Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:35][O:36][CH2:37][CH:38]1[N:42]([CH3:43])[CH2:41][CH:40]([NH:44][CH3:45])[CH2:39]1>>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:31])([F:32])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:44]([CH:40]4[CH2:39][CH:38]([CH2:37][O:36][CH3:35])[N:42]([CH3:43])[CH2:41]4)[CH3:45])=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CNC1CC(COC)N(C)C1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: COCC1CC(N(C)C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CN1C

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[(5-methoxymethyl-1-methyl-pyrrolidin-3-yl)-methyl-amino]-thiazol-4-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and (5-Methoxymethyl-1-methyl-pyrrolidin-3-yl)-methyl-amine following General Procedure C.
Reaction SMILES: Cl.[CH3:2][O:3][C@H:4]([CH2:27][CH3:28])[CH2:5][C@H:6]1[CH2:17][CH2:16][C:15]2[S:14][C:13]3[N:12]=[CH:11][N:10]=[C:9]([O:18][CH:19]4[CH2:24][CH2:23][CH:22]([NH:25][CH3:26])[CH2:21][CH2:20]4)[C:8]=3[C:7]1=2.C=O.[BH3-][C:32]#N.[Na+]>CO>[CH3:2][O:3][C@H:4]([CH2:27][CH3:28])[CH2:5][C@H:6]1[CH2:17][CH2:16][C:15]2[S:14][C:13]3[N:12]=[CH:11][N:10]=[C:9]([O:18][CH:19]4[CH2:20][CH2:21][CH:22]([N:25]([CH3:32])[CH3:26])[CH2:23][CH2:24]4)[C:8]=3[C:7]1=2
Reactant: CC[C@H](C[C@H]1CCc2sc3ncnc(OC4CCC(NC)CC4)c3c21)OC
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC[C@H](C[C@H]1CCc2sc3ncnc(OC4CCC(N(C)C)CC4)c3c21)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.3 %

Procedure:
A solution of 4-[[(3R)-3-[(2R)-2-methoxybutyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]-N-methylcyclohexan-1-amine hydrochloride (120 mg, 0.28 mmol, 1.00 equiv) and HCHO (0.8 mL in methanol (6 mL) was stirred at room temperature. The resulting solution was stirred for 0.5 h at room temperature. Then NaBH3CN (97.02 mg, 1.54 mmol, 5.48 equiv) was added. The resulting solution was allowed to react, with stirring, for an additional 2 h at room temperature. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×50 mL of chloroform/iso-propanol (3/1) and the organic layers combined and concentrated under vacuum. The crude product (100 mg) was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-016(Waters)): column: SunFire Prep C18, 19*150 mm 5 um; mobile phase: water with 50 mL HCOOH and CH3CN (5.0% CH3CN up to 45.0% in 11 min, up to 95.0% in 2 min, down to 5.0% in 2 min); Detector, UV 254/220 nm. This resulted in 34.2 mg (30%) of Compound I-117 as a colorless oil. 1H NMR (CD3OD, 300 MHz): δ 8.47 (1H, s), 5.26-5.27 (1H, m), 3.31-3.35 (1H, m), 3.26-3.30 (4H, m), 3.08-3.11 (1H, m), 2.95-3.00 (1H, m), 2.64 (1H, m), 2.20-2.42 (10H, m), 1.97-2.08 (3H, m), 1.47-1.75 (7H, m), 0.96-1.01 (3H, t). MS: m/z 404 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[C:13]([O:17][CH3:18])[CH:12]=[CH:11][C:4]=1[CH2:5][CH2:6][NH:7][C:8](=O)[CH3:9].O=P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH3:9][C:8]1[C:11]2[C:4](=[C:3]([O:2][CH3:1])[C:14]([O:15][CH3:16])=[C:13]([O:17][CH3:18])[CH:12]=2)[CH2:5][CH2:6][N:7]=1
Reactant: COc1ccc(CCNC(C)=O)c(OC)c1OC
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc2c(c(OC)c1OC)CCN=C2C
Yield: 88.9 %

Procedure:
A solution of the acetamide 43 (280 mg, 1.1 mmol) in toluene (5 mL) containing POCl3 (0.8 mL, 8.5 mmol) was heated at reflux under Ar for 2 h. The excess POCl3 and the solvent were evaporated under vacuum. The black residue was washed with petroleum ether (10 mL). The residue was dissolved in distilled water (10 mL) and made basic by 5% NH4OH aq (10 mL). The aqueous solution was extracted with CHCl3 (20, 10, and 5 mL). The combined CHCl3 layer was washed successively with water (10 mL) and saturated NaCl solution (10 mL) and dried over anhydrous Na2SO4. Evaporation of the filtrate and chromatography (ether:ethanol, 98:2 by volume, silica gel 230-400 mesh) gave compound 44 as a pale brown oil (230 mg, 89.2%): 1H NMR (CDCl3, 200 MHz) δ6.84 (s, 1H), 3.92 (s, 3H), 3.89 (s, 3H), 3.85 (s, 3H), 3.61 (t, 2H, J=8 Hz), 2.64 (t, 2H, J=8 Hz), 2.36 (s, 3H). EIMS m/e 235 (M+, 84).
Reaction SMILES: [O:1]=[C:2]1[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]2[CH:13]=[C:14]([O:17][C:18](=[O:22])[C:19](Cl)=[O:20])[CH:15]=[CH:16][C:4]=2[O:3]1.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1[OH:31]>C1(C)C=CC=CC=1>[O:1]=[C:2]1[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]2[CH:13]=[C:14]([O:17][C:18](=[O:22])[C:19]([O:31][C:25]3[C:26]([CH3:30])=[CH:27][CH:28]=[CH:29][C:24]=3[CH3:23])=[O:20])[CH:15]=[CH:16][C:4]=2[O:3]1
Reactant: Cc1cccc(C)c1O
Reactant: O=C(Cl)C(=O)Oc1ccc2c(c1)C(c1ccccc1)C(=O)O2
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1OC(=O)C(=O)Oc1ccc2c(c1)C(c1ccccc1)C(=O)O2
Yield: 38 %

Procedure:
Reaction of chloro-oxo-acetic acid 2-oxo-3-phenyl-2,3-dihydro-benzofuran-5-yl ester prepared as Example 11 reacted in toluene at the reflux with 2,6-dimethylphenol gave after purification oxalic acid (2,6-dimethyl-phenyl) ester (2-oxo-3-phenyl-2,3-dihydro-benzofuran-5-yl) ester (38% yield). Analysis C,70.6; H,4.1; C24H18O6 requires C,71.8; H,4.2%. Mass Spectrometry shows a molecular ion at 402.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH:7]=O)([O-:3])=[O:2].[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:24]=1)=[O:21]>>[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][N:32]([CH2:7][C:6]3[CH:9]=[CH:10][C:11]([N:12]4[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]4)=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[CH2:31][CH2:30]2)[CH:24]=1)=[O:21]
Reactant: O=Cc1ccc(N2CCCCC2)c([N+](=O)[O-])c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(N4CCCCC4)c([N+](=O)[O-])c3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 3-nitro-4-(1-piperidinyl)benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 465.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:22]=[CH:21][C:7]([NH:8][C:9]2[NH:10][C:11](=[O:20])[C:12]([C:15]([O:17]CC)=[O:16])=[CH:13][N:14]=2)=[CH:6][CH:5]=1)[CH3:3].[OH-].[Na+].O>C(O)(=O)C>[CH3:3][N:2]([C:4]1[CH:22]=[CH:21][C:7]([NH:8][C:9]2[NH:10][C:11](=[O:20])[C:12]([C:15]([OH:17])=[O:16])=[CH:13][N:14]=2)=[CH:6][CH:5]=1)[CH3:1]
Reactant: CCOC(=O)c1cnc(Nc2ccc(N(C)C)cc2)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CN(C)c1ccc(Nc2ncc(C(=O)O)c(=O)[nH]2)cc1
Reaction time: 1 h
Yield: 73.5 %

Procedure:
Ethyl 1,6-dihydro-2-[4-(N,N-dimethylamino)anilino]-6-oxo-5-pyrimidinecarboxylate (7.5 g) and sodium hydroxide (3.0 g) are added to water (150 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the reaction mixture is acidified with acetic acid, and the resulting solid is collected by filtration and recrystallized from DMF. The precipitate is collected by filtration and added to water (50 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the resulting product is collected by filtration and dried at 80° C. under reduced pressure to give 1,6-dihydro-2-[4-(N,N-dimethylamino)anilino]-6-oxo-5-pyrimidinecarboxylic acid (5 g). M.p. 261°-263° C.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:11]O)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.C([O-])(O)=O.[Na+].O=S(Cl)[Cl:20]>>[Cl:20][CH2:11][C:3]1[C:2]([F:1])=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc2c(cc1F)OCO2
Agent: O=C([O-])O
Agent: [Na+]
Product: Fc1cc2c(cc1CCl)OCO2
Temperature: 25 °C
Yield: 90 %

Procedure:
(6-Fluoro-benzo[1,3]dioxol-5-yl)-methanol (650 mg, 3.8 mmol) was added to SOCl2 (20 mL) in portions at 0° C. The mixture was warmed to room temperature for 1 h and then heated at reflux for 1 h. The excess SOCl2 was evaporated under reduced pressure to give the crude product, which was basified with sat. NaHCO3 solution to pH˜7. The aqueous phase was extracted with EtOAc (50 mL×3). The combined organic layers were dried over Na2SO4 and evaporated under reduced pressure to give 5-chloromethyl-6-fluoro-benzo[1,3]dioxole (640 mg, 90%), which was directly used in the next step.
Reaction SMILES: [C:1]12([OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([OH:11])([CH2:4]3)[CH2:2]1)[CH2:8]2.[O:13]=O>C(O)(=O)C>[C:5]12([OH:13])[CH2:10][C:1]3([OH:12])[CH2:8][CH:7]([CH2:9][C:3]([OH:11])([CH2:2]3)[CH2:4]1)[CH2:6]2
Reactant: OC12CC3CC(C1)CC(O)(C3)C2
Reactant: O=O
Solvent: CC(=O)O
Product: OC12CC3CC(O)(C1)CC(O)(C3)C2
Yield: 80 %

Procedure:
To 25 ml of acetic acid were added 10 mmol of 1,3-adamantanediol, 1 mmol of NHPI and 0.05 mmol of acetylacetonatovanadium (III) (V(AA)3), and the resultant mixture was stirred in an oxygen atmosphere at a temperature of 75° C. for 6 hours. And, as a result, the 1,3-adamantanediol was converted into a 1,3,5-adamantanetriol (yield: 80%) with a conversion of 99%.
Reaction SMILES: [CH2:1]1[O:12][CH:4]([CH2:5][CH:6]2[CH:10]=[CH:9][CH2:8][C:7]2=[O:11])[S:3][CH2:2]1.CC(O)([C:16]#[N:17])C.C([O-])([O-])=O.[Na+].[Na+]>CO.O>[CH2:1]1[O:12][CH:4]([CH2:5][CH:6]2[CH:10]([C:16]#[N:17])[CH2:9][CH2:8][C:7]2=[O:11])[S:3][CH2:2]1
Reactant: CC(C)(O)C#N
Reactant: O=C1CC=CC1CC1OCCS1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#CC1CCC(=O)C1CC1OCCS1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
18 g of the mixture of (2-oxo-cyclopent-4-enyl)acetaldehyde-ethylenethioacetal and (2-oxo-cyclopent-5-enyl)acetaldehyde-ethylene-thioacetal according to stage 2 were dissolved in 150 ml of methanol and 9.2 g of acetonecyanohydrin and a solution of 7.5 g of Na2CO3 in 20 ml of water were added. After stirring for 3 hours at room temperature, all the solvent was distilled off in vacuo, the residue was taken up in 500 ml of diethyl ether and 100 ml of H2O, and the ether phase was washed twice with 50 ml of H2O, dried over sodium sulfate and condensed. The residue was triturated with a small amount of ether and 12 g of crude product were obtained which melted at about 98° C.
Reaction SMILES: CS(O[CH2:6][CH:7]([N:9]1[C:17]2[C:12](=[C:13]([C:20]([F:23])([F:22])[F:21])[C:14]([C:18]#[N:19])=[CH:15][CH:16]=2)[CH:11]=[C:10]1[CH3:24])[CH3:8])(=O)=O.[CH3:25][S-:26].[Na+]>CN(C=O)C.O>[CH3:24][C:10]1[N:9]([CH:7]([CH3:8])[CH2:6][S:26][CH3:25])[C:17]2[C:12]([CH:11]=1)=[C:13]([C:20]([F:21])([F:23])[F:22])[C:14]([C:18]#[N:19])=[CH:15][CH:16]=2
Reactant: C[S-]
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1C(C)COS(C)(=O)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCC(C)n1c(C)cc2c(C(F)(F)F)c(C#N)ccc21
Reaction time: 1.5 h
Yield: 74.9 %

Procedure:
To a solution of 2-(5-cyano-2-methyl-4-(trifluoromethyl)-1H-indol-1-yl)propyl methanesulfonate (0.145 g, 0.402 mmol) in DMF (3 mL) was added sodium thiomethoxide (0.056 g, 0.805 mmol) in one portion. After 90 min, additional sodium thiomethoxide (2 eq) was added, and the mixture stirred for another 1 h. The reaction mixture was diluted with water (25 mL) and extracted with EtOAc (30 mL). The organic phase was washed with 0.1N HCl (1×20 mL) and brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed over silica gel using a 0-30% EtOAc-hexane gradient to give 2-methyl-1-(1-(methylthio)propan-2-yl)-4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.094 g, 71% yield) as a colorless oil: MS (ESI): m/z 313 (MH+).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3]1.[CH:22]1([CH2:28][CH2:29][C:30](=O)[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH2:34]([O:33][C:31]([C@H:30]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3]1)[CH2:29][CH2:28][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1)=[O:32])[CH3:35]
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CSc2ccccc21
Reactant: CCOC(=O)C(=O)CCC1CCCCC1
Product: CCOC(=O)[C@@H](CCC1CCCCC1)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Yield: 12.2 %

Procedure:
In a manner similar to that described in Example 1, the reaction of 1.5 g of tert-butyl 3(R)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate with 5 g of ethyl 4-cyclohexyl-2-oxobutyrate obtained in Reference Example 5 is carried out, and the product is purified by silica gel column chromatography (hexane:ethyl acetate=4:1). From the first fraction is obtained 0.3 g of tert-butyl 3(R)-[1(R)-ethoxycarbonyl-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as a colorless oil.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[N:10][N:9]3[C:12]([C:15]4[CH:16]=[C:17]([NH:21][C:22]([NH:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[O:23])[CH:18]=[CH:19][CH:20]=4)=[CH:13][N:14]=[C:8]3[CH:7]=2)[CH:3]=[N:2]1.[C:30](#[N:39])[CH:31]=[CH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[C:30]([CH2:31][CH:32]([N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[N:10][N:9]3[C:12]([C:15]4[CH:16]=[C:17]([NH:21][C:22]([NH:24][CH2:25][C:26]([F:28])([F:27])[F:29])=[O:23])[CH:18]=[CH:19][CH:20]=4)=[CH:13][N:14]=[C:8]3[CH:7]=2)[CH:3]=[N:2]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)#[N:39]
Reactant: N#CC=Cc1ccccc1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cn[nH]c4)cnn23)c1
Product: N#CCC(c1ccccc1)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 89, Step 2 starting from N-{3-[7-(1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea and cinnamonitrile. LCMS (M+H)+: m/z=531.2.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH:5]=[CH:6][C:7](=[O:23])[NH:8][CH2:9][C:10]1[CH:19]=[C:18]([Br:20])[CH:17]=[C:16]2[C:11]=1[NH:12][C:13](=[O:22])[C:14](=[O:21])[NH:15]2)C.O.[OH-].[Li+].O>O1CCCC1.O>[Br:20][C:18]1[CH:17]=[C:16]2[C:11]([NH:12][C:13](=[O:22])[C:14](=[O:21])[NH:15]2)=[C:10]([CH2:9][NH:8][C:7]([CH:6]=[CH:5][C:4]([OH:24])=[O:3])=[O:23])[CH:19]=1
Reactant: CCOC(=O)C=CC(=O)NCc1cc(Br)cc2[nH]c(=O)c(=O)[nH]c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C=CC(=O)NCc1cc(Br)cc2[nH]c(=O)c(=O)[nH]c12
Reaction time: 18 h

Procedure:
144 mg (0.36 mmol) of 3-[(7-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethyl)-carbamoyl]-acrylic acid ethyl ester (Example 10) and 76 mg of lithium hydroxide hydrate are dissolved in 18 ml of tetrahydrofuran/water (2:1) and the solution is stirred for 18 hours. 50 ml of water are added, the tetrahydrofuran is concentrated by evaporation and the solution is acidified with 1 N hydrochloric acid. The solid is filtered off, washed with water and dried.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.CCOC(C)=O>CN(C=O)C>[F:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:6]2[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=2[N+:8]([O-:10])=[O:9])=[CH:20][CH:19]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1Oc1ccc(F)cc1
Temperature: 80 °C

Procedure:
To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20 mL) at rt, solid potassium carbonate (30 mmol) was added followed by addition of 4-fluorophenol (10 mmol) to the reaction mixture and heating to 80° C. until the reaction was complete as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was poured into EtOAc (100 mL), washed with H2O (2×50 mL) and brine (50 mL), and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-fluorophenoxy-1-nitrobenzene. The crude product may be used for further transformation.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][C:20]([C:26]#[N:27])=[CH:19]2.[H-].[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:19]2[C:18]3[C:23](=[CH:24][CH:25]=[C:16]([I:15])[CH:17]=3)[N:22]=[CH:21][C:20]=2[C:26]#[N:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1cnc2ccc(I)cc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCC(Oc2c(C#N)cnc3ccc(I)cc23)CC1

Procedure:
Similar procedure as described in example 28a was used, starting from 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester, 6-iodo-quinoline-3-carbonitrile (example 14c) and sodium hydride to give 4-(3-cyano-6-iodo-quinolin-4-yloxy)-piperidine-1-carboxylic acid tert-butyl ester. LC-MS m/e 480 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][CH:25]=[CH:26][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[N+:27]([C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][C:38]=1[N+:39]([O-:41])=[O:40])[C:33](O)=[O:34])([O-:29])=[O:28].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:16][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][C:38]([N+:39]([O-:41])=[O:40])=[C:30]([N+:27]([O-:29])=[O:28])[CH:31]=3)[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][CH:25]=[CH:26][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2OC(=O)c2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.8 %

Procedure:
1.2 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 1.16 g of 3,4-dinitrobenzoic acid and 0.76 g of dicyclohexylcarbodiimide are dissolved in 20 ml of methylene chloride, and the solution is stirred at room temperature overnight. After the reaction, the precipitates are collected by filtration. The filtrate is washed with water, dried and then evaporated to remove solvent. The residue is purified by silica gel chromatography (solvent, chloroform:methanol=100:3), whereby 0.8 g of (+)-cis-2-(4-methoxyphenyl)-3-(3,4-dinitrobenzoyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one is obtained as an oil.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([O:10][CH3:11])=[N:8][C:7]([Br:12])=[CH:6][N:5]=1.[C:13]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:16]=[CH:17][CH:18]=1.Cl>C(COC)OC.O>[Br:12][C:7]1[N:8]=[C:9]([O:10][CH3:11])[C:4]([NH:3][S:19]([C:14]2[C:13]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:21])=[O:20])=[N:5][CH:6]=1
Reactant: COc1nc(Br)cnc1N
Reactant: O=S(=O)(Cl)c1ccccc1-c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1nc(Br)cnc1NS(=O)(=O)c1ccccc1-c1ccccc1
Reaction time: 0.25 h
Yield: 55.3 %

Procedure:
Sodium hydride (60% dispersion in oil; 0.198 g) was suspended in dimethoxyethane (5 ml) and 2-amino-5-bromo-3-methoxypyrazine (0.405 g) was added with stirring. After 15 minutes, 2-biphenylsulphonyl chloride (0.5 g) was added and the mixture was stirred for 18 hours. The reaction mixture was poured into water (20 ml) and acidified to pH2 with concentrated hydrochloric acid and extracted with ethyl acetate (3×25 ml). The combined organic extracts were evaporated and the residue was purified by flash chromatography on silica gel (30 g), eluting with hexane/ethyl acetate/glacial acetic acid (160/40/1 v/v), to give N-(5-bromo-3-methoxy-2-pyrazinyl)-2-biphenylsulphonamide (0.46 g); 1H NMR (d6 -DMSO): 3.82(s,3H), 7.2-7.4(m,6H), 7.53-7.7(m,2H), 7.78(s,1H), 8.08(dd,1H), 10.33(br,1H); mass spectrum (+ve FAB, methanol/NBA): 420(M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[Br:15]Br.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Br:15][CH:9]([C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:14])[C:10]([O:12][CH3:13])=[O:11]
Reactant: BrBr
Reactant: COC(=O)CC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)C(Br)C(=O)c1ccc(F)cc1
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a solution of methyl 3-(4-fluorophenyl)-3-oxopropanoate 76 (1 equiv, 500 mg, 2.55 mmol) in DCM (17 mL) was added a solution of bromine (1.3 equiv, 530 mg, 3.31 mmol) in DCM (1.5 mL) in a drop wise manner at 0° C. The reaction mixture was stirred further for an additional 1 h and then treated with 10% aqueous K2CO3 (5 mL) solution. The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to afford methyl 2-bromo-3-(4-fluorophenyl)-3-oxopropanoate 78 (700 mg, 100% yield). LRMS (ESI): (calc) 273.96 (found) 275.108 (MH+)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[C:14]2[NH:20][C:21]1[C:26]([CH3:27])=[CH:25][N:24]=[CH:23][C:22]=1[CH3:28].[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH3:28][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([CH3:27])[C:21]=1[NH:20][C:14]1[C:13]2[C:18](=[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[C:10]([O:29][CH3:30])=[CH:11][CH:12]=2)[NH:17][C:16](=[O:19])[CH:15]=1
Reactant: COc1ccc2c(Nc3c(C)cncc3C)cc(=O)[nH]c2c1OCCCCCCCl
Reactant: C1CCNC1
Product: COc1ccc2c(Nc3c(C)cncc3C)cc(=O)[nH]c2c1OCCCCCCN1CCCC1

Procedure:
The title compound was prepared from 8-(6-chlorohexyloxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (Intermediate 6) and pyrrolidine following the procedure outlined in Example 15 (modifications: 40° C., 18 h). 1H NMR (400 MHz, DMSO-d6; HCl salt): δ 10.51 (br, 1H), 9.73 (s, 1H), 8.58 (s, 1H), 8.44 (s, 2H), 7.92 (d, 1H), 7.03 (d, 1H), 4.63 (s, 1H), 3.97 (t, 2H), 3.90 (s, 3H), 3.46 (m, 2H), 3.06 (m, 2H), 2.93 (m, 2H), 2.15 (s, 6H), 1.95 (m, 2H), 1.84 (m, 2H), 1.76 (m, 2H), 1.67 (m, 2H), 1.43 (m, 2H), 1.35 (m, 2H); MS (ESI): 465.4.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[N:3]=1.[CH3:9][NH2:10]>C(O)C>[CH3:9][NH:10][C:4]1[N:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=1
Reactant: CN
Reactant: Brc1cccc(Br)n1
Solvent: CCO
Product: CNc1cccc(Br)n1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
30 g (0.13 mol) of 2,6-dibromopyridine are added to a solution of 225 ml (2.39 mol) of methylamine in ethanol (33% by weight, Aldrich) precooled to 0° C. The reaction is heated at 80° C. with stirring for 20 hours, in a glass system equipped with a manometer. The reaction is monitored by TLC control. The reaction medium is cooled to 0° C. and the assembly is opened. The slightly brown solution thus obtained is concentrated under vacuum to a volume of 60 ml, and water (240 ml) is then added, followed by addition of aqueous sodium carbonate solution (2N, 240 ml). The beige-coloured precipitate formed is filtered off, washed with water and dissolved in dichloromethane (200 ml). The solution is dried over magnesium sulfate and the solvent is evaporated off. The addition of heptane allows the precipitation of 17.5 g (74%) of 6-methylamino-2-bromopyridine in the form of a beige-coloured powder.