Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]2[N:7]=[CH:8][S:9][C:5]=2[CH:4]=1)#[N:2].C([Li])CCC.[Cl:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28])=[O:20].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[F:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[C:19]([C:8]1[S:9][C:5]2[CH:4]=[C:3]([C:1]#[N:2])[CH:11]=[CH:10][C:6]=2[N:7]=1)([OH:20])[CH2:18][Cl:17]
Reactant: O=C(CCl)c1ccc(F)cc1F
Reactant: N#Cc1ccc2ncsc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#Cc1ccc2nc(C(O)(CCl)c3ccc(F)cc3F)sc2c1
Temperature: -98 °C
Yield: 42.5 %

Procedure:
After 6-cyanobenzothiazole (1.60 g) was dissolved in tetrahydrofuran (80 ml), and the solution was cooled to -98° C. in a nitrogen atmosphere, a 1.6M solution (5.9 ml) of n-butyllithium in hexane was added dropwise over 10 minutes, and the resultant mixture was stirred for 5 minutes. A solution of 2-chloro-2',4'-difluoroacetophenone (2.85 g) in tetrahydrofuran (20 ml) was added dropwise to this mixture. After the liquid reaction mixture was heated to -10° C., an aqueous solution of ammonium chloride was added thereto. After the mixture was heated to room temperature, an organic layer was taken out, and the solvent was distilled out under reduced pressure. A water layer was extracted with ethyl acetate and the extract was then put together with the residue of the organic layer. This organic layer was washed with water and then with saturated saline, dried over magnesium sulfate and then distilled under reduced pressure. The residue was subjected to column chromatography on silica gel (solvent: hexane/ethyl acetate=20/1, next, hexane/ethyl acetate=5/1), thereby obtaining the intended compound (1.49 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS([Cl:21])(=O)=O.C(N(CC)CC)C>ClCCl>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:11]([CH2:12][Cl:21])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cccc(OCc2ccccc2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: ClCc1cccc(OCc2ccccc2)c1
Reaction time: 8 h
Yield: 67.5 %

Procedure:
To a solution of 3-benzyloxybenzyl alcohol (3.0 g, 14.0 mmol) in dichloromethane (30 mL) was added methanesulfonyl chloride (1.39 mL, 16.8 mmol) and triethylamine (2.34 mL, 16.8 mmol) on an ice bath, and the solution was stirred overnight. The reaction solution was diluted with dichloromethane, washed with aqueous solution of 5% sodium bicarbonate, and then, dried over anhydrous magnesium sulfate. The solvent was evaporated, then, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1), and 1-benzyloxy-3-chloromethyl-benzene (2.2 g, 67%) was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].C([O:7][C@H:8]1[CH2:25][C@@:23]2([CH3:24])[C@@H:19]([CH2:20][CH2:21][C@@H:22]2OS(C)(=O)=O)[C@H:18]2[C@@:9]1([F:33])[C@:10]1([CH3:32])[C:15]([CH2:16][CH2:17]2)=[CH:14][C:13](=[O:31])[CH:12]=[CH:11]1)(=O)C.O>CN(C)C=O>[CH2:1]([S:3][C@@H:22]1[CH2:21][CH2:20][C@H:19]2[C@H:18]3[C@:9]([F:33])([C@@H:8]([OH:7])[CH2:25][C@:23]12[CH3:24])[C@:10]1([CH3:32])[C:15](=[CH:14][C:13](=[O:31])[CH:12]=[CH:11]1)[CH2:16][CH2:17]3)[CH3:2]
Reactant: CC(=O)O[C@H]1C[C@]2(C)[C@@H](OS(C)(=O)=O)CC[C@H]2[C@@H]2CCC3=CC(=O)C=C[C@]3(C)[C@@]12F
Reactant: CCS
Solvent: CN(C)C=O
Solvent: O
Product: CCS[C@@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Temperature: 25 °C

Procedure:
A suspension of 50% sodium hydride-paraffin (300 mg, 6.5 mmole) in dry dimethylformamide (20 ml) was cooled and stirred in an ice-water bath and ethanethiol (0.67 ml, 9.0 mmole) was added. The ice bath was then removed and the mixture was stirred at room temperature until a clear solution resulted. Then, (11β,17β)-11-(acetyloxy)-9-fluoro-17-(methanesulfonyloxy)androsta-1,4-dien-3-one (540 mg, 1.21 mmole) was added. The resulting solution was heated in a bath at 110°-120° C. under an atmosphere of nitrogen for 5.0 hours. After cooling to room temperature, water (1.0 ml) was added and the mixture was stirred for 20 minutes. The mixture was then added into water (150 ml) and was extracted with chloroform (3×50 ml). The extracts were combined, washed with water, dried (anhydrous magnesium sulfate) and evaporated to afford the title compound as a solid contaminated with paraffin. It was dissolved in chloroform-hexane (7:3; 20 ml) and absorbed on a column of silica gel (15 g). The column was then successively eluted with chloroform and chloroform:ethyl acetate (85:15) to afford the homogeneous (tlc) title compound as a solid (380 mg) from the later fractions. One crystallization from ethyl acetate-hexane followed by drying (110° C., 0.3 mm of Hg, 6 hours) gave the analytical specimen (362 mg), melting point 196°-197° C. with consistent spectral data.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[CH:17]([CH:18]=[CH:19][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:21])[CH2:16][CH2:15][C:10]21OCC[O:11]2>Cl>[O:21]=[C:20]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH:19]=[CH:18][CH:17]1[CH:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])[C:10](=[O:11])[CH2:15][CH2:16]1
Reactant: O=C(C=CC1CCC2(OCCO2)C1CCCCCCCO)c1ccccc1
Agent: Cl
Product: O=C(C=CC1CCC(=O)C1CCCCCCCO)c1ccccc1
Reaction time: 1 h
Yield: 18.1 %

Procedure:
A suspension of 6-(7-hydroxyheptyl)-7-(3-phenyl-3-oxoprop-1-enyl)-1,4-dioxaspiro[4,4]nonane [1.0 g; prepared as hereinafter described in Example 9(ii)] in dilute hydrochloric acid (2N; 30 ml.) was stirred at 60°-65° C. for 1 hour. The mixture was extracted with diethyl ether and then the combined ethereal extracts were washed with aqueous sodium bicarbonate solution (10% w/v) and then with water, and then dried over anhydrous magnesium sulphate. The solution was evaporated and the residue was purified by preparative thin layer chromatography on silica gel, using a mixture of diethyl ether, n-hexane and ethyl acetate (2:1:1 by volume) as eluant, to give 7-[5-(3-oxo-3-phenylprop-1-enyl)-2-oxocyclopentyl]heptanol (0.16 g.), in the form of a yellow oil. [Elemental analysis: Found: C, 76.9; H, 8.9%; C21H28O5 requires C, 76.8; H, 8.6%, νmax 990 cm-1, 1620 cm-1, 1665 cm-1, 3400 cm-1. N.M.R. (approximately 10% w/v solution in deuterochloroform): triplet at 3.6δ (J=6 cycles/second), multiplets at 7,85-8.05δ, 7.4-7.65δ, 6.85-7.15δ, 2-2.9δ and 1.1-2.0δ].
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:11][C:10]([C:12](Cl)=[O:13])=[CH:9][CH:8]=2)=[CH:5][C:4]([C:15]([F:18])([F:17])[F:16])=[N:3]1.C1COCC1.[CH2:24]([NH2:26])[CH3:25]>O>[CH2:24]([NH:26][C:12]([C:10]1[S:11][C:7]([C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:5]=2)=[CH:8][CH:9]=1)=[O:13])[CH3:25]
Reactant: Cn1nc(C(F)(F)F)cc1-c1ccc(C(=O)Cl)s1
Reactant: CCN
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)c1ccc(-c2cc(C(F)(F)F)nn2C)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-(1-Methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiophene-2-carbonyl chloride (150 mg) and THF (2 ml) were added to a mixture of 70% ethylamine aqueous solution (1 ml) and THF (2 ml), followed by stirring at room temperature for 2 hours. Water was added to the reaction solution, the thus formed product was extracted with ethyl acetate and then the extract was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under a reduced pressure. The resulting residue was recrystallized from a mixed solvent ethyl acetate and n-hexane to give N-ethyl-5-(1-methyl-3-trifluoromethy-1H-pyrazol-5-yl)thiophene-2-carboxamide (96 mg) as colorless powder crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH3:21][S:22]([O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33]O)=[CH:28][CH:27]=1)(=[O:24])=[O:23].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3](=[O:20])[CH:4]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:33][CH2:32][C:29]2[CH:28]=[CH:27][C:26]([O:25][S:22]([CH3:21])(=[O:23])=[O:24])=[CH:31][CH:30]=2)=[CH:8][CH:7]=1
Reactant: CCCCCCOC(Cc1ccc(O)cc1)C(=O)OC
Reactant: CS(=O)(=O)Oc1ccc(CCO)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCOC(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)OC
Reaction time: 18 h
Yield: 66.9 %

Procedure:
2-Hexyloxy-3-(4-hydroxyphenyl)propanoic acid methyl ester (0.33 g, 1.19 mmole) and 2-(4-methanesulfonyloxyphenyl)ethanol (0.2578 g; 1.19 mmole) was dissolved in dichloromethane (5 ml) under argon. Azodicarbonyl dipiperidine (0.451 g; 1.789 mmole) was added followed by addition of triphenylphosphine (0.375 g; 1.423 mmole). The reaction mixture was stirred at room temperature and after 2 hours more dichloromethane (2 ml) was added. The reaction mixture was stirred for another 18 hours and then filtered. The filtrate was washed with water, sodium hydrogen carbonate solution, diluted potassium hydrogen sulfate solution and brine, dried with sodium sulfate and evaporated. Chromatography of the residue on silica gel using heptane:ethyl acetat (2:1 to 1:1) as eluant gave 0.381 g (67% yield) of 2-hexyloxy-3-[4-(2-{4-methanesulfonyloxyphenyl}-ethoxy)phenyl]propanoic acid methyl ester.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.Cl.[NH:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[CH2:18][N:19]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH2:23][S:22][C:21]2[CH:30]=[CH:31][CH:32]=[CH:33][C:20]1=2>C(Cl)(Cl)Cl>[NH:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[CH2:18][N:19]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH2:23][S:22](=[O:9])[C:21]2[CH:30]=[CH:31][CH:32]=[CH:33][C:20]1=2
Reactant: c1ccc2c(c1)CSc1ccccc1N2C[C@@H]1CCCN1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: O=S1Cc2ccccc2N(C[C@@H]2CCCN2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.9 %

Procedure:
A solution of meta-chloroperbenzoic acid (105 mg) in chloroform (5 ml) was added to a solution of (S)-5,11-dihydro-5-(2-pyrrolidinylmethyl)dibenzo[b,e][1,4]thiazepine hydrochloride (see Preparation 21) (200 mg) in chloroform (10 ml) and the mixture stirred at room temperature for 4 hours, washed with 10% aqueous sodium carbonate solution, dried over sodium sulphate and evaporated under reduced pressure to give the title compound as a colourless gum, (180 mg, 96%).
Reaction SMILES: C([CH:3]([C:14]([NH2:16])=[O:15])[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])C.[CH2:17](N)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].CN(C)C=O.Cl>C1(C)C=CC=CC=1>[CH2:17]([NH:16][C:14](=[O:15])[CH2:3][C:4]([NH:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:5])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCN
Reactant: CCC(C(N)=O)C(=O)NCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCCCCCCCNC(=O)CC(=O)NCc1ccccc1
Yield: 0.1 %

Procedure:
A solution of 1.1 g (5.0 mol) of ethyl N-benzylmalonamide in 30 mL of toluene was heated to reflux under nitrogen and 1.29 g (10.0 mol) of n-octylamine was added. The reaction was heated to reflux for 5 h and 5 mL of N,N-dimethylformamide was added. This mixture was kept at reflux for 12 h and poured into 5% aqueous hydrochloric acid. the organic layer was washed with saturated aqueous sodium bicarbonate, water, brine, and dried over magnesium sulfate. Filtration and removal of solvents afforded a crude solid which was recrystallized from 50% ethyl acetate/hexane to give 0.8 g (53% yield) of N-n-octyl-N'-benzylmalonamide.
Reaction SMILES: CC1(C)C2C3C=C(S([O-])(=O)=O)C=C(S([O-])(=O)=O)C=3C=CC=2N(CCCS([O-])(=O)=O)/C/1=C/C=C(\C1C=CC=C(CCCCC([NH:77][CH2:78][CH2:79][N:80]2[C:84](=[O:85])[CH2:83][CH2:82][C:81]2=[O:86])=O)C=1)/C=C/C1C(C)(C)C2C3C=C(S([O-])(=O)=O)C=C(S([O-])(=O)=O)C=3C=CC=2[N+]=1CCCS([O-])(=O)=O.[Na+:88].[Na+].[Na+].[Na+].[Na+].[CH3:93][C:94]1([CH3:161])[C:102]2[C:97](=[CH:98][CH:99]=[C:100]([S:103]([O-:106])(=[O:105])=[O:104])[CH:101]=2)[N:96]([CH2:107][CH2:108][CH2:109][S:110]([O-:113])(=[O:112])=[O:111])/[C:95]/1=[CH:114]/[CH:115]=[C:116](\[C:141]1[CH:146]=[CH:145][CH:144]=[C:143]([CH2:147][CH2:148][CH2:149][CH2:150][C:151](ON2C(=O)CCC2=O)=[O:152])[CH:142]=1)/[CH:117]=[CH:118]/[C:119]1[C:127]([CH3:129])([CH3:128])[C:126]2[C:121](=[CH:122][CH:123]=[C:124]([S:130]([O-:133])(=[O:132])=[O:131])[CH:125]=2)[N+:120]=1[CH2:134][CH2:135][CH2:136][S:137]([O-:140])(=[O:139])=[O:138].[Na+].[Na+].[Na+]>>[CH3:93][C:94]1([CH3:161])[C:102]2[C:97](=[CH:98][CH:99]=[C:100]([S:103]([O-:106])(=[O:105])=[O:104])[CH:101]=2)[N:96]([CH2:107][CH2:108][CH2:109][S:110]([O-:113])(=[O:112])=[O:111])/[C:95]/1=[CH:114]/[CH:115]=[C:116](\[C:141]1[CH:146]=[CH:145][CH:144]=[C:143]([CH2:147][CH2:148][CH2:149][CH2:150][C:151]([NH:77][CH2:78][CH2:79][N:80]2[C:84](=[O:85])[CH:83]=[CH:82][C:81]2=[O:86])=[O:152])[CH:142]=1)/[CH:117]=[CH:118]/[C:119]1[C:127]([CH3:129])([CH3:128])[C:126]2[C:121](=[CH:122][CH:123]=[C:124]([S:130]([O-:133])(=[O:132])=[O:131])[CH:125]=2)[N+:120]=1[CH2:134][CH2:135][CH2:136][S:137]([O-:140])(=[O:139])=[O:138].[Na+:88].[Na+:88].[Na+:88]
Reactant: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc4c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc4c3C2(C)C)c2cccc(CCCCC(=O)NCCN3C(=O)CCC3=O)c2)=[N+](CCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c21
Reactant: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)c2cccc(CCCCC(=O)ON3C(=O)CCC3=O)c2)=[N+](CCCS(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc21
Agent: [Na+]
Product: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)c2cccc(CCCCC(=O)NCCN3C(=O)C=CC3=O)c2)=[N+](CCCS(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc21

Procedure:
Compound 23 is prepared analogously to compound 21 (Example 27), except that compound 15 is used as a starting material.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([O:11][C:12](=[O:20])[CH:13]([C:17](=O)[CH3:18])[C:14](=O)[CH3:15])[CH3:10].N1C=CC=CC=1>C(O)C>[CH2:9]([O:11][C:12]([C:13]1[C:14]([CH3:15])=[N:8][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:17]=1[CH3:18])=[O:20])[CH3:10]
Reactant: NNc1ccccc1
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)c1c(C)nn(-c2ccccc2)c1C

Procedure:
Similar to Example 1, phenyl hydrazine (7.5 mmol, 0.8 g) and 2-acetyl-3-oxo-butyric acid ethyl ester (7.5 mmol, 1.3 g) were mixed in a solution of 50% pyridine in ethanol. The solvents were removed under vacuum and the oil resuspended in chloroform. The resulting suspension was washed with 5% sodium bicarbonate, 5% hydrochloric acid, and then brine. The organic layer was dried over NaSO4, the solids filtered, and the solvents removed under vacuum. The crude material was purified over silica gel to yield the named product as an oil. 1H-NMR (CDCl3, ppm): 1.37 t (3H); 2.51 s (6H); 4.32 q (2H); 7.42 bs (5H).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Br:4][C:5]1[C:10]([F:11])=[C:9](F)[CH:8]=[CH:7][C:6]=1[N+:13]([O-:15])=[O:14]>CS(C)=O>[Br:4][C:5]1[C:10]([F:11])=[C:9]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[N+:13]([O-:15])=[O:14]
Reactant: C[O-]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1Br
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc([N+](=O)[O-])c(Br)c1F
Reaction time: 3 h

Procedure:
NaOMe (9.5 g) was added portion wise to a solution of 2-bromo-3,4-difluoro-1-nitro-benzene (21.0 g) dissolved in DMSO (250 ml) at room temperature under nitrogen atmosphere. The mixture was stirred for 3 hrs and then poured onto water and extracted with ethyl acetate. The organic phase was extracted with water and brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude product, 2-bromo-3-fluoro-4-methoxy-1-nitro-benzene was used as such in Step 2 described below. 1H NMR (CDCl3) δ ppm: 7.85 (1H, dd); 6.99 (1H, dd); 3.99 (3H, s).
Reaction SMILES: C(O[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(C)(C)C.[NH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][OH:19]>C(Cl)(Cl)Cl>[C:6]([CH:14]([NH2:13])[CH2:15][O:16][CH2:17][CH2:18][OH:19])([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:12]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: NCCOCCO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)C(N)COCCO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.1 %

Procedure:
This compound was prepared by a modification of the procedure described by, Lebeau, L, et al., “Synthesis of New Phospholipids Linked to Steroid-Hormone Derivatives Designed for Two-Dimensional Crystallization of Proteins,” Helv. Chim. Acta 1991, 74, 1697-1706, the contents of which are incorporated herein by reference. A solution of di-tert-butylcarbonate (10.27 g, 47.2 mmol) in chloroform (40 mL) was added to a solution of 2-(2-aminoethoxy)-ethanol (1, 5.0 g, 47.62 mmol) in chloroform (40 mL) and the mixture was stirred at room temperature for 1.5 hours. The solution was washed with water (30 mL) and the organic layer was dried over anhydrous MgSO4 and concentrated in vacuo to give the product (9.6 g, 99%): 1H NMR δ1.45(s, 9H, t-Bu), 3.32 (m, 2H, NHCH2), 3.43 (bs, 1H, OH), 3.56 (m, 4H, CH2OCH2), 3.73 (t, 2H, J=5.4, CH2OH), 5.43 (bs, 1H, NH); 13C NMR δ28.21 40.21, 61.31, 70.08, 72.14, 77.18, 79.06, 156.06.
Reaction SMILES: [C:1]1([C:9]([CH:11]([C:13]2[CH:20]=[CH:19][C:16]([O:17][CH3:18])=[CH:15][CH:14]=2)O)=[O:10])[CH:8]=[CH:7][C:4]([O:5][CH3:6])=[CH:3][CH:2]=1.C(Cl)[Cl:22].S(Cl)(Cl)=O>N1C=CC=CC=1>[Cl:22][CH:11]([C:13]1[CH:20]=[CH:19][C:16]([O:17][CH3:18])=[CH:15][CH:14]=1)[C:9](=[O:10])[C:1]1[CH:8]=[CH:7][C:4]([O:5][CH3:6])=[CH:3][CH:2]=1
Reactant: ClCCl
Reactant: COc1ccc(C(=O)C(O)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: COc1ccc(C(=O)C(Cl)c2ccc(OC)cc2)cc1
Reaction time: 0.83 h

Procedure:
Anisoin (2.87 g), 100 mL of methylene chloride, and pyridine (2.02 g) are placed in a flask under nitrogen. Thionyl chloride (1.60 ml) is added dropwise over 5 minutes using a water bath to maintain the reaction temperature between 25° C. and 30° C. After allowing the mixture stir for 50 minutes the reaction is quenched by washing with water (2×100 mL) and 100 mL of brine. The organics are dried over sodium sulfate, filtered, then concentrated. The resulting oil is taken up in 25 mL of diethyl ether and filtered. The filter cake is rinsed with 25 ml of diethyl ether. To the filtrate is added 25 ml of ethanol and the solution is concentrated. Crystals are allowed to form over 24 hours. The precipitate which forms is filtered, washed with 25 mL of ethanol, and dried in vacuo at 45° C. to give 4.00 g of product. (69%). Analysis calculated for C16H14ClO3 : C, 66.10; H, 5.20; Cl, 12.19. Found: C, 66.29; H, 5.32; Cl, 12.56. MS(FD) 290.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:17][CH:16]=2)(O)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[CH2:22]([O:21][C:18]1[CH:17]=[CH:16][C:15]([C:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=2)=[CH:20][CH:19]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCOc1ccc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCOc1ccc(C2=CCNCC2)cc1
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
To a solution of 1-tert-butoxycarbonyl-4-(4-hexyloxyphenyl)-4-hydroxypiperidine (6.856 g) in dichloromethane (34 ml) was added trifluoroacetic acid (17 ml) and stirred for 30 minutes at 4° C. The reaction mixture was adjusted to pH 12 with 2M aqueous NaOH. The organic layer was separated, washed with water and dried over magnesium sulfate and evaporated under reduced pressure to give 4-(4-hexyloxyphenyl)-1,2,3,6-tetrahydropiridine (3.59 g)
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].CC1(C)C(C)(C)OB([C:23]2[NH:27][N:26]=[CH:25][CH:24]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:14][O:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:2]([C:23]2[NH:27][N:26]=[CH:25][CH:24]=2)[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1c(Br)cccc1OC
Reactant: CC1(C)OB(c2ccn[nH]2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1c(OC)cccc1-c1ccn[nH]1
Temperature: 100 °C
Yield: 33 %

Procedure:
In a microwave vial was dissolved ethyl 2-bromo-6-methoxybenzoate (500 mg, 1.54 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (330 mg, 1.70 mmol) in DME (10 mL) and water (2 mL). Na2CO3 (259 mg, 3.09 mmol) was then added followed by Pd(PPh3)4 (89 mg, 0.077 mmol) and the reaction mixture was degassed with N2 for 10 minutes. The reaction mixture was then heated at 100° C. for 1 h in the microwave. The mixture was cooled to room temperature, filtered through Celite and washed with EtOAc and DCM. The crude solution was concentrated in vacuo and directly purified via silica gel chromatography (10-80% EtOAc in hexanes) to afford the title compound (125 mg, 33%). MS (ESI) mass calcd. for C13H14N2O3, 246.3. m/z found 247.1 [M+H]+. 1H NMR (400 MHz, Chloroform-d) δ 7.63 (d, J=2.2 Hz, 1H), 7.44-7.37 (m, 1H), 7.24 (d, J=8.1 Hz, 1H), 6.94 (dd, J=8.3, 0.9 Hz, 1H), 6.53 (d, J=2.3 Hz, 1H), 4.29 (q, J=7.2 Hz, 2H), 3.88 (s, 3H), 1.25-1.16 (m, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1.O>CN1CCCC1=O>[F:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:2]3[CH:7]=[C:6]([CH:5]=[CH:4][N:3]=3)[C:8]#[N:9])[CH2:19][CH2:18]2)=[CH:15][CH:16]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: N#Cc1ccnc(Cl)c1
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1ccnc(N2CCN(c3ccc(F)cc3)CC2)c1
Temperature: 100 °C
Reaction time: 10 h
Yield: 85.5 %

Procedure:
2-Chloro-4-cyanopyridine (0.40 g, 2.9 mmol) was dissolved in N-methylpyrrolidone (2.0 ml), and 1-(4-fluorophenyl)piperazine (1.0 g, 5.6 mmol) was added thereto. The reaction mixture was stirred at 100° C. for 10 hrs, combined with water to give precipitates, which were collected by filtration to give the titled compound (0.70 g, 86%).
Reaction SMILES: [Cl-].[NH4+].Cl[C:4]1(Cl)[C:7](=[O:8])[CH2:6][CH:5]1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C@@H:21]([CH3:26])[C:22]([F:25])([F:24])[F:23])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][CH:10]=1.ClCCl>C1COCC1.[Zn]>[F:23][C:22]([F:24])([F:25])[C@H:21]([CH3:26])[CH:15]([C:12]1[CH:11]=[CH:10][C:9]([CH:5]2[CH2:6][C:7](=[O:8])[CH2:4]2)=[CH:14][CH:13]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(c1ccc(C2CC(=O)C2(Cl)Cl)cc1)[C@@H](C)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)C(c1ccc(C2CC(=O)C2)cc1)[C@@H](C)C(F)(F)F
Temperature: 75 °C
Reaction time: 5 h

Procedure:
100 ml of saturated aqueous ammonium chloride solution were added to 4.57 g (11.51 mmol) of ethyl (3R)-2-[4-(2,2-dichloro-3-oxocyclobutyl)phenyl]-4,4,4-trifluoro-3-methylbutanoate and 3.76 g (57.5 mmol) of zinc dust in 100 ml of THF, and the mixture was then stirred at 75° C. for 5 h. After cooling to room temperature and addition of dichloromethane, the reaction mixture was washed with water. After separation of the phases, the aqueous phase was back-extracted three times with dichloromethane. The combined organic phases were then dried over magnesium sulphate, filtered and concentrated under reduced pressure. This gave 1.21 g of the title compound (32% of theory).