Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12]/[C:11](=[C:19]3/[C:20]([CH2:25][CH2:26][CH3:27])=[N:21][NH:22][C:23]/3=[O:24])/[CH:10]=2)=[CH:4][CH:3]=1.[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33](Cl)=[O:34]>C1COCC1>[O:24]=[C:23]1[NH:22][N:21]=[C:20]([CH2:25][CH2:26][CH3:27])/[C:19]/1=[C:11]1/[NH:12][C:13]2[C:18]([C:9]([S:8][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:33]([C:29]4[O:28][CH:32]=[CH:31][CH:30]=4)=[O:34])=[CH:7][CH:6]=3)=[CH:10]/1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(N)cc2)c2ccccc2N1
Reactant: O=C(Cl)c1ccco1
Solvent: C1CCOC1
Product: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(NC(=O)c3ccco3)cc2)c2ccccc2N1

Procedure:
The title compound was synthesized using (Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one and 2-furoyl chloride in THF according to the procedure described in the synthesis of Example 26. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.68 (t, J=7.33 Hz, 3H) 1.25-1.36 (m, J=7.39, 7.39, 7.39, 7.39 Hz, 2H) 2.25 (t, J=6.69 Hz, 2H) 6.73-6.83 (m, 2H) 7.41 (d, J=3.28 Hz, 1H) 7.63 (t, J=7.58 Hz, 1H) 7.74 (d, J=8.59 Hz, 2H) 7.83-7.95 (m, 2H) 8.00 (s, 1H) 8.08 (d, J=8.59 Hz, 2H) 8.15 (d, J=8.08 Hz, 1H) 10.55 (s, 1H); ESI-MS: m/z calc'd for C26H22N4O3S 470.54. found 471.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][CH2:13]/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:22]([NH2:25])[CH:23]=[CH2:24].C(=O)([O-])O.[Na+]>>[CH2:22]([NH:25][C:2]1[N:3]=[C:4]([NH:12][CH2:13]/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1)[CH:23]=[CH2:24]
Reactant: Cc1csc2c(NC/C=C/c3ccccc3)nc(Cl)nc12
Reactant: C=CCN
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NC/C=C/c2ccccc2)c2scc(C)c2n1
Yield: 81.4 %

Procedure:
316 mg (1.0 mmol) of 2-chloro-4-(trans-cinnamylamino)-7-methylthieno[3,2-d]pyrimidine and 914 mg (16.0 mmol) of allylamine were heated in a sealed tube at 160° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, followed by adding a saturated aqueous sodium hydrogen carbonate solution thereto and extraction with ethyl acetate (50 ml×2). After the organic layer was washed with brine and dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/4) to give 274 mg (yield: 81.5%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].Cl.[CH:15](N)=N.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][CH:15]=[N:13][S:10](=[O:11])(=[O:12])[C:3]=2[CH:4]=1
Reactant: COc1ccc(N)c(S(N)(=O)=O)c1
Reactant: N=CN
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)S(=O)(=O)N=CN2
Temperature: 80 °C

Procedure:
There is stirred for 1 night at 80° C. a suspension of 3.0 g of 2-amino-5-methoxybenzene-sulphonamide in the presence of 1.31 g of formamidine hydrochloride and 2.27 ml of triethylamine in 50 ml of toluene. The toluene is evaporated off in vacuo. The residue is taken up in water and the precipitate is filtered off.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](N(OC)C)=[O:13])[C:9]([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][O:26][CH3:27])[CH2:20][CH2:19]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:28][Mg]Br>O1CCCC1>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:13])[CH3:28])[C:9]([N:18]2[CH2:19][CH2:20][N:21]([CH2:24][CH2:25][O:26][CH3:27])[CH2:22][CH2:23]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: COCCN1CCN(c2c(C(=O)N(C)OC)cc(Cl)c3cccnc23)CC1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COCCN1CCN(c2c(C(C)=O)cc(Cl)c3cccnc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
To a mixture of 5-chloro-N-methoxy-8-[4-(2-methoxyethyl)piperazin-1-yl]-N-methylquinoline-7-carboxamide (63 mg, 0.16 mmol) in tetrahydrofuran (0.2 mL) was added 1.40 M methylmagnesium bromide in tetrahydrofuran (0.69 mL, 0.96 mmol). The reaction was stirred at room temperature overnight, quenched with saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and then concentrated to dryness under reduced pressure. The resultant residue was purified on silica gel, eluting with 0 to 10% MeOH in dichloromethane, to give the desired product (22 mg, 39%). LCMS calculated for C18H23ClN3O2(M+H)+: m/z=348.1; found: 348.1.
Reaction SMILES: [I-].[CH3:2][N+:3]1[CH:8]=[CH:7][C:6]([C:9]([N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)=[O:10])=[CH:5][CH:4]=1>[Pt]=O.CO>[CH3:2][N:3]1[CH2:4][CH2:5][CH:6]([C:9]([N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)=[O:10])[CH2:7][CH2:8]1
Reactant: C[n+]1ccc(C(=O)N2CCc3ccccc3C2)cc1
Agent: O=[Pt]
Agent: [I-]
Solvent: CO
Product: CN1CCC(C(=O)N2CCc3ccccc3C2)CC1
Reaction time: 12 h

Procedure:
4 g (10.5 mmol) of 1-methyl-4-[(1,2,3,4-tetrahydro-2-isoquinolyl)carbonyl]pyridinium iodide and 0.4 g of platinum oxide are introduced into 250 ml of methanol, and the mixture is subjected to hydrogenation for 12 h under a pressure of approximately 0.41 MPa. The catalyst is filtered off, the solvent evaporated off and the residue neutralized, and an oil is obtained which crystallizes and which is used without further treatment in the following stage.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH3:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([CH:26]=O)[CH:21]=1.O>O1CCCC1>[CH3:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22](/[CH:26]=[CH:9]/[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH:21]=1
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Reactant: Cc1ccnc(C=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccnc(/C=C/C(=O)OC(C)(C)C)c1
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
A solution of tert-butyl diethylphosphonoacetate (6.2 g, 24 mmol) in tetrahydrofuran (20 ml) was added dropwise to a mixture of sodium hydride (60% in oil, 1.1 g, 26 mmol) and tetrahydrofuran (120 ml) at 0° C., and the mixture was stirred at the same temperature for 30 minutes. Successively, a solution of 4-methyl-2-pyridinecarbaldehyde (1.5 g, 12 mmol) in tetrahydrofuran (30 ml) was added dropwise to the mixture at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was combined with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated. The residue was subjected to a silica gel column chromatography. The fractions eluted with ethylacetate-hexane (1:5, v/v) were collected and concentrated to give the titled compound (1.9 g, 70%).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][C:21]2[C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[O:26][C:20]=2[CH2:19]1)([OH:4])=[O:3].[CH2:31](O)[CH3:32]>>[CH2:31]([O:3][C:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][C:21]2[C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[O:26][C:20]=2[CH2:19]1)=[O:4])[CH3:32]
Reactant: CCO
Reactant: O=C(O)c1ccc2[nH]cc(CCCCN3CCc4c(oc5ccccc45)C3)c2c1
Agent: Cl
Product: CCOC(=O)c1ccc2[nH]cc(CCCCN3CCc4c(oc5ccccc45)C3)c2c1
Reaction time: 48 h

Procedure:
HCl is passed for 2 hours into a solution of 3.88 g of 2-[4-(5-carboxy-3-indolyl)butyl]-1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridine in 50 ml of absolute ethanol. The mixture is then allowed to stand at 20° for 48 hours, the usual working up is carried out, and 2-[4-(5-ethoxycarbonyl-3-indolyl)butyl]-1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridine is obtained.
Reaction SMILES: [CH3:1][CH:2]([O:5][C:6](=[O:24])[C:7]1[CH:12]=[CH:11][C:10]([O:13]C(OCC2C=CC=CC=2)=O)=[CH:9][CH:8]=1)[CH2:3][CH3:4].[H][H]>C(OCC)(=O)C.[C].[Pd]>[CH3:1][CH:2]([O:5][C:6](=[O:24])[C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)[CH2:3][CH3:4]
Reactant: CCC(C)OC(=O)c1ccc(OC(=O)OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC(C)OC(=O)c1ccc(O)cc1
Yield: 92.7 %

Procedure:
A solution of 10 m moles(3.1 g) of the above 4-carbobenzoxyoxybenzoic acid 1-methylpropyl ester and 0.5 g of palladium carbon (5% catalyst) in 40 ml of ethyl acetate was reacted for four hours in an atmosphere of hydrogen gas. After the reaction, palladium carbon was filtered out using a membrane filter, and the filtrate was concentrated, then purified by column chromatography to obtain 1.7 g of 4-hydroxybenzoic acid 1-methylpropyl ester. (yield: 86%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[N:11]=[C:10]([CH2:20][OH:21])[C:9]=2[CH2:22][CH2:23][OH:24])=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[N:11]=[C:10]3[C:20](=[O:21])[O:24][CH2:23][CH2:22][C:9]=23)=[CH:4][CH:3]=1
Reactant: COc1ccc2nc(CO)c(CCO)c(-c3ccc(F)cc3)c2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: COc1ccc2nc3c(c(-c4ccc(F)cc4)c2c1)CCOC3=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of a crude crystal (1.0 g) of 2-[4-(4-fluorophenyl)-2-hydroxymethyl-6-methoxyquinolin-3-yl]-1-ethanol in chloroform (100 ml), manganese dioxide (10 g) was added, followed by stirring at room temperature for 2 hours. After the manganese dioxide was filtered off, the reaction mixture was concentrated under reduced pressure; the residue obtained was recrystallized from THF to yield the title compound (335 mg).
Reaction SMILES: [OH-].[Na+].O1CCCC1.C[O:9][C:10]([C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]#[N:23])[CH:20]=2)[N:15]=[C:14]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:13]=1)=[O:11].Cl>ClCCl>[C:22]([C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:13]=[C:12]2[C:10]([OH:11])=[O:9])#[N:23]
Reactant: COC(=O)c1cc(-c2ccccc2)nc2ccc(C#N)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: N#Cc1ccc2nc(-c3ccccc3)cc(C(=O)O)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
An aqueous sodium hydroxide solution was added to a tetrahydrofuran (20.0 mL) solution of 6-cyano-2-phenyl-4-quinolinecarboxylic acid methyl ester (0.6354 g, 2.20 mmol) obtained above, and the mixture was stirred at room temperature for 3 hours. To the reaction solution, dichloromethane was added. The mixture was neutralized with 1 N hydrochloric acid, and then washed with water and saturated saline, and dried over anhydrous sodium sulfate. After that, the solvent was distilled off. The obtained residue was purified by silica gel column chromatography to obtain the title compound (0.5852 g, 2.13 mmol) as a pale yellow powder.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:15]([NH:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=1.[H][H].[ClH:36]>CO>[NH2:1][C@H:2]([C:15]([NH:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=1.[ClH:36]
Reactant: CCOC(=O)CNC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: Cl
Solvent: CO
Product: CCOC(=O)CNC(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1

Procedure:
19.78 g (43 mmoles) of Z-Tyr(But)-Gly-OEt are dissolved in 200 ml of methanol. A Pd-on-charcoal catalyst is added to this solution and hydrogen is passed through the solution while stirring and adding approx. 2N methanolic HCL at pH 4.5 (autotitrator), until no further methanolic HCl is taken up. The catalyst is then filtered off and the filtrate is concentrated. The residue is stirred with ether and suction-drained. Yield 14.87 g (93.7%), melting point 140°-142°, [α]D22 =+30.9° (c=1, methanol).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Br.Br.[CH2:23]([N:25]1[CH2:32][C:31]2[CH2:30][NH:29][CH2:28][C:27]=2[CH2:26]1)[CH3:24].N12CCCN=C1CCCCC2>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:29]4[CH2:30][C:31]5[CH2:32][N:25]([CH2:23][CH3:24])[CH2:26][C:27]=5[CH2:28]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCN1CC2=C(CNC2)C1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCN1CC2=C(C1)CN(c1c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)C2
Yield: 73.5 %

Procedure:
1-Cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.48 g), N-ethyl-3,7-diazabicyclo [3.3.0] oct-1(5)-ene dihydrobromide (0.57 g) and 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU, 0.87 ml) were dissolved in acetonitrile (20 ml) and refluxed for 3 hours. After cooling the reaction mixture, the produced precipitate was collected by filteration and washed with acetonitrile (10 ml) and methanol (10 ml) to give the title compound (0.5 g, yield 73%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH:12][C:13]1[CH:14]=[C:15]([CH:28]=[CH:29][CH:30]=1)[C:16]([NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)=[O:17])(=[O:11])=[O:10].CO[C:33]1C=CC=C[C:34]=1S(Cl)(=O)=O>>[CH2:33]([O:24][C:23](=[O:25])[C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:16](=[O:17])[C:15]2[CH:28]=[CH:29][CH:30]=[C:13]([NH:12][S:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])(=[O:11])=[O:10])[CH:14]=2)=[CH:27][CH:26]=1)[CH3:34]
Reactant: COc1ccccc1S(=O)(=O)Nc1cccc(C(=O)Nc2ccc(C(=O)O)cc2)c1
Reactant: COc1ccccc1S(=O)(=O)Cl
Product: CCOC(=O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3ccccc3OC)c2)cc1

Procedure:
4-[3-(2-Methoxy-benzenesulfonylamino)-benzoylamino]-benzoic acid, MS (ISP): m/e=425.1 (M−H), was prepared in analogy to example 1, steps A to D. Step C was performed using 2-methoxy-benzenesulfonyl chloride and yielded 4-[3-(2-methoxy-benzenesulfonylamino)-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.C[Si]([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])(C)C.[F-].[K+]>CN1CCCC1=O.[Cu](I)I>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: C[Si](C)(C)C(F)(F)C(F)(F)F
Agent: I[Cu]I
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: FC(F)(F)C(F)(F)c1ccc(Br)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
A solution of 4-bromo-iodobenzene (500 mg, 1.77 mmol), trimethylsilylpentafluoroethane (679 mg, 3.53 mmol), copper iodide (672 mg, 3.53 mmol) and potassium fluoride (205 mg, 3.53 mmol) in N-methylpyrolidone (1.0 mL) was heated with stirring at 100° C. for three hours in a sealed reaction vessel. After cooling to room temperature, the reaction mixture was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to give 1-bromo-4-pentafluoroethylbenzene as a colorless liquid (253 mg, 52%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[C:24]4[N:23]=[CH:22]N=CC=4NN=3)=[O:15])=[CH:11][NH:10][N:9]=2)[CH:7]=1.[H-].[Na+].Br[CH:30]([F:36])[C:31]([O:33]CC)=[O:32]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:11]=[N:10][N:9]4[CH:8]=[CH:6][CH:22]=[N:23][C:24]=34)=[O:15])=[CH:11][N:10]([CH:30]([F:36])[C:31]([OH:33])=[O:32])[N:9]=2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1n[nH]cc1NC(=O)c1n[nH]c2cncnc12
Reactant: CCOC(=O)C(F)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1-c1nn(C(F)C(=O)O)cc1NC(=O)c1cnn2cccnc12
Reaction time: 8 h
Yield: 59.8 %

Procedure:
To N-(3-(5-chloro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo pyrimidine-3-carboxamide (37.1 mg, 0.10 mmol) in 1.5 DMF was added sodium hydride (10 mg, 0.40 mmol) and the mixture stirred for 5 min at which time ethyl bromofluoroacetate (37 mg, 0.20 mmol) was added. The mixture was stirred overnight, then purified by reverse phase HPLC and lyophilized to afford 13.3 mg (30%) of 2-(3-(5-chloro-2-methoxyphenyl)-4-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-1H-pyrazol-1-yl)-2-fluoroacetic acid as a colorless solid. LCMS (ESI) m+H=445.1. 1H NMR (400 MHz, DMSO) δ 9.71 (s, 1H), 9.33 (d, J=7.0 Hz, 1H), 8.76-8.71 (m, 1H), 8.66 (d, J=8.3 Hz, 1H), 8.38 (s, 1H), 7.58-7.20 (m, 5H), 5.98 (d, J=56.5 Hz, 1H), 3.84 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[N:8][C:9](=[O:11])O.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[N:14]=1.O>CN(C=O)C>[OH:19][C:15]1[N:14]=[C:13]([NH:12][C:9]([N:8]=[C:3]2[NH:4][C:5](=[O:7])[CH2:6][N:2]2[CH3:1])=[O:11])[CH:18]=[CH:17][CH:16]=1
Reactant: Nc1cccc(O)n1
Reactant: CN1CC(=O)NC1=NC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: CN1CC(=O)NC1=NC(=O)Nc1cccc(O)n1
Temperature: 85 °C
Yield: 29.5 %

Procedure:
A mixture of 3.0 g (12.8 mM) of the phenyl carbamate 8 and 1.5 g (12.8 mM) of 2-amino-6-hydroxypyridine in 25 ml of anhydrous DMF was heated at 85° C. for 5 hrs., cooled, and poured into 100 ml of water. The resulting precipitate was collected, washed successively with water, ethanol, ethyl acetate, and ether. Recrystallization from ethanol gave 1.0 g of the above urea as a yellow solid, m.p. 233°-234° C. (dec.).
Reaction SMILES: [Cl-].[NH4+].[CH3:3][O:4][C:5]1[C:10]([N+:11]([O-])=O)=[CH:9][C:8]([Br:14])=[CH:7][C:6]=1[C:15]([CH3:18])([CH3:17])[CH3:16]>CO.O.[Fe]>[Br:14][C:8]1[CH:7]=[C:6]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:5]([O:4][CH3:3])=[C:10]([CH:9]=1)[NH2:11]
Reactant: COc1c([N+](=O)[O-])cc(Br)cc1C(C)(C)C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COc1c(N)cc(Br)cc1C(C)(C)C
Yield: 90.2 %

Procedure:
Ammonium chloride (38 g) was added to a solution of 4-bromo-2-(tert-butyl)-6-nitrophenyl methyl ether (20.6 g) in methanol-water (140 ml-140 ml) and iron (20 g) was gradually added while heating to reflux. The mixture was heated to reflux for 2 hours and then the reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure, ethyl acetate was added to the residue and the mixture was washed 3 times with brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to yield a crude product of the title compound (16.65 g) as a brown oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:23][CH2:22][C:5]2[N:6]([CH2:14][CH2:15][CH2:16][C:17](OCC)=[O:18])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH2:24]([NH2:26])[CH3:25]>>[CH2:24]([NH:26][C:17](=[O:18])[CH2:16][CH2:15][CH2:14][N:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=2[C:4]2[CH2:3][N:2]([CH3:1])[CH2:23][CH2:22][C:5]1=2)[CH3:25]
Reactant: CCOC(=O)CCCn1c2c(c3cc(C)ccc31)CN(C)CC2
Reactant: CCN
Product: CCNC(=O)CCCn1c2c(c3cc(C)ccc31)CN(C)CC2

Procedure:
Ethyl 4-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)butanoate (80 mg, 0.2 mmol) was stirred with ethylamine (0.8 ml) at 100-120° C. for 3-4 h to obtain 40 mg of N-ethyl-4-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)butanamide after purification on neutral alumina chromatography eluting with methanol-dichloromethane gradient.
Reaction SMILES: Cl[C:2](=[N:14][OH:15])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11]CC)=[O:10])[CH2:5][CH2:4]1.O1CCN([C:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=2)CC1.C(N(CC)CC)C>ClCCl>[O:15]1[C:23]2[CH2:24][CH2:25][CH2:26][CH2:27][C:22]=2[C:2]([C@@H:3]2[CH2:4][CH2:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][CH2:8]2)=[N:14]1
Reactant: C1=C(N2CCOCC2)CCCC1
Reactant: CCOC(=O)[C@H]1CC[C@H](C(Cl)=NO)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)[C@H]1CC[C@@H](c2noc3c2CCCC3)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 31.3 %

Procedure:
To a solution of cis/trans-ethyl 4-(chloro(hydroxyimino)methyl)cyclohexanecarboxylate (1.20 g, 5.13 mmol) and 1-morpholinocyclohexene (1.72 g, 10.3 mmol) in dichloromethane (50 ml) was added triethylamine (0.72 ml, 5.1 mmol) at 0-5° C. The cooling bath was removed 30 minutes after completed addition. After stirring for 4 h the solvent was evaporated. The residue was redissolved in 6 M aqueous hydrochloric acid solution (50 ml), and the mixture was and heated at reflux for 1 h. After cooling to room temperature the reaction mixture was partitioned between crushed ice (100 g) and ethyl acetate (50 ml). The layers were separated. The aqueous layer was extracted with two 50-ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification with n-heptane/ethyl acetate as eluent gave cis-4-(4,5,6,7-tetrahydro-benzo[d]isoxazol-3-yl)-cyclohexanecarboxylic acid (0.40 g, 31%) as white solid (MS m/e: 248 ([M−H]−)) and trans-4-(4,5,6,7-tetrahydro-benzo[d]isoxazol-3-yl)-cyclohexanecarboxylic acid (0.09 g, 7%) as white solid (MS m/e: 248 ([M−H]−)).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:12]=O.[NH2:14][NH:15][C:16]([NH:18][NH2:19])=[O:17]>>[OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:12]=[N:14][NH:15][C:16](=[O:17])[NH:18][N:19]=[CH:12][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[OH:1]
Reactant: NNC(=O)NN
Reactant: O=Cc1c(O)ccc2ccccc12
Product: O=C(NN=Cc1c(O)ccc2ccccc12)NN=Cc1c(O)ccc2ccccc12
Yield: 97 %

Procedure:
Following the general procedure of Example 1, condensation of 2-hydroxy-1-naphthaldehyde and carbohydrazide gave a white solid (97%): mp>285° C. (dec); 1H NMR d 11.90 (br s, 2 H); 11.05 (s, 2 H), 9.23 (s, 2 H), 8.33 (d, 2 H, J=8.4 Hz), 7.88 (d, 2 H, J=9.0 Hz), 7.87 (d, 2 H, J=7.8 Hz), 7.59 (t, 2 H, J=7.6 Hz), 7.38 (t, 2 H, J=7.5 Hz), 7.22 (d, 2 H, J=9.0 Hz); 13C NMR d 156.71, 151.56, 143.24, 131.88, 131.50, 128.72, 127.87, 127.56, 123.35, 121.58, 118.61, 109.40; MS (CI) m/e 399.0 (M +H)+; Anal. (C23H18N4O3 0.3 H2O) C, H, N.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.Br[CH2:18][CH2:19][O:20][C:21]1[CH:34]=[CH:33][C:24]([C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:26])=[C:23]([OH:35])[CH:22]=1>>[S:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:18][CH2:19][O:20][C:21]2[CH:34]=[CH:33][C:24]([C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:26])=[C:23]([OH:35])[CH:22]=2)=[CH:7][CH:6]=1
Reactant: O=C(c1ccccc1)c1ccc(OCCBr)cc1O
Reactant: Oc1ccc(-c2nc3ccccc3s2)cc1
Product: O=C(c1ccccc1)c1ccc(OCCOc2ccc(-c3nc4ccccc4s3)cc2)cc1O

Procedure:
A hot solution of 16 g. of zinc, o-aminophenylmercaptide and 12.5 g. of p-hydroxybenzaldehyde in 1 l. of acetic acid was treated with hydrogen sulfide for two hours, filtered hot, diluted with an equal volume of water and cooled. 2-(p-Hydroxyphenyl)benzothiazole (47% yield, m.p. 227°-229° F.) was obtained. The 2-(p-hydroxyphenyl)benzothiazole was reacted with 4-(2-bromoethoxy)-2-hydroxybenzophenone as in Example 1 to produce 4-{2-[4-(2-benzothiazolyl)phenoxy]ethoxy}-2-hydroxybenzophenone.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12].C([O-])(=O)C.[Na+].[Br:18]Br>C(O)(=O)C>[Br:18][C:8]1[NH:7][C:6]2[C:5](=[O:11])[NH:4][C:3](=[O:12])[N:2]([CH3:1])[C:10]=2[N:9]=1
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cn1c(=O)[nH]c(=O)c2[nH]c(Br)nc21
Temperature: 65 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a stirring suspension of 3-methylxanthine (7.9 g 47.6 mmol) and sodium acetate (7.81 g, 95.2 mmol) in glacial acetic acid (120 ml) was added bromine (9.14 g, 57.1 mmol). The mixture was stirred at 65° C. for 2 hours. After cooling to room temperature the precipitate was filtered, washed with acetic acid (2×15 ml), water (3×50 ml) and dried under vacuum to give 8-bromo-3-methylxanthine (10.5 g, 90% yield) as a beige powder.