Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.[OH:16][C@@H:17]([C@H:19]1[CH2:23][N:22]([C@@H:24]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH3:25])[C:21](=[O:34])[CH2:20]1)[CH3:18].[Cl:35][C:36]1[N:41]=[C:40](S(C)(=O)=O)[C:39]2[N:46]([CH3:49])[CH:47]=[N:48][C:38]=2[CH:37]=1>CN(C=O)C>[Cl:35][C:36]1[N:41]=[C:40]([O:16][C@@H:17]([C@H:19]2[CH2:23][N:22]([C@@H:24]([C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)[CH3:25])[C:21](=[O:34])[CH2:20]2)[CH3:18])[C:39]2[N:46]([CH3:49])[CH:47]=[N:48][C:38]=2[CH:37]=1
Reactant: Cn1cnc2cc(Cl)nc(S(C)(=O)=O)c21
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)O)CC2=O)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(Cl)cc4ncn(C)c34)CC2=O)cc1
Temperature: 25 °C
Reaction time: 0.3 h

Procedure:
A solution of NaHMDS in THF (1.0 M, 1.05 mL, 1.05 mmol) was added to a solution of (R)-4-((R)-1-hydroxyethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 1.04 (277 mg, 1.05 mmol) in DMF (14 mL) at room temperature. After 18 minutes, a suspension of 6-chloro-3-methyl-4-(methylsulfonyl)-3H-imidazo[4,5-c]pyridine 2.04 (237 mg, 0.967 mmol) in DMF (4 mL) was added and mixture stirred at room temperature. After 40 minutes, LC/MS indicated full conversion to desired product. Reaction mixture was quenched with 15 mL of water, poured into 30 mL of water and extracted with ethyl acetate (3×50 mL). Combined organics were washed with 50% Brine (2×50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to a residue. This residue was purified by silica gel column chromatography (0-10% methanol in dichloromethane) to yield (R)-4-((R)-1-(6-chloro-3-methyl-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 2.05.
Reaction SMILES: [Li][C@H]1CC(C(O)=O)N([Li])C1=O.[Li]CCCC.[CH3:17][C:18]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[C:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1>CCOCC>[CH:19]1([CH:18]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH3:17])[CH:23]=[CH:22][CH:21]=[CH:20]1
Reactant: CC(=C1C=CC=C1)c1ccccc1
Agent: [Li]CCCC
Agent: [Li][C@H]1CC(C(=O)O)N([Li])C1=O
Solvent: CCOCC
Product: CC(c1ccccc1)C1C=CC=C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of 0.77 g of dilithio (s)-(-)-2-pyrrolidone-5-carboxylic acid (6 mmol) in 40 mL of ether was added 7.8 mL of n-BuLi (1.6M solution in hexances, 13 mmol) at 0° C. This solution was stirred for 30 min at room temperature. 6-Methyl-6-phenylfulvene, 1.0 g, (6 mmol) in 5 mL of ether was added dropwise at -78° C. and the color of the reaction mixture turned green. The resulting solution was stirred for 7 h at -78° C. and the solution warmed to room temperature. The organic layer was separated and washed with aqueous NaHCO3, H2O and then dried over MgSO4. Removal of solvent gave 1.0 g (99% yield) of 1-cyclopentadienyl-1-phenyl-ethane as a light yellow oil. [α]D =6.0° (CHCl3), 17.4% ee.
Reaction SMILES: [OH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:11]([O-])([O-:13])=[O:12].[Na+]>S(=O)(=O)(O)O>[OH:1][C:2]1[N:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(O)c1cccnc1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)c1cc([N+](=O)[O-])cnc1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 45 %

Procedure:
To 2-hydroxy-nicotinic acid (3.6 mmol) in sulfuric acid (30% free SO3, 2 ml) was added sodium nitrate (7.2 mmol) portionwise over 20 min. The solution was allowed to stir for 20 h at room temperature. The solution was then poured onto ice-water and the precipitate that formed was filtered off, washed with water and dried in a vacuum oven to afford a pale yellow solid (45%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=4[CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>>[Cl:30][C:19]1[CH:20]=[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=2[CH3:29])[C:15]2[O:14][CH:13]([CH2:12][NH:32][CH3:31])[CH2:17][C:16]=2[CH:18]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4cccc(C)c4C)c3O2)cc1
Product: CNCC1Cc2cc(Cl)cc(-c3cccc(C)c3C)c2O1

Procedure:
The title compound was prepared (0.054 g, 47%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-chloro-7-(2,3-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.149 g, 0.33 mmol) and methylamine (0.102 g, 3.3 mmol). mp 148-150° C.
Reaction SMILES: [N:1]1C=CC=CC=1C=O.[C:9]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19](=[CH2:23])[C:20]([OH:22])=[O:21])[CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>>[C:9]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19](=[CH2:23])[C:20]([OH:22])=[O:21])[CH:14]=1)([CH3:12])([CH3:11])[CH3:10].[N:16]1[CH:17]=[CH:18][CH:13]=[CH:14][C:15]=1[C:19](=[CH2:23])[C:20]([NH2:1])=[O:21]
Reactant: O=Cc1ccccn1
Agent: C=C(C(=O)O)c1cc(C(C)(C)C)ccn1
Product: C=C(C(N)=O)c1ccccn1

Procedure:
The Scheme 3 shows a proposed process for synthesizing pyridinyl acrylic amide (16) with t-butyl group. Substituted pyridinecarboxaldehyde with t-butyl group (12) is prepared by reduction followed by radical substitution method (J. Heterocyclic Chem., 1989, 25, 45-48). Substituted nicotinic ester (10) is converted to corresponding pyridine-3-methanol (11). Pyridinyl-3-methanol is reacted with pivalic acid and silver nitrate to give pyridinecarboxaldehyde (12) via Tada's radical substitution. Compound (14) is synthesized from compound (12) with similar method of scheme 2. 4-t-Butylpyridinyl acrylic acid (14) is reacted with compound (15) to yield compound (16).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([NH2:10])OCC)C.[CH3:12][C:13]1[CH:21]=[CH:20][C:16]([CH2:17][NH:18][NH2:19])=[CH:15][CH:14]=1.N1C=CC=CC=1>C(O)C.O>[NH2:10][C:6]1[NH:19][N:18]([CH2:17][C:16]2[CH:20]=[CH:21][C:13]([CH3:12])=[CH:14][CH:15]=2)[C:4](=[O:3])[CH:5]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: Cc1ccc(CNN)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: CCO
Product: Cc1ccc(Cn2[nH]c(N)cc2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
17.5 g of β-amino-β-ethoxyacrylic acid ethyl ester and 13.6 g of 4-methylbenzylhydrazine are introduced into 75 ml of pyridine. The mixture is stirred for 8 hours at room temperature and the pyridine is driven off under reduced pressure. The reisidue is treated with a solution of 4.6 g of Na in 100 ml of ethanol and the mixture is warmed to 60° for 1 hour. The alcohol is driven off and the residue is taken up in 100 ml of water. The aqueous phase is extracted with ether, clarified with charcoal and acidified. A yellow-colored precipitate is obtained, which melts at 149° after recrystallisation from alcohol. The yield is 7.3 g of the compound identified above, corresponding to 36% of theory.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[O:18][CH2:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[C:21]1([CH3:34])[CH:26]=[CH:25][C:24]([C:27]2[S:28][CH:29]=[C:30]([CH:32]=O)[N:31]=2)=[CH:23][CH:22]=1>>[CH2:19]([O:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[CH:2]1[N:1]([CH2:32][C:30]2[N:31]=[C:27]([C:24]3[CH:25]=[CH:26][C:21]([CH3:34])=[CH:22][CH:23]=3)[S:28][CH:29]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1)[CH3:20]
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OCC
Reactant: Cc1ccc(-c2nc(C=O)cs2)cc1
Product: CCOc1cccc(F)c1C1CC(C)C(=O)N1Cc1csc(-c2ccc(C)cc2)n1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-ethoxy-6-fluorophenyl)-2-methylbutanoate with commercially available 2-(p-tolyl)thiazole-4-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.98 min.; [M+H]+: 425.01 g/mol.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([NH:13][O:14][CH3:15])=[O:12])[C:5]([CH:20]2[CH2:22][CH2:21]2)=[CH:4][N:3]=1.[CH3:23][N:24]1[C:28]([NH2:29])=[CH:27][C:26]([CH3:30])=[N:25]1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH:20]1([C:5]2[C:6]([NH:8][C:9]3[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=3[C:11]([NH:13][O:14][CH3:15])=[O:12])=[CH:7][C:2]([NH:29][C:28]3[N:24]([CH3:23])[N:25]=[C:26]([CH3:30])[CH:27]=3)=[N:3][CH:4]=2)[CH2:22][CH2:21]1
Reactant: CONC(=O)c1ccccc1Nc1cc(Cl)ncc1C1CC1
Reactant: Cc1cc(N)n(C)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CONC(=O)c1ccccc1Nc1cc(Nc2cc(C)nn2C)ncc1C1CC1
Reaction time: 0.58 h

Procedure:
To a 10 mL microwave tube were added 2-(2-chloro-5-cyclopropyl-pyridin-4-ylamino)-N-methoxy-benzamide (0.075 g, 0.24 mmol, 1 eq), 2,5-dimethyl-2H-pyrazol-3-ylamine (0.05 g, 0.47 mmol, 2 eq), Cs2CO3 (0.23 g, 0.71 mmol, 3 eq), and 1,4-dioxane (3 mL). The resulting mixture was degassed with N2 for 15 min. To this was added Pd2(dba)3 (0.015 g, 0.014 mmol, 0.06 eq) and xanthphos (0.03 g, 0.06 mmol, 0.25 eq) and the mixture was again degassed with N2 for 30 min. The resulting mixture was irradiated in a CEM microwave at 120° C., 150 W for 35 min. After completion of reaction, solvent was removed under reduced pressure and crude compound was purified using column chromatography over silica gel (100-200 mesh) using 1% MeOH-DCM as the eluant followed by prep HPLC. Solid compound so obtained was washed with diethyl ether and pentane to give the title compound as an off white solid (11 mg, 12%). 1H-NMR (400 MHz, DMSO-d6): δ 0.52-0.60 (m, 2H), 0.82-1.00 (m, 2H), 1.50-1.62 (m, 1H), 2.05 (s, 3H), 3.52 (s, 3H), 3.70 (s, 3H), 5.96 (s, 1H), 6.67 (s, 1H), 6.98-7.10 (m, 1H), 7.40-7.60 (m, 3H), 7.73 (s, 1H), 8.39 (s, 1H), 9.46 (s, 1H), 11.88 (brs, 1H). LC-MS [M+H]+=393.4.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10]1(I)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1>CC([O-])=O.CC([O-])=O.[Pd+2]>[C:18]1([C:2]2[CH2:3][C:4]3[C:9]([CH:1]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:19]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: Ic1cccc2ccccc12
Reactant: C1=Cc2ccccc2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: C1=C(c2cccc3ccccc23)Cc2ccccc21
Temperature: 25 °C
Yield: 31 %

Procedure:
20 ml of triethylarine, 2.2 g (20 mmole) of indene, 5.08 g (20 mmole) of 1-naphtyl-iodide and 0.134 g (0.6 mmole) of Pd(OAc)2 were stirred under reflux for 10 h. After that the mixture was cooled to room temperature and evaporated. The residual oil was recrystallized from ethanol and dried under vacuum to obtain 1.5 g (31%) of the product.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]2[N:9]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]4[NH:31][N:30]=[N:29][N:28]=4)=[CH:17][CH:16]=3)[C:10]([CH2:12][CH3:13])=[N:11][C:6]2=[C:5]([CH3:32])[CH:4]=1)#[N:2].C[Sn]([N:37]=[N+:38]=[N-:39])(C)C.C1(C)C=CC=CC=1>CN(C=O)C>[CH2:12]([C:10]1[N:9]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:19][CH:20]=2)[C:7]2=[N:8][C:3]([C:1]3[NH:39][N:38]=[N:37][N:2]=3)=[CH:4][C:5]([CH3:32])=[C:6]2[N:11]=1)[CH3:13]
Reactant: CCc1nc2c(C)cc(C#N)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCc1nc2c(C)cc(-c3nnn[nH]3)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 110 °C
Yield: 79 %

Procedure:
A mixture of 5-Cyano-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine (54 mg), trimethylstannyl azide (79 mg), toluene (5 mL), and DMF (1 mL) was heated to 110° C. for 24 hour. Concentration and purification (SiO2, 70/30/1 CH2Cl2 /MeOH/NH4OH) gave 47 mg solid. 1H NMR (300 MHz, CD3OD) δ7.93 (s, 1H), 7.56-7.38 (m, 4H), 7.14-7.05 (AB quartet, 4H), 5.61 (s, 2H), 2.86 (q, 2H, J=7.5 Hz), 2.71 (s, 3H), 1.27 (t, 3H, J=7.5 Hz)
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=[CH:27][N:26]=3)[CH2:21][CH2:20]2)=[O:18])=[C:11]([N+:35]([O-])=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.Cl[Sn]Cl>CO>[NH2:35][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:14]([O:15][CH3:16])=[CH:13][C:12]=1[C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=[CH:27][N:26]=2)[CH2:21][CH2:20]1)=[O:18]
Reactant: COc1cc(C(=O)N2CCN(c3ncnc4ccccc34)CC2)c([N+](=O)[O-])cc1OCc1ccccc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)N2CCN(c3ncnc4ccccc34)CC2)c(N)cc1OCc1ccccc1
Yield: 119.3 %

Procedure:
[4-(Benzyloxy)-5-methoxy-2-nitrophenyl][4-(4-quinazolinyl)piperazino]methanone (600 mg, 1.2 mmol) was dissolved in methanol (10 mL), SnCl2.2H2O (810 mg, 3.6 mmol) was added and refluxed until the TLC indicated the completion of the reaction. The methanol was evaporated by vacuum and the aqueous layer was then adjusted to pH 8 with 10% NaHCO3 solution and extracted with ethyl acetate (2×30 mL). The combined organic phase was dried over Na2SO4 and evaporated under vacuum to afford the crude (450 mg, 95% yield). This was further purified by column chromatography using ethyl acetate:hexane (6:4) as a solvent system to obtain the pure product (8d) (672 mg, 80% yield). 1H NMR (CDCl3) δ 3.20-3.30 (m, 4H), 3.65-3.75 (m, 4H), 3.95 (s, 3H), 5.20 (s, 2H), 6.20 (s, broad NH2), 6.45-6.55, (t, 1H) 6.70 (s, 1H), 7.30-7.50 (m, 5H), 7.55-7.65 (t, 1H), 7.65 (s, 1H), 7.70-7.90, (m, 2H), 7.85-7.95, (m, 2H); FABMS: 470 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:34]#[N:35])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][C:25]3([C:29]([F:32])([F:31])[F:30])[CH2:28][CH2:27][CH2:26]3)[C:17]([O:19]C(C)(C)C)=[O:18])[C:10](=[O:33])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:34]#[N:35])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][C:25]3([C:29]([F:31])([F:32])[F:30])[CH2:28][CH2:27][CH2:26]3)[C:17]([OH:19])=[O:18])[C:10](=[O:33])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC2(C(F)(F)F)CCC2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(CC2(C(F)(F)F)CCC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
119 mg (purity 91%, 0.21 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[1-(trifluoromethyl)cyclobutyl]propanoate (racemate) were hydrolysed with TFA according to General Method 6A. Yield: 91 mg (purity 69%, 65% of theory)
Reaction SMILES: C(O)(=[O:3])C.[CH2:5]([O:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([CH:20]=[O:21])=[CH:16][CH:15]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O>[CH2:5]([O:12][C:13]([C:14]1[CH:15]=[CH:16][C:17]([C:20]([OH:3])=[O:21])=[CH:18][CH:19]=1)=[O:22])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(=O)O
Reactant: O=Cc1ccc(C(=O)OCc2ccccc2)cc1
Solvent: O
Product: O=C(O)c1ccc(C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
To 50 ml of an acetic acid solution containing 7.34 g (30.5 mmol) of 4-formylbenzoic acid benzyl ester were dropwise added 4.53 g (4.35 mmol) of chromic acid anhydride, 40 ml of acetic acid and 1.3 ml of water with stirring at room temperature for a period of 2 hours. The oxidation of a formyl group was further carried out overnight at room temperature. The reaction mixture was put into water, and the deposited black-green crystal was collected by filtration, followed by drying. The resultant crystal was recrystallized from acetone to obtain 4.08 g of 4-benzyloxycarbonylbenzoic acid as a white needle crystal (isolated yield: 49%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:21]=[CH:20][C:12]([C:13]([O:15]C(C)(C)C)=[O:14])=[C:11]([NH:22][C:23](=[O:32])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=2[CH3:31])[CH:10]=1>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:21]=[CH:20][C:12]([C:13]([OH:15])=[O:14])=[C:11]([NH:22][C:23](=[O:32])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=2[CH3:31])[CH:10]=1
Reactant: Cc1cccc(C(=O)Nc2cc(-c3ccc(F)cc3F)ccc2C(=O)OC(C)(C)C)c1C
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(C(=O)Nc2cc(-c3ccc(F)cc3F)ccc2C(=O)O)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 mL of trifluoroacetic acid was added to the obtained tert-butyl 4-(2,4-difluorophenyl)-2-(2,3-dimethylbenzamido)benzoate and stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and methanol was added to the obtained residue and a solid substance was separated by filtration to obtain 17 mg of 4-(2,4-difluorophenyl)-2-(2,3-dimethylbenzamido)benzoic acid as white solid. 1H-NMR (DMSO-d6) δ: 2.31 (3H, s), 2.31 (3H, s), 7.21-7.30 (2H, m), 7.31-7.49 (4H, m), 7.63-7.70 (1H, m), 8.11 (1H, d, J=8.0 Hz), 8.89 (1H, s), 11.58 (1H, s).
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][CH2:11][Br:12])=[N:5][N:4]=[N:3]1.[OH:13]O>C(O)=O.O>[Br:12][CH2:11][CH2:10][CH2:9][CH2:8][S:7]([C:6]1[N:2]([CH3:1])[N:3]=[N:4][N:5]=1)=[O:13]
Reactant: OO
Reactant: Cn1nnnc1SCCCCBr
Solvent: O
Solvent: O=CO
Product: Cn1nnnc1S(=O)CCCCBr
Temperature: 25 °C

Procedure:
1-Methyl-5-(4-bromobutyl)thio-1,2,3,4-tetrazole prepared in Reference Example 2 is dissolved in formic acid (50 ml). 30% Aqueous hydrogen peroxide (2.3 g) is added to the solution with stirring at room temperature and the mixture is allowed to stand at room temperature for 2 overnights. The mixture is diluted with water and extracted with chloroform. The chloroform solution is washed with water, saturated aqueous sodium bicarbonate and then saturated aqueous sodium chloride and dried over magnesium sulfate. Chloroform is distilled off to obtain 1-methyl-1,2,3,4-tetrazol-5-yl 4-bromobutyl sulfoxide (5.5 g) as colorless liquid.
Reaction SMILES: C(OC1C=CC([C:13]#[C:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([F:26])([F:25])([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=CC=1)CCCC.[C:27]1([CH3:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>[Pd]>[CH2:33]([C@H:27]1[CH2:32][CH2:31][C@H:30]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([F:25])([F:26])([F:23])([F:24])[F:22])=[CH:17][CH:16]=2)[CH2:29][CH2:28]1)[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: Cc1ccccc1
Reactant: CCCCCOc1ccc(C#Cc2ccc(S(F)(F)(F)(F)F)cc2)cc1
Agent: [Pd]
Product: CCCCC[C@H]1CC[C@H](CCc2ccc(S(F)(F)(F)(F)F)cc2)CC1

Procedure:
A mixture of 11.4 g of 4-(2-(4-trans-pentylcyclo-hexyl)-ethynyl)-phenyl sulfur pentafluoride (prepared as in EXAMPLE 7), 50 ml of toLuene and 10 mg of palladium-on-active charcoal is hydrogenated at room temperature under normal pressure. The solid constituents are filtered off and the filtrate is concentrated and worked up in the customary manner to give 4-(2-(trans-4-pentyl-cyclohexyl)-ethyl)-phenyl-sulfur pentafluoride.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26])#[N:21]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[C:25]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:26])#[N:21]
Reactant: c1ccc2c(c1)NCS2
Reactant: COc1ccc(C(=O)Cl)cc1C#N
Agent: C=O
Agent: Nc1ccccc1S
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)N2CSc3ccccc32)cc1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (1.89 g) and 37% formalin (1.25 mL) in the same manner as in Example 1 was dissolved in chloroform (20 mL), and triethylamine (2.08 mL) and 3-cyano-4-methoxybenzoyl chloride were added to the solution, and then the mixture was stirred at room temperature for 2 hours. The organic solvent was distilled off under reduced pressure and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was used for the synthesis of (e).
Reaction SMILES: C[Sn](C)C.C[Sn](C)C.[C:9]([CH:11]1[CH2:14][N:13]([C:15](=[O:39])[C@H:16]([NH:18][C:19]([C:21]2[C:29]3[C:24](=[N:25][CH:26]=[C:27](Br)[N:28]=3)[N:23]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:22]=2)=[O:20])[CH3:17])[CH2:12]1)#[N:10].I[C:41]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=[CH:43][N:42]=1.IN1C2C(=CC=CC=2)C=CC1>C1(C)C=CC=CC=1.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.[Cu]I.CN(C=O)C>[C:9]([CH:11]1[CH2:14][N:13]([C:15](=[O:39])[C@H:16]([NH:18][C:19]([C:21]2[C:29]3[C:24](=[N:25][CH:26]=[C:27]([C:41]4[C:50]5[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=5)[CH:44]=[CH:43][N:42]=4)[N:28]=3)[N:23]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:22]=2)=[O:20])[CH3:17])[CH2:12]1)#[N:10]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CC(C#N)C1
Reactant: Ic1nccc2ccccc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Sn](C)C
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nccc4ccccc34)nc12)C(=O)N1CC(C#N)C1
Temperature: 95 °C
Reaction time: 1.5 h
Yield: 46.8 %

Procedure:
To a solution of hexamethylditin (90 mg, 0.28 mmol) and 2-bromo-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (100 mg, 0.20 mmol) in toluene (2 mL) was added Pd(Ph3P)4 (23 mg, 0.02 mmol). A stream of nitrogen gas was gently bubbled through the reaction mixture for 15 min then it was heated to 95° C. After 1.5 h 1-iodoisoquinoline (50 mg, 0.20 mmol) and Pd(Ph3P)4 (23 mg, 0.02 mmol) were added as solids in one portion. Heating was continued at 95° C. for 1.5 h and additional 1-iodoisoquinoline (25 mg, 0.10 mmol), DMF (0.5 mL) and copper (I) iodide (5 mg) were added. The reaction mixture was heated at 95° C. overnight. Additional 1-iodoquinoline (25 mg, 0.10 mmol) and Pd(Ph3P)4 (23 mg, 0.02 mmol) were added and heating was continued for 8 h. The reaction was cooled to room temperature, quenched with water, and extracted with EtOAc (3×). The combined organics were washed with water (3×) and brine, then dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 30% to 80% EtOAc/hexanes to afford 52 mg (48%) of 2-isoquinolin-1-yl-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a yellow foam.