Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Br[CH2:21][C:22]#[C:23][CH2:24][CH3:25].C([O-])([O-])=O.[K+].[K+].C1CCN2C(=NCCC2)CC1>CO>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][C:22]#[C:23][CH2:24][CH3:25])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Reactant: CCC#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: CCC#CCN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (4 g) is alkylated using 1-bromo-2-pentyne (3.1 ml; 30.4 mmol) and K2CO3 (4.2 g; 30.4 mmol) at 40° C. for 20 h. After aqueous work-up only a part of the crude material (1 g; 3.04 mmol) is de-acetylated under reflux using DBU (0.9 ml) in MeOH (80 ml). After aqueous work-up the crude 5-amino-3,3-dimethyl-6-nitro-1-(pent-2-ynyl)-1,3-dihydro-indol-2-one (0.87 g) is used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16](N(CC)CC)[CH3:17].C(OC(ON=C(C#N)C(N)=O)=O)C>C(OCC)(=O)C.O1CCCC1>[CH2:16]([O:14][C:13](=[O:15])[CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:17]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CCN(CC)CC
Agent: CCOC(=O)ON=C(C#N)C(N)=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of N-benzyloxycarbonylglycine (1.05 g) and triethylamine (0.73 ml) in ethyl acetate (10 ml) and tetrahydrofuran (10 ml), 2-ethoxycarbonyloxyimino-2-cyanoacetic acid amide (1.11 g) is added, and the resulting mixture is stirred for 2 hours. The reaction mixture is treated as in Example A to give N-benzyloxycarbonylglycine ethyl ester (1.2 g) as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH:13]([Mg]Br)=[CH2:14].Cl>O1CCCC1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:7]([OH:8])[CH:13]=[CH2:14])[CH:9]=1
Reactant: C=C[Mg]Br
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Product: C=CC(O)c1cc(O)ccc1[N+](=O)[O-]
Temperature: -78 °C
Yield: 73 %

Procedure:
5-Hydroxy-2-nitrobenzaldehyde (60 g) is dissolved in dry tetrahyrofuran (90 ml) and thereto is added dropwise vinylmagnesium bromide (2.3 equivalents) with stirring at -78° C. The temperature of the reaction mixture is raised gradually. After completion of the reaction, 1N HCl is added to the reaction mixture, and the mixture is extracted with ethyl acetate, and the organic layer is separated, washed with an aqueous saturated saline solution, dried over sodium sulfate, and then distilled off the solvent. The residue is purified with a silica gel column chromatography to give 1-(5'-hydroxy-2'-nitrophenyl)-2-propen-1-ol (5.09 g) as yellowish brown powders.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1.[CH3:25][N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][C:33]=2[CH:35]=O)[CH:28]=[CH:27]1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:33]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:34]=2[N:26]([CH3:25])[CH:27]=[CH:28]3)[CH:21]=[CH:22][CH:23]=1
Reactant: Cn1ccc2cccc(C=O)c21
Reactant: Nc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Product: Cn1ccc2cccc(CNc3cccc(-c4c(-c5ccccc5)nnc5c(Cl)cccc45)c3)c21

Procedure:
The title compound was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenylamine and 1-methyl-1H-indole-7-carbaldehyde according to the procedure of Step 5 Example 6. MS (ES) m/z 474.9.
Reaction SMILES: Cl[CH2:2][CH2:3][C@H:4]([CH3:16])[CH2:5][CH2:6][CH2:7][C@H:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13].C([O-])(=[O:19])C.[K+].[OH-].[K+]>C(Cl)(Cl)Cl.CN(C)C=O>[CH3:16][C@H:4]([CH2:5][CH2:6][CH2:7][C@H:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:3][CH2:2][OH:19]
Reactant: CC(C)CCC[C@@H](C)CCC[C@@H](C)CCCl
Reactant: CC(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)CCC[C@@H](C)CCC[C@@H](C)CCO
Yield: 94 %

Procedure:
For the verification of the optical purity the compound obtained is hydrogenated on pre-hydrogenated platinum dioxide to (3R,7R)-1-chloro-3,7,11-trimethyldodecane; boiling point at 0.07 mm; 90°; αD =-1.2° (4.08% in CHCl3), which is converted by heating with dry potassium acetate in dimethylformamide (4 hours at 170°). This ester is purified by adsorption on silicagel (elution agent: n-hexane/ether 4+1), then further reacted to (3R,7R)-3,7,11-trimethyl-1-dodecanol by stirring with 4-N aqurous caustic potash (30 min. at room temperature). The mixture is extracted, washed neutral, dried, concentrated, distilled in the bulb-tube (115°, 0.20 Torr) and there is obtained (3R,7R)-3,7,11-trimethyl-1-dodecanol in 94% yield (based on (3R,7R)-1-chloro-3,7,11-trimethyldodecane employed). The product has an optical rotation value of [α]D20 =+3.7° (4.14% in n-octane) and is accordingly identical with authentic material.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[CH:11]=[CH:12][C:13]([C:15](=[O:26])[C:16]([C:19]4[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=4)=[N:17]O)=[CH:14][C:9]=3[N:8]([CH3:27])[C:7]2=[O:28])[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:29].[H][H]>C(O)C.C(OCC)C.[Pd]>[ClH:29].[NH2:17][CH:16]([C:19]1[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=1)[CH:15]([C:13]1[CH:12]=[CH:11][C:10]2[N:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[C:7](=[O:28])[N:8]([CH3:27])[C:9]=2[CH:14]=1)[OH:26]
Reactant: [H][H]
Reactant: Cc1cccc(C(=NO)C(=O)c2ccc3c(c2)n(C)c(=O)n3C2CCCC2)c1
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: Cc1cccc(C(N)C(O)c2ccc3c(c2)n(C)c(=O)n3C2CCCC2)c1
Reaction time: 3 h
Yield: 92.4 %

Procedure:
1-(1-Cyclopentyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-2-m-tolyl-ethane-1,2-dione 2-oxime (5 gm, 13.2 mmol) was dissolved in ethanol (300 mL) in a Parr bottle. Concentrated HCl (3.3 mL, 40 mmol) was added, followed by 10% Pd on carbon (approximately 0.5 gm). The resulting mixture was placed on a Parr hydrogenation apparatus and hydrogenated at a hydrogen pressure of 40 psi. Hydrogen consumption slowed considerably after 3 hours, with the amino ketone being formed initially. Hydrogenation was continued overnight, after which time the reaction was determined to be complete. The mixture was filtered through a celite plug and the filtrate was concentrated in vacuo to afford a viscous yellow oil, which was triturated/repulped in diethyl ether to afford 4.90 gm of a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[CH:10][C:5]2[N:6]=[C:7]([CH3:9])[O:8][C:4]=2[CH:3]=1.S(Cl)([Cl:16])(=O)=O>C(OCC)(=O)C.C(Cl)Cl>[NH2:1][C:2]1[C:11]([F:12])=[CH:10][C:5]2[N:6]=[C:7]([CH3:9])[O:8][C:4]=2[C:3]=1[Cl:16]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1nc2cc(F)c(N)cc2o1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1nc2cc(F)c(N)c(Cl)c2o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6-Amino-5-fluoro-2-methylbenzoxazole (12 g, 72.22 mMole) was dissolved in ethyl acetate (100 mL) containing dry pryidine (5.8 mL, 72.22 mMole). At room temperature and with good stirring, sulfuryl chloride (7.0 mL, 86.66 mMole) was added drop by drop over a 20-minute period. After stirring at room temperature for about 30 minutes, the reaction was diluted with ethyl acetate, washed with 2N-HCl, dried (MgSO4), filtered and concentrated to give a solid. This solid was dissolved in methylene chloride and passed through a short column of silica gel eluting with methylene chloride to give the product. Yield 5.0 g.
Reaction SMILES: [S:1]([O-])(=O)(=O)[CH3:2].S[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[N:10]1[CH:11]=[CH:12][CH:7]=[CH:8][C:9]=1[S:1][C:2]1[CH:12]=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: Sc1ccncc1
Reactant: CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: c1ccc(Sc2ccccn2)nc1
Yield: 71 %

Procedure:
This product (4) is treated with 4-mercaptopyridine (2.45 g; 1.3 equivalents) and sodium carbonate (1.8 g; 1 equivalents) at room temperature for 2 hours to give 4-pyridyl sulfide (7) (7.87 g) as in Example F-2. Yield: 71%.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH:4][C@H:5]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:27])[C@:11]3([OH:28])[CH2:12][CH2:13][C@@H:14]2/[CH:15]=[CH:16]/[CH:17]=O)[CH2:6]1>[OH-].[Na+].O1CCOCC1.O>[OH:3]/[N:2]=[CH:17]/[CH:16]=[CH:15]/[C@H:14]1[CH2:13][CH2:12][C@:11]2([OH:28])[C@H:10]3[C@H:22]([CH2:21][CH2:20][C@:19]12[CH3:27])[C@:23]1([CH3:26])[C@@H:7]([CH2:6][C@@H:5]([OH:4])[CH2:25][CH2:24]1)[CH2:8][CH2:9]3
Reactant: NO
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](/C=C/C=O)CC[C@]12O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](/C=C/C=N/O)CC[C@]12O
Yield: 63.9 %

Procedure:
To a solution of 0.65 g of hydroxylamine hydrochloride in 41 ml of 1N NaOH and 30 ml of dioxane a solution of 2.70 g of (E)-3β,14β-dihydroxy-5β-pregn-20-ene-21-carboxaldehyde (Fullerton D. S. et al., J. Med. Chem., 1976, 19,1330) in 40 ml of dioxane was added dropwise at room temperature. After 20 hrs the solution was diluted with water and extracted with methylene chloride. The crude product was purified by flash chromatography (SiO2) using hexane/ethyl acetate 1/1 as the eluant. The fractions containing the title compound were collected and evaporated to dryness. The residue was ground with di-iso-propyl ether to give 1.80 g of the title compound (I-am), as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:13][C:14]([NH:16][CH3:17])=[O:15])=[CH:9][CH:10]=2)[NH:5][N:4]=1.N1C2C(=CC=CC=2C(C2C=CC=CC=2)CC(NC)=O)C=C1>>[CH3:1][O:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([CH:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:13][C:14]([NH:16][CH3:17])=[O:15])=[CH:9][CH:10]=2)[NH:5][N:4]=1
Reactant: CNC(=O)C=C(c1ccc2c(OC)n[nH]c2c1)c1ccccn1
Agent: CNC(=O)CC(c1ccccc1)c1cccc2cc[nH]c12
Product: CNC(=O)CC(c1ccc2c(OC)n[nH]c2c1)c1ccccn1

Procedure:
3-(3-Methoxy-1H-indazol-6-yl)-N-methyl-3-pyridin-2yl-propionamide CCXLVI was prepared from 3-(3-methoxy-1H-indazol-6-yl)-N-methyl-3-pyridin-2yl-acrylamide using the procedure described for preparation of 3-(1H-Indol-7-yl)-N-methyl-3-phenyl-propionamide XIX (Example 4). The crude product (90% yield) was purified via chiral preparative HPLC by multiple injections onto 20×250 mm Chiralpak AD preparative column using a mixture of 60/40 hexane/isopropanol at 7 ml/min affording the enatiomer CCXLVI-A (αD=−0.269°) and the enantiomer CCXLVI-B (αD=+0.209°).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:17])=[C:6]([CH:8]=[N:9][C:10]([O:12][Si](C)(C)C)=[CH2:11])[CH:7]=1.[C:18]([O:22][C:23]([N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([Cl:34])[CH:32]=2)/[C:27](=[CH:35]/[C:36]2[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:37]=2[O:43][CH2:44][C:45]2([C:50]#[N:51])[CH2:49][CH2:48][CH2:47][CH2:46]2)/[C:26]1=[O:52])=[O:24])([CH3:21])([CH3:20])[CH3:19].CO>C1(C)C=CC=CC=1>[C:18]([O:22][C:23]([N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([Cl:34])[CH:32]=2)[C:27]2([CH:35]([C:36]3[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:37]=3[O:43][CH2:44][C:45]3([C:50]#[N:51])[CH2:49][CH2:48][CH2:47][CH2:46]3)[CH2:12][C:10](=[O:11])[NH:9][CH:8]2[C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[CH3:17])[C:26]1=[O:52])=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1C(=O)/C(=C\c2cc(Cl)ccc2OCC2(C#N)CCCC2)c2ccc(Cl)cc21
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCC2(C#N)CCCC2)C12C(=O)N(C(=O)OC(C)(C)C)c1cc(Cl)ccc12
Temperature: 70 °C
Yield: 6.2 %

Procedure:
To a solution of 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (30 mmol) in toluene (30 mL) was added E/Z-6-Chloro-3-[5-chloro-2-(1-cyano-cyclopentylmethoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (6 g, 11.7 mmol). Then the reaction mixture were heated at 70° C. overnight. After the solution was cooled to room temperature, methanol was added. The solution was concentrated and the residue was purified by flash column to give the title compound as a white solid (500 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([O:11][CH:12]([CH3:14])[CH3:13])(=[O:10])=[O:9].F[C:16]1C=CC=CC=1S(Cl)(=O)=O.C([Li])CCC.IC.FC1C=CC=C(C)C=1S(OC(C)C)(=O)=O>>[F:1][C:2]1[C:7]([CH3:16])=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([O:11][CH:12]([CH3:14])[CH3:13])(=[O:9])=[O:10]
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: CC(C)OS(=O)(=O)c1ccccc1F
Agent: Cc1cccc(F)c1S(=O)(=O)OC(C)C
Agent: [Li]CCCC
Solvent: CI
Product: Cc1cccc(S(=O)(=O)OC(C)C)c1F

Procedure:
Isopropyl 2-fluorobenzenesulfonate was made from 2-fluorobenzenesulfonyl chloride and treated first with butyl lithium and then with iodomethane in a manner analogous to that set forth above in Example to yield isopropyl 2-fluoro-6-methylbenzenesulfonate (formed as a 2:1 mixture with isopropyl 2-fluoro-3-methylbenzenesulfonate as the minor isomer).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:20])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[OH:19].[C:21](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:20])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[O:19][CH3:21]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C(=O)Nc2ccc(F)cc2F)c(O)c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc(C(=O)Nc2ccc(F)cc2F)c(OC)c1
Temperature: 25 °C

Procedure:
To a solution of compound 4a (0.56 g, 2 mmole) in anhydrous acetone (10 mL) were added potassium carbonate (0.69 g, 5 mmole) and iodomethane (0.28 mL, 4.4 mmole) and refluxed 8 hr. After cooled to room temperature, the reaction mixture was filtered through Celite and concentrated. The residue was extracted with ethyl acetate and dried over anhydrous magnesium sulfate, then concentrated and recrystallized with hot methanol.
Reaction SMILES: [S:1]1[C:5]2[NH:6][C:7]([C:9]([O:11][CH3:12])=[O:10])=[CH:8][C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)=[O:18]>CN(C=O)C>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([C:17](=[O:18])[CH2:16][N:6]2[C:7]([C:9]([O:11][CH3:12])=[O:10])=[CH:8][C:4]3[CH:3]=[CH:2][S:1][C:5]2=3)=[CH:20][CH:21]=1
Reactant: COC(=O)c1cc2ccsc2[nH]1
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccsc2n1CC(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 55.2 %

Procedure:
To a solution of methyl 6H-thieno[2,3-b]pyrrole-5-carboxylate (100 mg, 0.55 mmol) in DMF (2 mL) was added sodium hydride (15 mg, 0.63 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour before 2-bromo-1-(4-methoxyphenyl)ethanone (251 mg, 1.1 mmol) was added. After 5 minutes, the reaction was allowed to warm to room temperature and stirred for 1 hour. The mixture was then poured into ice water and the resulting precipitate collected by filtration and washed with hexanes to yield methyl 6-[2-(4-methoxyphenyl)-2-oxoethyl]-6H-thieno[2,3-b]pyrrole-5-carboxylate (100 mg, 55% yield) as a white solid. ESI-MI m/z [M+H]+ 330.15. 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J=8.8 Hz, 2H), 7.25 (s, 1H), 7.02 (d, J=5.3 Hz, 1H), 6.99 (d, J=8.8 Hz, 2H), 6.91 (d, J=5.3 Hz, 1H), 5.84 (s, 2H), 3.90 (s, 3H), 3.78 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:21](I)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[F:23][C:24]1[CH:25]=[N:26][CH:27]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:29]=1.CCCCCC>C(Cl)Cl>[Cl:1][C:2]1[C:21]([C:28]2[CH:27]=[N:26][CH:25]=[C:24]([F:23])[CH:29]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(I)c1
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Solvent: CCCCCC
Solvent: ClCCl
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2cncc(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 223.1 using 6-chloro-5-iodo-N-(4-(trifluoromethoxy)phenyl)nicotinamide and 3-fluoropyridine-5-boronic acid pinacol ester. The crude product was dissolved in DCM (20 mL) and treated with n-hexane. The resulting solid was filtered off, washed with n-hexane and dried to afford the title product as a beige solid. UPLC-MS (Condition 3) tR=1.13 min, m/z=412 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14](=[NH:16])[NH2:15])=[N:6]1.O=[C:22]([CH3:28])[CH2:23][C:24](OC)=[O:25]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:24]([OH:25])[CH:23]=[C:22]([CH3:28])[N:16]=2)=[N:6]1
Reactant: N=C(N)c1nn(Cc2ccccc2F)c2ncccc12
Reactant: COC(=O)CC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc(O)nc(-c2nn(Cc3ccccc3F)c3ncccc23)n1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
2.00 g (7.43 mmol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide (example I, step 5) are dissolved together with 1.04 g (8.91 mmol) of methyl 3-oxobutanoate in 10 ml of absolute toluene under argon and stirred under reflux for 8 hours. A further 8.91 mmol of methyl 3-oxobutanoate are added, and stirring under reflux temperature is continued for 24 hours. This is followed by cooling to 0° C., removal of the precipitated solid by filtration and drying under high vacuum. 1.98 g (72% of theory) of the product are obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:34])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:17]2[C:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:23](Br)[O:22][C:18]=2[N:19]=[CH:20][N:21]=1.[CH3:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:7][O:8][C:9](=[O:34])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:17]2[C:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:23]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[CH3:35])[O:22][C:18]=2[N:19]=[CH:20][N:21]=1
Reactant: COC(=O)CCCCCNc1ncnc2oc(Br)c(-c3ccc(OC)cc3)c12
Reactant: Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)CCCCCNc1ncnc2oc(-c3ccccc3C)c(-c3ccc(OC)cc3)c12
Reaction time: 15 h

Procedure:
Add 0.5 ml of 2 M aqueous potassium carbonate solution to a mixture of 224 mg (0.50 mmol) 6-{[6-bromo-5-(4-methoxyphenyl)furo[2,3-d]pyrimidin-4-yl]amino}hexanoic acid methyl ester and 29 mg (0.03 mmol) tetrakis(triphenylphosphine)palladium(0) in 2.5 ml 1,2-dimethoxyethane. Next, add 85 mg (0.63 mmol) (2-methylphenyl)boronic acid and stir the mixture for 15 h under reflux. Filter the reaction mixture and purify directly by preparative RP-HPLC (gradient: water/acetonitrile). 68 mg (30% of theor.) of the desired product is obtained.
Reaction SMILES: CN(C)C=O.[CH3:6][C:7]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:8]=1.CS(O[CH2:27][CH2:28][C:29]([CH3:33])=[C:30]([F:32])[F:31])(=O)=O.C(=O)([O-])O.[Na+]>O>[CH3:6][C:7]1[C:12]([C:13]([O:15][CH2:27][CH2:28][C:29]([CH3:33])=[C:30]([F:32])[F:31])=[O:14])=[CH:11][N:10]=[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:8]=1
Reactant: Cc1nc(-c2ccccc2)ncc1C(=O)O
Reactant: CC(CCOS(C)(=O)=O)=C(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(CCOC(=O)c1cnc(-c2ccccc2)nc1C)=C(F)F
Temperature: 100 °C
Reaction time: 3 h
Yield: 73.3 %

Procedure:
To 5 ml of N,N-dimethylformamide were dissolved 0.34 g (1.6 mmol) of 4-methyl-2-phenylpyrimidine-5-carboxylic acid, synthesized in accordance with a method described in “J. Chem. Soc.”, page 2183 (1923), and 0.30 g (1.5 mmol) of 4,4-difluoro-3-methyl-3-butenyl methanesulfonate, followed by the addition of 0.27 g (3.2 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 3 hours. The reaction liquid was then poured in water and extracted with diethtyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (diisopropyl ether:hexane=1:4) to obtain 0.35 g (yield: 73%) of 4,4-difluoro-3-methyl-3-butenyl 4-methyl-2-phenylpyrimidine-5-carboxylate.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:11]3([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]3)[CH2:10][N:9]([C:23]([O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[O:24])[C:6]2=[CH:7][CH:8]=1)=[O:2].[BH4-].[Na+].O>C(O)C>[OH:2][CH2:1][C:3]1[CH:4]=[C:5]2[C:11]3([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:12]3)[CH2:10][N:9]([C:23]([O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[O:24])[C:6]2=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(C1)CN(C(=O)OCC[Si](C)(C)C)c1ccc(C=O)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(C1)CN(C(=O)OCC[Si](C)(C)C)c1ccc(CO)cc12
Reaction time: 0.5 h
Yield: 85 %

Procedure:
1-(2-(Trimethylsilyl)ethyl) 1′-tert-butyl 5-formylspiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (553 mg, 1.24 mmol) was dissolved in ethanol (12 mL). Thereafter, sodium borohydride (76.0 mg, 2.01 mmol) was added to the above obtained solution under cooling on ice, and the thus obtained mixture was then stirred at the same temperature as above for 30 minutes. Thereafter, water was added to the reaction solution, and the mixed solution was then extracted with chloroform. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain 1-(2-(trimethylsilyl)ethyl) 1′-tert-butyl 5-(hydroxymethyl)spiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (473 mg, 85%) in the form of a light yellow solid.