Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:23]([CH2:27][CH:28]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][NH2:35])[CH2:29]1)[CH2:24][CH2:25][CH3:26])[CH2:21][CH3:22]>C(#N)C>[CH2:20]([N:23]([CH2:27][CH:28]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][NH:35][C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:29]1)[CH2:24][CH2:25][CH3:26])[CH2:21][CH3:22]
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: CCCN(CCC)CC1CCN(CCN)C1
Solvent: CC#N
Product: CCCN(CCC)CC1CCN(CCNC(=O)N2c3ccccc3C(=O)Nc3cccnc32)C1
Yield: 22 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[3-[(dipropylamino)methyl]-pyrrolidin-1-yl]ethanamine in a yield of 22% of theory. Colourless crystals, m.p. 134°-138° C. (acetonitile).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[O:6][CH:7]([CH3:11])[C:8]([OH:10])=O)([O-:3])=[O:2].[N+]([O-])(O)=O.[O:20]([CH2:24][CH2:25][NH2:26])[N+:21]([O-:23])=[O:22].C(OC(C)C)(C)C>>[O:20]([CH2:24][CH2:25][NH:26][C:8](=[O:10])[CH:7]([O:6][C:5]1[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=1[N+:1]([O-:3])=[O:2])[CH3:11])[N+:21]([O-:23])=[O:22]
Reactant: CC(Oc1ccccc1[N+](=O)[O-])C(=O)O
Reactant: NCCO[N+](=O)[O-]
Solvent: O=[N+]([O-])O
Solvent: CC(C)OC(C)C
Product: CC(Oc1ccccc1[N+](=O)[O-])C(=O)NCCO[N+](=O)[O-]
Yield: 42.4 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.75 g of 2-(2-nitrophenoxy)propionic acid and 0.6 g of 2-nitroxyethylamine nitrate, 0.45 g of the title compound was obtained as pale yellow needles (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:12][C:11](/[CH:13]=[C:14](\[CH2:18][CH3:19])/[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.C(Cl)(Cl)Cl>C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[C:1]([O:5][C:6]([C:8]1[S:12][C:11]([CH2:13][CH:14]([CH2:18][CH3:19])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC/C(=C\c1ccc(C(=O)OC(C)(C)C)s1)C(=O)O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCC(Cc1ccc(C(=O)OC(C)(C)C)s1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
(E)-3-(5-tert-butoxycarbonylthiophen-2-yl)-2-ethylpropenoic acid (20.43 g, 72.4 mmol) was dissolved in ethyl acetate (300 mL), methanol (20 mL) and chloroform (10 mL), palladium hydroxide (2.0 g) was added, and the mixture was stirred at room temperature overnight under a hydrogen atmosphere. After completion of the reaction, palladium hydroxide was removed by celite filtration, and the solvent was evaporated under reduced pressure to give the title compound (20.6 g, quantitative).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH3:10])=[CH:4][C:3]1=[O:12].[Cl:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=O)=[CH:19][CH:18]=1>>[Cl:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[C:8]([C:5]2[CH:6]=[CH:7][N:2]([CH3:1])[C:3](=[O:12])[CH:4]=2)[CH2:9][CH3:10])=[CH:19][CH:18]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1
Reactant: CCC(=O)c1ccn(C)c(=O)c1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccn(C)c(=O)c1

Procedure:
Following general procedure of McMurry reaction as described in example 1, step B, 1-methyl-4-propionylpyridin-2(1H)-one (105 mg, 1.0 eq) was reacted with (4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (352 mg, 2.0 eq) to give the desired product (Z/E=1:1).
Reaction SMILES: S(C1C=CC(C)=CC=1)(O)(=O)=O.O[CH2:13][CH:14]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15]1.[O:22]1[C:27]2[CH:28]=[CH:29][C:30]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[CH:31][C:26]=2[O:25][CH2:24][CH2:23]1.C([O-])([O-])=O.[K+].[K+]>C(C(C)=O)C(C)C>[CH:14]1([CH2:13][N:35]2[CH2:36][CH2:37][N:32]([C:30]3[CH:29]=[CH:28][C:27]4[O:22][CH2:23][CH2:24][O:25][C:26]=4[CH:31]=3)[CH2:33][CH2:34]2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15]1
Reactant: OCC1Cc2ccccc21
Reactant: c1cc2c(cc1N1CCNCC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: c1ccc2c(c1)CC2CN1CCN(c2ccc3c(c2)OCCO3)CC1
Temperature: 100 °C

Procedure:
2.26 g (7.8×10-3 mol) of 1-hydroxymethylbenzocyclobutane tosylate, 1.7 g (7.8×10-3 mol) of 4-(2,3-dihydrobenzo-1,4-dioxin-6-yl)piperazine and 2.16 g (15.6×10-3 mol) of K2CO3 in 50 ml of methyl isobutyl ketone are mixed together. That mixture is heated at 100° C. for 8 hours and then cooled. The mixture is concentrated and the residue is taken up in water and ethyl acetate. Separation is carried out and the organic phase then extracted with 1N HCl. The aqueous phase is rendered basic with 1N NaOH and then extracted with methylene chloride and dried over MgSO4. The oil obtained is purified by flash chromatography (eluant CH2Cl2/CH3OH: 95/5). 1 g (yield=38%) of an oil that corresponds to the title compound is obtained, the dihydrochloride of which is prepared in acetonitrile. M.p. 242°-245° C.
Reaction SMILES: [Na].O[CH:3]=[C:4]1[CH2:9][CH2:8][CH2:7][O:6][C:5]1=[O:10].Cl.[CH3:12][O:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16]>C(O)C>[CH3:12][O:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH:16][CH:3]=[C:4]1[CH2:9][CH2:8][CH2:7][O:6][C:5]1=[O:10]
Reactant: O=C1OCCCC1=CO
Reactant: COc1ccccc1N
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: COc1ccccc1NC=C1CCCOC1=O
Reaction time: 2 h
Yield: 54.2 %

Procedure:
The sodium salt of 3-(hydroxymethylene)-tetrahydropyran-2-one (25 g, 0.17 mol) and 2-methoxyaniline hydrochloride (32 g, 0.2 mol) in ethanol (750 ml) were warmed to 70° C. with stirring for 2 hours, then filtered hot. After evaporation of the ethanol, the crude product was taken up in dichloromethane, washed with dilute hydrochloric acid, dried and evaporated. Trituration with ether gave 3-(2-methoxyphenylaminomethylene)tetrahydropyran-2-one (21.5 g, 55%) as a mixture of E and Z isomers, m.p. 85°-100°.
Reaction SMILES: C[O:2][C:3]1[C:11]2[S:10][C:9]([C:12]([F:15])([F:14])[F:13])=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.B(Br)(Br)Br.CO.O>ClCCl>[F:15][C:12]([F:13])([F:14])[C:9]1[S:10][C:11]2[C:3]([OH:2])=[CH:4][CH:5]=[CH:6][C:7]=2[N:8]=1
Reactant: COc1cccc2nc(C(F)(F)F)sc12
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: Oc1cccc2nc(C(F)(F)F)sc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 7-methoxy-2-(trifluoromethyl)-1,3-benzothiazole (C26) (398 mg, 1.71 mmol) in dichloromethane (10 mL) at −78° C. was treated with boron tribromide (1 M in dichloromethane, 3.41 mL, 3.41 mmol), warmed to room temperature and stirred for 18 hours. Methanol (3.0 mL) was added to the mixture at −78° C. and the mixture was warmed to room temperature. Water (30 mL) was added and the mixture was extracted with dichloromethane (2×10 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 20% methyl tert-butyl ether in heptanes) afforded the title compound as a colorless solid. Yield: 251 mg, 1.15 mmol, 67%. GCMS m/z 219 (M+). 1H NMR (400 MHz, CDCl3) δ 6.44 (br s, 1H), 6.95 (d, J=7.8 Hz, 1H), 7.47 (dd, J=8.2, 8.0 Hz, 1H), 7.82 (d, J=8.2 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[Cl:33])=[N:10][C:11]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)=[C:12]([CH:16]=2)[C:13](Cl)=[O:14])=[CH:4][CH:3]=1.Cl.[CH2:35]([NH2:37])[CH3:36].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[Cl:33])=[N:10][C:11]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)=[C:12]([CH:16]=2)[C:13]([NH:37][CH2:35][CH3:36])=[O:14])=[CH:4][CH:3]=1
Reactant: CCN
Reactant: O=C(Cl)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1Oc1ccc(F)c(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1Oc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The crude acid chloride from Step A was dissolved in methylene chloride (1 mL) and treated with ethylamine hydrochloride (0.018 g; 0.217 mmol) and triethylamine (0.06 mL; 0.434 mmol) then stirred at room temperature for 1 h. The volatiles were removed in vacuo and purified by MPLC (silica gel; 0-50% ethyl acetate:hexane gradient) to afford the desired product: m/e=534 (M+2); Rt=4.57 min on LCMS.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=O.CCN(CC)CC.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([OH:32])=[O:31])=[CH:25][CH:24]=1.C1CCN2C(=NCCC2)CC1>C(#N)C.Cl>[F:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[C:30](=[O:32])[O:31][CH2:2][C:3]=2[C:5]2[CH:6]=[CH:7][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:9][CH:10]=2)=[CH:27][CH:28]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: CS(=O)(=O)c1ccc(C(=O)CBr)cc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C2=C(c3ccc(F)cc3)C(=O)OC2)cc1
Reaction time: 0.75 h
Yield: 68.2 %

Procedure:
To the product of Step 1 (216 mg) dissolved in acetonitrile (4 mL) was added Et3N (0.26 mL), followed by 4-fluorophenylacetic acid (102 mg). After 1.5 h at room temperature 0.23 nL of DBU was added. The reaction mixture was stirred for another 45 min and then treated with 5 mL of IN HCl. The product was extracted with EtOAc, dried over Na2S04 and concentrated. The residue was purified by flash chromatography (40% EtOAc in hexane) to yield 150 mg of the title compound as a solid. 1H NMR (CD3COCD3) d 3.15 (3H, s), 5.36 (3H, s), 7.18 (2H, J=8.9 Hz, t), 7.46 (2H, m), 7.7 (2H, J=8.65 Hz, d), 7.97 (2H, J=8.68, d).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=1.[O:9]1[CH2:13][CH2:12][CH2:11][C:10]1=O>C([O-])(O)=O.[Na+]>[NH2:7][C:4]1[CH:5]=[CH:6][C:1]([N:8]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:9])=[CH:2][CH:3]=1
Reactant: O=C1CCCO1
Reactant: Nc1ccc(N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: Nc1ccc(N2CCCC2=O)cc1

Procedure:
800 mg Benzene-1,4-diamine and 600 μl Dihydro-furan-2-one were heated for 1 h to 200° C. under microwave irradiation (200 W, CEM Discover™ apparatus). Finally, 10 mL saturated NaHCO3 solution were added and the mixture was directly purified by chromatography on silica gel eluting with a gradient of DCM/MeOH 100%->50%. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 860 mg.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@@H:18]([C:25]([NH2:27])=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:11][C:12](=[O:14])[OH:13])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C(N(CC)CC)C.[NH:35]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[C@H:36]([C:47](ON1C(=O)CCC1=O)=[O:48])[CH2:37][C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[NH:40][CH:39]=1>CN(C=O)C>[NH:35]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[C@H:36]([C:47]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@@H:18]([C:25]([NH2:27])=[O:26])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[CH2:11][C:12](=[O:13])[OH:14])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:48])[CH2:37][C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[NH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)ON1C(=O)CCC1=O
Reactant: CC(C)C[C@H](N)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](C(N)=O)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](C(N)=O)c1ccccc1
Reaction time: 4 h
Yield: 72.8 %

Procedure:
2.25 g (5.93 mmoles) of H-Leu-Asp-D-Phg-NH2, prepared as described in Example 5, Step 2, are dissolved in a mixture of 50 ml of DMF and 10 ml of HMFA, and 0.84 ml (5.93 mmoles) of triethylamine and 2.65 g (6.6 mmoles) of BOC-Trp-OSu are added to the solution. The reaction mixture is stirred for 4 hours, whereupon a clear mixture is obtained. The mixture is allowed to stand overnight, and then DMF is evaporated in vacuo. The residual mixture containing HMFA is diluted with water, the obtained suspension is allowed to stand at a cool place, and then the precipitate is filtered off. The resulting crude product, weighing 4.31 g, is boiled twice in ethyl acetate, and the suspension is filtered when hot. 2.87 g (72.8%) of BOC-Trp-Leu-Asp-D-Phg-NH2 are obtained; m.p.: 195°-200° C., Rf5 : 0.55. The product is used in the next step without further purification.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:12]([O:15][CH2:16][C:17]1[CH2:18][S:19][C@@H:20]2[CH:27]([NH2:28])[C:26](=[O:29])[N:21]2[C:22]=1[C:23]([OH:25])=[O:24])(=[O:14])[CH3:13].ClC(Cl)C([O:34][N:35]=[C:36]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:37](Cl)=[O:38])=O.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(#N)C.CC(N(C)C)=O.C(#N)C.CCO>[C:12]([O:15][CH2:16][C:17]1[CH2:18][S:19][C@@H:20]2[C@H:27]([NH:28][C:37](=[O:38])[C:36](=[N:35][OH:34])[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:26](=[O:29])[N:21]2[C:22]=1[C:23]([OH:25])=[O:24])(=[O:14])[CH3:13]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: O=C(Cl)C(=NOC(=O)C(Cl)Cl)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(=NO)c3ccccc3)[C@H]2SC1
Temperature: 25 °C

Procedure:
To a suspension of 3-acetoxymethyl-7-aminoceph-3-em-4-carboxylic acid p-toluenesulphonic acid salt (4.8 g) in acetonitrile:dimethylacetamide (6:1, 25 ml.) was added dropwise with stirring at room temperature a 3 M solution of 2-dichloroacetoxyimino-2-phenylacetyl chloride (syn isomer) in acetonitrile (5 ml.). The reaction was stirred at room temperature until the solution was homogeneous, then poured into saturated aqueous sodium bicarbonate solution. The solution was washed with ethyl acetate, acidified to pH 1.0 (2 N-hydrochloric acid) and extracted with ethyl acetate. The combined extracts were washed with water, dried and concentrated to ca. 10 ml. The concentrate was added dropwise to petroleum spirit (b.p. 40°-60°) with vigorous stirring. This produced a gummy solid which was stirred with ethyl acetate (50 ml.) and the solution filtered and added dropwise to petroleum spirit (300 ml.). The precipitated solid was filtered and dried to give the title acid (1.47 g; 29%), [α]D +57° (c 0.7 DMSO) λmax. (EtOH) 253.5 nm (ε 15,800).
Reaction SMILES: C1(CO[C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[NH:11]3)CCC1.[O:19]=[C:20]1[C:25]2[C:26]([CH2:29][OH:30])=[CH:27][O:28][C:24]=2[CH2:23][CH2:22][CH2:21]1.C(OC(C1NC2C(C=1)=C(O)C=CC=2)=O)C>>[O:19]=[C:20]1[C:25]2[C:26]([CH2:29][O:30][C:7]3[CH:15]=[CH:14][CH:13]=[C:12]4[C:8]=3[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[NH:11]4)=[CH:27][O:28][C:24]=2[CH2:23][CH2:22][CH2:21]1
Reactant: O=C1CCCc2occ(CO)c21
Reactant: O=C(O)c1cc2c(OCC3CCC3)cccc2[nH]1
Agent: CCOC(=O)c1cc2c(O)cccc2[nH]1
Product: O=C(O)c1cc2c(OCc3coc4c3C(=O)CCC4)cccc2[nH]1

Procedure:
4-(4-Oxo-4,5,6,7-tetrahydro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (16f) is synthesized analogous to 16a from 4-oxo-4,5,6,7-tetrahydro-benzofuran-3-ylmethanol and 4-hydroxy-1H-indole-2-carboxylic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:22][C:23]([F:26])([F:25])[F:24])(=O)=O>C(#N)C.CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH2:22][C:23]([F:26])([F:25])[F:24]
Reactant: Oc1cc(F)ccc1Br
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: Fc1ccc(Br)c(OCC(F)(F)F)c1
Temperature: 150 °C
Yield: 186.6 %

Procedure:
To a stirred solution of 2-bromo-5-fluorophenol (1.5 g) in acetonitrile (0.5 mL) and DMF (8.5 mL) in a microwave tube was added potassium carbonate (2.1 g) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.37 g). The mixture was heated to 150° C. in a microwave oven for 30 minutes. In a second microwave tube the same reaction was repeated. Both mixtures were combined. The solvent was removed in vacuum, ethyl acetate and hexane (1:1) was added and the mixture was washed with water. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 4.0 g of the title compound.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.P(Br)(Br)[Br:20]>O1CCCC1>[Br:20][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCCCCC1CCCCC1
Reactant: BrP(Br)Br
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: BrCCCCCC1CCCCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 5-cyclohexylpentanol (1.74 g., 10.25 mmol) and pyridine (0.94 g., 11.1 mmol) at 0° under argon was added phosphorus tribromide (1.21 g., 4.5 mmol) dropwise. The reaction mixture became viscous, therefore 25 ml tetrahydrofuran was added. This mixture was stirred for 1.5 hours at room temperature, then partitioned between ethyl ether and 5% aqueous hydrochloric acid. The organic portion was washed with a 5% sodium bicarbonate solution, water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give a dark yellow oil. Purification by flash chromatography (silica, hexane) yielded the desired alkyl halide.
Reaction SMILES: C[C:2]1(C)[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])O1.N1[CH:16]=[CH:15][CH:14]=[CH:13]C=1.C1([ClH]C(Cl)=O)CCC1>ClCCl>[CH3:2][O:9][C:7](=[O:8])[CH2:6][C:4]([CH:13]1[CH2:14][CH2:15][CH2:16]1)=[O:5]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CC(=O)C1CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
22 g of meldrum's acid (2,2-dimethyl-1,3-dioxane-4,6-dione) (152.7 mmol) and 36.9 ml of pyridine (457.2 mmol) were dissolved in 200 ml of dichloromethane. 18.1 g of cyclobutylcarbonic acid chloride were added at 0 to 10° C. The reaction mixture was stirred overnight at room temperature, washed with 1 N HCl and extracted with dichloromethane. The organic layer was washed with water, dried over magnesium sulfate, filtered, and then concentrated to dryness. The oily residue was dissolved in 300 ml of methanol and heated under reflux for 2 h. The reaction mixture was concentrated to dryness and the residue purified via silica gel chromatography with ethyl acetate as eluent. Yield: 21.2 g
Reaction SMILES: Br[CH2:2][C:3](=O)[CH:4]([CH3:6])[CH3:5].[CH3:8][CH2:9][O:10][C:11]([C:13]([NH2:15])=[S:14])=[O:12]>>[CH2:9]([O:10][C:11]([C:13]1[S:14][CH:2]=[C:3]([CH:4]([CH3:6])[CH3:5])[N:15]=1)=[O:12])[CH3:8]
Reactant: CCOC(=O)C(N)=S
Reactant: CC(C)C(=O)CBr
Product: CCOC(=O)c1nc(C(C)C)cs1
Temperature: 25 °C
Yield: 50.2 %

Procedure:
Step B) A neat solution of 5.58 g (34 mmol) of 1-Bromo-3-methyl-butan-2-one and 4.50 g (34 mmol) of ethyl thioxamate (Aldrich) was heated at 70° C. over 18 h and then cooled to room temperature. The mixture was partitioned between sat. aqueous NaHCO3 and EtOAc, the EtOAc layer dried (MgSO4), concentrated and chromatographed over SiO2 (eluted with 2% to 40% EtOAc/hexanes) to afford 3.4 g (48% overall) of 4-isopropylthiazole-2-carboxylic acid ethyl ester as an oil: 1H NMR (500 MHz, CDCl3) δ 1.32 (d, J=7 Hz, 6H), 1.42 (t, J=7.2 Hz, 3H), 3.23 (m, 1H), 4.46 (q, J=7.2 Hz, 2H), 7.18 (s, 1H).
Reaction SMILES: C([N:8]1[CH2:18][CH2:17][C:11]2([O:15][C:14](=[O:16])[NH:13][CH2:12]2)[CH2:10][CH2:9]1)C1C=CC=CC=1>[Pd].C(O)C>[O:15]1[C:11]2([CH2:10][CH2:9][NH:8][CH2:18][CH2:17]2)[CH2:12][NH:13][C:14]1=[O:16]
Reactant: O=C1NCC2(CCN(Cc3ccccc3)CC2)O1
Agent: [Pd]
Solvent: CCO
Product: O=C1NCC2(CCNCC2)O1
Reaction time: 18 h
Yield: 106.8 %

Procedure:
A mixture of 6.2 g 8-benzyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one, 50 ml ethanol and 0.5 g, 10% palladium on carbon is hydrogenated at 60 psi and 50° for 18 hours. After filtration and removal of solvent there is obtained 4.2 g 1-oxa-3,8-diazaspiro[4.5]decan-2-one, mp 158°-161°.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]#[C:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[CH:14]=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1>>[N:1]1([CH2:7][CH2:8][C:9]#[C:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[CH2:14][N:19]2[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=Cc1cccc(C#CCCN2CCOCC2)c1
Reactant: OC1CCNCC1
Product: OC1CCN(Cc2cccc(C#CCCN3CCOCC3)c2)CC1

Procedure:
May be prepared analogously to Example 15 using the product of Example 10 and piperidin-4-ol.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[C:10]([O:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])=[C:9]([C:19](=[O:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:8]([CH3:26])=[CH:7][C:5]=2[N:6]=1.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2>C1(C)C=CC=CC=1>[Br:1][C:2]1[S:3][C:4]2[C:10]([O:11][S:12]([C:15]([F:18])([F:16])[F:17])(=[O:14])=[O:13])=[C:9]([C@H:19]([OH:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:8]([CH3:26])=[CH:7][C:5]=2[N:6]=1
Reactant: CCOC(=O)C(=O)c1c(C)cc2nc(Br)sc2c1OS(=O)(=O)C(F)(F)F
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H](O)c1c(C)cc2nc(Br)sc2c1OS(=O)(=O)C(F)(F)F
Temperature: -35 °C
Reaction time: 0.33 h

Procedure:
To a solution of 30 (8.30 g, 17.4 mmol) in toluene (70 mL) was added ((R)-2-methyl-CBS-oxazaborolidine (725 mg, 2.61 mmol). The reaction mixture was then cooled to −35° C. and a solution of catecholborane (freshly distilled) (1 M in toluene, 20.9 mL, 20.9 mmol) was added via addition funnel over 30 min. The reaction was stirred for 20 min while warming to −20° C. A 2 M solution of Na2CO3 was added (50 mL). The layers were separated, and the organic layer was washed with additional Na2CO3 solution (3×25 mL). The organic layer was dried, filtered, and concentrated in vacuo to give 31, which had analytical data to match 29. The compound was taken on to the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]2[N:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]3=[N:13][C:12]=2[CH2:20][N:21]2C(=O)C3C(=CC=CC=3)C2=O)[CH:6]=[CH:7][CH:8]=1.O.NN>C(O)C>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]2[N:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]3=[N:13][C:12]=2[CH2:20][NH2:21])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1nc2ccccn2c1C#Cc1cccc(C(F)(F)F)c1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1nc2ccccn2c1C#Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.6 %

Procedure:
1.41 g (3.08 mmol) of 2-((3-((3-(trifluoromethyl)phenyl)ethynyl) imidazo[1,2-a]pyridin-2-yl)methyl) isoindoline-1,3-dione were solubilised in 30 ml of ethanol with magnetic stirring, 0.978 ml (30.8 mmol) of hydrazine monohydrate were added. The mixture gradually became milky and was stirred at r.t. for 1.5 h. The suspended solid was isolated by filtration and washed with 2×25 ml of ethanol. The filtrate was concentrated in vacuo. The residue was triturated in 20 ml of ethanol, the solid was isolated by filtration and the filtrate concentrated in vacuo in order to obtain 0.715 g (yield=69%) of (3-((3-(trifluoromethyl)phenyl)ethynyl)imidazo[1,2-a]pyridin-2-yl)methanamine as a pale yellow solid. LC-MS: m/z=316 (MH+); UV purity at 254 nm=94%. 1H NMR (300 MHz, DMSO) δ 8.73 (d, J=6.7 Hz, 1H), 8.12 (s, 1H), 7.98 (d, J=7.7 Hz, 1H), 7.82-7.63 (m, 3H), 7.49-7.40 (m, 1H), 7.13 (td, J=6.8, 1.1 Hz, 1H), 3.96 (s, 2H).