Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])=O.[NH2:13][C:14]([NH2:16])=[S:15]>C(O)C>[CH3:12][O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]1[N:13]=[C:14]([NH2:16])[S:15][CH:2]=1
Reactant: NC(N)=S
Reactant: COc1ccccc1C(=O)CBr
Solvent: CCO
Product: COc1ccccc1-c1csc(N)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
2-Bromo-1-(2-methoxy-phenyl)-ethanone (0.6388 g, 2.789 mmol) and thiourea (0.2289 g, 3.007 mmol) were dissolved in a 20 mL of ethanol. The reaction mixture was allowed to stir overnight at room temperature. The ethanol was evaporated to dryness and the crude product was dissolved in a minimum of dichloromethane. The crude product was then extracted twice with 1M sodium hydroxide and once with a saturated aqueous solution of sodium chloride. The organic layer was then dried over sodium sulfate, filtered, and evaporated to dryness to yield the pure product (0.529 g, 2.56 mmol, 92.0%). ESI-MS m/z calc. 206.3, found 207.1 (M+1)+ Retention time 1.86 minutes. 1H NMR (400 MHz, CD3CN) δ 3.91 (s, 3H), 5.54 (s, 2H), 6.97-7.02 (m, 1H), 7.03-7.06 (m, 1H), 7.23 (s, 1H), 7.24-7.29 (m, 1H), 8.06 (dd, J=7.8, 1.8 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.P([O-])(O)(O)=[O:25].[Na+].CC(=CC)C.Cl([O-])=O.[Na+].Cl>O1CCCC1.C(O)(C)(C)C.O>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:21]=[CH:20][C:17]([C:18]([OH:25])=[O:19])=[CH:16][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(-c2noc(-c3ccc(C(F)(F)F)cc3)n2)cc1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2noc(-c3ccc(C(F)(F)F)cc3)n2)cc1
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a mixture of 4-[5-(4-trifluoromethylphenyl)-1,2,4-oxadiazol-3-yl]benzaldehyde (1.30 g), sodium dihydrogen phosphate (0.51 g), 2-methyl-2-butene (1.3 ml), water (15 ml), t-butanol (15 ml) and tetrahydrofuran (30 ml) was slowly added sodium chlorite (0.75 g) at 0° C., and the mixture was stirred for 2 hrs. To the reaction mixture was added conc. hydrochloric acid (3 ml), and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained colorless crystals were recrystallized from tetrahydrofuran-hexane to give 4-[5-(4-trifluoromethylphenyl)-1,2,4-oxadiazol-3-yl]benzoic acid (1.21 g, yield 89%). melting point: 286–287° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9]2[N:17]=[CH:18][CH:19]=[CH:20][C:8]=2[N:7]=1.[H-].[Na+].[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27]Cl>>[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27][N:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[N:7][C:8]2[CH:20]=[CH:19][CH:18]=[N:17][C:9]1=2
Reactant: CN(C)CCCCl
Reactant: c1csc(C2=Nc3cccnc3Nc3ccccc32)c1
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCCN1c2ccccc2C(c2cccs2)=Nc2cccnc21

Procedure:
Following the procedure of Example 23, 6-(2-thienyl)-11H-pyrido[2,3-b][1,4]benzodiazepine is reacted with sodium hydride followed by reaction with 3-dimethylaminopropyl chloride to give the title compound.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:12])([C:10]#[CH:11])[CH3:9])[CH:5]=[CH:4][CH:3]=1.[N:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N+:14]=[N-:15].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CC(O)(C)C.O.C([O-])(O)=O.[Na+]>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][N:13]1[CH:11]=[C:10]([C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=2)([OH:12])[CH3:9])[N:15]=[N:14]1)[CH3:21]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: C#CC(C)(O)c1cccc(Br)n1
Agent: O=C([O-])O
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)Cn1cc(C(C)(O)c2cccc(Br)n2)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(6-Bromopyridin-2-yl)but-3-yn-2-ol (300 mg, 1.33 mmol) and ethyl azidoacetate (0.82 mL, 1.46 mmol) were combined in t-BuOH (3.0 mL) and water (1.0 mL). CuSO4.5H2O (17 mg, 0.066 mmol) in water (1.0 mL) was added, followed by sodium ascorbate (53 mg, 0.27 mmol) in water (1.0 mL). The reaction was stirred at room temperature overnight, diluted with saturated NaHCO3, and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated. Purification by flash chromatography (10-100% EtOAc/hexanes) afforded the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([F:12])[CH:6]=1.C([BH3-])#N.[Na+]>>[F:12][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[CH3:11])[CH2:4][NH:3][O:2][CH3:1]
Reactant: CON=Cc1ccc(C)c(F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CONCc1ccc(C)c(F)c1

Procedure:
Reduction of 3-fluoro-4-methyl-benzaldehyde O-methyloxime with sodium cyanoborohydride as described in the preparation of compound 3-B gave the title hydroxylamine as a clear oil after chromatography on silica gel (elution hexane-ethyl acetate 8:2) (57% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 2.25 (3H, broad s, CH3), 3.50 (3H, s, OCH3), 3.99 (2H, broad s, NCH2), 5.71 (1H, broad, NH), 7.01 (2H, m, aromatics), 7.13 (1H, m, aromatic). The hydrochloride salt was obtained as a white solid: mp 140-142° C. Anal. calcd for C9H12FNO—HCl: C, 52.56; H, 6.37; N, 6.81. Found: C, 52.63; H, 6.30; N, 6.78.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:19][CH:20]([CH3:22])[CH3:21])[S:9]([C:12]2[CH:13]=[N:14][C:15](Cl)=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C(#N)C.CCOC(C)=O>[C:33]([O:32][C:30]([N:27]1[CH2:28][CH2:29][CH:24]([NH:23][C:15]2[CH:16]=[CH:17][C:12]([S:9](=[O:11])(=[O:10])[N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:13][N:14]=2)[CH2:25][CH2:26]1)=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CC(C)CN(c1ccc(F)cc1)S(=O)(=O)c1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)CN(c1ccc(F)cc1)S(=O)(=O)c1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: 160 °C
Yield: 31 %

Procedure:
To a solution of 6-chloro-pyridine-3-sulfonic acid (4-fluoro-phenyl)-isobutyl-amide (150 mg, 439 μmol) and 4-amino-1-boc piperidine (114 mg, 570 μmol) in acetonitrile (3 mL) was added DIPEA (115 μl, 658 μmol) and the reaction was heated at 160° C. in a microwave reactor for 2.5 hours. EtOAc and saturated aqueous NaHCO3 were added, extracted, washed with brine, dried with Na2SO4 then concentrated and purified by silica gel column chromatography (0-50% EtOAc in cyclohexane) to give 4-{5-[(4-fluoro-phenyl)-isobutyl-sulfamoyl]-pyridin-2-ylamino}-piperidine-1-carboxylic acid tert-butyl ester (69 mg, 31%). LCMS (m/z, Method A) ES− 506 [M−1]−.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]([CH:45]([CH3:47])[CH3:46])[CH:43]=[N:42][CH:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.CSC.O>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]([CH:45]([CH3:47])[CH3:46])[CH:43]=[N:42][CH:41]=5)=[O:57])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cncn4C(C)C)cc2)CCN3CC(C)C)cc1
Solvent: O
Solvent: ClCCl
Solvent: CSC
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4C(C)C)cc2)CCN3CC(C)C)cc1
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[1-isopropylimidazol-5-yl]methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (1.0 g) in dichloromethane (15 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (388 mg) in dichloromethane (15 ml) at −78° C. Dimethylsulfide (0.1 ml) was added to the mixture, and the mixture was allowed to be at room temperature, and stirred for 30 minutes. To the mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by basic silica gel column chromatography (ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[1-isopropylimidazol-5-yl]methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (634 mg) (Compound 384) as yellow amorphous.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[C:13]([F:15])([F:14])[C:12]([CH3:17])([CH3:16])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[F:21][C:22]([F:35])([F:34])[CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([C:31](O)=[O:32])=[N:29][CH:30]=1>>[NH2:18][C:10]1[O:11][C:12]([CH3:16])([CH3:17])[C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:31]([C:28]3[CH:27]=[CH:26][C:25]([O:24][CH2:23][C:22]([F:35])([F:34])[F:21])=[CH:30][N:29]=3)=[O:32])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: CC1(C)OC(N)=N[C@](C)(c2cc(N)ccc2F)C1(F)F
Reactant: O=C(O)c1ccc(OCC(F)(F)F)cn1
Product: CC1(C)OC(N)=N[C@](C)(c2cc(NC(=O)c3ccc(OCC(F)(F)F)cn3)ccc2F)C1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-2) and 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid following procedure I yielded the title compound as a white foam. MS (ISP): m/z=491.2 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][N:36]1[C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42]>CN(C=O)C>[NH2:24][C:15]1[N:14]=[C:13]([O:12][CH2:8][CH2:9][CH2:10][CH3:11])[N:21]=[C:20]2[C:16]=1[N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][N:36]1[C:41]([O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:42]
Reactant: O=C(OCc1ccccc1)N1CCCCC1CCCBr
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3C(=O)OCc3ccccc3)c2n1
Reaction time: 8 h
Yield: 44.7 %

Procedure:
2-(Butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetate (1.834 g, 5.22 mmol) was heated at 60° C. with potassium carbonate (2.89 g, 20.88 mmol) in DMF (23 ml) for 1 hour. Phenylmethyl 2-(3-bromopropyl)-1-piperidinecarboxylate (2.131 g, 6.26 mmol) was added and heating continued at 50° C. overnight (20 hours). The reaction mixture was partitioned between water (250 mL) and ethyl acetate (150 mL). The aqueous was further extracted with ethyl acetate (100 ml). The combined organic layers were washed with brine (100 ml) and passed through a hydrophobic frit to dry, then stripped to dryness (rotary evaporator) to give an orange liquid. The material was loaded onto 2×70 g aminopropyl cartridge and eluted on the Flashmaster system in gradient of 0-100% ethylacetate in cyclohexane over 40 mins. Appropriate product fractions were combined and evaporated in vacuo to give the title compound as a clear oil (1.16 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][S:14]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH3:26])[CH2:21][CH2:20]3)(=[O:16])=[O:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1COCC1>[CH3:26][N:22]1[C:23]2[C:19](=[CH:18][C:17]([S:14]([NH:13][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)(=[O:16])=[O:15])=[CH:25][CH:24]=2)[CH:20]=[CH:21]1
Reactant: COc1cc(NS(=O)(=O)c2ccc3c(c2)CCN3C)cc(OC)c1OC
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Product: COc1cc(NS(=O)(=O)c2ccc3c(ccn3C)c2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.5 %

Procedure:
A 0° C. slurry of N-(3,4,5-trimethoxyphenyl)-1-methylindoline-5-sulfonamide (11.3 g, 0.030 mol) in THF (130 mL) was treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (7.15 g, 0.0315 mol), stirred for 4 hours, warmed to 25° C., and stirred for 10 hours. The mixture was concentrated to half of its original volume, diluted with methyl tert-butyl ether (70 mL), cooled to 0° C., stirred for 2 hours, and filtered. The resulting solid was washed with methyl tert-butyl ether (50 mL), dried, and recrystallized from acetonitrile and methyl tert-butyl ether to provide 9.2 g of the desired product (81%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([NH:18][C:19]([C:21]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[O:25][C:24]3[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=3[CH:22]=2)=[O:20])[CH:11]2[CH2:15][CH:14]([CH3:16])[C:13](=[O:17])[O:12]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:36]([NH2:40])[CH2:37][CH2:38][CH3:39]>>[CH2:36]([NH:40][C:13]([CH:14]([CH3:16])[CH2:15][CH:11]([OH:12])[CH:10]([NH:18][C:19]([C:21]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[O:25][C:24]2[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=2[CH:22]=1)=[O:20])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1)=[O:17])[CH2:37][CH2:38][CH3:39]
Reactant: CC1CC(C(Cc2cc(F)cc(F)c2)NC(=O)C2=Cc3ccccc3Oc3ccccc32)OC1=O
Reactant: CCCCN
Product: CCCCNC(=O)C(C)CC(O)C(Cc1cc(F)cc(F)c1)NC(=O)C1=Cc2ccccc2Oc2ccccc21
Reaction time: 16 h

Procedure:
Dibenzo[b,f]oxepine-10-carboxylic acid [2-(3,5-difluoro-phenyl)-1-(4-methyl-5-oxo-tetrahydrofuran-2-yl)-ethyl]-amide (50 mg, 0.105 mmol) is dissolved in 2 ml butylamine and stirred for 16 h. The solution is concentrated in vacuo and the residual solid recrystallized from EtOAc/hexane. Yield 27 mg (48%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH:11]([CH:20]([C:25]([O:27][CH3:28])=[O:26])[C:21]([O:23][CH3:24])=[O:22])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)([O-:3])=[O:2].[H-].[Na+].I[CH3:32].Cl>CN(C)C=O.C(OCC)(=O)C>[CH3:32][C:20]([CH:11]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])([C:25]([O:27][CH3:28])=[O:26])[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)C(C(=O)OC)C(Cc1ccccc1[N+](=O)[O-])c1ccc(OC)cc1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C(=O)OC)C(Cc1ccccc1[N+](=O)[O-])c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of [2-(2-nitrophenyl)-1-(4-methoxyphenyl)ethyl]propanedioic acid, dimethyl ester (4.0 g, 10.33 mmol) in 19 ml of dimethylformamide (0° C., argon) was added sodium hydride dispersion (0.5 g, 12.40 mmol). Stirring at 0° C. was continued for 5 minutes. Iodomethane was added (3.21 ml, 51.63 mmol) and the reaction was carried out at room temperature for 2 hours, 15 minutes. Ethyl acetate and 1M hydrochloric acid were added, the aqueous layer was washed with ethyl acetate, the combined ethyl acetate layers were washed with 1M hydrochloric acid (two times), saturated aqueous potassium carbonate solution, brine, dried over magnesium sulfate and evaporated in vacuo to yield 4.61 g of a viscous yellow oil. The oil was washed with several portions of hexane. Recrystallization of the residue (3.88 g of a sticky yellow solid) from methanol two times, (1 crop each) yielded 2.69 g of a white crystalline solid, melting point 82°-84° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([O:20][CH3:21])=[CH:8][C:9]2[O:14][C:13](=[O:15])[C:12]3[CH2:16][CH2:17][CH2:18][C:11]=3[C:10]=2[CH:19]=1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(O)C.C([O-])(=O)/C=C/C([O-])=O>O>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[C:7]([O:20][CH3:21])=[CH:8][C:9]3[O:14][C:13](=[O:15])[C:12]4[CH2:16][CH2:17][CH2:18][C:11]=4[C:10]=3[CH:19]=2)[CH2:31][CH2:30]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: COc1cc2oc(=O)c3c(c2cc1OCCCCl)CCC3
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CCO
Solvent: O
Product: COc1cc2oc(=O)c3c(c2cc1OCCCN1CCN(c2ccccc2F)CC1)CCC3
Yield: 59 %

Procedure:
Method B (50 h at 60° C.); starting materials: 8-(3-chloropropoxy)-2,3-dihydro-7-methoxy-cyclopenta[c][1]benzopyran-4(1H)-one (example 83) and 1-(2-fluorophenyl)piperazine; yield 59%; fusion point 148°-150° C. (from ethanol). Fumarate (×H2O): method E; yield 78%; the fusion point being 205°-210° C. (from water).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([OH:28])[C:22]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:28][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:16])[C:22]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CCOC(=O)c1c(C)cccc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1c(C)cccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (112 mg), ethyl 6-methylsalicylate (360 mg), and 4-dimethylaminopyridine (244 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight and was further stirred at 140° C. for 2 hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (168 mg, yield 91%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1)([O-:3])=[O:2].Cl.[CH3:22]O>C(Cl)Cl>[CH3:22][O:19][C:18](=[O:20])[CH2:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:12][CH:13]=1
Reactant: O=C(O)Cc1ccc(Nc2ccccc2[N+](=O)[O-])cc1
Reactant: CO
Agent: Cl
Solvent: ClCCl
Product: COC(=O)Cc1ccc(Nc2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
A mixture of 1.0 g of [4-(2-nitro-phenylamino)-phenyl]-acetic acid and 0.4 ml of HCl conc. in 20 ml of MeOH is stirred and refluxed for 1 hour. The mixture obtained is allowed to cool to rt, and is concentrated in vacuo. The concentrate obtained is diluted with CH2Cl2, the mixture obtained is washed with an aqueous saturated solution of NaHCO3, H2O, and brine, dried (Na2SO4), filtered and concentrated. The concentrate obtained is subjected to silica gel column chromatography. [4-(2-Nitro-phenylamino)-phenyl]-acetic acid methyl ester is obtained in the form of an oil: ES-MS: 287.0 [M+H]+; single peak at tR=5.01 min (System 1); Rf=0.20 (Hexane/EtOAc, 4:1).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].N1C=CN=C1.CN(C=O)C>O>[C:15]([Si:12]([CH3:14])([CH3:13])[O:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:10]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.2 %

Procedure:
A mixture of 4-nitrobenzylalcohol (10.0 g), tert-butyl-dimethylsilyl chloride (11.8 g), imidazole (11.2 g) and DMF (50 ml) was stirred at room temperature for 1.5 hours. To the mixture was added water (500 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane=1/7) to give tert-butyldimethyl-4-nitrobenzyloxysilane (17.5 g) as pale yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][NH2:15])[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:34]=[C:35]([Cl:37])[CH:36]=1)[CH2:20][O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][C:31](O)=[O:32])[CH2:26][CH2:25]1)=[O:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O.C(OCC)(=O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][NH:15][C:31](=[O:32])[CH2:30][CH:27]2[CH2:28][CH2:29][N:24]([C:22]([O:21][CH2:20][C:19]3[CH:18]=[C:17]([Cl:16])[CH:36]=[C:35]([Cl:37])[CH:34]=3)=[O:23])[CH2:25][CH2:26]2)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCc1cn(Cc2ccccc2)nn1
Reactant: O=C(O)CC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(CC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1)NCCc1cn(Cc2ccccc2)nn1

Procedure:
A reaction mixture comprising of 2-(1-benzyl-1H-1,2,3-triazol-4-yl)ethanamine (59.1 mg, 0.292 mmol), 2-(1-(((3,5-dichlorobenzyl)oxy)carbonyl)piperidin-4-yl)acetic acid (101 mg, 0.292 mmol), HATU (222 mg, 0.584 mmol) and TEA (122 μl, 0.877 mmol) in DMF (0.97 ml) was stirred for 3 hours at room temperature. The reaction mixture was diluted with water and ethyl acetate. The organic layer was removed and dried over MgSO4, filtered and concentrated under reduced pressure. Further purification was carried out using preparative LC-MS. The resulting product fractions were concentrated under reduced pressure to give aqueous solutions which were extracted with ethyl acetate. The organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]3[CH:29]=[C:28]([CH3:30])[O:27][N:26]=3)(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[K+].C(O)C.C(O)=O>O>[OH:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]3[CH:29]=[C:28]([CH3:30])[O:27][N:26]=3)(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1cc(C#Cc2ccc(S(=O)(=O)Nc3cc(C)on3)cc2)ccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: O=CO
Product: Cc1cc(NS(=O)(=O)c2ccc(C#Cc3ccc(O)c(C(=O)O)c3)cc2)no1
Reaction time: 0.08 h

Procedure:
Ethyl 2-hydroxy-5-[[4-[(5-methyl-3-isoxazolyl)aminosulfonyl] phenyl]ethynyl]benzoate (1.5 g) was added to a boiling solution of potassium hydroxide (6 g, 92 mmol) in water (100 ml). After 5 min, ethanol (25 ml) was added and the solution acidified with formic acid. The precipitate was collected by filtration, washed with water and dried. Yield 1.4 g, quantitative.