23])=[O:2]
Reactant: COC(=O)C(=O)c1ccc(OCCCOc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCCCOc2ccccc2)cc1
Yield: 56.5 %

Procedure:
A mixture of alpha-oxo-4-[[(3-phenoxy)propyl]oxy]benzeneacetic acid methyl ester (0.63 g) in methanol and 0.5N sodium hydroxide (8 mL) was treated as in Example 19. Extraction with dichloromethane provided material which was crystallized from diethyl ether-hexane to give 0.34 g of colorless alpha-oxo-4-[[(3-phenoxy)propyl]oxy]benzeneacetic acid, mp 50°-52° C.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:9])([CH3:8])[C:4]#[C:5][CH2:6][CH3:7].[Br:10][CH:11]([CH2:15][CH3:16])[C:12](Br)=[O:13].C(N(CC)CC)C.O>ClCCl.CCCCCC.C(OCC)C>[Br:10][CH:11]([CH2:15][CH3:16])[C:12]([NH:2][C:3]([CH3:9])([CH3:8])[C:4]#[C:5][CH2:6][CH3:7])=[O:13]
Reactant: CCC(Br)C(=O)Br
Reactant: CCC#CC(C)(C)N
Agent: Cl
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: CCC#CC(C)(C)NC(=O)C(Br)CC
Temperature: 5 °C

Procedure:
5-Amino-5-methylhex-3-yne hydrochloride (2.21 g) was dissolved in dry dichloromethane (50 ml) and cooled to 5° C. with stirring. 2-Bromobutyryl bromide (3.45 g) was added to the mixture and dry triethylamine (4.17 ml) was added dropwise while maintaining the reaction temperature between 8–15° C. by cooling during the addition. The suspension, which had formed during the reaction, was diluted with further dry dichloromethane (20 ml) and stirred at 5° C. for 0.5 hours. The mixture was allowed to warm to ambient temperature and stirred for a further 2 hours. The reaction was treated with water and extracted with dichloromethane. The organic phase was separated, washed with water (three times), dried over magnesium sulphate and evaporated under reduced pressure to give a brown oil. The oil was fractionated by chromatography (silica; hexane/diethyl ether, 1:1 by volume) to give the required product, as a pale yellow solid, 3.17 g, m.p. 53–55° C.
Reaction SMILES: [OH-].[K+].[F:3][C:4]([F:15])([F:14])[CH:5]([F:13])[C:6]([F:12])([F:11])[S:7]([O-:10])(=[O:9])=[O:8].[OH:16][C:17]1[CH:22]=[CH:21][C:20]([IH+:23])=[CH:19][CH:18]=1.[OH:24][C:25]1[CH:30]=[CH:29][C:28]([IH+])=[CH:27][CH:26]=1.F[C:33](F)(F)[CH:34](F)[C:35](F)(F)S([O-])(=O)=O.[Cl-].[C:46](Br)([CH3:49])([CH3:48])[CH3:47]>C(O)C.C(OCC)C>[F:15][C:4]([F:3])([F:14])[CH:5]([F:13])[C:6]([F:11])([F:12])[S:7]([O-:10])(=[O:8])=[O:9].[C:34]([O:16][C:17]1[CH:22]=[CH:21][C:20]([I+:23][C:28]2[CH:29]=[CH:30][C:25]([O:24][C:46]([CH3:49])([CH3:48])[CH3:47])=[CH:26][CH:27]=2)=[CH:19][CH:18]=1)([CH3:35])([CH3:4])[CH3:33]
Reactant: Oc1ccc([IH+])cc1
Reactant: CC(C)(C)Br
Agent: O=S(=O)([O-])C(F)(F)C(F)C(F)(F)F
Agent: [Cl-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCO
Product: CC(C)(C)Oc1ccc([I+]c2ccc(OC(C)(C)C)cc2)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
6.2 g (0.11 mol) of potassium hydroxide was dissolved in 250 ml of ethanol. 27.2 g (0.05 mol) of bis-(4-hydroxyphenyliodonium) 3,3,3,2,1,1-hexafluoropropane sulfonate (prepared from a metathesis reaction of chloride) was added to the solution. The mixture was stirred for 3 hours. The solution was then heated to 50° C., and 15.1 g (0.11 mol) of t-butyl bromide was added dropwise thereto. The mixture was heated under reflux for 6 hours. The precipitates were removed by filtration. The solvent was removed from the filtrate by distillation. The residue was dissolved in 250 ml of ethyl acetate. The solution was washed several times with water, and then dried. The solvent was removed to obtain a yellow oil. The contemplated material was obtained by recrystallization from diethyl ether. The structure was confirmed by 1H-NMR (CDCl3): δ=1.43 (s, 18H), 5.00-5.30 (d[m], 1H), 7.17-7.21 (d, 4H), 7.55-7.59 ppm (d, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Cl:26])=[CH:4][N:3]=1.[N:27]1([CH2:33][CH2:34][O:35][C:36]2[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=2)[CH:39]=O)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CCO.CN(C=O)C.C(Cl)Cl.N>[Cl:26][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)=[C:7]2[N:8]=[C:39]([C:38]3[CH:41]=[CH:42][CH:43]=[C:36]([O:35][CH2:34][CH2:33][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH:37]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: O=Cc1cccc(OCCN2CCOCC2)c1
Reactant: Nc1ncc(Cl)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C(CN1CCN(c2c(Cl)cnc3[nH]c(-c4cccc(OCCN5CCOCC5)c4)nc23)CC1)Nc1nccs1
Temperature: 85 °C

Procedure:
To a mixture of 2-(4-(2-amino-5-chloro-3-nitropyridin-4-yl)piperazin-1-yl)-N-(thiazol-2-yl)acetamide (0.060 g, 0.15 mmol, 1 eq) in EtOH (2.6 mL) and DMF (0.35 mL), 3-(2-morpholin-4-ylethoxy)benzaldehyde (0.039 g, 0.17 mmol, 1.1 eq) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.45 mL, 0.45 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 94:6). The title compound was obtained after trituration with diethyl ether as a pale yellow solid (0.018 g, 21%); 1H-NMR (500 Mz, DMSO-d6): 2.68-2.85 (m, 6H), 3.41 (s, 2H, NCH2CO), 3.55-3.65 (m, 4H), 3.71-3.80 (m, 4H), 4.12-4.25 (s, 2H), 7.06-7.12 (m, 1H), 7.23 (d, J=3.5 Hz, 1H, thiazole H-5 or thiazole H-4), 7.40-7.50 (m, 2H, thiazole H-4 or thiazole H-4 and ArH), 7.75-7.82 (m, 2H, ArH), 8.13 (s, 1H, imidazo[4,5-b]pyridine 5-H), 11.70-12.10 (br s, 1H, NHCO), 13.18 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 2.62 min—583/585 [(M+H)+, Cl isotopic pattern].
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[CH:7][C:6]=1[NH:14][C:15](=[O:35])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[C:24]=1[O:33][CH3:34])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2].[NH2:36][C:37]1[CH:42]=[N:41][CH:40]=[CH:39][N:38]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[NH:36][C:37]2[CH:42]=[N:41][CH:40]=[CH:39][N:38]=2)=[CH:7][C:6]=1[NH:14][C:15](=[O:35])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[C:24]=1[O:33][CH3:34])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:3])([CH3:4])[CH3:2]
Reactant: Nc1cnccn1
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1ccc(OC)c(OC)c1OC
Product: CCCCCC(CC(=O)Nc1cc(C(=O)Nc2cnccn2)ccc1C(C)(C)C)c1ccc(OC)c(OC)c1OC

Procedure:
Following a similar procedure to that described in Example 8, but using N-(2-t-butyl-5-carboxyphenyl)-3-(2,3,4-trimethoxyphenyl)octanamide (prepared as described in Preparation 74A) and 2-aminopyrazine, the title compound was obtained as a colorless foam-like substance.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[N:15]([CH2:30][CH2:31]OS(C)(=O)=O)[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=4)[N:18]=3)[CH2:10][CH2:9]2)[C:3]=1[C:37]#[N:38].[CH:39]1([CH2:42][NH2:43])[CH2:41][CH2:40]1>>[NH2:1][C:2]1[C:3]([C:37]#[N:38])=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[N:15]([CH2:30][CH2:31][NH:43][CH2:42][CH:39]4[CH2:41][CH2:40]4)[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=4)[N:18]=3)[CH2:10][CH2:9]2)[N:5]=[CH:6][N:7]=1
Reactant: NCC1CC1
Reactant: CS(=O)(=O)OCCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1
Product: N#Cc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCNCC2CC2)CC1
Yield: 40 %

Procedure:
The title compound was prepared by stirring methanesulfonic acid 2-[2-[1-(6-amino-5-cyano-pyrimidin-4-yl)-piperidin-4-yl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-imidazol-1-yl]-ethyl ester (85.0 mg; 0.15 mmol; 1.00 eq) in cyclopropylmethylamine (54.6 mg, 0.77 mmol; 5.0 eq) at ambient temperature. The reaction mixture was purified via flash chromatography using a gradient of 0-10% methanol in dichloromethane to give 4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile (32.7 mg; 0.06 mmol; 40.3%). LC-MS: (M+1=529, obsd.=529).
Reaction SMILES: C([Mg]Cl)(C)C.[CH:6]1([NH2:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[CH2:13]([Si:15](OCC)([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[CH3:14]>O1CCCC1>[CH2:13]([Si:15]([NH:12][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[CH3:14]
Reactant: CCO[Si](CC)(OCC)OCC
Reactant: NC1CCCCC1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCO[Si](CC)(NC1CCCCC1)OCC
Temperature: 70 °C
Yield: 83 %

Procedure:
Following the same general procedure described in Example 1, a 500 ml, four-necked flask fitted with a pressure equalizing funnel was charged with 0.5 mol of isopropylmagnesium chloride in 250 ml of tetrahydrofuran. Cyclohexylamine, 0.55 mol (52 g), was added over 30 minutes via a pressure equalizing funnel. The contents were refluxed for 15 minutes to complete the evolution of gas. Ethyltriethoxysilane, 0.5 mol (96 g) was added via the pressure equalizing funnel. The contents were refluxed at a pot temperature of 70° C. for two hours. Ethyl(cyclohexylamino)diethoxysilane was filtered under nitrogen atmosphere from the magnesium ethoxychloride. The filter cake was washed with ether (2×100 ml) to obtain the residual product. The solvent was removed via rotary evaporation. The residue was distilled under vacuum to yield 102 g of ethyl(cyclohexylamino)diethoxysilane as a colorless oil (purity>98%); bp 68° C./0.5 mm. The total yield was 83% of theoretical.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16](=O)[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:12][CH:11]=1)([O-])=O.Cl(O)(=O)(=O)=O>C(O)(=O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:12][CH:11]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccccc2[N+](=O)[O-])cc1
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Product: Nc1ccccc1-c1ccc(CCCC(=O)O)cc1

Procedure:
6 gm (0.02 mol) of 4-(2'-nitro-4-biphenylyl)-4-oxo-butyric acid were hydrogenated in 60 ml of acetic acid and 2.5 ml of perchloric acid in the presence of 2.5 gm of palladium/barium sulfate (5%) as catalyst at room temperature and at a pressure of 5 atmospheres in a Parr-autoclave. After absorption of the calculated quantity of hydrogen, the catalyst was vacuum-filtered off, and the solvent was removed in vacuo. The residue was dissolved in water and admixed with ether. By addition of sodium bicarbonate solution, the aqueous phase was adjusted to a pH-value of about 5. Now, the ether solution was separated, washed with water and the solvent was removed. The obtained 4-(2'-amino-4-biphenylyl)-butyric acid was dissolved in ether and mixed with cyclohexylamine; the precipitated cyclohexylamine salt was collected and recrystallized from methylene chloride and then from acetone/ether. Melting point 123°-126° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:19])[CH:14]([NH2:18])[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)([CH3:6])[CH3:5].[OH:21][C@@H:22]([CH:26]([CH3:28])[CH3:27])[C:23](O)=[O:24]>>[CH3:1][O:2][C:3](=[O:20])[C:4]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:19])[CH:14]([NH:18][C:23](=[O:24])[CH:22]([OH:21])[CH:26]([CH3:28])[CH3:27])[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)([CH3:5])[CH3:6]
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)C(=O)OC)cn1
Reactant: CC(C)[C@H](O)C(=O)O
Product: CCCC(NC(=O)C(O)C(C)C)C(=O)Nc1cn(C(C)(C)C(=O)OC)cn1

Procedure:
2-[4-(2-Amino-pentanoylamino)-imidazol-1-yl]-2-methyl-propionic acid methyl ester was coupled with (S)-2-hydroxy-3-methyl-butyric acid to provide the title compound: C13 NMR (100 MHz, CDCl3) 13.8, 15.9, 19.1, 19.4, 26.1, 26.2, 32.1, 35.5, 52.6, 53.3, 61.2, 76.4, 106.1, 131.9, 137.5, 169.6, 172.6, 173.9; MS 383.2 m/z (M+1).
Reaction SMILES: Cl.O1CCOCC1.C(OC([NH:18][C:19]1[N:23]([CH:24]=[C:25]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:26](OCC)=[O:27])[N:22]=[C:21]([CH3:36])[CH:20]=1)=O)C1C=CC=CC=1>>[OH:27][C:26]1[C:25]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:24][N:23]2[N:22]=[C:21]([CH3:36])[CH:20]=[C:19]2[N:18]=1
Reactant: CCOC(=O)C(=Cn1nc(C)cc1NC(=O)OCc1ccccc1)C(=O)OCC
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1cn2nc(C)cc2nc1O
Reaction time: 22 h
Yield: 72.6 %

Procedure:
4 N Hydrochloric acid/1,4-dioxane (2 ml) was added to the diethyl 2-(5-benzyloxycarbonylamino-3-methylpyrazol-1-ylmethylene)m alonate (100 mg) obtained above and stirred for 22 hours. Precipitated crystals were collected by filtration and dried under reduced pressure to give ethyl 5-hydroxy-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylate (40 mg, Y.:73%).
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][CH2:5][C@@:6]1([CH3:25])[C:15](=[O:16])[CH2:14][CH2:13][CH:12]2[CH:7]1[CH2:8][CH2:9][C@:10]1([CH3:24])[C@@H:19]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][CH2:17][CH:11]12.[CH3:27][N+](C)=C.[I-].CI.CCN(CC)CC.C1CCN2C(=NCCC2)CC1.Cl>ClCCl.O>[CH3:23][O:22][C:20]([C@@H:19]1[C@@:10]2([CH3:24])[CH2:9][CH2:8][CH:7]3[CH:12]([CH:11]2[CH2:17][CH2:18]1)[CH2:13][C:14](=[CH2:27])[C:15](=[O:16])[C@@:6]3([CH2:5][CH2:4][C:3]([OH:2])=[O:26])[CH3:25])=[O:21]
Reactant: C=[N+](C)C
Reactant: COC(=O)CC[C@@]1(C)C(=O)CCC2C1CC[C@@]1(C)C2CC[C@@H]1C(=O)OC
Agent: Cl
Agent: [I-]
Solvent: CI
Solvent: O
Solvent: CCN(CC)CC
Product: C=C1CC2C(CC[C@@]3(C)C2CC[C@@H]3C(=O)OC)[C@@](C)(CCC(=O)O)C1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-1 (24.5 g, 69.9 mmol) in 250 mL dichloromethane was added the Eschenmoser's salt (16.4 g, 174.8 mmol). The mixture was refluxed over 48 hr and then cooled to room temperature. After addition of MeI (8.7 mL, 139.8 mmol) and Et3N (24.4 mL, 174.8 mmol), the mixture was stirred at room temperature for 48 hr and concentrated. The residue was dissolved in dichloromethane (150 mL). DBU (21 mL, 139.8 mmol) was added. The mixture was stirred overnight and diluted with water (150 mL) and acidified with 6N HCl until pH=4. After removal of the solvent, the residue was extracted with EtOAc (×3). The combined organic layers was washed with brine and dried (MgSO4). Concentration of the mixture afforded a yellow solid as the desired product 4-2 which was further purified by recrystalization (methanol/water). MS calculated M-H2O: 344.5. Found 345.0
Reaction SMILES: C(Br)CCCCC.[CH2:8]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH2:22][CH2:23][C:24](=[O:27])[NH:25][N:26]=1)[CH2:9]CCCC>>[CH2:8]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH2:22][CH2:23][C:24](=[O:27])[NH:25][N:26]=1)[CH3:9]
Reactant: CCCCCCOc1ccccc1C1=NNC(=O)CC1
Solvent: CCCCCCBr
Product: CCOc1ccccc1C1=NNC(=O)CC1

Procedure:
Similarly prepared using hexyl bromide in place of ethyl bromide was: 6-(o-Hexyloxyphenyl)-4,5-dihydro-3(2H)-pyridazinone m.p. 75°-77°C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:11][CH2:12][C:13]2([CH:18]([CH3:20])[CH3:19])OCC[O:14]2)[CH3:9])=[CH:4][CH:3]=1.Cl.C([O-])(O)=O.[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([NH:10][CH2:11][CH2:12][C:13](=[O:14])[CH:18]([CH3:20])[CH3:19])[CH3:9])=[CH:6][CH:7]=1
Reactant: CC(C)C1(CCN[C@@H](C)c2ccc(Br)cc2)OCCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(C)C(=O)CCN[C@@H](C)c1ccc(Br)cc1
Temperature: 65 °C
Yield: 97.1 %

Procedure:
To a solution of (S)-1-(4-bromophenyl)-N-(2-(2-isopropyl-1,3-dioxolan-2-yl)ethyl)ethanamine (6.5 g, 19 mmol) in MeOH (60 mL) was added conc HCl (60 mL). The mixture was stirred at 65° C. till the reaction was finished. The mixture was cooled to 0° C., and the pH of the mixture was adjusted to 7 by adding the satd aq NaHCO3. The mixture was concentrated, and the residue was extracted with EtOAc (3×100 mL). The organic layer was washed with brine, dried over Na2SO4, and concentrated to give (S)-1-(1-(4-bromophenyl)ethylamino)-4-methylpentan-3-one (5.5 g, 97% yield), which was used for the next step without further purification. 1H NMR (CDCl3): δ 1.07 (d, J=6.8 Hz, 6H), 1.29 (d, J=6.4 Hz, 3H), 1.89 (br, 1H), 2.54-2.62 (m, 4H), 2.66-2.69 (m, 1H), 3.68-3.72 (m, 1H), 7.18-7.20 (m, 2H), 7.41-7.44 (m, 2H).
Reaction SMILES: [OH:1][C@H:2]1[C@@H:8]2[CH2:9][C@@H:7]2[C@H:6]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:3]12[CH2:4][CH3:5])[C@@H:18]1[C:13](=[CH:14][C:15](=[O:22])[CH2:16][CH2:17]1)[CH2:12][CH2:11]3.[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[C:23]([O:1][C@H:2]1[C@@H:8]2[CH2:9][C@@H:7]2[C@H:6]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:3]12[CH2:4][CH3:5])[C@@H:18]1[C:13](=[CH:14][C:15](=[O:22])[CH2:16][CH2:17]1)[CH2:12][CH2:11]3)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@H]1C[C@H]1[C@@H]2O
Solvent: c1ccncc1
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@H]1C[C@H]1[C@@H]2OC(C)=O
Temperature: 0 °C

Procedure:
5.0 g. of natural 17β-hydroxy-18-methyl-15α,16α-methylene-4-estren-3-one is allowed to stand at room temperature in 20 ml. of pyridine and 10 ml. of acetic anhydride for 18 hours. The mixture is then stirred into ice water, the thus-obtained precipitate is filtered off and dissolved in methylene chloride. The methylene chloride phase is washed successively with dilute hydrochloric acid, water, sodium bicarbonate solution, and water. After drying and evaporation, 5.5 g. of natural 17β-acetoxy-18-methyl-15α,16α-methylene-4-estren-3-one is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([O:30]C(=O)C(C)(C)C)[CH:24]=[CH:23][C:22]=3[CH2:21]2)=O)=[CH:4][CH:3]=1.Cl[CH2:40][C:41]([N:43]([CH2:48][CH2:49][O:50][CH3:51])[CH2:44][CH2:45][O:46][CH3:47])=O>>[CH3:47][O:46][CH2:45][CH2:44][N:43]([CH2:48][CH2:49][O:50][CH3:51])[CH2:41][CH2:40][O:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([OH:30])[CH:24]=[CH:23][C:22]=3[CH2:21]2)=[CH:4][CH:3]=1
Reactant: COCCN(CCOC)C(=O)CCl
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCC(=O)c2ccc(O)cc2)c1
Product: COCCN(CCOC)CCOc1ccc(CCCCNc2cc(OC)ccc2C2CCc3cc(O)ccc3C2)cc1
Yield: 15.8 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)propylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (21 mg) and 2-chloro-N,N-bis(2-methoxyethyl)acetamide (17 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (3.7 mg) was obtained.
Reaction SMILES: ClCCCS(N[CH2:9][CH:10]([O:34]C1C=CON=1)[CH2:11]OC(=O)NCCCCCCCCCCCCCCCCCC)(=O)=O.[CH2:40]([S:56][CH2:57][CH:58](OC)[CH2:59][NH:60][S:61]([CH2:64][CH2:65][CH2:66][I:67])(=[O:63])=[O:62])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]>>[CH2:40]([S:56][CH2:57][CH:58]([CH2:9][C:10](=[O:34])[CH3:11])[CH2:59][NH:60][S:61]([CH2:64][CH2:65][CH2:66][I:67])(=[O:62])=[O:63])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)Oc1ccon1
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)CC(C)=O

Procedure:
1-(3-Chloropropylsulfonylamino)-3-hexadecylthio-2-(2-oxopropan-1-yl)propane III m2 is allowed to react by the same procedure as described in (5). The summary of the experimental condition and the physical data of the product are listed in Table 8.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][C:11]1[C:16]([N+:17]([O-])=O)=[CH:15][CH:14]=[CH:13][N:12]=1)=O.[Sn](Cl)(Cl)(Cl)Cl.O.O>Cl.C(O)C>[S:6]1[C:5]2[C:3](=[O:2])[NH:17][C:16]3[CH:15]=[CH:14][CH:13]=[N:12][C:11]=3[NH:10][C:9]=2[CH:8]=[CH:7]1
Reactant: COC(=O)c1sccc1Nc1ncccc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: CCO
Product: O=C1Nc2cccnc2Nc2ccsc21
Temperature: 25 °C
Yield: 56.4 %

Procedure:
3-(3-Nitropyridin-2-yl)aminothiophene-2-carboxylic acid methylester (14.6 g) is added to a suspension of dihydrate tin chloride (64 g) in conc. HCl (210 ml) and ethanol (235 ml). The reaction mixture is refluxed for 2 hours obtaining the gradual dissolution of the reagents and subsequent precipitation of a solid. After cooling at the room temperature, the solid is filtered and triturated with a saturated solution of NaHCO3, filtered, washed with H2O and dried to give 6.4 g (56%) of the title product, melting at 273°-279° C.
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([N:13]1[CH2:18][CH2:17][C:16]([CH2:20][NH:21][CH2:22][C:23]([CH3:25])=[CH2:24])([OH:19])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:26](=[O:29])(O)[O-:27].[Na+]>C(#N)C>[CH2:6]([N:13]1[CH2:18][CH2:17][C:16]2([O:19][C:23]([CH3:25])([CH3:24])[CH2:22][N:21]([C:26]([O:27][C:7]([CH3:12])([CH3:8])[CH3:6])=[O:29])[CH2:20]2)[CH2:15][CH2:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C=C(C)CNCC1(O)CCN(Cc2ccccc2)CC1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(C)(C)OC2(CCN(Cc3ccccc3)CC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Concentrated sulfuric acid (12 ml) was added to 1-benzyl-4-((2-methylallylamino)methyl)piperidin-4-ol (Example 271, step a) (2.2 g) and the mixture was allowed to stand for 2 hours at room temperature. The reaction mixture was treated with ice/water (100 mL) followed by solid sodium bicarbonate, portionwise, until the mixture was basic. Acetonitrile (50 mL) was added followed by BOC-anhydride (1.925 g) and the reaction mixture stirred at room temperature for 18 hours. The reaction mixture was extracted with ethyl acetate (×2) and the combined organics were dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography, eluting with 1% methanol in dichloromethane switching to 1% methanol in dichloromethane with 1% triethylamine. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.8 g.