Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:10]([CH2:11][OH:12])[O:9][C@H:8]2[C@H:4]([N:5]=[C:6]([N:13]([CH2:21][CH2:22][CH3:23])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[S:7]2)[C@H:3]1[OH:24].C(N(CC)CC)C.[C:32]([Si:36](Cl)([CH3:38])[CH3:37])([CH3:35])([CH3:34])[CH3:33]>CN(C1C=CN=CC=1)C.ClCCl>[Si:36]([O:12][CH2:11][C@H:10]1[O:9][C@H:8]2[C@H:4]([N:5]=[C:6]([N:13]([CH2:21][CH2:22][CH3:23])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:17])[CH3:18])[S:7]2)[C@@H:3]([OH:24])[C@@H:2]1[OH:1])([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:38])[CH3:37]
Reactant: CCCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.7 %

Procedure:
To a stirred solution of tert-butyl (3aR,5R,6S,7R,7aR)-6,7-dihydroxy-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl(propyl)carbamate (45 g, 124 mmol), DMAP (760 mg, 6 mmol) and triethylamine (25.1 g, 248 mmol) in dichloromethane (300 mL) was added tert-butylchlorodimethylsilane (22.4 g, 149 mmol). After stirred for 6 h at room temperature, the mixture was condensed to provide a residue, which was purified by silica gel column, eluted with 10-30% ethyl acetate in petroleum ether to give compound 17 as a yellow oil (43 g. 65%). (ES, m/z): [M+H]+ 477.1; 1H NMR (300 MHz, CDCl3) δ 6.12-6.14 (d, J=6.3 Hz, 1H), 4.40-4.45 (m, 1H), 3.84-3.96 (m, 4H), 3.64-3.71 (m, 1H), 3.13-3.30 (m, 3H), 1.67-1.74 (m, 2H), 1.53 (s, 9H), 0.93-0.98 (m, 3H), 0.92 (s, 9H), 0.12 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:12]=[C:11](Br)[CH:10]=[CH:9][C:8]2=[O:14])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][C:32]([OH:34])=[O:33])=[CH:27][CH:26]=2)O1>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[C:8](=[O:14])[CH:9]=[CH:10][C:11]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][C:32]([OH:34])=[O:33])=[CH:27][CH:26]=3)=[CH:12]2)=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2ccc(CC(=O)O)cc2)OC1(C)C
Reactant: O=c1ccc(Br)cn1Cc1ccc(Cl)cc1
Product: O=C(O)Cc1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3)c2)cc1
Yield: 101.2 %

Procedure:
According to Scheme 3 Method A: The title compound was prepared according to Example 2 Step 2, from 1-(4-chlorobenzyl)-5-bromopyridin-2(1H)-one (1 eq, 0.67 mmol, 0.20 g, Example 2 Step 1) and 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid (1.5 eq, 1.00 mmol, 0.26 g). Reaction conditions: 4.5 hours at 90° C. The reaction mixture was made acidic then extracted with AcOEt. The organic layer washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography over silicagel (AIT Flashsmart prepacked column 25 g SiO2, AcOEt/MeOH 95/5), yielding the title compound (0.24 g, 100%) as a white solid. LC (XTerra RP18, 3.5 μm, 3.0×50 mm Column): RT=3.53 min; MS m/z (CI) [MH]+=354, 356.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[C@H:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][NH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C(Cl)Cl>[C:20]1([S:26]([N:10]2[CH2:11][CH2:12][C@@H:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH2:9]2)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Clc1cccc([C@@H]2CNCC[C@H]2c2ccccc2)c1
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)N1CC[C@@H](c2ccccc2)[C@H](c2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
To the hydrochloride salt of rac-trans-3-(m-chlorophenyl)-4-phenylpiperidine (CAS Reg. No.: [134823-41-9]) (500 mg) in methylene chloride (10 mL) triethylamine (677 μL) and benzenesulfonyl chloride (229 μL) were added. The reaction mixture was stirred at room temperature for 4 h, water was added, the phases were separated, and the inorganic one was extracted with ethyl acetate (×3). The organic layers were combined, washed with brine, dried (Na2SO4) and concentrated in vacuo. Column chromatography (SiO2, n-heptane/ethyl acetate 3:1) yielded trans-1-benzenesulfonyl-3-(3-chloro-phenyl)-4-phenyl-piperidine (0.66 g, 98%) as a white foam, MS: 411 (M, 1 Cl).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH3:13][CH2:14][CH2:15][CH:16]([NH2:20])[CH2:17][CH2:18][CH3:19]>>[CH3:13][CH2:14][CH2:15][CH:16]([NH:20][C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH:2]=[CH:3][C:4]=2[CH:9]=1)=[O:12])[CH2:17][CH2:18][CH3:19]
Reactant: CCCC(N)CCC
Reactant: O=C(O)c1ccc2occc2c1
Product: CCCC(CCC)NC(=O)c1ccc2occc2c1
Yield: 41 %

Procedure:
Prepared in a similar manner to example 4 using benzofuran-5-carboxylic acid and heptan-4-amine. Yield 41%. MS (M+H, 260.2).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][CH2:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][N:20]=1)(=[O:12])=[O:11].[C:27]1([CH:37]=O)[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][N:28]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]([CH2:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][N:20]=1)[CH2:37][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][N:28]=1)(=[O:12])=[O:11]
Reactant: O=Cc1nccc2ccccc12
Reactant: Cc1cnc(CNCCCCS(=O)(=O)c2nc3ccccc3[nH]2)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CN(CCCCS(=O)(=O)c2nc3ccccc3[nH]2)Cc2nccc3ccccc23)c(C)c1
Yield: 50 %

Procedure:
Using General Procedure B: Reaction of [4-(1H-benzoimidazole-2-sulfonyl)-butyl]-(3,5-dimethyl-pyridin-2-ylmethyl)-amine and isoquinoline-1-carbaldehyde in CH2Cl2 with NaBH(OAc)3 gave COMPOUND 177 as a white foam (50% yield). 1H NMR (CDCl3) δ 1.51-1.63 (m, 4H), 2.10 (s, 3H), 2.27 (s, 3H), 2.42-2.45 (m, 2H), 3.26-3.30 (m, 2H), 3.81 (s, 2H), 4.17 (s, 2H), 7.12 (t, 1H, J=8 Hz), 7.27 (s, 1H), 7.37-7.42 (m, 2H), 7.50-7.55 (m, 2H), 7.69-7.74 (m, 3H), 8.05 (d, 1H, J=8 Hz), 8.28 (br s, 1H), 8.40 (d, 1H, J=6 Hz); 13C NMR (CDCl3) δ 17.9, 18.3, 21.4, 23.7, 53.1, 54.4, 57.7, 58.7, 117.2, 120.8, 124.8, 125.9, 126.9, 127.6, 130.2, 132.4, 133.1, 136.3, 139.5, 140.9, 146.2, 148.0, 153.1, 158.2; ES-MS m/z 514 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[F:27])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:29][OH:30].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[F:27])[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:29]\[OH:30])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cn1cc(C(=O)CC(c2ccc(Br)cc2)c2ccc(Cl)cc2F)ccc1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2ccc(Br)cc2)c2ccc(Cl)cc2F)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 5-[3-(4-bromo-phenyl)-3-(4-chloro-2-fluoro-phenyl)-propionyl]-1-methyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing 12% of the corresponding Z isomer as an off-white foam, MS (ESI+): m/z=463.0 [M+H]+.
Reaction SMILES: [F-:1].[K+].ClCl.[Cl:5][C:6]1[C:14]([Cl:15])=[C:13]([Cl:16])[C:12]([Cl:17])=[CH:11][C:7]=1[C:8](Cl)=[O:9].F>>[Cl:5][C:6]1[C:14]([Cl:15])=[C:13]([Cl:16])[C:12]([Cl:17])=[CH:11][C:7]=1[C:8]([F:1])=[O:9]
Reactant: O=C(Cl)c1cc(Cl)c(Cl)c(Cl)c1Cl
Reactant: [F-]
Agent: ClCl
Agent: F
Agent: [K+]
Product: O=C(F)c1cc(Cl)c(Cl)c(Cl)c1Cl

Procedure:
The quantity of potassium fluoride to be used depends on the number of chlorine atoms which are to be exchanged. At least one mole of KF is used, but in general 1.1-1.5 mole, for 1 chlorine atom. A maximum of 2 moles of KF is used for 1 chlorine; beyond this, the quantity of KF has virtually no effect on the degree of fluorination, and the process becomes uneconomic. However, it is possible to save part of the costly KF when the 2,3,4,5-tetrachlorobenzoyl chloride is previously fluorinated with hydrofluoric acid, and the 2,3,4,5-tetrachlorobenzoyl fluoride, which results in virtually quantitative yield from this reaction, is used for the Cl/F exchange reaction with KF. Because of the greater activation by the more electronegative fluorocarbonyl group, its greater thermal stability, and the reduced load of KCl in the reaction mixture, this two-stage fluorination leads to an overall improvement in the balance of the nuclear fluorination.
Reaction SMILES: Cl[CH2:2][O:3][CH2:4][C:5]1[CH:9]=[N:8][S:7][N:6]=1.Cl.[Cl:11][C:12]1[CH:13]=[N:14][C:15](=[O:18])[NH:16][CH:17]=1.C(N(CC)CC)C>ClCCl>[S:7]1[N:8]=[CH:9][C:5]([CH2:4][O:3][CH2:2][N:16]2[CH:17]=[C:12]([Cl:11])[CH:13]=[N:14][C:15]2=[O:18])=[N:6]1
Reactant: ClCOCc1cnsn1
Reactant: O=c1ncc(Cl)c[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1ncc(Cl)cn1COCc1cnsn1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
3-(Chloromethyl)oxymethyl-1,2,5-thiadiazole (see Preparation 10) (0.18 mmol) in dichloromethane (1 ml) was added dropwise with stirring at room temperature to a solution of 5-chloropyrimidin-2-one hydrochloride (18 mmol) and triethylamine (0.36 mmol) in dichloromethane (3 ml). The mixture was stirred for 11/2 hours at 40° C. before the solvent was distilled off. The residue was triturated with water, extracted into chloroform and the dried (MgSO4) solution evaporated. Trituration of the residue with ether left the title compound in 20% (11 mg) yield, m.p. 106° C. 1H NMR (CDCl3): δ5.00 (CH2Het), 5.40 (OCH2), 7.73 and 8.47 (H-4, H-6, J 3 Hz), 8.50 (H-31).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][C:7]2=[N:8][CH:9]=1)([O-])=O>C(O)(=O)C.[Fe]>[C:13]1([C:11]2[NH:10][C:7]3=[N:8][CH:9]=[C:4]([NH2:1])[CH:5]=[C:6]3[N:12]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1cnc2[nH]c(-c3ccccc3)nc2c1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1cnc2[nH]c(-c3ccccc3)nc2c1
Temperature: 80 °C

Procedure:
12.0 g 6-nitro-2-phenyl-3H-imidazo[4,5-b]pyridine were dissolved in 1 l acetic acid. 18 g iron powder were added and the mixture heated to 80° C. with stirring. After 2 hrs the mixture was cooled to room temperature and filtered over Celite. The celite pad was washed with methanol and the combined filtrates were evaporated. The residue was dissolved methanol/dichloromethane 1:1 and filtered over silica. The filtrate was concentrated to a volume of 100 ml, the resulting precipitate collected by filtration and washed with methanol.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>C(Cl)(Cl)Cl.CN(C)C=O>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(I)cc1

Procedure:
A round bottom flask was charged with 4-iodobenzoic acid (3.0 g, 12.1 mmol) in chloroform (100 mL). To the solution was added thionyl chloride (5.0 mL) in chloroform (10 mL) and 2-3 drops of dimethylformamide (DMF). The slurry was heated at reflux for 2 hours. while monitoring the reaction through an oil bubbler. A clear solution of 4-iodobenzoyl chloride was obtained. The volatiles were removed and a colorless oil was obtained which solidified upon cooling.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[Br:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>C1COCC1.[Cl-].[Na+].O>[Br:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([S:16]([N:3]2[CH:7]=[CH:6][CH:5]=[CH:4]2)(=[O:18])=[O:17])=[CH:14][CH:15]=1
Reactant: c1cc[nH]c1
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(c1ccc(CBr)cc1)n1cccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 15 %

Procedure:
NaH (60% dispersion in mineral oil. 40 mg, 1.0 mmol) was added to a solution of pyrrole (67 mg, 1.0 mmol) in THF (2.0 mL) and the mixture was stirred at room temperature for 5 min. Then 4-(bromomethyl)benzenesulfonyl chloride (269 mg, 1.0 mmol) was added to the mixture. After stirring at room temperature for additional 10 min, brine (15 mL) was added and the mixture was extracted with AcOEt (40 mL×2). The combined extracts were dried over MgSO4. The solvent was removed under reduced pressure to afford an oil which was purified by column chromatography (SiO2, 10% AcOEt/hexane) to give 1-[4-(bromomethyl)benzenesulfonyl]pyrrole: 46 mg, 15% yield, colorless oil. The purity was determined by GC/MS (>95%), m/e 299 (M+, C11H10NO2BrS).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.[CH3:15][CH:16]1[CH2:21][CH:20]([CH3:22])[CH2:19][NH:18][CH2:17]1>C(#N)C>[CH3:15][CH:16]1[CH:21]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=2)[CH:20]([CH3:22])[CH2:19][NH:18][CH2:17]1
Reactant: O=[N+]([O-])c1ccc(Cl)c2ccccc12
Reactant: CC1CNCC(C)C1
Solvent: CC#N
Product: CC1CNCC(C)C1c1ccc([N+](=O)[O-])c2ccccc12

Procedure:
A Pyrex tube was charged with 1-chloro-4-nitronaphthalene (52 mg, 0.25 mmol) and 3,5-dimethylpiperidine (133 μL, 1.0 mmol) followed by acetonitrile (2 mL). The tube was capped and the reaction tube was exposed to microwave irradiation (180° C., 5 min). The reaction mixture was filtered and the solid washed with cold ethanol. If needed the compound was purified according to Purification method C. Yield: 58 mg (82%).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([Cl:10])[CH:3]=1.[CH2:11]([O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)[CH3:12]>>[Cl:10][C:4]1[CH:3]=[C:2]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([O:13][CH2:11][CH3:12])[CH:19]=2)[CH:8]=[C:7]([F:9])[C:5]=1[NH2:6]
Reactant: CCOc1cccc(B(O)O)c1
Reactant: Nc1c(F)cc(Br)cc1Cl
Product: CCOc1cccc(-c2cc(F)c(N)c(Cl)c2)c1
Yield: 67.7 %

Procedure:
The title compound (0.360 g) was prepared from 4-bromo-2-chloro-6-fluoroaniline (0.5 g, 2.0 mmol) and 3-ethoxyphenylboronic acid (0.441 g, 2.65 mmol) as a yellow liquid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.43-7.38 (m, 2H), 7.27 (t, J 7.9, 1H), 7.14 (d, J 7.9, 1H), 7.10 (s, 1H), 6.82 (dd, J 2.1, 8.1, 1H), 5.51 (s, 2H), 4.07 (q, J 7, 2H), 1.32 (t, J 7, 3H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:18]#[CH:19])[CH:7]=[C:8]3[C:13]=2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]3([CH3:17])[CH3:16])[CH2:3][CH2:2]1.[CH3:20][O:21][C:22](=[O:31])[CH2:23][C:24]1[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=1.C(N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:20][O:21][C:22](=[O:31])[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:19]#[C:18][C:6]2[CH:7]=[C:8]3[C:13](=[C:4]([CH:1]4[CH2:3][CH2:2]4)[CH:5]=2)[O:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]3([CH3:17])[CH3:16])=[CH:28][CH:29]=1
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: C#Cc1cc(C2CC2)c2c(c1)C(C)(C)CC(C)(C)O2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC(C)(C)O3)cc1

Procedure:
Following general procedure F and using 8-cyclopropyl-6-ethynyl-2,2,4,4-tetramethylchroman (Intermediate 34, 0.096 g, 0.38 mmol), methyl-4-iodo phenyl acetate (Reagent B, 0.094 g, 0.34 mmol), triethyl amine (3 mL), tetrahydrofuran (3 mL), copper(I)iodide (0.025 g, 0.13 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.075 g, 0.11 mmol) the title compound was obtained (0.137 g, 90%). 1H NMR (300 MHz, CDCl3): δ 7.47 (d, 2H, J=7.9 Hz), 7.29 (d, 1H, J=1.8 Hz), 7.24 (d, 2H, J=7.9 Hz), 6.82 (d, 1H, J=2.1 Hz), 3.70 (s, 3H), 3.63 (s, 2H), 2.22-2.13 (m, 1H), 1.85 (s, 2H), 1.38 (s, 6H), 1.36 (s, 6H), 0.94-0.86 (m, 2H), 0.68-0.63 (m, 2H).
Reaction SMILES: [OH:1][C:2]1([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[C:5]([CH3:14])([CH3:13])[CH2:4][CH2:3]1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>C(Cl)Cl.CCOC(C)=O>[C:21]([O:1][C:2]1([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[C:5]([CH3:13])([CH3:14])[CH2:4][CH2:3]1)(=[O:23])[CH3:22]
Reactant: CCOC(=O)CC1(O)CCC(C)(C)c2ccc(Br)cc21
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1(OC(C)=O)CCC(C)(C)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (+/−) ethyl 2-(1-hydroxy-1,2,3,4-tetrahydro-4,4-dimethyl-7-bromo-naphthalen-1-yl)acetate (Compound E47, 200.0 mg, 0.586 mmol) and 4-NN-dimethylaminopyridine (86.0 mg, 0.703 mmol) in 4.0 mL CH2Cl2 at 0° C. was added acetic anhydride (239.3 mg, 2.344 mmol). The resulting solution was warmed to room temperature and stirred overnight. The reaction was warmed to 50° C. for 3 h, cooled to room temperature, and diluted with EtOAc (70 mL). The solution was washed with H2O, saturated aqueous NaHCO3, 10% aqueous HCl, and saturated aqueous NaCl, before being dried over MgSO4. Removal of the solvents under reduced pressure followed by column chromatography afforded the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([N+:15]#[C-:16])=[C:6](Br)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Br:13])[CH3:2].C(N(CC)CC)C.[CH2:25]([NH2:29])[CH:26]([CH3:28])[CH3:27]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:5]1[N:15]=[CH:16][N:29]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Br:13])=[O:17])[CH3:2]
Reactant: [C-]#[N+]C(C(=O)OCC)=C(Br)c1ccccc1Br
Reactant: CC(C)CN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ncn(CC(C)C)c1-c1ccccc1Br
Yield: 71 %

Procedure:
A 0.5 M solution of 3-bromo-3-(2-bromophenyl)-2-isocyano-acrylic acid ethyl ester (2.55 g; 7.11 mM) and triethylamine (990 μl; 7.11 mM) in dimethylformamide (DMF) is added drop by drop at room temperature with isobutylamine (850 μl; 8.53 mM). The reaction mixture is kept at room temperature until complete reaction, then is quenched with a NaHCO3 saturated solution, extracted with ethyl acetate, washed with water, dried over Na2SO4, and evaporated under reduced pressure. The crude is purified by flash chromatography, eluting with ethyl acetate, to obtain 1.77 g of 5-(2-bromophenyl)-1-isobutyl-1H-imidazole-4-carboxylic acid ethyl ester. (Yield: 71%).
Reaction SMILES: O[CH:2]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH2:6][CH2:5]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1.CCOC(/N=N/C(OCC)=O)=O>ClCCl>[CH3:17][O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([N:43]2[CH2:47][CH2:46][CH2:45][CH2:44]2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:5][CH2:6]1
Reactant: C1CCNC1
Reactant: COc1ccccc1N1CCN(CC(O)c2ccccc2)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CC(c2ccccc2)N2CCCC2)CC1
Temperature: 0.5 °C

Procedure:
A mixture of 1-(2-hydroxy-2-phenylethyl)-4-(2-methoxyphenyl)-piperazine (5.65 g; 0.018 m), triphenylphosphine (5.69 g, 0.022m) and pyrollidine (15 ml; 0.18 m) in dichloromethane (100 ml) was stirred at 0.5° C. and a solution of diethylazodicarboxylate (3.8 ml, 0.024 m) in dichloromethane (5 ml) was added over 5 minutes. The resulting yellow solution was stirred at ambient temperature for 48 hrs. The residue on evaporation was partitioned between ether and 3N aq. hydrochloric acid. The combined HCl layers were washed with ether and then basified with ammonia and shaken with 3 portions of ether. The ether layers were washed well with water and dried over magnesium sulfate to give an oil which was chromatographed to give 0.96 g of the title compound. The crude oil in ethanol was acidified with ethanolic hydrogen chloride. The solvent was evaporated, and the residual foam solidified when triturated with ethanol and ether. The solid was recrystallised from ethanol to give the title compound as the dihydrochloride (0.45 g), m.p. 214°-18° C(d).
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:13][O:14][CH2:15][CH2:16][CH2:17][C:18](O)=O>Cl>[CH3:13][O:14][CH2:15][CH2:16][CH2:17][C:18]1[NH:1][C:2]2[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][CH:9]=[CH:10][C:11]=2[N:12]=1
Reactant: COC(=O)c1cccc(N)c1N
Reactant: COCCCC(=O)O
Agent: Cl
Product: COCCCc1nc2cccc(C(=O)OC)c2[nH]1
Temperature: 25 °C

Procedure:
A solution of 4 g of methyl 2,3-diaminobenzoate and 8.53 g of 4-methoxybutyric acid in 70 ml of 4N HCl is stirred at reflux over 21 hours. The reaction mixture is cooled to room temperature and partitioned between ethyl acetate and water. The aqueous phase is concentrated by evaporation—the residue is diluted with 100 ml of methanol and 2 ml of conc. H2SO4 and stirred at reflux over 45 hours. The reaction mixture is cooled to room temperature, neutralized with saturated aqueous sodium bicarbonate solution and concentrated by evaporation. The residue is diluted with water and extracted with ethyl acetate (2×)—the combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a red solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.31 (95:5 dichloromethane-methanol); Rt=2.53.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N+:6]([O-])[CH:7]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:7]1[N:6]=[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:3][C:2]=1[CH3:1]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cc(C)c[n+]([O-])c1C(=O)OCC
Product: CCOC(=O)c1cc(C)c(Cl)nc1C(=O)OCC
Temperature: 25 °C

Procedure:
199.9 g (0.79 mol) of diethyl 5-methylpyridine-2,3-dicarboxylate N-oxide were introduced a little at a time, in the course of 1 hour at from 60° to 70° C, into 1 l of phosphoryl chloride, and the mixture was refluxed for 5 hours. After cooling to 25° C., the reaction mixture was evaporated down under reduced pressure and the residue was taken up in methylene chloride. After filtering through a suction funnel containing silica gel and evaporating down, 148.2 g (69% of theory) of the title compound were obtained as a pale syrup, which subsequently solidified. Mp. 84°-86° C.
Reaction SMILES: [C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[C:14]([N:17]4[CH2:22][CH2:21][N:20](CC(OC(C)(C)C)=O)[CH2:19][CH2:18]4)[S:15][CH:16]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:31]>C(OCC)C.CO>[ClH:31].[C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[S:15][CH:16]=3)[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)CN1CCN(c2nc(C3=NOC(c4ccccc4)C3)cs2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: c1ccc(C2CC(c3csc(N4CCNCC4)n3)=NO2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1,1-dimethylethyl 4-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]-1-piperazineacetate (i.e. the product of Example 7, Step D) (0.7 g, 1.686 mmol) in diethyl ether (10 mL) was added a 2 M solution of hydrogen chloride in methanol (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 8 h. The resulting white precipitate was filtered, and dried to give 500 mg of the title compound as a white solid.