Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[NH:8][C:5]2=[N:6][CH:7]=1.[C:15](=O)([O-])[O-].[K+].[K+].IC>[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:8]([CH3:15])[C:5]2=[N:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc2cc(Cl)cnc2[nH]1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COC(=O)c1cc2cc(Cl)cnc2n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a stirred solution of methyl 5-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (0.986 g, 4.68 mmol) N,N-dimethylformamide (20 ml) at room temperature under a nitrogen atmosphere was added potassium carbonate (0.647 g, 4.68 mmol). After 30 minutes iodomethane (0.321 ml, 5.15 mmol) was added and the resulting mixture was stirred at room temperature overnight. Brine was added and the mixture was extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was coated onto hydromatrix and purified by column chromatography (silica gel; heptane/ethyl acetate 4/1) to give methyl 5-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (0.89 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][N:6]=1)=[O:4].Br[CH2:13][C:14]#[C:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:13][C:14]#[C:15][CH3:16])=[CH:7][N:6]=1)=[O:4]
Reactant: CC#CCBr
Reactant: COC(=O)c1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(C(=O)OC)nc1
Temperature: 100 °C
Yield: 73.2 %

Procedure:
A mixture of 5-hydroxy-pyridine-2-carboxylic acid methyl ester (271 mg) and 1-bromo-2-butine (283 mg) in DMF (5 ml) was treated with potassium carbonate (367 mg) and heated to 100° C. for 16 h. the mixture was partitioned between water and ethyl acetate, the organic layer was dried, evaporated and the residue was purified by chromatography using heptane/ethyl acetate (gradient from 0-80% ethyl acetate) to give the title product (266 mg) as a pale yellow solid. MS: m/z=206.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:38]=[CH:37][C:27]([CH2:28][P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])=[C:26]([F:39])[C:25]=1[O:40][CH3:41]>>[F:39][C:26]1[C:25]([O:40][CH3:41])=[C:24]([NH:23][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[C:11](=[O:12])[NH:13][CH3:14])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=2)[CH:38]=[CH:37][C:27]=1[CH2:28][P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32]
Reactant: CCOP(=O)(Cc1ccc(N)c(OC)c1F)OCC
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(=O)NC)n2)c(OC)c1F)OCC

Procedure:
The title compound was prepared according to the procedure from Example 102 using 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (Compound 104A) and Diethyl (4-amino-2-fluoro-3-methoxybenzyl)phosphonate (Compound 147A). 1H NMR (CD3OD, 400 MHz): δ=1.26-1.36 (m, 6H), 1.44 (t, J=6.95 Hz, 3H), 3.32-3.39 (m, 2H), 4.04-4.15 (m, 4H), 4.22 (q, J=7.07 Hz, 2H), 7.00 (dd, J=8.34, 1.77 Hz, 1H), 7.21 (d, J=1.77 Hz, 1H), 7.75 (d, J=8.34 Hz, 1H). MS (ES+): m/z 586.14 [MH+] (TOF, polar).
Reaction SMILES: [CH2:1]([S:4]([N:7]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]1)(=[O:6])=[O:5])[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([S:4]([N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)(=[O:5])=[O:6])[CH2:2][CH3:3]
Reactant: CCCS(=O)(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCS(=O)(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirring ice-cold solution of tert-butyl 4-(propylsulfonyl)piperazine-1-carboxylate (2, 15.70 g, 53.69 mmol) in CH2Cl2 (200 mL) was slowly added trifluoroacetic acid (21.4 mL, 268.45 mmol). The mixture stirred at room temperature for 16 h under an atmosphere of N2. The mixture was washed with 2 N NaOH (3×50 mL), H2O (50 mL), brine (50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to afford 1-(propylsulfonyl)piperazine (3) as a crystalline solid (10.30 g quantitative): 1H NMR (500 MHz, CDCl3) δ 7.91 (d, J=1.7 Hz, 1H), 7.48 (d, J=1.6 Hz, 1H), 7.21 (m, 1H), 7.14 (s, 1H), 7.09 (s, 1H), 3.96 (s, 3H), 3.75 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C@H:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]3[C:25]([Cl:26])=[CH:24][N:23]=[C:22]([Cl:27])[N:21]=3)=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2].[H-].[Na+].I[CH3:32]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C@H:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][CH2:18][N:19]([C:20]3[C:25]([Cl:26])=[CH:24][N:23]=[C:22]([Cl:27])[N:21]=3)[CH3:32])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCNc3nc(Cl)ncc3Cl)ccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCN(C)c3nc(Cl)ncc3Cl)ccc21
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a solution of Example 441 (520 mg, 1.23 mmol) in DMF (15 mL) at 0° C. was added portionwise NaH (95 mg, 2.45 mmol, 60% dispersion in mineral oil) [H2 evolution]. The heterogeneous mixture was stirred for 30 min, then iodomethane (0.31 mL, 4.90 mmol) was added. After 18 h of agitation at rt, the excess NaH was quenched by the slow addition of NH4Cl (10% solution in water) [H2 evolution]. The resulting mixture was concentrated under reduced pressure, brought to basic pH using a saturated solution of NaHCO3, and the product was extracted with EtOAc. The combined organic layers were washed with water and brine, after which they were dried (Na2SO4), filtered, and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (4:1 hexanes/EtOAc) to yield the product (442 mg, 82%). 1H NMR (400 MHz, CDCl3): δ 1.30 (t, 3H), 1.75-1.82 (m, 1H), 2.12-2.20 (m, 2H), 2.30-2.45 (m, 2H), 2.70 (dd, 1H), 2.72-2.90 (m, 2H), 3.30 (s, 3H), 3.44-3.54 (m, 1H), 3.84 (t, 2H), 3.95 (t, 2H), 4.16 (q, 2H), 6.65 (d, 1H), 6.75 (s, 1H), 7.05 (d, 1H), 8.15 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][CH:5]=1)([OH:3])=[O:2].O[N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[N:15]1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[NH:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:2][C:1]([C:4]3[CH:5]=[CH:6][C:7]([B:10]([OH:12])[OH:11])=[CH:8][CH:9]=3)=[O:3])[C:17]=2[N:16]=[N:15]1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(Oc1cccc2[nH]nnc12)c1ccc(B(O)O)cc1

Procedure:
To a solution of 4-carboxy-phenylboronic acid (CPBA, Example 1, 2 g, 0.0121 mol) in N,N-dimethylformamide (DMF) was added 1-hydroxybenzotriazole (HBT, 2.04 g, 0.0151 mol) and N,N'-dicyclohexyl-carbodiimide (DCC, 4.98 g, 0.024 mol) both dissolved in DMF (the total volume was 170 ml DMF). The solution was left to react overnight (approx. 12 hours) under a nitrogen atomosphere and at ambient temperature, and then filtered to remove the insoluble urea byproduct (DCU). The title compound was used in subsequent reactions without further purification.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([Mg]Br)=[CH:29][C:28]=1[CH3:35]>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:30]3[CH:31]=[CH:32][C:27]([Cl:26])=[C:28]([CH3:35])[CH:29]=3)=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: Cc1cc([Mg]Br)ccc1Cl
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)ccc1Cl

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 90 mg (0.22 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 0.98 mL 0.5M 4-chloro-3-methylphenylmagnesium bromide. Yield: 54 mg of a white solid. LC-MSD, m/z for C23H16BrClN2O2 [M+H]+=467.0, 469.0; HPLC retention time: 2.6 min.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:8]=1[NH2:9].O[CH2:16][CH:17]([CH2:19]O)O>[I-].[Na+]>[F:14][C:13]1[C:7]([F:6])=[C:8]2[C:10]([CH:16]=[CH:17][CH:19]=[N:9]2)=[CH:11][CH:12]=1
Reactant: Nc1cccc(F)c1F
Reactant: OCC(O)CO
Agent: O=S(=O)(O)O
Agent: [I-]
Agent: [Na+]
Product: Fc1ccc2cccnc2c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
In a 3 L eggplant-shaped flask containing a stir bar, 80% sulfuric acid (607.7 g, 49.57 mol) was introduced and cooled to 0° C., and then 2,3-difluoroaniline (160.0 g, 1.24 mol) was slowly added. After the addition, the mixture was stirred for 1 hour at room temperature, sodium iodide (1.85 g, 12.3 mmol) was further added thereto, and then the mixture was heated in an oil bath until the temperature thereof reached 150° C. (temperature of the bath). When it reached this temperature, glycerin (125.5 g, 1.36 mol) was added dropwise over a period of one hour, and the mixture was stirred for 1 hour at 150° C. The temperature of the bath was further elevated to 180° C., and the water was evaporated over a period of 2 hours using a distillation apparatus. After confirming that the starting material had disappeared, the mixture was neutralized using 10N aqueous sodium hydroxide while cooling with an ice-water bath (the inner temperature is 60 to 70° C.). After the neutralization, before the inner temperature returned to room temperature, the resultant was subjected to extraction with ethyl acetate, and the extract was dried with magnesium sulfate, filtered, and concentrated. The thus obtained crude product was purified by silica gel column chromatography (normal hexane:ethyl acetate) to obtain 185.5 g of 7,8-difluoroquinoline (91%) as a hazel solid.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[NH:13]1[CH:17]=[CH:16][N:15]=[CH:14]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N:13]1([CH:2]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([O:5][CH3:6])=[O:4])[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: c1c[nH]cn1
Reactant: COC(=O)C(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C(c1ccccc1)n1ccnc1
Yield: 81.4 %

Procedure:
(RS) Methyl 2-bromo-2-phenylacetate (171.75 g), imidazole (102 g) and potassium carbonate (227.7 g) were stirred in acetone (1.75 liters for 60 hours. After settling, the supernatant was decanted off and the residue washed thoroughly with acetone. The acetone was evaporated under reduced pressure and the residue in ethyl acetate was washed with water and extracted twice with 2M hydrochloric acid. The combined acid extracts, after washing once with ether, were basified with solid potassium carbonate and extracted with toluene containing 10% ethyl acetate. The organic extracts were dried over magnesium sulphate and evaporated under reduced pressure to give the title compound as a yellow oil (132 g, 8i%).
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH2:15][CH2:16][CH2:17][Cl:18]>[OH-].[Na+].CC(C)=O>[Cl:18][CH2:17][CH2:16][CH2:15][N:5]1[CH2:6][CH2:7][C:2]([OH:1])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3][CH2:4]1
Reactant: ClCCCBr
Reactant: OC1(c2ccccc2)CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: OC1(c2ccccc2)CCN(CCCCl)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-hydroxy-4-phenylpiperidine (35.4 g, 0.2 mole) in 50 ml of 20% NaOH and 250 ml of acetone was cooled at <15° and 1-bromo-3-chloropropane (31.4 g, 0.2 mole) was added dropwise. The mixture was stirred at room temperature for 18 hours and concentrated in vacuo at <40°. The concentrate was converted to the HCl salt with HCL(g)/2-PrOH and concentrated in vacuo to an oil. The oil crystallized in hot acetone and the solid salt was collected and dried. The salt was warmed in 2-PrOH, cooled and filtered to remove 8 g of quaternary salt. mp >260°. The filtrate was warmed and diluted with ethyl acetate to obtain the desired salt. Yield 13 g (22.5%), m.p. 173°-6° (dec.).
Reaction SMILES: [CH:1]1([NH:9][C@H:10]([C:20]([OH:22])=O)[CH2:11][CH:12]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13]([OH:15])=[O:14])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC([N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][C@H:31]1[CH2:36][CH2:37][O:38][C:39]1[CH:40]=[C:41]2[C:46](=[CH:47][CH:48]=1)[C:45]([NH:49][C:50]([O:52][CH2:53][CH:54]=[CH2:55])=[O:51])=[N:44][CH:43]=[CH:42]2)=O)(C)(C)C>>[CH:1]1([NH:9][C@H:10]([C:20]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]2[CH2:36][CH2:37][O:38][C:39]2[CH:40]=[C:41]3[C:46](=[CH:47][CH:48]=2)[C:45]([NH:49][C:50]([O:52][CH2:53][CH:54]=[CH2:55])=[O:51])=[N:44][CH:43]=[CH:42]3)=[O:22])[CH2:11][CH:12]([C:16]([CH3:17])([CH3:18])[CH3:19])[C:13](=[O:14])[OH:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: C=CCOC(=O)Nc1nccc2cc(OCC[C@@H]3CCCCN3C(=O)OC(C)(C)C)ccc12
Reactant: CC(C)(C)C(C[C@H](NC1CCCCCCC1)C(=O)O)C(=O)O
Product: C=CCOC(=O)Nc1nccc2cc(OCCC3CCCCN3C(=O)[C@H](CC(C(=O)O)C(C)(C)C)NC3CCCCCCC3)ccc12
Yield: 53.1 %

Procedure:
N-Cyclooctyl-γ-tert-butyl-L-glutamic acid (8a, 344 mg, 1.1 mmol) and 2-(2-(1-allyloxycarbonylamino-isoquinolin-6-oxy)-ethyl)-piperidine (1g, 391 mg, 1.1 mmol) were coupled, using the methodology described in Example 1i, providing 380 mg (58%) of the title compound as a colourless oil. ESI-MS: 651.3 (M+H)+. Rf (silica gel; dichloromethane/methanol, 9:1, v/v): 0.23.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12](=[O:14])[CH3:13])=[CH:6][CH:5]=1.C([O-])([O-])=O.[K+].[K+].[F:23][C:24]([F:34])([F:33])[C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1>CCO.O>[F:23][C:24]([F:33])([F:34])[C:25]1[CH:26]=[CH:27][C:28](/[CH:29]=[CH:13]/[C:12](=[O:14])/[CH:11]=[CH:10]/[C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:15])([F:16])[F:1])=[CH:9][CH:8]=2)=[CH:31][CH:32]=1
Reactant: CC(=O)/C=C/c1ccc(OC(F)(F)F)cc1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C(/C=C/c1ccc(OC(F)(F)F)cc1)/C=C/c1ccc(C(F)(F)F)cc1
Reaction time: 1 h
Yield: 32.3 %

Procedure:
A solution of (E)-4-(4-(trifluoromethoxy)-phenyl)-but-3-en-2-one (623 mg, 2.7 mmol) in EtOH (10 mL) was stirred for 5 min at 0° C. A solution of K2CO3 (748 mg, 5.4 mmol) in H2O (4 mL) was added and the reaction mixture was stirred for further 1 h. After the dropwise addition of 4-(trifluoromethyl)-benzaldehyde (392 μl, 2.9 mmol), the mixture was continued to stir for 4 h at 0° C. and for 2 h at ambient temperature. The resulting yellow precipitate was filtered and dried in vacuo to obtain NW337 as a pale yellow solid (337 mg, 34%). mp: 97-99° C. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.76 (d, 3J=16.1 Hz, 1H, Hvin), 7.75 (d, 3J=15.7 Hz, 1H, Hvin), 7.74 (d, 3J=8.8 Hz, 2H, HAr), 7.69 (d, 3J=8.1 Hz, 2H, HAr), 7.67 (d, 3J=8.7 Hz, 2H, HAr), 7.29 (d, 3J=8.0 Hz, 2H, HAr), 7.15 (d, 3J=16.0 Hz, 1H, Hvin), 7.07 (d, 3J=16.0 Hz, 1H, Hvin). 13C NMR (75 MHz, CDCl3) δ (ppm): 188.2 (C), 150.7 (C), 142.1 (CH), 141.6 (CH), 138.1 (q, 4J(C, F)=1.3 Hz, CH), 133.2 (C), 132.0 (q, 2J(C, F)=32.7 Hz, C), 129.9 (CH), 128.5 (CH), 127.3 (CH), 126.0 (q, 3J(C, F)=3.8 Hz, CH), 125.9 (CH), 122.1 (C), 122.0 (C), 121.2 (CH), 118.7 (C). MS (FAB) m/z: 387.1 (M+). Anal. calcd for C19H12F6O2.0.5H2O: C, 57.73; H, 3.31. Found: C, 57.75; H, 3.20%.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2.[CH2:14](Br)[CH:15]=[CH2:16]>CN(C)C=O>[CH2:16]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)[CH:15]=[CH2:14]
Reactant: Oc1ccc2ncccc2c1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc2ncccc2c1
Reaction time: 1 h
Yield: 89.2 %

Procedure:
To a suspension of sodium hydride (60%, 0.33 g, 8.3 mmol) in anhydrous N,N-dimethylformamide (30 ml) was added 6-hydroxyquinoline (1.0 g, 6.9 mmol) at room temperature. The reaction mixture was stirred for 1 hour, then allyl bromide (0.72 ml, 8.3 mmol) was added. The reaction mixture was allowed to stir for 1 hour at room temperature, quenched with water and extracted with methylene chloride. The organic layer was washed with water, dried over anhydrous sodium sulfate and filtered. The solvent was removed under vacuum. Chromatography (50% hexanes-ethyl acetate) afforded 1.14 g (89%) of 6-allyloxyquinoline as brown oil. MS ESI m/z 185 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH2:11][C:12]#[N:13])[CH:5]=1)#[N:2].Cl.N[C:16]1[C:21]([F:22])=[C:20]([F:23])[CH:19]=[CH:18][C:17]=1[SH:24]>>[F:22][C:21]1[C:16]2[N:13]=[C:12]([CH2:11][C:6]3[CH:5]=[C:4]([CH2:3][C:1]#[N:2])[CH:9]=[C:8]([CH3:10])[CH:7]=3)[S:24][C:17]=2[CH:18]=[CH:19][C:20]=1[F:23]
Reactant: Nc1c(S)ccc(F)c1F
Reactant: Cc1cc(CC#N)cc(CC#N)c1
Agent: Cl
Product: Cc1cc(CC#N)cc(Cc2nc3c(F)c(F)ccc3s2)c1
Yield: 16.7 %

Procedure:
The procedure of Example 22-i) was repeated using 1,3-biscyanomethyl-5-methylbenzene (680 mg, 4 mmol) and 2-amino-3,4-difluorothiophenol hydrochloride (888 mg, 4.5 mmol) and the resultant product was recrystallized from ethyl acetate-hexane to give 3-[(4,5-difluorobenzothiazol-2-yl)methyl]-5-methylphenylacetonitrile (210 mg, 17%) as a colorless powder.
Reaction SMILES: [CH:1]1([CH2:5]O)[CH2:4][CH2:3][CH2:2]1.[CH2:7]([O:9][C:10]([CH:12]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:11])[CH3:8].N1C=CC=CC=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH:1]1([CH:5]=[CH:12][C:10]([O:9][CH2:7][CH3:8])=[O:11])[CH2:2][CH2:3][CH2:4]1
Reactant: OCC1CCC1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C=CC1CCC1
Temperature: 70 °C
Reaction time: 20 h
Yield: 24.4 %

Procedure:
A mixture of cyclobutyl-methanol (8.00 g, 93.02 mmol), ethoxycarbonylmethylene triphenylphosphorane (19.42 g, 55.81 mmol) and pyridine (3 mL) were dissolved in dry chloroform (100 mL) and heated at 70° C. Manganese dioxide (97.11 g, 1.12 mol) was added portion wise over a period of 5 h (with 1 h gap between each addition) and refluxing was continued for 20 h. The reaction mixture was cooled to room temperature, filtered over celite and washed with chloroform. The filtrate was concentrated and the residue subjected to column chromatography over silica gel (60-120 mesh) using 0% to 15% of ethyl acetate in pet ether as eluent to afford ethyl 3-cyclobutylprop-2-enoate (2.10 g, 15%) as a liquid.
Reaction SMILES: [S:1]1[C:5]2[NH:6][CH:7]=[CH:8][C:9](=[O:10])[C:4]=2[CH:3]=[CH:2]1.[N+:11]([O-])([OH:13])=[O:12]>C(O)(=O)CC>[N+:11]([C:8]1[C:9](=[O:10])[C:4]2[CH:3]=[CH:2][S:1][C:5]=2[NH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: O=c1cc[nH]c2sccc12
Reactant: O=[N+]([O-])O
Solvent: CCC(=O)O
Product: O=c1c([N+](=O)[O-])c[nH]c2sccc12
Temperature: 130 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a solution of 3.4 g of thieno[2,3-b]pyridin-4(7H)-one 5 in 105 ml of propionic acid is added 2.79 g of concentrated nitric acid (d=1.38) at 100° C., and then the mixture is stirred at 130° C. (bath temperature) for 1 hour. After cooling the reaction mixture, the resulting precipitate is collected by filtration and washed successively with water, methanol and acetone to afford 3.4 g (77%) of Compound 6 as pale yellow crytals melting at 288°-291° C.
Reaction SMILES: Br[CH:2]([C:4]1[O:5][C:6](=[O:20])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3].[NH:21]1[C:25]2=[N:26][CH:27]=[N:28][C:29]([NH2:30])=[C:24]2[CH:23]=[N:22]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:30][C:29]1[N:28]=[CH:27][N:26]=[C:25]2[N:21]([CH:2]([C:4]3[O:5][C:6](=[O:20])[C:7]4[C:12]([C:13]=3[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH3:3])[N:22]=[CH:23][C:24]=12
Reactant: CC(Br)c1oc(=O)c2ccccc2c1-c1ccccc1
Reactant: Nc1ncnc2[nH]ncc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1ncc2c(N)ncnc21
Yield: 34.3 %

Procedure:
The title compound was made in a similar way as that of the compound of example 15, 3-(1-bromoethyl)-4-phenyl-1H-isochromen-1-one (intermediate C7, 70 mg, 0.213 mmol), 1H-pyrazolo[3,4-d]pyrimidin-4-amine (40.2 mg, 0.298 mmol) and K2CO3 (41.1 mg, 0.298 mmol) in DMF (1 ml) at 80° C. for 4 hrs to give the title compound (28 mg, 34%).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:29])[CH2:14][CH2:15][C@@H:16]3[C@@:21]4([CH3:27])[CH2:22][CH2:23][C@@H:24]([OH:26])[CH2:25][C@H:20]4[CH2:19][C@@H:18]([OH:28])[C@H:17]3[C@@H:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.CN(C1C=CC=CN=1)C.CS(Cl)(=O)=[O:47]>ClCCl>[CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:29])[C@@H:14]([OH:47])[CH2:15][C@@H:16]3[C@@:21]4([CH3:27])[CH2:22][CH2:23][C@@H:24]([OH:26])[CH2:25][C@H:20]4[CH2:19][C@@H:18]([OH:28])[C@H:17]3[C@@H:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Temperature: 0 °C

Procedure:
Methyl chenodeoxycholate (27 g, 61.5 mmol) is dissolved in 100 mL dichloromethane (DCM), pyridine (20 mL). Dimethylaminopyridine (DMAP) (1.22 g, 10 mmol) is then added. The reaction mixture is chilled to 0° C., and methanesul-fonyl chloride (7.5 mL, 11.0 g, 96.7 mmol) is added dropwise. The reaction mixture is heated at 60° C. for 3 h, cooled to r.t., washed with 5% HCl, water, sodium bicarbonate, brine, and dried over sodium sulfate. The solvent is evaporated under reduced pressure (1 mm Hg, 80° C. in a bath) to give mesylate 1 as a thick oil, weight 27 g (90%). This material is used in the next step without further purification.
Reaction SMILES: [O:1]1[C:5]2([CH2:9][CH:8]=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl[N:11]([Na])[S:12]([C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:14])=[O:13].[Br-].[Br-].[Br-].C[N+](C)(C)C1C=CC=CC=1.C[N+](C1C=CC=CC=1)(C)C.C[N+](C1C=CC=CC=1)(C)C>C(#N)C>[CH3:16][C:15]([S:12]([N:11]1[CH:8]2[CH:7]1[CH2:6][C:5]1([CH2:9]2)[O:4][CH2:3][CH2:2][O:1]1)(=[O:14])=[O:13])([CH3:18])[CH3:17]
Reactant: CC(C)(C)S(=O)(=O)N([Na])Cl
Reactant: C1=CCC2(C1)OCCO2
Agent: C[N+](C)(C)c1ccccc1
Agent: [Br-]
Solvent: CC#N
Product: CC(C)(C)S(=O)(=O)N1C2CC3(CC21)OCCO3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1,4-dioxaspiro[4.4]non-7-ene (370 mg, 2.93 mmol) and N-chloro-2-methyl-N-sodiopropane-2-sulfonamide (Intermediate 43; 965 mg, 4.99 mmol) in acetonitrile (16 ml) was added trimethylphenylammonium tribromide (CAS number 4207-56-1; 110 mg, 0.29 mmol) under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 2 hours then heated to 40° C. for 18 hours. The reaction mixture was filtered through a plug of silica, washed with diethyl ether and the filtrate concentrated in vacuo. The crude material was purified column chromatography (silica, 0-50% diethyl ether/petroleum) to afford the title compound.