Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[C:4](\[C:6]1[C:7]([O:20][CH2:21][CH2:22][CH3:23])=[CH:8][C:9]2[C:10]([CH3:19])([CH3:18])[CH2:11][CH2:12][C:13]([CH3:17])([CH3:16])[C:14]=2[CH:15]=1)/[CH3:5].C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH3:17][C:13]1([CH3:16])[CH2:12][CH2:11][C:10]([CH3:18])([CH3:19])[C:9]2[CH:8]=[C:7]([O:20][CH2:21][CH2:22][CH3:23])[C:6](/[C:4](/[CH3:5])=[CH:3]\[CH:2]=[O:1])=[CH:15][C:14]1=2
Reactant: CCCOc1cc2c(cc1/C(C)=C\CO)C(C)(C)CCC2(C)C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CCCOc1cc2c(cc1/C(C)=C\C=O)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
(2Z)-3-[5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-(n-propyloxy)naphthalen-3-yl]-but-2-en-1-al (Structure 9 of Schemes 1 and 2, where R1, R4, R6=H, R1and R3 together form a tetramethyl saturated six-membered carbocyclic ring, R5=methyl, R7=n-propyl). To an oven-dried 10-mL r.b. flask containing (2Z)-3-(4-hydroxy-2-buten-2-yl)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-(n-propyloxy)naphthalene (25.0 mg, 0.08 mmol) and N-methylmorpholine N-oxide (NMO, 14 mg, 0.12 mmol, 1.5 equiv) in 0.5 mL CH2Cl2 at 0° C. was added tetra-n-propylammonium perruthenate (TPAP, 1.3 mg, 5 mol%), and the mixture was allowed to warm to room temperature. After 1 h at room temperature, the reaction mixture was filtered through a pad of silica gel, washing with an additional 50 mL CH2Cl2. The solvent was then removed under reduced pressure to afford 25 mg (99%) of (2Z)-3-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-(n-propyloxy)naphthalen-3-yl]-but-2-en-1-al as a colorless low-melting solid. The aldehyde thus obtained was of greater than 98% purity as judged by the 1H NMR spectrum, and was used directly in the next step without further purification. 1H NMR (400 MHz, CDCl3) 9.36 (d, 1H, J=8.1 Hz), 6.99 (s, 1H), 6.79 (s, 1H), 6.09 (dd, 1H, J=8.4, 1.1 Hz), 3.90 (t, 2H, J=6.4 Hz), 2.29 (d, 3H, J=1.1 Hz), 1.76 (m, 2H), 1.68 (d, 4H, J=1.6Hz), 1.30 and 1.23 (2s, 2×3H) 1.00 (t, 3H, J=7.5Hz). 13C NMR (100 MHz, CDCl3) 194.0, 161.7, 153.3, 146.9, 136.6, 129.7, 128.6, 125.3, 109.5, 69.7, 35.1, 35.0, 34.6, 33.6, 31.9, 31.8, 25.9, 22.6, 10.7. IR (thin film) 2922 (br, m), 1674 (s), 1202 (s), 1147 (s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([N:17]=[CH:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]([O:27]CC)=[O:26])[CH2:21][CH2:20]3)=[CH:13][CH:12]=2)=[O:10])=[C:4]([C:30](=[O:40])[NH:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]#[CH:39])=[CH:34][CH:33]=2)[CH:3]=1>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([N:17]=[CH:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]([OH:27])=[O:26])[CH2:21][CH2:20]3)=[CH:13][CH:12]=2)=[O:10])=[C:4]([C:30](=[O:40])[NH:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]#[CH:39])=[CH:34][CH:33]=2)[CH:3]=1
Reactant: C#Cc1ccc(NC(=O)c2cc(Cl)ccc2NC(=O)c2ccc(N=CN3CCC(C(=O)OCC)CC3)cc2)cc1
Solvent: CCO
Product: C#Cc1ccc(NC(=O)c2cc(Cl)ccc2NC(=O)c2ccc(N=CN3CCC(C(=O)O)CC3)cc2)cc1
Reaction time: 3 h

Procedure:
To a solution of ethyl 1-{[4-(N-{4-chloro-2-[N-(4-ethynylphenyl)carbamoyl]phenyl}carbamoyl)-phenyl]iminomethyl}piperidine-4-carboxylate in EtOH was added 1N aq. LIOH (1 mL). The mixture was stirred for 3 hours, concentrated and purified by RP-HPLC to give the titled compound. MS found for C29H25ClN4O4 (M+1)+: 529.1.
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:16](Br)=[C:17]2[C:22](=[CH:23][C:24]=1[CH3:25])[NH:21][C:20](=[O:26])[CH:19]=[CH:18]2)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.C(OCC)(=O)C.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>[C:1]([O:7][CH2:8][C@@H:9]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:15]1[C:16]([C:32]2[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=2)=[C:17]2[C:22](=[CH:23][C:24]=1[CH3:25])[NH:21][C:20](=[O:26])[CH:19]=[CH:18]2)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: Cc1cc2[nH]c(=O)ccc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: OB(O)c1ccc(Cl)cc1
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
Solvent: CCOC(C)=O
Product: Cc1cc2[nH]c(=O)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 100 °C
Yield: 60 %

Procedure:
The mixture of (S)-2-(5-bromo-7-methyl-2-oxo-1,2-dihydroquinolin-6-yl)-2-tert-butoxyethyl pivalate (34 mg, 0.078 mmol), Pd(PPh3)4 (9 mg), 4-chlorophenylboronic acid (16 mg, 0.1 mmol), aqueous K2CO3 solution (0.15 mL, 2 M, 0.3 mmol) in 1,2-dimethoxyethane (2 mL) was heated at 100° C. for 90 minutes. The residue was diluted with ethyl acetate (100 mL), washed with NaHCO3 solution, water and brine, dried over Na2SO4. Concentration and purification gave (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-oxo-1,2-dihydroquinolin-6-yl)ethyl pivalate (22 mg). LCMS-ESI+ (m/z): 470.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][NH:14]C(OCC2C=CC=CC=2)=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][NH2:14])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(Cc2ccccc2)CCN(CCNC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C1(Cc2ccccc2)CCN(CCN)CC1

Procedure:
4-Benzyl-1-(2-benzyloxycarbonylamino-ethyl)-piperidine-4-carboxylic acid ethyl ester (4.25 g, 10 mmol) is dissolved in MeOH (100 mL) and Pd—C (10%, 0.5 g) is added. The mixture is hydrogenated (7 bar, 20° C.) for 2 h. The catalyst is filtered off and the solvent evaporated to provide the title compound.
Reaction SMILES: [CH:1]([CH:3]1[CH2:5][C:4]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH2:2].S(NN)(C1C=CC(C)=CC=1)(=O)=O>COCCOCCOC>[CH2:1]([CH:3]1[CH2:5][C:4]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: C=CC1CC1(C(=O)OCC)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Solvent: COCCOCCOC
Product: CCOC(=O)C1(C(=O)OCC)CC1CC

Procedure:
Diethyl 2-vinylcyclopropane-1,1-dicarboxylate (5 g; 0.024 mol) was combined with 8.8 g (0.047 mol) tosyl hydrazine in 20 mls diglyme and the mixture heated with agitation to reflux for one hour. The reaction mixture was then allowed to cool and 2.73 g crude product obtained after washing with water and petroleum ether. The purified diethyl 2-ethylcyclopropane-1,1-dicarboxylate, obtained by distillation, contained 61.89% carbon and 8.33% hydrogen (calculated 61.66% C, 8.47% H) and the nuclear magnetic resonance spectra verified that the product was completely reduced.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([O:9]CC)=[O:8])[N:4]=[N:3]1.[OH-].[Na+].Cl>CO>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[N:4]=[N:3]1
Reactant: CCOC(=O)c1cn(C)nn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1cc(C(=O)O)nn1
Yield: 49.9 %

Procedure:
Using ethyl 1-methyl-1H-1,2,3-triazole-4-carboxylate (1.48 g, 9.54 mmol), methanol (22 mL), 1N sodium hydroxide (15 mL) and 1N hydrochloric acid (15 mL) as starting materials and in the same manner as in Reference Example 12, the title compound (605 mg, 50%) was obtained as a white powder.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)#[N:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:23][CH2:24][CH2:25][CH2:26][CH2:27]I>>[Cl:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:9]([C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)[C:10]([OH:12])=[O:11]
Reactant: N#Cc1ccc(CC(=O)O)cc1
Reactant: ClCCCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: N#Cc1ccc(C(CCCCCl)C(=O)O)cc1
Yield: 71.6 %

Procedure:
Step AU (1): 2-(4-Cyanophenyl)acetic acid (5.0 g, 31.0 mmol) was deprotonated with NaHMDS (2.0 M in THF, 46.5 mL, 93 mmol) and reacted with 1-chloro-4-iodobutane (10.2 g, 46.5 mmol) using a procedure analogous to Step AC (1) to afford, after purification by silica gel column chromatography, 6-chloro-2-(4-cyanophenyl)hexanoic acid (5.59 g, 22.2 mmol, 72% yield) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][C@@H:21]2[CH2:25][CH2:24][O:23][CH2:22]2)=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:14]=[CH:15][C:16]([NH2:19])=[N:17][CH:18]=2)[CH:7]=1.[CH3:26]N(C(OC)OC)C.[CH2:34]([O:36][C:37](=[O:40])[CH2:38]Br)[CH3:35].CO>C1(C)C=CC=CC=1>[CH2:34]([O:36][C:37]([C:38]1[N:17]2[CH:18]=[C:13]([N:9]3[CH2:10][CH2:11][CH2:12][CH:8]3[C:6]3[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[O:20][C@@H:21]3[CH2:25][CH2:24][O:23][CH2:22]3)[CH:14]=[CH:15][C:16]2=[N:19][CH:26]=1)=[O:40])[CH3:35]
Reactant: CCOC(=O)CBr
Reactant: COC(OC)N(C)C
Reactant: Nc1ccc(N2CCCC2c2cc(F)ccc2O[C@@H]2CCOC2)cn1
Solvent: CO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnc2ccc(N3CCCC3c3cc(F)ccc3O[C@@H]3CCOC3)cn12
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To stirred solution of 5-(2-(5-fluoro-2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)pyrrolidin-1-yl)pyridin-2-amine (2.4 g, 69.97 mmol) in dry toluene (6 ml) was added DMF-DMA (1.87 ml, 13.99 mmol) under N2 atm and stirred for 2 h at 120° C. during which complete consumption of starting material was observed by TLC, cool it to 10° C. then added Ethylbromoacetate (1.66 ml, 14.69 mmol) drop wise and methanol (2 ml) was added under N2 atm then stirred for 16 h at 120° C. Reaction mixture was cooled to room temperature and solvent was removed in vacuo and residue was dissolved in DCM (200 ml), washed with water and brine, dried over anhydrous Na2SO4 and concentrated under vacuum to get crude product. Crude was purified by column chromatography (eluted with 30-40% ethyl acetate/Hexane) to afford pale green solid (1.15 g, yield: 38.3), MS (ESI): 440.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:21]3[C:20]4[CH:19]=[CH:18][CH:17]=[C:16]([CH3:22])[C:15]=4[NH:14][C:13](=O)[C:12]=3[CH2:11][CH2:10]2)=[C:5]([CH3:24])[CH:4]=1.P(Cl)(Cl)([Cl:27])=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:21]3[C:20]4[CH:19]=[CH:18][CH:17]=[C:16]([CH3:22])[C:15]=4[N:14]=[C:13]([Cl:27])[C:12]=3[CH2:11][CH2:10]2)=[C:5]([CH3:24])[CH:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(N2CCc3c2c2cccc(C)c2[nH]c3=O)c(C)c1
Product: COc1ccc(N2CCc3c(Cl)nc4c(C)cccc4c32)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(4-methoxy-2-methylphenyl)-4-oxo-6-methyl-2,3,4,5-tetrahydropyrrolo[3,2-c]quinoline (1.0 g, 3.1 mmol) was dissolved in 10 ml of phosphoryl chloride (POCl3) and heated for 2 hours. The reaction mixture was stirred at room temperature for 30 minutes after cooling and addition of ice water. The reaction mixture was extracted with methylene chloride (20 ml×3). After washing with water (15 ml×3), the organic layer was dried by anhydrous magnesium sulfate and filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain 786 mg of desired compound as an oil in 75% of yield.
Reaction SMILES: C(OC([N:8]([CH2:33][C@@H:34]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=1)[OH:35])[CH2:9][CH2:10][C:11]1[CH:32]=[CH:31][C:14]([O:15][C:16]2[CH:30]=[CH:29][C:19]([O:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:17]=2)=[CH:13][CH:12]=1)=O)(C)(C)C.Cl>O1CCOCC1>[ClH:42].[Cl:42][C:38]1[CH:37]=[C:36]([C@@H:34]([OH:35])[CH2:33][NH:8][CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:29][CH:30]=3)=[CH:31][CH:32]=2)[CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(Oc2ccc(CCN(C[C@H](O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)COc1ccc(Oc2ccc(CCNC[C@H](O)c3cccc(Cl)c3)cc2)cc1
Yield: 180.4 %

Procedure:
A solution of tert-butyl [4-[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-amino]ethyl]phenoxy]phenoxy]acetate (305 mg) and 4N hydrochloride in 1,4-dioxane (5.0 ml) was stirred at room temperature for 24 hours. The resulting solid was collected by filtration and dried to give [4-[4-[2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenoxy]phenoxy]-acetic acid hydrochloride (220 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3(O)[CH2:21][CH2:20][CH:19]([CH:22]4[CH2:31][CH2:30][C:25]5([O:29][CH2:28][CH2:27][O:26]5)[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[C:12]([F:33])[CH:11]=2)[CH2:6][CH2:5]1)[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[CH2:1]([O:3][CH:4]1[CH2:5][CH2:6][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH2:21][CH2:20][CH:19]([CH:22]4[CH2:23][CH2:24][C:25]5([O:26][CH2:27][CH2:28][O:29]5)[CH2:30][CH2:31]4)[CH2:18][CH:17]=3)=[C:12]([F:33])[CH:11]=2)[CH2:8][CH2:9]1)[CH3:2]
Reactant: CCOC1CCC(c2ccc(C3(O)CCC(C4CCC5(CC4)OCCO5)CC3)c(F)c2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC1CCC(c2ccc(C3=CCC(C4CCC5(CC4)OCCO5)CC3)c(F)c2)CC1
Temperature: 30 °C
Yield: 56.2 %

Procedure:
The compound (23) (72.9 g), p-toluenesulfonic acid (2.19 g) and toluene (350 ml) were mixed, and the mixture was heated under reflux for 1.5 hours while water being distilled was removed. The reaction mixture was cooled to 30° C., and then water (700 ml) and toluene (900 ml) were added and mixed to it. The mixture was then allowed to stand until it had separated into two phases, the organic and aqueous phases, and an extractive operation to an organic phase was carried out. The organic phase was fractionated, and washed sequentially with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. Then the solvent of the solution was distilled off under reduced pressure, and the residue was purified with a fractional operation by means of column chromatography using a mixed solvent of toluene and ethyl acetate (toluene:ethyl acetate=7:3 by volume) as an eluent and silica gel as a stationary phase powder, and further purified by means of recrystallization from heptane, and dried, giving 39.4 g of 8-(4-(4-(4-ethoxycyclohexyl)-2-fluorophenyl)cyclohex-3-enyl)-1,4-dioxaspiro[4,5]decane (24). The yield based on the compound (No. 22) was 78.8%.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])([O-:3])=O.C[Si](C)(C)[O:19][C:20]#[C:21][CH3:22].C1(N=C=O)C=CC=CC=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH2:5]([C:4]1[CH:22]=[C:21]([CH2:20][OH:19])[O:3][N:1]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CC#CO[Si](C)(C)C
Reactant: CCCCCCCCCCCCC[N+](=O)[O-]
Solvent: O=C=Nc1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCc1cc(CO)on1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
To a solution of 1-nitrotridecane (10.5 g) and O-trimethylsilyl-propynol (5.88 g) in dry benzene (100 ml) was added dropwise a solution of freshly distilled phenylisocyanate (10.9 g) and triethylamine (5.56 g) in dry benzene (40 ml) at 40° C., with mechanical stirring. The mixture was heated to 60° C. for 3.5 hr, cooled, and filtered. The filtrate was evaporated, taken up in tetrahydrofuran (300 ml) and 1.0M tetrabutylammonium fluoride (8 ml) was added. After 30 mins, the mixture was evaporated and the residue was purified by flash chromatography (silica gel, 2% methanol:dichloromethane). The appropriate fractions were collected and evaporated to give 10.5 g (86%) of product, mp 61°-63° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])=[N:6][CH:7]=1.[N:13]1([CH2:18][C@@H:19]2[CH2:23][CH2:22][CH2:21][N:20]2[C:24]([C:26]2[CH:31]=[CH:30][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=2)=[O:25])[CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:11]([S:8]([C:5]1[N:6]=[CH:7][C:2]([C:29]2[CH:30]=[CH:31][C:26]([C:24]([N:20]3[CH2:21][CH2:22][CH2:23][C@H:19]3[CH2:18][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)=[O:25])=[CH:27][CH:28]=2)=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH3:12]
Reactant: CCS(=O)(=O)c1ccc(Cl)cn1
Reactant: CC1(C)OB(c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCS(=O)(=O)c1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)cn1

Procedure:
Procedure KK: Place 5-Chloro-2-ethanesulfonyl-pyridine (1.0 mmol), (2-(S)-Pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone (1.1 mmol), ethanol (0.10M), potassium carbonate (3.0 mmol) and dihydrogen di-μ-chlorotetrakis(di-tert-butylphosphino-kP)dipalladate (2-) (0,01 mmol, also known as POPd1) in a microwave reactor vessel with a stir bar. Run the reaction in a CEM microwave reactor for 1 hour at 90° C. and 65 W power with cooling. After this time, concentrate the reaction in vacuo. Purify the title compound via radial chromatography eluting with 2M ammonia and dichloromethane. MS (m/e): 428.2 (M+1)
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:22][C:23]([O:25]CC)=[O:24])[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:5]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:4]1.[OH-].[Li+].O>C1COCC1>[NH2:1][CH2:2][C:3]1([CH2:22][C:23]([OH:25])=[O:24])[CH2:4][C@@H:5]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[N:6]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:7]1
Reactant: CCOC(=O)CC1(CN)C[C@@H](C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H]1CC(CN)(CC(=O)O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Ester (2S)-di-tert-butyl 4-(aminomethyl)-4-(2-ethoxy-2-oxoethyl)pyrrolidine-1,2-dicarboxylate (C6) (560 mg, 1.45 mmol) was dissolved in THF (12 ml). To this was added 1N lithium hydroxide in water (2.9 ml, 2.9 mmol, 2.0 eq). The mixture was stirred at room temperature overnight. The reaction was cooled to 0° C. and quenched with 1N hydrochloric acid in water. The mixture was blown to dryness with N2 gas and stripped from acetonitrile several times to give 2-((5S)-3-(aminomethyl)-1,5-bis(tert-butoxycarbonyl)pyrrolidin-3-yl)acetic acid (D6) (1.45 mmol) as a glassy solid. 1H NMR (DMSO) δ 1.35 (m, 18H), 2.00 (m, 2H), 2.35 (m, 2H), 2.80 (m, 1H), 3.65 (m, 1H), 4.00 (m, 1H); LCMS for C17H30N2O6 358.21 [M], found ES+ 359.21 [M+H]+ and ES− 357.21 [M−H]− at 1.8 minutes retention time, using 10-90% acetonitrile/water (with 0.1% formic acid buffer) gradient over 5 minutes.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH3:18])[N:3]=1.Br[C:20]1[S:21][CH:22]=[C:23]([Br:25])[CH:24]=1>>[Br:25][C:23]1[CH:24]=[C:20]([C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[CH:5]=[C:4]([CH3:18])[N:3]=2)[S:21][CH:22]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(I)n1
Reactant: Brc1csc(Br)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cc(Br)cs2)n1

Procedure:
The title compound was prepared from 2-iodo-6-methyl-4-(4-trifluoromethyl-phenyl)pyridine (example A.31) (4.0 g, 9.36 mmol) and commercially available 2,4-dibromothiophene (2.518 g, 10.41 mmol) according to the general procedure IVc protocol b. Obtained as a white solid (2.12 g, 54%). MS (ISP) 398.0 [(M+H)+] and 400.0 [(M+2+H)+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][C:6]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][C:7]=1[C:8]#[N:9].Cl[C:21]1[CH:31]=[C:25]2[N:26]([CH3:30])[CH2:27][CH2:28][CH2:29][N:24]2[C:23](=[O:32])[N:22]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][C:6]1[CH:13]=[CH:12][C:11]([CH2:14][O:15][C:21]2[CH:31]=[C:25]3[N:26]([CH3:30])[CH2:27][CH2:28][CH2:29][N:24]3[C:23](=[O:32])[N:22]=2)=[CH:10][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1cc(CO)ccc1Oc1ccc(F)c(F)c1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCc1ccc(Oc3ccc(F)c(F)c3)c(C#N)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from 2-(3,4-difluorophenoxy)-5-(hydroxymethyl)benzonitrile and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:18]=[CH:17][C:8]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>C(O)(=O)C>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:17][CH:18]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(C=Cc2ccccn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C(O)c1ccc(C=Cc2ccccn2)cc1

Procedure:
2-(4-Methoxycarbonylstyryl) pyridine (2.00g) and 20% w/v aqueous sodium hydroxide (100 ml) were stirred and refluxed for 2 hours. The reaction mixture was cooled, acidified with glacial acetic acid the solid filtered off, dried and recrystallised from ethanol. This gave 1.68 g (90%) 2 Carboxy styryl) pyridine MPT 228°C.
Reaction SMILES: [CH3:1][Li].[C:3]1([C@@H:9]([CH3:14])[CH2:10][C:11]([OH:13])=O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CCOCC>[C:3]1([C@@H:9]([CH3:14])[CH2:10][C:11](=[O:13])[CH3:1])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: [Li]C
Reactant: C[C@@H](CC(=O)O)c1ccccc1
Solvent: CCOCC
Product: CC(=O)C[C@H](C)c1ccccc1
Temperature: 25 °C

Procedure:
1.6 M Methyl lithium (17.8 mL, 24.9 mmol) was added over 1 hour to a stirring 0° C. solution of (S)-3-Phenylbutyric acid (2.0147 g, 12.18 mmol) in dry Et2O (61 mL, 0.2 M): The ice bath was removed, and the reaction was allowed to stir at room temperature for 1½ additional hours. The reaction was then poured into rapidly stirring ice water containing aq. HCl. The organic layer was removed, washed with NaHCO3 and brine, then dried with Na2SO4, filtered and concentrated to achieve pure 77 (2.0487 g, (2.0487 g,˜100%): HPLC: 10.081 min. (Note: SM has HPLC retention time of 9.127 min.)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]([NH2:12])=[O:11])[C:5]([C:13]#[N:14])=[C:4]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[C:3]=1[C:20]#[N:21].[N:22]1([CH2:27][CH2:28][CH2:29]N)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[NH2:14][C:13]1[C:5]2[C:6](=[N:7][C:2]([NH:1][CH2:29][CH2:28][CH2:27][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[C:3]([C:20]#[N:21])[C:4]=2[C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[S:8][C:9]=1[C:10]([NH2:12])=[O:11]
Reactant: NCCCN1CCCC1
Reactant: N#Cc1c(N)nc(SCC(N)=O)c(C#N)c1-c1ccco1
Product: N#Cc1c(NCCCN2CCCC2)nc2sc(C(N)=O)c(N)c2c1-c1ccco1

Procedure:
If steps 1.1 and 1.2 according to Example 1 are carried out analogously with furan-2-carbaldehyde as “E1”, 2-(6-amino-4-furan-2-yl-3,5-dicyanopyridin-2-ylsulfanyl)acetamide (“2a”) is obtained. “2a” is subsequently reacted analogously to steps 2.1 to 2.3 according to Example 2, using 3-pyrrolidin-1-ylpropylamine as “E2” in step 2.2. 3-Amino-5-cyano-4-furan-2-yl-6-(3-pyrrolidin-1-ylpropylamino)thieno[2,3-b]pyridine-2-carboxamide “A51” is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[C:5](Br)=[CH:4][N:3]=1.[CH3:11]B1OB(C)OB(C)O1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[C:5]([CH3:11])=[CH:4][N:3]=1
Reactant: Cc1c(Br)cnc(N)c1C
Reactant: CB1OB(C)OB(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cnc(N)c(C)c1C
Temperature: 115 °C

Procedure:
23.0 g (0.11 mol) of 2-amino-5-bromo-3,4-dimethylpyridine was mixed with 14.1 g (0.11 mol) of trimethylboroxin (TMB), 12.9 g (0.011 mol) of Pd(Ph3)4, 46.0 g (0.33 mol) of K2CO3 and 220 mL of DMF. The reaction mixture was heated under nitrogen at 115° C. for 18 hours. The reaction mixture was purified by silica gel column. The desired product was confirmed by MS.