Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]2[C:18](=[CH:19][CH:20]=1)[CH2:17][C:7]1([C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]1=[O:16])[CH2:6]2.[O:21]=[C:22]1[N:26]2[CH2:27][C:28](=[O:34])[NH:29][C:30]3[CH:31]=[CH:32][CH:33]=[C:24]([C:25]=32)[N:23]1[CH2:35][C:36]([OH:38])=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[O:21]=[C:22]1[N:26]2[CH2:27][C:28](=[O:34])[NH:29][C:30]3[CH:31]=[CH:32][CH:33]=[C:24]([C:25]=32)[N:23]1[CH2:35][C:36]([N:2]([CH3:1])[C:3]1[CH:4]=[C:5]2[C:18](=[CH:19][CH:20]=1)[CH2:17][C:7]1([C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]1=[O:16])[CH2:6]2)=[O:38]
Reactant: O=C(O)Cn1c(=O)n2c3c(cccc31)NC(=O)C2
Reactant: CNc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)Cn1c(=O)n2c3c(cccc31)NC(=O)C2)c1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21

Procedure:
A mixture of 5-(methylamino)-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one, enantiomer B (14 mg, 0.053 mmol, described in Intermediate 19), (2,5-dioxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-1(2H)-yl)acetic acid (14 mg, 0.058 mmol, described in Intermediate 9), PyBOP (41 mg, 0.079 mmol), and N,N-diisopropylethylamine (0.028 mL, 0.158 mmol) was stirred in DMF (1 mL) at 50° C. for 20 h. The reaction mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions were combined and lyophilized to give the title compound. MS: m/z=495 (M+1). HRMS: m/z=495.1778; calculated m/z=495.1776 for C27H23N5O4.
Reaction SMILES: C1C=[C:9]2[C:4]([CH:5]=[C:6]([CH2:11][C@H:12]([NH2:16])[C:13]([OH:15])=[O:14])[CH:7]=[CH:8]2)=CC=1.C([O-])(=O)CC[C@H](NC(C1C=CC(NCC2CNC3N=C(NC(C=3N=2)=O)N)=CC=1)=O)C(O)=[O:22]>>[NH2:16][C@H:12]([C:13]([OH:15])=[O:14])[CH2:11][C:6]1[CH:7]=[CH:8][C:9]([OH:22])=[CH:4][CH:5]=1
Reactant: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: Nc1nc2c(c(=O)[nH]1)N=C(CNc1ccc(C(=O)N[C@@H](CCC(=O)[O-])C(=O)O)cc1)CN2
Product: N[C@@H](Cc1ccc(O)cc1)C(=O)O

Procedure:
An L-3-(2-naphthyl)-alanine mutant of mouse dihydrofolate reductase (DHFR) was generated and characterized to confirm the ability of the mtRNACUATyr/SS12-TyrRS pair to site-specifically incorporate L-3-(2-naphthyl)-alanine in response to an amber stop codon. The Tyr163 codon of the mouse DHFR gene was mutated to TAG, and a His6 tag was added to the COOH-terminus of DHFR to facilitate protein purification using Ni2+ affinity chromatography. As a positive control, wild-type M. jannaschii TyrRS was coexpressed with the mtRNACUATyr resulting in efficient suppression of the TAG codon with tyrosine (FIG. 4). When SS12-TyrRS was coexpressed with the mu tRNACUATyr in the presence of 1 mM L-3-(2-naphthyl)-alanine, full-length mouse DHFR was also generated (with yield of 2.2 mg/L in liquid GMML minimal medium). In the absence of either L-3-(2-naphthyl)-alanine, mtRNACUATyr, or SS12-TyrRS, no full length DHFR was produced. A penta-His antibody was used to detect the His6 tag at the COOH-terminus of DHFR in a Western blot. No DHFR could be detected in the absence of each of the above three components.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C:13]([CH3:39])([CH3:38])[C:14]([N:16]([CH3:37])[C:17]2[CH:18]=[N:19][C:20]([N:31]3[CH2:36][CH2:35]S[CH2:33][CH2:32]3)=[CH:21][C:22]=2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[CH3:30])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O[O:43][S:44]([O-:46])=O.[K+].S([O-])(O[O-])(=O)=O.[K+].[K+].S([O-])(O)=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CO>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C:13]([CH3:39])([CH3:38])[C:14]([N:16]([C:17]2[CH:18]=[N:19][C:20]([N:31]3[CH2:32][CH2:33][S:44](=[O:46])(=[O:43])[CH2:35][CH2:36]3)=[CH:21][C:22]=2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[CH3:30])[CH3:37])=[O:15])[CH:4]=[C:3]([C:2]([F:40])([F:41])[F:1])[CH:8]=1
Reactant: Cc1cc(F)ccc1-c1cc(N2CCSCC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=S([O-])OO
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O[O-]
Agent: O=S([O-])O
Solvent: CO
Product: Cc1cc(F)ccc1-c1cc(N2CCS(=O)(=O)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide can be produced by suspending 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-[4-(4-fluoro-2-methyl-phenyl)-6-thiomorpholin-4-yl-pyridin-3-yl]-isobutyramide in methanol and treating it at room temperature with oxone™ (potassium peroxymonosulfate). The suspension is then stirred for about 16 hours at room temperature and cooled to about 0° C., followed by the dropwise addition of sodium hydrogen sulfite solution. After stirring at room temperature, the pH is adjusted to about 8.5 with saturated aqueous sodium carbonate. The methanol is then evaporated under reduced pressure, and the residue is extracted with dichloromethane. The organic phase is washed with half-saturated aqueous sodium chloride. The solvent is exchanged under reduced pressure in a rotary evaporator with isopropanol, and the volume reduced. The solution is cooled to room temperature under stirring and stirred further for about 1 hour. The precipitate formed is filtered off, washed with isopropanol, and dried under high vacuum to yield 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(1,1-dioxothiomorpholin-4-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.[C:11]([O:20][CH3:21])(=[O:19])[C:12]([CH2:14][C:15](OC)=[O:16])=[CH2:13]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:15](=[O:16])[CH2:14][CH:12]([C:11]([O:20][CH3:21])=[O:19])[CH2:13]2)=[CH:5][CH:4]=1
Reactant: C=C(CC(=O)OC)C(=O)OC
Reactant: COc1ccc(CN)cc1
Solvent: CCOC(C)=O
Product: COC(=O)C1CC(=O)N(Cc2ccc(OC)cc2)C1
Temperature: 120 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
A mixture of (4-methoxyphenyl)methanamine (6.9 g) and dimethyl itaconate (7.9 g) was stirred at 120° C. for 2 hours. After cooling, ethyl acetate was added to the reaction solution. The organic layer was washed with 1 N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, and saturated saline in this order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (12.7 g).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)=[N:13][C:14](N)=[C:9]3[C:8]([C:22]#[N:23])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=[O:27].N([O-])=O.[Na+].[OH-].[NH4+]>C(O)(=O)C.O>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)=[N:13][C:14](=[O:27])[C:9]3=[C:8]([C:22]#[N:23])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1nn(C2CCCC2)c2nc(-c3ccncc3)nc(N)c12
Reactant: O=C(O)C(F)(F)F
Agent: O=N[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1[nH]n(C2CCCC2)c2nc(-c3ccncc3)nc(=O)c1-2
Temperature: -2.5 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a solution of 1-cyclopentyl-3-cyano-6-(4-pyridyl)pyrazolo(3,4-d)pyrimidin-4-amine (0.61 g, 2.0 mmol) in 50% acetic acid (70 ml) at -5 to 0° C. was added 50% trifluoroacetic acid (10 ml) followed by sodium nitrite (2.8 g, 40.6 mmol) in water (15 ml). The reaction mixture was stirred at -5 to 0° C. for 1 hour, then at room temperature for 3 hours. The reaction mixture was cooled back to -5 to 0° C. and sodium nitrite (1.4 g, 20.3 mmol) in water (5 ml) was added. The reaction mixture was warmed to room temperature and stirred for 3 hours. The mixture was poured onto ice-water, concentrated ammonium hydroxide was added, followed by acetic acid to adjust the pH to 5. The product was collected by filtration, washed with water and recrystallized from ethanol to afford 0.48 g (79%) of 1-cyclopentyl-3-cyano-6-(4-pyridyl) pyrazolo[3,4-d]pyrimidin-4-one as a white fluffy powder, m.p. >300° C. when dried at 110° C. for 96 hours in high vacuum.
Reaction SMILES: Br[CH2:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1>CC(C)=O>[S:4]1[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=[C:3]1[CH2:2][O:25][C:22]1[CH:23]=[CH:24][C:19]([NH2:18])=[CH:20][CH:21]=1
Reactant: BrCc1nc2ccccc2s1
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: Nc1ccc(OCc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 8.5 h
Yield: 52.4 %

Procedure:
4.56 g of 2-bromomethylbenzothiazole and 3.25 g of cesium carbonate were added to a solution of 2.17 g of 4-aminophenol in 70 ml of acetone, and the resulting mixture was stirred at room temperature for 8.5 hours, after which a further 3.25 g of cesium carbonate were added and the reaction mixture was stirred at room temperature for a further 4 hours. The reaction mixture was then filtered and the filtrate was concentrated by evaporation under reduced pressure. The resulting crude crystalline solid was purified by column chromatography through silica gel using a mixture of hexane and ethyl acetate as the eluent, initially using a gradient of the two solvents starting with a 1: 1 by volume mixture and changing to a final 3:2 by volume mixture to give 2.67 g (yield 52%) of the title compound as a solid having a melting point of 87° to 89° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8](=[O:15])[CH2:9][C:10](OCC)=[O:11])[CH:5]=[CH:6][CH:7]=1.[C:16]([OH:20])([CH3:19])([CH3:18])[CH3:17]>>[I:1][C:2]1[CH:3]=[C:4]([C:8](=[O:15])[CH2:9][C:10]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1cccc(I)c1
Reactant: CC(C)(C)O
Product: CC(C)(C)OC(=O)CC(=O)c1cccc(I)c1
Yield: 38 %

Procedure:
Ethyl 3-(3-iodophenyl)-3-oxopropanoate (29.3 g, 92.1 mmol) was heated to 120° C. in a sealed tube in t-butanol (80 mL) for 4 hours. The mixture was concentrated in vacuo and purified by column chromatography (0–3% ethyl acetate in hexanes) to provide the titled compound (12.1 g, 38%).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH:11]([CH3:13])[CH3:12])[N:3]=1.[B:14]1([OH:24])[C:18]2[CH:19]=[CH:20][C:21]([OH:23])=[CH:22][C:17]=2[CH2:16][O:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:24][B:14]1[C:18]2[CH:19]=[CH:20][C:21]([O:23][C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH:11]([CH3:13])[CH3:12])[N:3]=3)=[CH:22][C:17]=2[CH2:16][O:15]1
Reactant: CC(C)Oc1nc(Cl)ccc1C#N
Reactant: OB1OCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1nc(Oc2ccc3c(c2)COB3O)ccc1C#N
Temperature: 80 °C
Yield: 25.5 %

Procedure:
To a mixture of 6-chloro-2-isopropoxy-nicotinonitrile (0.73 g, 4.0 mmol) and 3H-Benzo[c][1,2]oxaborole-1,5-diol (0.40 g, 2.66 mmol) in DMF (10 mL) was added potassium carbonate (1.10 g, 7.98 mmol). The resulting suspension was heated at 80° C. overnight. DMF was removed under reduced pressure, the residue was diluted with EtOAc (50 mL), washed with water (10 mL) and brine (2×10 mL), dried over Na2SO4, filtered, and concentrated to give brown oil. Purification was accomplished by reverse phase preparative HPLC using MeOH/H2O (0.1% AcOH) as the eluent to yield the title compound (0.21 g, 21%) as white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.27 (s, 1H), 8.23 (d, J=8.6 Hz, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.29 (s, 1H), 7.22-7.14 (m, 1H), 6.70 (d, J=8.2 Hz, 1H), 4.99 (s, 2H), 4.85 (sept., J=6.3 Hz, 1H), 1.19 (d, J=6.3 Hz, 6H); MS (ES) m/z: 311 (M+1)+; HPLC purity 98.44% (Maxplot), 97.99% (220 nm).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[CH2:23]1OC(O)C[O:25][CH:24]1O.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[OH:25][CH2:24][CH2:23][NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:20])[F:21])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: Nc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Reactant: OC1COC(O)CO1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2ccccc2C(F)(F)F)cc2ccc(NCCO)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.4 %

Procedure:
350 mg (1.15 mmol) of the 7-amino-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in Example 38 was dissolved in 11.5 ml of methanol, and thereafter, 1.15 ml of acetic acid and 552.5 mg (4.60 mmol) of glycolaldehyde dimer were added thereto. Thereafter, 722 mg (11.5 mmol) of sodium cyanoborohydride was added to the mixture under cooling on ice. The temperature of the mixture was increased to a room temperature, and the mixture was then stirred for 8 hours. Thereafter, a saturated sodium bicarbonate aqueous solution was added to the reaction solution, and the mixture was then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and was then concentrated. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=20:1 to 12:1), so as to obtain 61.8 mg (15%) of 7-(2-hydroxyethylamino)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one in the form of a yellow amorphous substance, as well as 369.3 mg (82%) of 7-[bis(2-hydroxyethyl)amino]-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one in the form of a yellow foaming substance.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[CH:5][CH2:4][CH2:3]1.[C:17](Cl)(=O)C>CO>[O:1]=[C:2]1[C:7]([CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC(=O)Cl
Reactant: O=C(O)CCC/C=C\CC1C=CCCC1=O
Solvent: CO
Product: COC(=O)CCC/C=C\CC1=CCCCC1=O
Reaction time: 62.4 h

Procedure:
A solution of 13.0 g of crude 7-(6-oxocyclohex-2-enyl)hept-5Z-enoic acid in 200 ml of dry methanol was stirred under argon as 2 ml of acetyl chloride was added. The resultant yellow solution was left to stand for 2.6 days (on another occasion 16 hr was found to be sufficient). Solvent was removed by evaporation in vacuo and the residue was dissolved in ether and washed with saturated aqueous sodium bicarbonate. The wash solution was back extracted with ether. The combined ether extracts were dried (MgSO4) and evaporated in vacuo to yield 11.6 g of crude methyl 7-(6-oxocyclohex-1-enyl)hept-5Z-enoate as a yellow oil. This product was purified by chromatography on silicic acid-Celite (85:15) using benzene to ethyl acetate gradient elution to give 0.78 g of ca. 80% pure material and 8.41 g of pure material.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][CH2:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]#[N:17])=[CH:11][C:10]=1[CH2:18][CH3:19])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:22][OH:23].CCN(CC)CC>CO>[C:1]([O:5][C:6](=[O:20])[CH2:7][CH2:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16](=[NH:17])[NH:22][OH:23])=[CH:11][C:10]=1[CH2:18][CH3:19])([CH3:3])([CH3:4])[CH3:2]
Reactant: NO
Reactant: CCc1cc(C#N)cc(C)c1CCC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCc1cc(C(=N)NO)cc(C)c1CCC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 98.6 %

Procedure:
A solution of 3-(4-cyano-2-ethyl-6-methyl-phenyl)-propionic acid tert-butyl ester (37.0 g, 135 mmol), hydroxylamine hydrochloride (14.1 g, 203 mmol) and NEt3 (27.4 g, 271 mmol) in MeOH (400 mL) is heated to reflux for 7 h before it is cooled to rt. The solvent is evaporated and the residue is taken up in isopropylacetate (500 mL) and washed twice with water (500 mL). The org. extract is dried over MgSO4, filtered, evaporated and dried to give 3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenyl]-propionic acid tert-butyl ester (40.8 g) as a pale yellow solid; 1H NMR δ 1.26 (t, J=7.5 Hz, 3H), 1.49 (s, 9H), 2.33-2.41 (m, 5H), 2.66-2.74 (m, 2H), 2.93-3.01 (m, 2H), 4.85 (s, 1H), 7.28 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=1B(O)O>CN(C=O)C>[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1
Reactant: Cc1ccc(F)c(B(O)O)c1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Solvent: CN(C)C=O
Product: Cc1ccc(F)c(-c2ccncc2N(C)C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 2-fluoro-5-methylphenylboronic acid (CAS RN 166328-16-1) and using DMF as reaction solvent. Pale yellow solid (26%). MS (ESI): m/z=457.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].O[N:21]=[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:25]=1)[NH2:23]>>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:12][N:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:25]=3)[N:21]=2)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19]
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Reactant: CS(=O)(=O)c1cccc(C(N)=NO)c1
Product: COCc1cc(-c2nc(-c3cccc(S(C)(=O)=O)c3)no2)ccc1-c1ccccc1C

Procedure:
The title compound was obtained following procedure described for example 54 step 1 but starting from Intermediate 28 (112 mg; 0.44 mmol) and Intermediate 64 (197 mg; 0.44 mmol). Purification by column chromatography (EtOAc:cHex from 10:90 to 50:50) yielded to a colorless oil. Trituration in ACN/pentane followed by filtration gave the title compound as an off-white powder. 1H NMR (DMSO-d6, 300 MHz) δ 8.59 (t, J=1.7 Hz, 1H), 8.47 (m, 1H), 8.35 (d, J=1.7 Hz, 1H), 8.21 (m, 2H), 7.93 (t, J=8.0 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.33 (m, 3H), 7.15 (d, J=7.1 Hz, 1H), 4.23 (d, J=13.8 Hz, 1H), 4.17 (d, J=13.8 Hz, 1H), 3.35 (s, 3H), 3.26 (s, 3H), 2.04 (s, 3H). LC/MS (Method B): 435.3 (M+H)+. HPLC (Method A) Rt 5.35 min (Purity: 97.6%).
Reaction SMILES: [OH-].[Na+].[O:3]=[C:4]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:8][CH:7]=[CH:6][C:5]1=2.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCCl>[C:13]1([S:19]([N:8]2[C:9]3[CH2:10][CH2:11][CH2:12][C:4](=[O:3])[C:5]=3[CH:6]=[CH:7]2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCCc2[nH]ccc21
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: O=C1CCCc2c1ccn2S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaOH (4.44 g) in 1,2-dichloroethane (250 mL) was added 4-oxo-4,5,6,7-tetrahydroindole (5.0 g). The mixture was then cooled to 0° C. and stirred for 30 min, following which a solution of phenylsulfonyl chloride (5.7 mL) in 1,2-dichloroethane (50 mL) was added dropwise over a period of 30 min. After 30 min of stirring, the reaction mixture was allowed to come to room temperature and stirred overnight. The reaction was quenched by pouring onto distilled water (100 mL). The organic layer was separated, and the aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic extract was washed with distilled water to neutrality, dried over MgSO4, and concentrated in vacuo to afford 7.0 g of the title compound.
Reaction SMILES: [CH2:1]([CH:8]([C:14]([O:16]CC)=[O:15])[C:9]([O:11]CC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C.O>[CH2:1]([CH:8]([C:9]([OH:11])=[O:10])[C:14]([OH:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C(Cc1ccccc1)C(=O)O

Procedure:
Diethyl benzylmalonate (100 g, 400 mmol) was dissolved in ethanol (300 mL) and treated with a solution of potassium hydroxide (134.4 g, 2.4 mol) in water (500 mL). The mixture was heated under reflux for 5 hours and then allowed to cool. Ethanol was removed under reduced pressure and the remaining aqueous solution cooled in ice and acidified to pH1 with concentrated HCl. The product was extracted with ethyl acetate (3×200 mL). The combined extracts were washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure to yield benzylmalonic acid as a white crystalline solid. The solid was taken-up in ethanol (250 mL) and treated portionwise with piperidine (33 g, 397 mmol) followed by an aqueous solution of formaldehyde (37%, 150 mL) which resulted in formation of a white precipitate. The reaction mixture was heated and treated with methanol (50 mL) to give a homogeneous solution. Following dissolution the reaction mixture was heated under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure. The aqueous residue was acidified to pH1 with 1 M HCl and the product extracted with ethyl acetate (3×150 mL). The combined extracts were washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure to yield 2-benzyl-acrylic acid as a colourless oil which crystallized on standing (45 g, 75%). 1H-NMR; δ (CDCl3), 7.32-7.17 (5H, m), 6.36 (1H, s), 5.54 (1H, d, J=1.3 Hz), 3.61 (2H, s).
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(OCC)=O)C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:27][C:28]1[S:32][C:31]([CH:33]=O)=[CH:30][CH:29]=1>C1COCC1>[CH3:33][C:31]1[S:32][C:28](/[CH:27]=[CH:9]/[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[CH:29][CH:30]=1
Reactant: Cc1ccc(C=O)s1
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(/C=C/C(=O)OC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of tert-butyl diethylphosphonoacetate (1.12 mL, 4.76 mmol) in THF (5 mL) at −78° C. was added LHMDS (1.0M in THF, 4.76 mL, 4.76 mmol). After 5 min at −78° C. 5-methyl-2-thiophene-carboxaldehyde (0.43 mL, 3.96 mmol) was added. The reaction mixture was warmed to RT, stirred for 10 min and poured onto EtOAc/H2O. The layers were separated and the organic layer was washed with H2O, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica (gradient elution; hexanes to 4:1 hexanes:EtOAc) to give tert-butyl (2E)-3-(5-methylthien-2-yl)prop-2-enoate as a clear oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:15]=[CH:14][NH:13][N:12]=3)=[N:9][N:8]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[C:5]2=[CH:6][N:7]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.C([O-])(=O)C.[K+].O>C(=O)([O-])[O-].[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[NH:13]1[CH:14]=[CH:15][C:11]([C:10]2[C:4]3[C:5](=[CH:6][N:7]=[C:2]([C:24]4[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=4)[CH:3]=3)[N:8]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[N:9]=2)=[N:12]1
Reactant: OB(O)c1cccnc1
Reactant: Brc1cc2c(-c3cc[nH]n3)nn(C3CCCCO3)c2cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: c1cncc(-c2cc3c(-c4cc[nH]n4)nn(C4CCCCO4)c3cn2)c1
Temperature: 130 °C
Yield: 48 %

Procedure:
A microwave reaction vials was charged with 5-bromo-3-(1H-pyrazol-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine as an off-white solid (153.7 mg 0.44 mmol), 3-Pyridylboronic acid (81.62 mg, 0.66 mmol), 1,1′-Bis(diphenylphosphino)ferrocenepalladium (II) chloride (36.15 mg, 0.044 mmol), 1.00 M of Potassium acetate in Water (0.66 mL, 0.66 mmol), 1.00 M of Sodium carbonate in Water (0.66 mL, 0.66 mmol), and Acetonitrile (3 mL). The reaction mixture was heated under microwave at 130° C. for 20 minutes The mixture was concentrated and the residue was purified on silica eluted with 0 to 7% MeOH in DCM with 1% NH4OH to afford 3-(1H-pyrazol-3-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine (73.4 mg, 48%).