Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.P([O-])([O-])(O)=O.[Na+].[Na+].[C:17]([NH:20][C:21]1[CH:26]=[C:25]([NH2:27])[CH:24]=[CH:23][C:22]=1[N:28]=[N:29][C:30]1[CH:39]=[CH:38][C:37]2[C:36]([S:40]([OH:43])(=[O:42])=[O:41])=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]=1[S:44]([OH:47])(=[O:46])=[O:45])(=[O:19])[CH3:18].[OH-].[Na+]>O>[C:17]([NH:20][C:21]1[CH:26]=[C:25]([NH:27][C:2]2[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([Cl:6])[N:4]=2)[CH:24]=[CH:23][C:22]=1[N:28]=[N:29][C:30]1[CH:39]=[CH:38][C:37]2[C:36]([S:40]([OH:43])(=[O:42])=[O:41])=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]=1[S:44]([OH:47])(=[O:45])=[O:46])(=[O:19])[CH3:18]
Reactant: CC(=O)Nc1cc(N)ccc1N=Nc1ccc2c(S(=O)(=O)O)cccc2c1S(=O)(=O)O
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=P([O-])([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1cc(Nc2nc(Cl)nc(Cl)n2)ccc1N=Nc1ccc2c(S(=O)(=O)O)cccc2c1S(=O)(=O)O

Procedure:
19 parts of cyanuric chloride are stirred vigorously into 50 parts of water, with addition of a wetting agent and 5 parts of disodium hydrogen phosphate, at a temperature of 0° C. A neutral solution of 48 parts of 2-(2-acetylamino-4-aminophenylazo)naphthalene-1,5-disulfonic acid in 450 parts of water is added dropwise, during which the pH is kept at a value of 4.5 by addition of sodium hydroxide solution. A solution of 2-[2-acetylamino-4-(4,6-dichloro-1,3,5-triazin-2-ylamino)phenylazo]-naphthalene-1,5-disulfonic acid is obtained (solution 2).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][C:13]([OH:21])([CH2:14]3)[CH2:12]1)[CH2:18]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([N:26]=[C:27]=[O:28])([CH3:25])([CH3:24])[CH3:23].C[Si](Cl)(C)C>C(Cl)Cl>[C:22]([NH:26][C:27]([O:21][C:13]12[CH2:19][CH:17]3[CH2:16][CH:15]([CH2:20][C:11]([C:9](=[O:10])[NH:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)([CH2:18]3)[CH2:12]1)[CH2:14]2)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: O=C(NCc1ccccc1)C12CC3CC(CC(O)(C3)C1)C2
Reactant: CC(C)(C)N=C=O
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Product: CC(C)(C)NC(=O)OC12CC3CC(C1)CC(C(=O)NCc1ccccc1)(C3)C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a clear solution of 1-benzylcarbamoyladamantane-3-ol (1.00 g: 3.32 mmol) and tert-butylisocyanate (380 μl, 3.32 mmol) in 30 ml of methylene chloride is syringe-added trimethylsilyl chloride (20.0 μl, 0.17 mmol). This reaction is then stirred at room temperature for 18 hours, concentrated (rotovap) and purified on silica gel employing a SIMS/Biotage apparatus and 20% ethyl acetate in hexane as eluent to yield 3-[[(tertbutylamino)carbonyl]oxy]-1-benzylcarbamoyladamantane as a white solid in quantitative yield.
Reaction SMILES: S(=O)(=O)(O)O.CC1C=CC2SC3C(=CC=C(F)C=3)C(=O)C=2C=1.[F:23][C:24]([F:42])([F:41])[C:25]1[CH:38]=[CH:37][C:36]2[S:35][C:34]3[C:29](=[C:30]([CH3:39])[CH:31]=[CH:32][CH:33]=3)[C:28](=[O:40])[C:27]=2[CH:26]=1>CC(C)=O>[F:42][C:24]([F:41])([F:23])[C:25]1[CH:38]=[CH:37][C:36]2[S:35][C:34]3[C:33](=[CH:32][CH:31]=[C:30]([CH3:39])[CH:29]=3)[C:28](=[O:40])[C:27]=2[CH:26]=1
Reactant: Cc1cccc2sc3ccc(C(F)(F)F)cc3c(=O)c12
Agent: Cc1ccc2sc3cc(F)ccc3c(=O)c2c1
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: Cc1ccc2c(=O)c3cc(C(F)(F)F)ccc3sc2c1

Procedure:
This was then treated with sulphuric acid as described for 2-methyl-6-fluoro-9-thioxanthone. The resulting substance consisted mainly of 2-trifluoro-6-methyl-9-thioxanthone with some 2-trifluoromethyl-8-methyl-9-thioxanthone. When boiling this mixture with acetone the more soluble 8-methyl-compound will go into solution. The remaining 2-trifluoromethyl-6-methyl-9-thioxanthone was obtained as a yellow crystalline substance, which melts at 174-178 degrees Centrigrade. Yield: 80 grams.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[C:12]([CH2:14][OH:15])[N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[CH2:1]([O:8][C:9]1[CH:13]=[C:12]([CH:14]=[O:15])[N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cc(OCc2ccccc2)nn1-c1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: O=Cc1cc(OCc2ccccc2)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
A mixture of (3-benzyloxy-1-phenyl-1H-pyrazol-5-yl)methanol (11.20 g), activated manganese dioxide (30.00 g) and tetrahydrofuran (300 mL) was stirred overnight at room temperature. The insoluble material was removed by filtration, and the mother liquid was concentrated. The residue was subjected to silica gel column chromatography to give 3-benzyloxy-1-phenyl-1H-pyrazole-5-carbaldehyde (10.10 g, yield 91%) as a pale-yellow oil from a fraction eluted with ethyl acetate-hexane (1:2, v/v).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([NH:16][CH2:17][CH2:18][N:19](C(OC(C)(C)C)=O)[CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12][C:13]([OH:15])=[O:14])=[CH:2]1.C(OCC)C.[ClH:40]>CO>[ClH:40].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([NH:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:12][C:13]([OH:15])=[O:14])=[CH:2]1
Reactant: CC(C)(C)OC(=O)N(CCN[C@H](CC(=O)O)Cc1c[nH]c2ccccc12)CCc1ccccc1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: O=C(O)C[C@H](Cc1c[nH]c2ccccc12)NCCNCCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Combine 2-[(S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino]-N-(t-butoxycarbonyl)-N-(2-phenyl-ethyl)-ethylamine (4.77 g, 10 mmol) and diethyl ether (50 mL). Cool to 0° C. in an ice-bath. Slowly pass hydrogen chloride gas through the solution for 30 minutes. Stir for 4 hour at 0° C. Warm to ambient temperature and stir for 1 hour. Evaporate in vacuo to give a residue. Dissolve the residue in methanol and triturate the residue with diethyl ether to form a solid. Filter and dry under vacuum to give the title compound. Elem. Anal. calculated for C22H27N3O2.0.50 H2O: C, 59.06; H, 6.76; N, 9.39. Found: C, 58.90; H, 7.01; N, 9.18.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[OH:11][NH:12][CH:13]([CH2:38][C@@H:39]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH3:40])[CH2:14][S:15]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[C:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)(=[O:17])=[O:16]>C(Cl)Cl>[OH:11][N:12]([CH:13]([CH2:14][S:15]([N:18]1[CH2:19][CH2:20][N:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[C:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:28][CH:29]=2)[CH2:22][CH2:23]1)(=[O:16])=[O:17])[CH2:38][C@@H:39]([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[CH3:40])[CH:1]=[O:3]
Reactant: O=CO
Reactant: C[C@@H](CC(CS(=O)(=O)N1CCN(c2ccc(C#Cc3ccccc3)cc2)CC1)NO)c1ccccc1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: C[C@@H](CC(CS(=O)(=O)N1CCN(c2ccc(C#Cc3ccccc3)cc2)CC1)N(O)C=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 90.7 %

Procedure:
To formic acid (2.5 mL, 65 mmol) at 0° C. was added acetic anhydride (500 μL, 5.2 mmol) and the mixture was stirred at 0° C. for 10 minutes. This was added to a solution of 1-{[(4S)-2-(hydroxyamino)-4-phenylpentyl]sulfonyl}-4-[4-(phenylethynyl)phenyl]piperazine (345 mg, 0.685 mmol) in CH2Cl2 (5 mL) cooled to 0° C. The reaction was brought to RT and stirred for one hour. Volatiles were then removed in vacuo. The residue was then precipitated in MeOH (10 mL) and heated to 40° C. for two hours, dissolving. The solution was then cooled to RT and concentrated in vacuo. The residue was then purified by flash chromatography (silica gel, 1–2% MeOH in CH2Cl2) to give the title compound as a white foam (330 mg, 0.621 mmol, 91%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH:15]1[CH:16]=[CH:17][C:12]([NH:11][C:2]2[C:3]([N+:8]([O-:10])=[O:9])=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: Nc1ccccc1
Product: O=[N+]([O-])c1ccccc1Nc1ccccc1

Procedure:
As is known, a nitro group activates halogen substituents in both the ortho- and the para-positions. For example, if 2-chloronitrobenzene is reacted with aniline at from 175 to 205° C., 2-nitrodiphenylamine is obtained in quantitative yield. By contrast, 4-chloronitrobenzene does not react at all with aniline at from 175 to 205° C.(Houben-Weyl, Methoden der Organischen Chemie [Methods of Organic Chemistry], IVth Edition, Volume XI/1, pages 63 and 64). This behavior shows that the nitro group activates the chlorine in the ortho- position to a very great extent, while its activating effect on the chlorine in the para-position is insufficient to permit the substitution reaction.
Reaction SMILES: [O:1]=[C:2]1[CH2:5][C:4]([C:11]([O:13]CC)=[O:12])([C:6]([O:8]CC)=[O:7])[NH:3]1.[OH-].[Na+:17]>CO>[O:1]=[C:2]1[CH2:5][C:4]([C:6]([O-:8])=[O:7])([C:11]([O-:13])=[O:12])[NH:3]1.[Na+:17].[Na+:17]
Reactant: CCOC(=O)C1(C(=O)OCC)CC(=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1CC(C(=O)[O-])(C(=O)[O-])N1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1(c) 5.72 g of diethyl 2-oxoazetidine-4,4-dicarboxylate (prepared as described above) were dissolved in 25 ml of methanol. 53.2 ml of a 1N aqueous solution of sodium hydroxide were added to the resulting solution, and the mixture was stirred at room temperature for 1 day. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure to give crystals, which were washed with methanol and with diethyl ether to give 5.3 g of the title compound as crystals.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([OH:8])=O)=[N:2]1.F[P-](F)(F)(F)(F)F.CN(C(=[N+](C)C)ON1C2=NC=CC=C2N=N1)C.C(N(C(C)C)C(C)C)C.[F:42][C:43]1[CH:44]=[N:45][CH:46]=[CH:47][C:48]=1[C:49]1[C:50]([C:57]2[CH:58]=[N:59][CH:60]=[CH:61][CH:62]=2)=[N:51][C:52]([NH2:56])=[C:53]([NH2:55])[CH:54]=1>CN(C=O)C>[NH2:56][C:52]1[N:51]=[C:50]([C:57]2[CH:58]=[N:59][CH:60]=[CH:61][CH:62]=2)[C:49]([C:48]2[CH:47]=[CH:46][N:45]=[CH:44][C:43]=2[F:42])=[CH:54][C:53]=1[NH:55][C:6]([C:3]1[N:4]=[CH:5][NH:1][N:2]=1)=[O:8]
Reactant: Nc1cc(-c2ccncc2F)c(-c2cccnc2)nc1N
Reactant: O=C(O)c1nc[nH]n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nc(-c2cccnc2)c(-c2ccncc2F)cc1NC(=O)c1nc[nH]n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 35.1 %

Procedure:
A solution of 1H-1,2,4-triazole-3-carboxylic acid (0.072 g, 0.64 mmol), N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methylmethanaminium hexafluorophosphate (0.243 g, 0.64 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.205 mL, 1.17 mmol) in DMF (1.5 mL) was stirred for 15 minutes under argon. Finally, 3″-fluoro-3,2′:3′,4″-terpyridine-5′,6′-diamine (Intermediate 1, 0.15 g, 0.53 mmol) in DMF (3 mL) was added and the mixture was stirred at room temperature for 20 hours. The solvent was evaporated and the crude mixture was purified by silica gel flash chromatography (90:10 dichloromethane/methanol) to give the title compound (0.070 g, 35% of yield).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH:7]=[C:6]([OH:17])[C:3]=1[CH:4]=O.[N+:18](CC)([O-])=O.C(O)(=O)C>O>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH:7]=[C:6]([OH:17])[C:3]=1[C:4]#[N:18]
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1c(O)cc(OCc2ccsc2)cc1F
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1c(O)cc(OCc2ccsc2)cc1F
Temperature: 25 °C
Yield: 25.3 %

Procedure:
A mixture of 2-fluoro-6-hydroxy-4-(3-thienylmethoxy)benzaldehyde (1 g), nitroethane (0.6 g) sodium acetate (0.66 g) and glacial acetic acid (1 mL) is heated at reflux for 2 hours. The reaction mixture is cooled to ambient temperature, water (50 mL) is added and the mixture is extracted three times with ethyl acetate (50 mL). The combined organic phases are washed with saturated brine (50 mL), dried over magnesium sulphate, filtered and concentrated under reduced pressure to leave a brown oil. The residue is purified by flash chromatography on silica eluting with a mixture of ethyl acetate and pentane (1:2 v/v). Fractions homogeneous in the required product are combined and evaporated to give 2-fluoro-6-hydroxy-4-(3-thienylmethoxy)benzonitrile (250 mg), as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH:16]=[C:15]([C:17]2[N:22]=[N:21][C:20]([N:23]3[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]3)=[CH:19][CH:18]=2)[CH:14]=[N:13]1>>[CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:26]2[CH2:27][CH2:28][N:23]([C:20]3[N:21]=[N:22][C:17]([C:15]4[CH:14]=[N:13][N:12]([CH3:11])[CH:16]=4)=[CH:18][CH:19]=3)[CH2:24][CH2:25]2)=[CH:4][CH:3]=1
Reactant: Cn1cc(-c2ccc(N3CCC(=O)CC3)nn2)cn1
Reactant: Cc1ccc2c(c1)NCC2
Product: Cc1ccc2c(c1)N(C1CCN(c3ccc(-c4cnn(C)c4)nn3)CC1)CC2

Procedure:
The title compound was prepared following the procedure as described in Example 5, STEP 4, reacting 6-methylindoline and 1-(6-(1-methyl-1H-pyrazol-4-yl)pyridazin-3-yl)piperidin-4-one.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1.[C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[CH:18]=[CH2:19].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:22]([O:21][C:17](=[O:20])[CH:18]=[CH:19][C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Brc1ccc2c(c1)CCc1ccccc1N2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C=Cc1ccc2c(c1)CCc1ccccc1N2
Temperature: 100 °C
Yield: 33.6 %

Procedure:
A mixture of 2-bromo-10,11-Dihydro-5H-dibenzo[b,f]azepin (4.11 g, 15 mmol, prepared as described in Tetrahedron (1992), 48, 4779) tert-butyl acrylate (2.91 g, 22.5 mmol), palladium acetate (40 mg, 0.2 mmol), tri-o-tolylphosphine (183 mg, 0.6 mmol) and triethylamine (20 ml) in an screw cap ampoule was heated at 100° C. for 20 h. The cooled reaction mixture was diluted with ethyl acetate (50 ml), washed with water (3×20 ml), dried (MgSO4), filtered and evaporated in vacuo. The residue (3.9 g) was purified by column chromatography on silicagel (600 ml) using a mixture of ethyl acetate and heptane (1:6) as eluent which afforded 1.62 g (34%) of 3-(10,11-dihydro-5H-dibenzo[b,f]azepin-2-yl)acrylic acid tert-butyl ester as a solid.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][C:5]1[C:6]2[O:28][CH2:27][CH2:26][C:7]=2[C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]3)[CH2:13][CH2:12]2)=[N:9][CH:10]=1.[CH3:29][O:30][CH2:31][CH2:32][C:33](O)=[O:34]>>[CH3:29][O:30][CH2:31][CH2:32][C:33]([NH:25][C@H:22]1[CH2:21][CH2:20][C@H:19]([CH2:18][CH2:17][N:14]2[CH2:13][CH2:12][N:11]([C:8]3[C:7]4[CH2:26][CH2:27][O:28][C:6]=4[C:5]([CH3:4])=[CH:10][N:9]=3)[CH2:16][CH2:15]2)[CH2:24][CH2:23]1)=[O:34]
Reactant: COCCC(=O)O
Reactant: Cc1cnc(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)c2c1OCC2
Agent: Cl
Product: COCCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3ncc(C)c4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (53 mg, 82%), MS (ISP) m/z=431.6 [(M+H)+], mp 163.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(7-methyl-2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate G) (68.1 mg, 0.15 mmol) and 3-methoxypropionic acid.
Reaction SMILES: [OH-].[Na+].[CH2:3]([S:5]([C:8]1[CH:33]=[CH:32][C:11]([O:12][C:13]2[C:14]([C:28]([O:30]C)=[O:29])=[CH:15][C:16]3[N:20]=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[NH:18][C:17]=3[CH:27]=2)=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH3:4].Cl>>[CH2:3]([S:5]([C:8]1[CH:33]=[CH:32][C:11]([O:12][C:13]2[C:14]([C:28]([OH:30])=[O:29])=[CH:15][C:16]3[N:20]=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[NH:18][C:17]=3[CH:27]=2)=[CH:10][CH:9]=1)(=[O:6])=[O:7])[CH3:4]
Reactant: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2C(=O)OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2C(=O)O)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
10 ml of aqueous 1 N sodium hydroxide solution was added to 2.3 g of the methyl ester compound obtained in Example 174, and the reaction liquid was stirred overnight at 50° C. 4 ml of 3 N hydrochloric acid was added to the reaction liquid, and the precipitated deposit was taken out through filtration to obtain the entitled compound.
Reaction SMILES: Br[C:2]1[C:3]([F:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:9][N:10]1[CH2:15][CH2:14][CH:13]=[CH:12][C:11]1=[O:16].C1(CNCC2CCCCC2)CCCCC1>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O1CCOCC1>[F:8][C:3]1[C:2]([C:13]2[CH2:14][CH2:15][N:10]([CH3:9])[C:11](=[O:16])[CH:12]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CN1CCC=CC1=O
Reactant: Fc1ncccc1Br
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: C1CCC(CNCC2CCCCC2)CC1
Solvent: C1COCCO1
Product: CN1CCC(c2cccnc2F)=CC1=O
Temperature: 100 °C
Yield: 12.3 %

Procedure:
Into a sealed tube were placed 3-bromo-2-fluoropyridine (0.106 g, 0.602 mmol), 1-methyl-5,6-dihydropyridin-2(1H)-one (0.134 g, 1.205 mmol), bis(tri-tert-butylphosphine)palladium (0) (0.046 g, 0.090 mmol), N,N-dicyclohexylmethylamine (0.129 mL, 0.663 mmol), and 1,4-dioxane (0.5 mL). After the mixture was degassed for 5 min, the reaction was heated at 100° C. for 3 h. The cooled reaction was concentrated in vacuo, and the brown residue was directly purified via flash column chromatography (20% EtOAc/Hexanes to 100% EtOAc) to give 4-(2-fluoropyridin-3-yl)-1-methyl-5,6-dihydropyridin-2(1H)-one (0.0153 g, 12.32% yield) as a tan solid. [M+1]=207.1.
Reaction SMILES: [CH2:1](I)[CH2:2][CH3:3].[Br:5][C:6]1[CH:7]=[C:8]([OH:13])[CH:9]=[C:10]([F:12])[CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:5][C:6]1[CH:7]=[C:8]([O:13][CH2:1][CH2:2][CH3:3])[CH:9]=[C:10]([F:12])[CH:11]=1
Reactant: Oc1cc(F)cc(Br)c1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCOc1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Add propyl iodide (5.74 g, 33.77 mmol) to 3-bromo-5-fluoro-phenol (4.30 g, 22.51 mmol) and cesium carbonate (11.00 g, 33.77 mmol) in N,N-dimethylformamide (75 mL) and stir at room temperature 1 hour, then heat at 50° C. for 1 hour. Cool to room temperature and dilute with hexanes. Wash (water, 1N lithium chloride, saturated aqueous sodium chloride), dry (magnesium sulfate), filter and concentrate to give the desired compound as a colorless oil, 4.40 g (83.8%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][C:14]([CH2:22][CH2:23][CH2:24][N:25]3[C:34]4[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=4)[CH:28]=[CH:27][C:26]3=[O:37])([C:17]([O:19]CC)=[O:18])[CH2:13][CH2:12]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([S:8][CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][C:14]([CH2:22][CH2:23][CH2:24][N:25]3[C:34]4[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=4)[CH:28]=[CH:27][C:26]3=[O:37])([C:17]([OH:19])=[O:18])[CH2:15][CH2:16]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(CCCn2c(=O)ccc3ccc(OC)cc32)CCN(CCSc2cccc(F)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2ccc(=O)n(CCCC3(C(=O)O)CCN(CCSc4cccc(F)c4)CC3)c2c1
Temperature: 25 °C
Yield: 75.1 %

Procedure:
To 1.5 mL of an ethanol solution containing 90 mg of ethyl 1-(2-((3-fluorophenyl)thio)ethyl)-4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)piperidine-4-carboxylate, 0.50 mL of 20% aqueous sodium hydroxide solution was added and refluxed with heating for 3.5 hours. After the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, water was added, and adjusted to pH 6.5 with 6.0 mol/L hydrochloric acid. The resulting solid was filtered to give 64 mg of 1-(2-((3-fluorophenyl)thio)ethyl)-4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)piperidine-4-carboxylic acid as a pale yellow solid.
Reaction SMILES: C(C(CCCCCCCC)CO)CCCCC.[C:18]1([C:24]2[C:29]([C:30]([O:32]CC)=[O:31])=[CH:28][N:27]=[CH:26][N:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>[Hg]>[C:18]1([C:24]2[C:29]([C:30]([OH:32])=[O:31])=[CH:28][N:27]=[CH:26][N:25]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1cncnc1-c1ccccc1
Agent: CCCCCCCCC(CO)CCCCCC
Agent: [Hg]
Product: O=C(O)c1cncnc1-c1ccccc1

Procedure:
The 2-hexyldecyl ester of 4-phenylpyrimidine-5-carboxylic acid was prepared from 2-hexyldecanol and 4-phenyl-5-ethoxycarbonylpyrimidine using the general procedure of Example 7. The product had a boiling range of 206°-208° C. at 0.2 mm presssure of mercury.
Reaction SMILES: [SH:1][CH:2]1[CH2:7][O:6][C:4](=[O:5])[CH2:3]1.II>ClCCl>[S:1]([CH:2]1[CH2:7][O:6][C:4](=[O:5])[CH2:3]1)[S:1][CH:2]1[CH2:7][O:6][C:4](=[O:5])[CH2:3]1
Reactant: O=C1CC(S)CO1
Agent: II
Solvent: ClCCl
Product: O=C1CC(SSC2COC(=O)C2)CO1
Temperature: 20 °C
Reaction time: 18 h
Yield: 28.5 %

Procedure:
A solution of β-mercapto-γ-butyrolactone (106 mg, 0.9 mmol) in dichloromethane (2 ml) was treated with a solution of iodine (253 mg, 1 mmol) in dichloromethane (5 ml) and the mixture was stirred for 18 h at 20° C. The reaction mixture was diluted with dichloromethane and washed with aqueous sodium metabisulfite solution, dried (MgSO4), the solvent was removed under reduced pressure, and the residue was purified by preparative TLC on a single plate (20 cm×20 cm) run in ethyl acetate-cyclohexane (2:1) to give the title compound (30 mg, 28%):. MS (TSP+ve) m/z 252 (M+NH4)+ ; IR νmax (KBr) 1778, 1771, 1164, 1023, 989, 843 cm-1 ; NMR δ (CDCl3) 4.6 (2 H, dd, J 9 and 6 Hz), 4.35 (2 H, dt, J 5 and 4 Hz), 3.86-3.72 (2 H, m), 2.96 (2 H, dd, J 17 and 8 Hz), 2.66 (2 H, dt, J 18 and 5 Hz); HRMS (EI) found: 234.0017. C8H10O4S2 requires 234.0020.
Reaction SMILES: [N:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:9]1([CH2:12][CH2:13][NH:14][C:15]([C:17]2[N:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:21][CH:22]=2)=[O:16])[CH2:11][CH2:10]1>>[CH:9]1([CH2:12][CH2:13][NH:14][C:15]([C:17]2[N:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][N:26]([C:6]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:7])[CH2:25][CH2:24]3)=[CH:21][CH:22]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: O=C(Cl)N1CCCC1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)N3CCCC3)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use pyrrolidine-1-carbonyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder (54% yield). 1H NMR (400 MHz, CDCl3) δ 8.04, 7.98, 6.99, 3.79, 3.56, 3.47-3.45, 3.40, 1.87-1.85, 1.52, 0.80-0.72, 0.48-0.46, 0.10-0.09.
Reaction SMILES: [CH:1]([OH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:15][CH2:16][CH2:17]O.S(=O)(=O)(O)O>C(OCC)C>[C:2]1([CH:1]([O:14][CH2:17][CH2:16][F:15])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: OCCF
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: FCCOC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 79 %

Procedure:
To a stirred solution of 2.0 grams (0.011 mole) of benzhydrol in 15 ml of diethyl ether was added 4.0 ml (0.068 mole) of 2-fluoroethanol followed by the dropwise addition of 0.5 ml of concentrated sulfuric acid. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was extracted with diethyl ether. The organic extract was washed with water followed by an aqueous, saturated sodium bicarbonate solution. The washed extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to yield 2.0 grams of 2-fluoroethyl diphenylmethyl ether as a liquid.