Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10](S(C3C=CC=CC=3)(=O)=O)[CH:9]=2)[CH:5]=[C:4]([Cl:26])[N:3]=1.[NH2:27][CH2:28][CH2:29][C:30]1[CH:31]=[C:32]([OH:36])[CH:33]=[CH:34][CH:35]=1.Cl.C(N(C(C)C)CC)(C)C>C(#N)C.[Cl-].[Na+].O>[Cl:26][C:4]1[N:3]=[C:2]([NH:27][CH2:28][CH2:29][C:30]2[CH:31]=[C:32]([OH:36])[CH:33]=[CH:34][CH:35]=2)[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH:5]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cc(Cl)nc(Cl)c2)c2cccnc21
Reactant: NCCc1cccc(O)c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Oc1cccc(CCNc2cc(-c3c[nH]c4ncccc34)cc(Cl)n2)c1
Temperature: 60 °C

Procedure:
A mixture of Example 7a (75.0 mg, 0.186 mmol), 3-(2-aminoethyl)phenol.HCl (0.250 g, 1.44 mmol), and diisopropylethylamine (0.52 mL, 2.97 mmol) in acetonitrile (0.6 mL) was heated in a Biotage microwave reactor at 160° C. for 30 minutes. The reaction mixture was treated with 20% brine and extracted with EtOAc (2×). The combined organic layers were washed with 20% brine, dried over MgSO4, filtered, and concentrated. The crude was dissolved in dioxane (1.3 mL) and treated with 20% NaOH (0.12 mL). The mixture was heated at 60° C. for 1 hour and concentrated. The residue was treated with water, sonicated, filtered, washed with water, and dried. The crude material was purified on a 4 g column using the ISCO Companion flash system eluting with CH2Cl2/MeOH (97:3 to 90:10) to give 5.5 mg of the title compound. 1H NMR (500 MHz, DMSO-d6) ppm 2.77 (t, J=7.32 Hz, 2H), 3.46 (t, J=6.87 Hz, 2H), 6.61 (d, J=7.93 Hz, 1H), 6.65-6.74 (m, 2H), 6.87 (s, 1H), 6.89-6.98 (m, 2H), 7.09 (t, J=7.78 Hz, 1H), 7.21 (dd, J=7.93, 4.88 Hz, 1H), 8.14 (d, J=2.75 Hz, 1H), 8.25-8.35 (m, 2H), 9.27 (s, 1H), 12.16 (s, 1H). MS (DCI+) m/z 365.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH:19]([CH3:21])[CH3:20])=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:22](N=C(N(C)C)N(C)C)([CH3:25])([CH3:24])[CH3:23].BrCC(C)C>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:23][CH:22]([CH3:25])[CH3:24])[C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH:19]([CH3:21])[CH3:20])=[CH:14][N:13]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Reactant: Cc1cc(C(C)C)cnc1NS(=O)(=O)c1ccc(F)cc1
Solvent: CC(C)CBr
Solvent: CC#N
Product: Cc1cc(C(C)C)cnc1N(CC(C)C)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
4-fluoro-N-(5-isopropyl-3-methylpyridin-2-yl)benzenesulfonamide (127 mg, 0.41 mmol) was dissolved in acetonitrile (3 mL) and to this solution was added 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (0.09 mL, 0.41 mmol). The mixture was allowed to stir at room temperature for 30 minutes, 1-bromo-2-methylpropane (0.09 mL, 0.83 mmol) was then added to the mixture and the reaction vessel sealed and heated by microwaves to 150° C. for 1 hour. The reaction mixture was concentrated in vacuo and the crude product extracted to the organic phase of an aqueous workup between ethyl acetate and water. The organic phase was then passed through a hydrophobic frit, concentrated in vacuo and purified by mass directed autoprep (formic acid modifier) to give the title compound (73 mg). LCMS (2 min, formic) Rt 1.44 min, m/z (ES+) 365 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][N:12]2[N:21]=[C:20]([C:22]3[CH:23]=[N:24][C:25](Cl)=[CH:26][CH:27]=3)[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:29])=[O:10])=[CH:4][CH:3]=1>CO.CN(C=O)C.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][N:12]2[N:21]=[C:20]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:29])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(Cl)cc1)Nn1nc(-c2ccc(Cl)nc2)c2ccccc2c1=O
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(-c2cccnc2)c2ccccc2c1=O
Yield: 51.2 %

Procedure:
A mixture of the product of Example 5 (38 mg, 0.089 mmol) and a catalytic amount of 10% Pd/C in MeOH (1 mL) and DMF (0.5 mL) was stirred at room temperature under H2 (1 atm) for 3 hours, filtered through celite, and chromatographed (30-60% EtOAc/DCM) to give 17.8 mg of the title compound as a white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 11.75 (s, 1H), 8.78 (dd, J=2.2, 0.7 Hz, 1H), 8.76 (dd, J=4.8, 1.6 Hz, 1H), 8.40-8.43 (m, 1H), 8.06 (ddd, J=7.9, 2.2, 1.7 Hz, 1H), 7.94-8.02 (m, 2H), 7.67-7.75 (m, 1H), 7.61 (ddd, J=7.9, 4.8, 0.8 Hz, 1H), 7.40 (s, 4H), 3.71 (s, 2H); MS (ESI+) M/Z 391 (M+H)+.
Reaction SMILES: [C:1]([OH:10])(=O)[C@@H:2]([C@H:4]([C:6](O)=[O:7])[OH:5])[OH:3].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C(C)=CC=CC=1>[CH2:11]([N:18]1[C:6](=[O:7])[C@H:4]([OH:5])[C@@H:2]([OH:3])[C:1]1=[O:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Reactant: NCc1ccccc1
Solvent: Cc1ccccc1C
Product: O=C1[C@H](O)[C@@H](O)C(=O)N1Cc1ccccc1
Temperature: 150 °C

Procedure:
L-Tartaric acid (30 g) and benzylamine (22 ml) were added to xylene (150 ml), and the mixture was heated under reflux at 150° C. for 3 hours using a Dean-Stark trap. After the reaction mixture was allowed to cool overnight, crystals were collected by filtration and washed with acetone. The resultant crude product was recrystallized from ethanol to obtain the title compound (23.2 g).
Reaction SMILES: O[CH2:2][C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[C:10]([C:16]#[N:17])[C:11](=[CH:14][CH:15]=2)[C:12]#[N:13])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:27][S:28]([CH2:2][C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[C:10]([C:16]#[N:17])[C:11](=[CH:14][CH:15]=2)[C:12]#[N:13])=[CH:5][CH:4]=1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(Oc2ccc(CO)cc2)cc1C#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Cc1ccc(Oc2ccc(C#N)c(C#N)c2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of 4-[4-(hydroxymethyl)phenoxy]phthalonitrile (1.0 g, 3.9 mmol) prepared according to procedures described in literature, and triethylamine (0.80 ml, 5.8 mmol) in anhydrous CH2Cl2 (50 ml), kept at 0° C. under stirring and in an inert atmosphere, methylsulfonylchloride was added (0.33 ml, 4.3 mmol). The mixture was stirred at 0° C. for 1 hour, then ft was diluted with CH2Cl2 (50 ml) and washed with 1% HCl solution (60 ml), then with brine (50 ml), the organic layer was dried on Na2SO4 and the solvent was evaporated. 1.2 g (92%) of the title compound were obtained as a viscous fluid that crystallised on standing.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:33])[C:13](/[CH:23]=[CH:24]/[P:25](=[O:32])([O:29]CC)[O:26]CC)=[CH:14][N:15]3[CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:10][C:9]=2[F:34])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[Si](C)(C)C.C(O)C>C(Cl)(Cl)Cl>[CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:33])[C:13](/[CH:23]=[CH:24]/[P:25](=[O:26])([OH:32])[OH:29])=[CH:14][N:15]3[CH:18]([CH2:19][CH3:20])[CH2:21][CH3:22])=[CH:10][C:9]=2[F:34])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOP(=O)(/C=C/c1cn(C(CC)CC)c2cc(NC3CCCCC3)c(F)cc2c1=O)OCC
Agent: C[Si](C)(C)Br
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCC(CC)n1cc(/C=C/P(=O)(O)O)c(=O)c2cc(F)c(NC3CCCCC3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
13 g of diethyl {(E)-2-[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]vinyl}phosphonate was dissolved in 150 ml of chloroform, and 27.2 ml of bromotrimethylsilane was added, followed by overnight stirring at room temperature. Ethanol was added to the reaction mixture, followed by concentration under a reduced pressure. Aqueous 1 M sodium hydroxide solution and ether were added to the resulting residue to carry out layer separation operation. Concentrated hydrochloric acid was added to the aqueous layer, followed by stirring at room temperature for 2 hours. Then, the insoluble materials were collected by filtration and washed with water to obtain 10.32 g of {(E)-2-[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]vinyl}phosphonic acid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]([OH:16])[CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[S:19][C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])=[CH:21][C:22]=1[C:23]([NH2:25])=[O:24]>>[F:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:20]1[S:19][C:18]([NH:17][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]([OH:16])[CH2:9][N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:7]=2)=[C:22]([C:23]([NH2:25])=[O:24])[CH:21]=1
Reactant: OC(CN1CCOCC1)c1cccc(Br)n1
Reactant: NC(=O)c1cc(-c2ccccc2F)sc1N
Product: NC(=O)c1cc(-c2ccccc2F)sc1Nc1cccc(C(O)CN2CCOCC2)n1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using 1-(6-bromopyridin-2-yl)-2-morpholin-4-ylethanol (86 mg, 0.30 mmol) and 2-amino-5-(2-fluorophenyl)thiophene-3-carboxamide (72 mg, 0.31 mmol) as the starting materials.
Reaction SMILES: [Cl:1][C:2]1[CH:40]=[CH:39][CH:38]=[CH:37][C:3]=1[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:7]=1[N:13]1[C:17]([CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])=[N:16][N:15]=[C:14]1[CH2:25][NH:26][C:27](=[O:36])[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=1)=[O:5].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:40]=[CH:39][CH:38]=[CH:37][C:3]=1[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:7]=1[N:13]1[C:17]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[N:16][N:15]=[C:14]1[CH2:25][NH:26][C:27](=[O:36])[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=1)=[O:5]
Reactant: CCOC(=O)CCc1nnc(CNC(=O)c2ccc(Cl)c(Cl)c2)n1-c1sc(CC)cc1C(=O)c1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(CCC(=O)O)nnc2CNC(=O)c2ccc(Cl)c(Cl)c2)s1
Temperature: 50 °C
Reaction time: 3 h
Yield: 83.8 %

Procedure:
Ethyl 3-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-3-(3,4-dichlorobenzoylaminomethyl) [1,2,4]triazol-5-yl)propionate (0.7 g) and a 2M aqueous sodium hydroxide solution (1.13 ml) were added to methanol (10 ml), and the mixture was stirred at 50° C. for 3 hours. The solvent was evaporated, and the residue was dissolved in water. Ethyl acetate was added to the solution for washing. The aqueous layer was taken out, and citric acid was added to adjust the solution to pH 3. The solution was extracted with ethyl acetate. The extract was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from diisopropyl ether to give 0.56 g of 3-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-3-(3,4-dichlorobenzoylaminomethyl) [1,2,4]triazol-5-yl)propionic acid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([O:19][CH3:20])=[CH:11][C:10]=1[C:21](OC)=[O:22].[NH4+].[Cl-].Cl>CCOCC.C1COCC1.CO>[CH3:7][O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([O:19][CH3:20])=[CH:11][C:10]=1[CH2:21][OH:22]
Reactant: COC(=O)c1cc(OC)c2ccccc2c1OC
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(CO)c(OC)c2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
A solution of lithium aluminum hydride (29.2 mL, 29.2 mmol, 1 M in ether) in ether (30 mL) was heated to reflux under argon. A solution of ester 22 (7.18 g, 29.2 mmol) in ether (30 mL) and THF (8 mL) was added dropwise over 35 min via an addition funnel. The milky yellow mixture was refluxed for 3 h and then cooled to 0° C. Methanol (10 mL) was added dropwise and the resulting clear yellow solution was stirred for 1 h. Saturated NH4Cl (20 mL) and aqueous HCl (5 mL, 10%) were added and the mixture was extracted with ether (6×). The combined organic layers were washed with saturated Na2CO3 (2×) and H2O (2×), dried (MgSO4), filtered and evaporated. Column chromatography of the crude product (35:65 EtOAc:hexanes) afforded 23a (5.82 g, 92%) as a pink solid; Rf=0.48 (35:65 EtOAc:hexanes); mp=69–70° C.; lit mp=68–70° C.25; 1H NMR (CDCl3): δ 8.23 (dd, 1H), 8.03 (dd, 1H), 7.52 (m, 2H), 6.82 (s, 1H), 4.89 (s, 2H), 3.99 (s, 3H), 3.92 (s, 3H), 1.95 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.O.Cl>C(O)C.[Fe]>[NH2:12][C:11]1[C:2]([Cl:1])=[N:3][CH:4]=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: COC(=O)c1cnc(Cl)c(N)c1
Reaction time: 1 h

Procedure:
A solution of 1.08 g (5.00 mmol) of methyl 6-chloro-5-nitronicotinate (see A. H. Berrie, G. T. Newbold, and F. S. Spring in J. Chem. Soc., 2590, 1951) in 25 mL of absolute ethanol was mixed successively with 0.53 mL (29 mmol) of water, 3.2 g (57 mmol) of iron powder and 0.030 mL of concentrated hydrochloric acid and heated to boiling for one hour. Then equal quantities of water, iron powder and hydrochloric acid were added and the mixture was heated to boiling for 30 minutes. The precipitate formed on cooling was filtered off and washed with ethanol and the solvent was distilled off in vacuo. Yield: 0.75 g (81% of theory) of greenish-yellow solid, C7H7ClN2O2 (186.60); Rf value: 0.31 (silica gel; ethyl acetate/petroleum ether=1:4); YEF-Mass spectrum: M+=186 and 188 (chlorine isotopes).
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.[CH:28]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1>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]([CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]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)C1CCCC1
Solvent: C1CCOC1
Product: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(NC(=O)C3CCCC3)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 cyclopentanecarbonyl chloride in THF according to the procedure described in the synthesis of Example 26. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.69 (t, J=7.33 Hz, 3H) 1.32 (dq, J=14.97, 7.39 Hz, 2H) 1.54-1.63 (m, 2H) 1.65-1.77 (m, 4H) 1.82-1.92 (m, 2H) 2.20 (t, J=7.33 Hz, 2H) 2.83 (dt, J=15.41, 7.71 Hz, 1H) 6.73 (s, 1H) 7.59-7.70 (m, 3H) 7.83-7.94 (m, 4H) 8.13 (d, J=8.08 Hz, 1H) 10.26 (s, 1H); ESI-MS: m/z calc'd for C27H28N4O2S 472.6. found 473.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:16]=2[N:15]([CH2:17][CH2:18][CH3:19])[N:14]=[C:13]3[C:20]2[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:16]=2[N:15]([CH2:17][CH2:18][CH3:19])[N:14]=[C:13]3[C:20]2[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=2)=[CH:4][CH:3]=1
Reactant: CCCn1nc(-c2ccc(OC)cc2)c2cccc(-c3ccc(F)cc3)c21
Agent: BrB(Br)Br
Product: CCCn1nc(-c2ccc(O)cc2)c2cccc(-c3ccc(F)cc3)c21
Yield: 71.4 %

Procedure:
Prepared according to Method D step C from 7-(4-Fluorophenyl)-3-(4-methoxyphenyl)-1-propyl-1H-indazole (0.125 g, 0.35 mmol), BBr3 (0.066 mL, 0.7 mmol) to give the title compound as a white solid (0.087 g, 0.25 mmol, 72%).
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]1[CH:17]=[C:16]([CH2:18][O:19][CH:20]([CH3:22])[CH3:21])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)C>[OH-].[Na+].CO>[CH:20]([O:19][CH2:18][C:16]1[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=[C:5]([CH:17]=1)[C:4]([OH:23])=[O:3])([CH3:22])[CH3:21]
Reactant: CCCN(C)C(=O)c1cc(COC(C)C)cc(C(=O)OCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCN(C)C(=O)c1cc(COC(C)C)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Dissolve the crude 5-isopropoxymethyl-N-methyl-N-propyl-isophthalamic acid ethyl ester (0.23 mmol) in 5 N NaOH (1 mL) and methanol (2 mL). Stir at room temperature for 15 min, concentrate methanol and redissolve the residue in water (20 mL). Wash with diethyl ether (2×10 mL), acidify the aqueous layer with 5 N HCl to about pH=1. Extract with dichloromethane to give the title compound.
Reaction SMILES: [CH:1]1([CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]3[CH:23]=[C:22]([O:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:21]([C:29]4[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:30]=4[F:37])=[CH:20][N:19]=3)[CH:11]=2)[CH2:5][C:6]([O:8]C)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]3[CH:23]=[C:22]([O:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:21]([C:29]4[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:30]=4[F:37])=[CH:20][N:19]=3)[CH:11]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: COC(=O)CC(c1cccc(OCc2cc(OCC(C)C)c(-c3cc(OC)ccc3F)cn2)c1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)c(-c2cnc(COc3cccc(C(CC(=O)O)C4CC4)c3)cc2OCC(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.2 %

Procedure:
To a solution of methyl 3-cyclopropyl-3-(3-((5-(2-fluoro-5-methoxyphenyl)-4-isobutoxypyridin-2-yl)methoxy)phenyl)propanoate (128 mg) in THF (2.0 mL) and methanol (1.0 mL) was added 1N aqueous sodium hydroxide solution (2.0 mL), and the mixture was stirred at room temperature for 4 hr. 1N Hydrochloric acid (2.0 mL) was added to the reaction mixture at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure to give the title compound (121 mg) as a white amorphous solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][O:12][C:11]2=[O:15])=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:14][CH2:13][O:12][C:11]2=[O:15])=[CH:8][CH:9]=1
Reactant: O=C1OCCN1c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(N2CCOC2=O)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 3-(4-nitrophenyl)oxazolidin-2-one (800 mg, 3.8 mmol) in MeOH (10 mL) was added Pd/C (10%, 200 mg). After having been degassed and recharged with hydrogen from a balloon, the mixture was stirred at rt for 15 h. TLC showed no starting material existed. The solid Pd/C was separated by filtration and the crude product 3-(4-aminophenyl)oxazolidin-2-one was obtained by evaporation as a yellow solid (622 mg, yield 90%) and used directly for the next step.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH:20]([N-]C(C)C)(C)C.[Li+].IC.[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[C:9]([CH3:20])[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)[N-]C(C)C
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)ncnc21
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(I)c2c(Cl)ncnc2n1COCC[Si](C)(C)C
Temperature: -20 °C
Reaction time: 2 h

Procedure:
To a −78° C. solution of 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (C1) (15.0 g, 36.6 mmol) in tetrahydrofuran (500 mL) was added lithium diisopropylamide (2 M solution in heptane/tetrahydrofuran/ethylbenzene, 183 mL, 366 mmol), and the reaction mixture was stirred at −20° C. for 2 hours, then re-cooled to −78° C. Iodomethane (52.1 g, 367 mmol) was added at −78° C., and the reaction mixture was allowed to stir at −20° C. for 2 hours. Saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with water (100 mL) and with saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via chromatography on silica gel (Eluent: 10:1 petroleum ether/ethyl acetate) afforded the product as a yellow oil. Yield: 10 g, 24 mmol, 66%. LCMS m/z 424.1 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 5.69 (s, 2H), 3.48-3.54 (m, 2H), 2.60 (s, 3H), 0.88-0.95 (m, 2H), −0.05 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH:10](S(C)=O)SC)[CH:7]=[C:6]([F:16])[C:3]=1[C:4]#[N:5].S(=O)(=O)(O)[OH:18].O>C1COCC1>[F:1][C:2]1[CH:9]=[C:8]([CH:10]=[O:18])[CH:7]=[C:6]([F:16])[C:3]=1[C:4]#[N:5]
Reactant: CSC(c1cc(F)c(C#N)c(F)c1)S(C)=O
Reactant: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(F)cc(C=O)cc1F
Reaction time: 72 h

Procedure:
2,6-Difluoro-4[(methylsulfinyl)(methylthio)methyl]benzonitrile (2.17 g, 8.32 mmol; see step (i) above) was dissolved in 90 mL of THF and 3.5 mL of concentrated sulfuric acid was added. The mixture was left at room temperature for 3 days and subsequently poured into 450 mL of water. Extraction three times with EtOAc followed and the combined ethereal phase was washed twice with aqueous sodium bicarbonate and with brine, dried (Na2SO4) and evaporated. Yield: 1.36 g (98%). The position of the formyl group was established by 13C NMR. The signal from the fluorinated carbons at 162.7 ppm exhibited the expected coupling pattern with two coupling constants in the order of 260 Hz and 6.3 Hz respectively corresponding to an ipso and a meta coupling from the fluorine atoms.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4]Cl.ClC(Cl)(Cl)C1C=CC=CC=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([CH2:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:28])[CH:22]=1.[NH4+].[Cl-]>CCOCC.BrBr>[CH3:32][C:31]([CH3:34])([CH3:33])[CH2:30][CH2:29][C:27]([CH2:4][C:3]1[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:2]=1[Cl:1])([C:23]1[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=1)[OH:28]
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: CC(C)(C)CCC(=O)c1cccnc1
Agent: BrBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClC(Cl)(Cl)c1ccccc1
Solvent: CCOCC
Product: CC(C)(C)CCC(O)(Cc1ccc(Cl)cc1Cl)c1cccnc1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
A solution of 66.2 g of 2,4-dichlorobenzyl chloride in 150 ml of ether was added dropwise to 8.2 g of Mg in 100 ml of diethyl ether. After 20% of the amount of dichlorobenzyl chloride had been added, the reaction was started by adding a few drops of bromine. After completion of the dropwise addition of the 2,4-dichlorobenzyl chloride solution, the mixture was refluxed for 1/2 an hour. It was then added dropwise to a solution of 55 g of 3,3-dimethylbutyl pyridin-3-yl ketone in 100 ml of ether. After it had been refluxed for a further two hours, the reaction mixture was hydrolyzed by dropwise addition of saturated aqueous NH4Cl solution (until the pH was 8), while being cooled with ice. The mixture was stirred for 15 hours at room temperature (20° C.) and extracted with diethyl ether, and the ether phase was washed with water, dried over Na2SO4, concentrated and distilled. 52 g of 3,3-dimethylbutyl-2,4-dichlorobenzyl-pyridin-3 -yl-carbinol (active ingredient No. 36) were obtained; boiling point 196°-202° C./0.5 mbar.