Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:27])[CH2:25]Br)[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:28]1([OH:33])[CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:27])[CH2:25][O:33][CH:28]5[CH2:32][CH2:31][CH2:30][CH2:29]5)[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CBr)NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: OC1CCCC1
Product: O=C(COC1CCCC1)NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1

Procedure:
Using a procedure similar to that described in Example 21 except starting with N-(1-[9,10-dihydro-9,10-methanoanthracen-9-ylmethyl]-4-piperidyl)-2-bromoacetamide (described in Example 38a) and cyclopentanol, the title compound was obtained as a white solid (63%) mp 127.0°-8.0° C.; MS(CI): 431 (M+H); NMR (300 MHz,DMSO-d6): 1.48 (br m, 4H), 1.62(br m, 8H), 2.8(br m, 2H), 2.45(s, 2H), 2.94(br m, 2H), 3.34(s, submerged, 2H), 3.60(br m, 1H), 3,74(2, 2H), 3.89(sextet, 1H, J=3.9 Hz), 4.30(s, 1H), 6.91(br m, 4H), 7.18(d, 2H, J=6.2 Hz), 7.26(d, 2H, J=6.2 Hz), 7.33(d, 1H, J=8.3 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[C:10]=1[F:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S1(CCCC1)(=O)=O.[Li+].CC([N-]C(C)C)C.[Li]CCCC.[C:38](=[O:40])=[O:39]>O1CCOCC1.C(OCC)C.C1COCC1.CN1C(=O)N(C)CCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH2:1]([O:8][C:9]1[C:10]([F:17])=[C:11]([F:16])[C:12]([F:15])=[C:13]([CH:14]=1)[C:38]([OH:40])=[O:39])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(OCc2ccccc2)c(F)c1F
Reactant: O=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Solvent: CCOCC
Product: O=C(O)c1cc(OCc2ccccc2)c(F)c(F)c1F
Reaction time: 7.5 h

Procedure:
To a solution of 1-benzyloxy-2,3,4-trifluorobenzene in appropriate inert solvent (such as, but not limited to, aliphatic and aromatic hydrocarbon (such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene, toluene, xylene), ether (such as diethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane), sulfolane, HMPA, DMPU, prefer anhydrous THF, ethyl ether and dioxane) was added strong base (such as LDA, n-BuLi, LiHDMS) at low temperature (−50-−80° C., prefer −78° C.) under nitrogen atmosphere. The stirring was maintained at this temperature for several hours (such as 0.5-12 h, prefer 0.5-2 h). The mixture was transferred to a bottle with dry ice. The mixture is stirred for some time (such as 3-12 h, prefer 5-10 h). 5-Benzoxy-2,3,4-trifluorobenzoic acid is obtained after conventional workup.
Reaction SMILES: C(N(CC)CC)C.[F:8][CH:9]([F:32])[C:10]1[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([C:20]([O:22][CH2:23]C)=[O:21])=[C:12]([O:25]CC)[C:11]=1[C:28]([O:30][CH3:31])=[O:29].[OH-].[K+].S(Cl)(Cl)=O>CCO.CCOCC.[Pd].CO.O>[F:32][CH:9]([F:8])[C:10]1[C:11]([C:28]([O:30][CH3:31])=[O:29])=[C:12]([OH:25])[C:13]([C:20]([O:22][CH3:23])=[O:21])=[C:14]([C:16]([F:19])([F:17])[F:18])[N:15]=1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1OCC
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: O
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OC)c1O
Yield: 32 %

Procedure:
Product of Example 18 (23.34 g, 0.032 mol), 9.0 ml (0.064 mol) of triethylamine and 0.62 g of Pd/C (10%) in 100 ml of EtOH were reacted as described by the preparation of product of Example 22 affording 9.99 g of dark orange oil. A portion of this oil (5.0 g, 0.014 mol), 4.51 g (0.070 mol) of 87% KOH, 1 ml of H2O in 30 ml of EtOH was stirred at reflux for 5 days. Reaction mixture was concentrated and the residue was poured into water and washed with ether. The aqueous layer was acidified with conc HCl, extracted with ether, dried (MgSO4) and concentrated in vacuo to 4.26 g of foamy oil. This oil was treated as described in Example 19: 4.26 g (0.013 mol) of this foamy oil, 25 ml of thionyl chloride and 25 ml of MeOH were reacted affording a dark solid residue which was taken up in ether and extracted with 15% K2CO3 and water, acidified with concentrated HCl, extracted with ether, dried (MgSO4) and concentrated in vacuo in 2.7 g of solid. Recrystallization from hexane-ether afforded 1.37 g (32.0%) of product as a tan solid: mp 83°-84.5° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1[N:12]([CH3:32])[C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[N:25]=[CH:24]3)=[CH:18][CH:17]=2)=[N:14][CH:15]=1)=O>O1CCCC1>[N:23]1([CH2:22][C:19]2[CH:18]=[CH:17][C:16]([C:13]3[N:12]([CH3:32])[C:11]([CH2:9][OH:8])=[CH:15][N:14]=3)=[CH:21][CH:20]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[CH:24]1
Reactant: COC(=O)c1cnc(-c2ccc(Cn3cnc4ccccc43)cc2)n1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1c(CO)cnc1-c1ccc(Cn2cnc3ccccc32)cc1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
To a suspension of lithium aluminum hydride (60.8 mg, 1.6 mmol) in anhydrous tetrahydrofuran (4 mL) under nitrogen cooled to −5° C. was added dropwise a solution of 2-(4-benzoimidazol-1-ylmethyl-phenyl)-3-methyl-3H-imidazole-4-carboxylic acid methyl ester (280 mg, 0.8 mmol) in anhydrous tetrahydrofuran (2 mL) over 10 min and the reaction mixture was allowed to stir at for 1 h. The reaction mixture was quenched with water (0.06 mL), aqueous sodium hydroxide (2.5 N, 0.21 mL), and again water (0.06 mL), stirred for 30 min, then diluted with tetrahydrofuran (20 mL) and left overnight without stirring. The reaction mixture was diluted with dichloromethane (20 mL) and methanol (20 mL) and the solid was filtered off. The filtrate was evaporated under reduced pressure and the crude product was used in the next step without further purification. LCMS (ESI+) 319.2 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([CH2:7][C:8]#[N:9])=[O:6].[C:13]1([N:19](C2C=CC=CC=2)[CH:20]=N)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C(C)=CC=CC=1.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([C:7](=[CH:20][NH:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]#[N:9])=[O:6]
Reactant: N=CN(c1ccccc1)c1ccccc1
Reactant: N#CCC(=O)c1cccc(Br)c1
Solvent: CCOCC
Solvent: Cc1ccccc1C
Product: N#CC(=CNc1ccccc1)C(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.3 %

Procedure:
A mixture of 2-(3-bromobenzoyl)acetonitrile (16.5 g, 73.6 mmol) and N,N-diphenylformamidine (14.5 g, 73.6 mmol) in xylene (100 ml) was heated at reflux under a nitrogen atmosphere. After 3 h, the reaction was cooled to room temperature and diluted with ether to give 2-(3-bromobenzoyl)-3-phenylaminoacrylonitrile (17.9 g) as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:21])=[CH:4][C:5]([NH:8][C:9]2[O:10][C@:11]3([CH2:19][N:20]=2)[CH:16]2[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]2)[CH2:12]3)=[N:6][CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:30])C=1>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:21])=[CH:4][C:5]([NH:8][C:9]2[O:10][C@:11]3([CH2:19][N:20]=2)[CH:16]2[CH2:17][CH2:18][N+:13]([O-:30])([CH2:14][CH2:15]2)[CH2:12]3)=[N:6][CH:7]=1
Reactant: Cc1cc(NC2=NC[C@@]3(CN4CCC3CC4)O2)ncc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Product: Cc1cc(NC2=NC[C@@]3(C[N+]4([O-])CCC3CC4)O2)ncc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.2 %

Procedure:
To (R)—N-(5-Chloro-4-methylpyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.04 g, 0.13 mmol) in THF (10 mL) was added m-CPBA (0.025 g, 0.14 mmol). The reaction stirred at room temperature for 2 hours and was then concentrated to a crude powder. The product was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH) to yield (S)-2-(5-chloro-4-methylpyridin-2-ylamino)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]1′-oxide (0.019 g, 0.06 mmol, 44% yield) as a white powder. 1H NMR (500 MHz, MeOD) δ ppm 8.18 (s, 1H), 6.75-7.09 (m, 1H), 4.00 (d, J=10.4 Hz, 1H), 3.84 (d, J=10.4 Hz, 1H), 3.61-3.78 (m, 2H), 3.41-3.54 (m, 3H), 3.23-3.38 (m, 3H), 2.45 (br. s., 1H), 2.25-2.38 (m, 4H), 1.88-2.22 (m, 1H). MS (LC/MS) R.T.=0.91; [M+H]+=323.11.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:11][C:12]([NH:14][CH:15]([CH2:27][OH:28])[CH2:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:13])([CH3:10])([CH3:9])[CH3:8].[Cl-].[NH4+]>C(N(CC)CC)C.C(Cl)Cl.CS(C)=O>[C:7]([O:11][C:12]([NH:14][CH:15]([CH:27]=[O:28])[CH2:16][C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])=[O:13])([CH3:9])([CH3:10])[CH3:8]
Reactant: CC(C)(C)OC(=O)NC(CO)CC(=O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(C=O)CC(=O)OCc1ccccc1
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 79.5 %

Procedure:
8 ml of a methylene chloride solution containing 0.81 g (6.4 mmol) of oxalyl chloride was cooled to −70° C., and 2 ml of a methylene chloride solution containing 0.65 g of DMSO was added dropwise over 10 minutes. The mixture was stirred at −60° C. for 10 minutes, and then, 5 ml of a methylene chloride solution containing 1.01 g (3.27 mmol) of benzyl 3-t-butoxycarbonylamino-4-hydroxybutanoate was added dropwise over 10 minutes. The mixture was stirred at −50° C. for one hour, and then, 3.3 ml of triethylamine was added dropwise. After completion of the dropwise addition, the temperature of the mixture was gradually raised and when the temperature reached to 0° C., a saturated aqueous ammonium chloride solution was added to the mixture and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous saline solution and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by the silica gel column chromatography method (n-hexane/ethyl acetate=7/3) to obtain 0.80 g (2.6 mmol) of benzyl 3-t-butoxycarbonylamino-3-formylpropionate as pale yellowish oily product.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.FC(F)(F)S(O[CH2:15][C:16]([F:19])([F:18])[F:17])(=O)=O>>[I:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:15][C:16]([F:19])([F:18])[F:17])[C:4](=[O:8])[CH:3]=1
Reactant: O=c1cc(I)cc[nH]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Product: O=c1cc(I)ccn1CC(F)(F)F

Procedure:
4-iodo-1-(2,2,2-trifluoroethyl)pyridin-2(1H)-one was prepared from 4-iodopyridin-2(1H)-one and 2,2,2-trifluoroethyl trifluoromethanesulfonate following a procedure analogous to that described in Example 59 Step 1.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5](Br)=[CH:6][N:7]=1.[CH3:13][N:14]([CH3:26])[C:15]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)=[O:16].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.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>[NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([C:20]2[CH:21]=[CH:22][C:17]([C:15](=[O:16])[N:14]([CH3:13])[CH3:26])=[CH:18][CH:19]=2)=[CH:6][N:7]=1
Reactant: CN(C)C(=O)c1ccc(B(O)O)cc1
Reactant: COC(=O)c1nc(Br)cnc1N
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: O
Solvent: CC#N
Product: COC(=O)c1nc(-c2ccc(C(=O)N(C)C)cc2)cnc1N
Temperature: 110 °C

Procedure:
Methyl 3-amino-6-bromo-pyrazine-2-carboxylate (6.012 g, 25.91 mmol), [4-(dimethylcarbamoyl)phenyl]boronic acid (5 g, 25.91 mmol), sodium carbonate (5.492 g, 51.82 mmol) and Pd(PPh3)4 (2.994 g, 2.591 mmol) in a mixture of acetonitrile (28.85 mL) and water (28.85 mL) was heated at 110° C. The reaction mixture was allowed to cool and the residual solid filtered off. The filtrate was diluted with EtOAc and water and the layers separated. The aqueous layer was acidified to pH4 (by addition of 1M HCl) and then extracted with dichloromethane (3×), dried (MgSO4), filtered and concentrated in vacuo to leave the product as a yellow solid. The ethyl acetate extracts were concentrated in vacuo and combined with the filtered solid. Preabsorbed onto silica and purified by column chromatography on silica using the companion eluting with ethyl acetate/petroleum ether (0-100% EtOAc). Product eluted with 100% EtOAc. Product fractions combined and conc in vacuo to leave a yellow solid (1.95 g, 50% Yield). 1H NMR (400.0 MHz, DMSO) d 3.02 (3H, s), 3.15 (3H, s), 4.04 (3H, s), 7.54 (2H, m), 7.97 (2H, m), 8.71 (1H, s) ppm; MS (ES+) 301.13
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[CH:14](C1C=NC(NC2C=CC(F)=CC=2F)=CC=1)[OH:15].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C([O-])([O-])=O.[Na+].[Na+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)=[CH:4][C:3]=1[CH:14]=[O:15]
Reactant: OC(c1ccc(Nc2ccc(F)cc2F)nc1)c1cc(-c2ccncc2)ccc1Cl
Agent: O=[Cr](=O)=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: O=Cc1cc(-c2ccncc2)ccc1Cl

Procedure:
(2-Chloro-5-pyridin-4-yl-phenyl)-[6-(2,4-difluoro-phenylamino)-pyridin-3-yl]-methanol (111 mg; 0.26 mmol) is dissolved in acetone (20 ml) and treated with Jones reagent (0.45 ml; 1 mmol) for 20 min at room temperature. 2N Na2CO3 is added to the reaction mixture and extracted with ethyl acetate three times. The combined organic phases are dried over Na2SO4 and evaporated to dryness. Purification via chromatography (SiO2; CH2Cl2/MeOH 98/2) provides the title compound as a slightly colored foam (30 mg; 27%).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].OC1[CH2:25][CH2:24][CH2:23][O:22][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]C1>>[C:5]([O:4][CH:1]1[CH2:25][CH2:24][CH2:23][O:22][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:2]1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CCCCCCCCCCC(O)CCCO1
Product: CC(=O)OC1CCCCCCCCCCC(=O)OCCC1
Yield: 98 %

Procedure:
473 g (4.64 mol) of acetic anhydride are initially introduced into a flask and heated to 135°-140° C. (reflux). 982 g (3.83 mol) of 12-hydroxy-15-pentadecanolide (VII) are added dropwise. The mixture is allowed to after-react under reflux for a further hour. The excess acetic acid/acetic anhydride is then distilled off under a weak vacuum. 1120 g of 12-acetoxy-15-pentadecanolide are obtained;
Reaction SMILES: O=[C:2]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH2:3][N:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]([O:11]C)=O.[CH2:19]([NH2:22])[CH2:20][NH2:21]>O1CCOCC1>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:2]23[NH:22][CH2:19][CH2:20][N:21]2[C:9](=[O:11])[C:5]2[N:4]([CH:8]=[CH:7][CH:6]=2)[CH2:3]3)[CH:14]=1
Reactant: COC(=O)c1cccn1CC(=O)c1cccnc1
Reactant: NCCN
Solvent: C1COCCO1
Product: O=C1c2cccn2CC2(c3cccnc3)NCCN12
Yield: 86.7 %

Procedure:
To a solution of methyl 1-[2-oxo-2-(pyridin-3-yl)ethyl]-1H-pyrrole-2-carboxylate (84 mg, 0.34 mmol) in 1,4-dioxane (15 mL) was added ethane-1,2-diamine (0.65 mL, 9.7 mmol). The solution was heated at reflux for 3 days. The mixture was then concentrated in vacuo to give an oily solid. The material was purified by flash chromatography (Silica gel, gradient 5-9% methanol in CH2Cl2) to yield 10a-(pyridin-3-yl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (102) as an off-white solid (75 mg, yield 86%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1)\[CH3:7])[CH3:2].[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:16])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1)\[CH2:7][Br:17])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)/C=C(\C)Oc1cccc(Cl)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C=C(\CBr)Oc1cccc(Cl)c1
Yield: 64.8 %

Procedure:
To a stirred mixture of (E)-3-(3-chloro-phenoxy)-but-2-enoic acid ethyl ester (3.45 g, 0.014 mol) in carbon tetrachloride (20 mL) under a nitrogen atmosphere was added N-bromosuccinimide (2.79 g, 0.016 mol) and benzoyl peroxide (347 mg, 0.001 mol). Nitrogen gas was bubbled through the mixture for 5 min, and the resulting mixture was heated to reflux for 4 h. The reaction mixture was then placed in the refrigerator overnight. The solids formed were removed by filtration and the filtrate concentrated in vacuo. The crude product obtained was purified using flash column chromatography (silica gel (100-200 mesh), ethyl acetate/hexanes) to afford (E)-4-bromo-3-(3-chloro-phenoxy)-but-2-enoic acid ethyl ester (2.90 g, 63%) as a yellow oil.
Reaction SMILES: [C:1]1([CH:7](O)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C(F)(F)[F:17])C=CC=CC=1>C(Cl)Cl>[F:17][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8]
Reactant: FC(F)(F)c1ccccc1
Reactant: CC(O)c1ccccc1
Agent: *CC*
Solvent: ClCCl
Product: CC(F)c1ccccc1
Temperature: 20 °C
Reaction time: 2.5 h
Yield: 81 %

Procedure:
Under a protective gas atmosphere 0.83 g (6.8 mmol) of 1-phenylethanol is added dropwise in the course of 5 min to a solution of 2.32 g (7.56 mmol) of i-Prop2N═CHF+HF2−.HNEt3+.HF2− in 10 ml of CH2Cl2 in a polyethylene container. The mixture is stirred for several hours at 20° C. and the conversion rate is analysed by 19F-NMR (reference: PhCF3). After 2.5 h, 81% of 1-fluoroethylbenzene is obtained, and after a stirring time of 24 h, 96% of product is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([Br:22])=[C:11]2[C:16](=[CH:17][C:18]=1[N+:19]([O-])=O)[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC(O)=O.CCO.[Fe]>[CH2:1]([O:8][C:9]1[C:18]([NH2:19])=[CH:17][C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]=1[Br:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc2c(c(Br)c1OCc1ccccc1)CCCC2
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1cc2c(c(Br)c1OCc1ccccc1)CCCC2
Temperature: 100 °C

Procedure:
To a solution of 6-benzyloxy-5-bromo-7-nitro-1,2,3,4-tetrahydronaphthalene (0.50 g, 1.38 mmol) in AcOH/EtOH (3:1, 20 mL), is added iron powder (0.50 g, 9.25 mmol). The mixture is heated at 100° C. for 2 h. The precipitate is filtered through Celite. The filtrate is concentrated, extracted with water and CH2Cl2, and filtered. The crude material is purified via Biotage, eluting with 0-20% EtOAc/hexanes, to afford 3-benzyloxy-4-bromo-5,6,7,8-tetrahydronaphthalen-2-ylamine: (M+H)=333, 334.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[C:12](#[N:16])/[CH:13]=[CH:14]/[CH3:15].Cl>C(O)(C)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:9](=[O:11])[CH3:10])[CH:14]([CH3:15])[CH2:13][C:12]#[N:16])=[CH:6][CH:7]=1
Reactant: CC(=O)Cc1ccc(Cl)cc1
Reactant: C/C=C/C#N
Agent: Cl
Solvent: CC(C)(C)O
Product: CC(=O)C(c1ccc(Cl)cc1)C(C)CC#N
Temperature: 65 °C

Procedure:
Triton B (5.85 ml) was added dropwise to 4-chlorophenylacetone (21.8 grams) in 78 ml of tert. butanol. Next crotononitrile (9.17 grams) was likewise added with initial cooling to lower the temperature to about 20° C. Since the reaction was not exothermic, no additional cooling was necessary after the desired temperature was reached. The reaction was then heated to 65° C. for 21/2 hours and, after chilling in an ice bath, 262 ml of 1 N HCl was added in portions. Next the reaction mixture was extracted with ether, washed with water, dried, and evaporated in vacuo. An oil resulted which was distilled under vacuum, yield 18.6 grams, b.p. 130°-131° C.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13](B(O)O)=[CH:12][C:11]=3[CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[C:22]([F:28])[CH:21]=1.C(N(CC)CC)C>C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:20]4[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[C:22]([F:28])[CH:21]=4)=[CH:12][C:11]=3[CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: OB(O)c1cc2cc(C3CCCCC3)ccc2o1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=Cc1ccc(-c2cc3cc(C4CCCCC4)ccc3o2)cc1F
Yield: 65.9 %

Procedure:
A mixture of 5-cyclohexylbenzofuran-2-ylboronic acid (75 mg, 0.30 mmol), 4-bromo-2-fluorobenzaldehyde (48 mg, 0.24 mmol), triethylamine (1.1 mL, 7.5 mmol) and bis(triphenylphosphine)palladium(II)chloride (12 mg, 0.05 mmol) in ethanol (11 mL) was irradiated in a microwave instrument at 100° C. for 20 min. The reaction mixture was cooled, and the solvent was removed. The residue was treated with water and extracted with ethyl acetate. The organic layer was dried and concentrated in vacuo (the aqueous work-up is optional). Purification by silica gel chromatography on ISCO system gave the title compound (51 mg, 49% yield). 1H NMR (400 MHz, CDCl3) δ 10.04 (s, 1H), 8.00-7.97 (m, 2H), 7.46 (s, 1H), 7.43 (d, 2H), 7.32 (s, 1H), 7.25 (d, 1H), 2.62 (m, 1H), 1.95-1.77(m, 4H), 1.58-1.56 (m, 4H), 1.46-1.44 (m, 2H). MS (ESI) m/z: Calculated: 322.27; Observed: 323.2 (M++1).
Reaction SMILES: FC1C=CC([S:8]([Cl:11])(=[O:10])=[O:9])=CC=1OC.N[C:15]1[CH:16]=[CH:17][C:18]([C:21]#[N:22])=[N:19][CH:20]=1>>[C:21]([C:18]1[N:19]=[CH:20][C:15]([S:8]([Cl:11])(=[O:10])=[O:9])=[CH:16][CH:17]=1)#[N:22]
Reactant: N#Cc1ccc(N)cn1
Reactant: COc1cc(S(=O)(=O)Cl)ccc1F
Product: N#Cc1ccc(S(=O)(=O)Cl)cn1

Procedure:
The titled compound is prepared analogously to 4-fluoro-3-methoxy-benzenesulfonyl chloride (Intermediate 102a) by replacing 4-fluoro-3-methoxyaniline with 5-amino-pyridine-2-carbonitrile.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:12]=[C:13]4[C:22](=[CH:23][CH:24]=3)[C:16]3=[N:17][NH:18][C:19](=[O:21])[CH2:20][CH:15]3[CH2:14]4)[CH2:7][CH2:6]2)[O:4]CC1.N1(C2C=C3C(=CC=2)C2=NNC(=O)C=C2C3)C=CN=C1>>[OH:4][CH:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:12]=[C:13]3[C:22](=[CH:23][CH:24]=2)[C:16]2=[N:17][NH:18][C:19](=[O:21])[CH2:20][CH:15]2[CH2:14]3)[CH2:9][CH2:10]1
Reactant: O=C1CC2Cc3cc(N4CCC5(CC4)OCCO5)ccc3C2=NN1
Agent: O=c1cc2c(n[nH]1)-c1ccc(-n3ccnc3)cc1C2
Product: O=C1CC2Cc3cc(N4CCC(O)CC4)ccc3C2=NN1

Procedure:
2,4,4a,5-tetrahydro-7-(1,4-dioxa-8-azaspiro[4,5]dec-8-yl)-3H-indeno[1,2-c]pyridazin-3-one, and 2,5-dihydro-7-(1H-imidazol-1-yl)-3H-indeno[1,2-c]pyridazin-3-one.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([CH3:19])=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][CH:13]=2)[CH:9]=1)=[O:4].[OH-].[Li+].Cl>O1CCCC1.O>[I:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:8]2[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[O:6][C:7]=2[CH3:19])=[CH:13][CH:14]=1
Reactant: COC(=O)c1cc(COc2ccc(I)cc2)c(C)o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(C(=O)O)cc1COc1ccc(I)cc1
Yield: 70.4 %

Procedure:
A stirred solution of 4-(4-iodo-phenoxymethyl)-5-methyl-furan-2-carboxylic acid methyl ester (20) (2.7 g) in tetrahydrofuran (25 mL) was treated with a solution of lithium hydroxide (1.5 g) in water (2 mL). After 3 hours the reaction mixture was diluted with water and acidified to pH 2 with 1.0 M hydrochloric acid. The white precipitate was filtered off and dried in vacuo. The solid was triturated with ethyl acetate at 0° C. then collected by filtration to give compound 26 as a white solid (1.83 g). LC/MS system A: Rt=1.74 min.