Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]=[C:3]([CH3:5])[CH3:4].[CH3:6][OH:7]>>[CH3:1][CH:2]=[C:3]([CH3:5])[CH3:4].[CH3:6][O:7][C:3]([CH2:2][CH3:1])([CH3:5])[CH3:4]
Reactant: CO
Agent: CC=C(C)C
Product: CCC(C)(C)OC

Procedure:
In the described apparatus runs were carried out using a C5 -cut containing 8.5 w% iso-amylene (2-methyl-butene-1 and 2-methyl-butene-2), 4.250 g/h of C5 -cut were charged through line 10 into reactor stage 13, and 205 g/h of methanol (methanol/isoamylene mole ratio 1.24:1) were charged through line 14, 15, 16, LHSV approx. 2.5 g/h. Using the pumps 20 and 27 the recycle stream was maintained, as before, at 20 1/h each. The reaction pressure was 10 bar, the temperature was 60° C. Under these conditions a 90% conversion of iso-amylene into tert. amyl methyl ether (TAME) was obtained. In the reactor effluent a DME content of 200 ppm was observed.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:10]=[C:9]([C:11]3[CH:12]=[C:13]([CH:20]=[CH:21][CH:22]=3)[CH2:14][NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[C:39]3[CH:45]=[CH:44][NH:43][C:40]3=[N:41][CH:42]=2)O1>>[O:26]1[CH2:27][CH2:28][N:23]([C:4]2[C:5]3[N:10]=[C:9]([C:11]4[CH:12]=[C:13]([CH:20]=[CH:21][CH:22]=4)[CH2:14][NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[S:8][C:6]=3[N:7]=[C:2]([C:37]3[CH:38]=[C:39]4[CH:45]=[CH:44][NH:43][C:40]4=[N:41][CH:42]=3)[N:3]=2)[CH2:24][CH2:25]1
Reactant: CS(=O)(=O)NCc1cccc(-c2nc3c(N4CCOCC4)nc(Cl)nc3s2)c1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Product: CS(=O)(=O)NCc1cccc(-c2nc3c(N4CCOCC4)nc(-c4cnc5[nH]ccc5c4)nc3s2)c1
Yield: 31.6 %

Procedure:
N-[3-(5-Chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-yl)-benzyl]-methanesulfonamide (120 mg) was reacted with 80 mg of 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine via General Procedure A. The product was purified by reverse phase HPLC to yield 45 mg of 115. MS (Q1) 522.2 (M)+.
Reaction SMILES: [NH2:1][C:2]1([CH2:8][C:9]([OH:11])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[OH-].[Na+].[C:14]1([N:20]=[C:21]=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCOCC1.O>[NH:20]([C:21]([NH:1][C:2]1([CH2:8][C:9]([OH:11])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC1(CC(=O)O)CCCCC1
Reactant: O=C=Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CC1(NC(=O)Nc2ccccc2)CCCCC1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 55.7 %

Procedure:
To a solution of (1-aminocyclohexyl)acetic acid (0.232 mg, 1.48 mmol) in a mixture of 1,4-dioxane (9 ml) and water (3 ml) was added 30% aqueous sodium hydroxide solution to pH 9. Phenylisocyanate (0.24 ml, 2.22 mmol) was added dropwise at 35° C. and 30% aqueous sodium hydroxide solution was added to adjust the solution to pH9. The reaction mixture was stirred at 40° C. for 1.5 hrs and concentrated under reduced pressure. 5N Hydrochloric acid was added to acidify the solution (pH3) and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried (over anhydrous MgSO4). After concentration under reduced pressure, the precipitated solid was collected by filtration and washed with diisopropyl ether to give the title compound (0.228 g) as a colorless powder with contamination.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26](O)=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:33][C:34]1[O:35][CH:36]=[C:37]([C:39]2([NH2:42])[CH2:41][CH2:40]2)[N:38]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:27])[NH:42][C:39]5([C:37]6[N:38]=[C:34]([CH3:33])[O:35][CH:36]=6)[CH2:41][CH2:40]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: Cc1nc(C2(N)CC2)co1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5coc(C)n5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 14 h

Procedure:
5-(2-(4-Fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.15 g, 0.34 mmol, 1 eq), 1-(2-methyloxazol-4-yl)cyclopropanamine (0.047 g, 0.34 mmol, 1 eq), EDCI.HCl (0.076 g, 0.4 mmol, 1.2 eq), HOBT (0.054 g, 0.4 mmol, 2 eq) and TEA (0.14 ml, 1.02 mmol, 3 eq) were dissolved in dichloromethane and the reaction was stirred at room temperature for 14 h. The reaction was diluted with water and the product was extracted with dichloromethane and purified by preparative HPLC yielding the desired product. Yield: 47 mg (25%) 1H NMR (400 MHz, DMSO-d6): δ 1.12-1.15 (m, 2H), 1.21-1.24 (m, 2H), 2.29 (s, 3H), 2.34 (s, 3H), 2.81-2.82 (d, 3H, J=4.60 Hz), 3.95 (s, 3H), 7.12 (s, 1H), 7.31-7.32 (m, 1H), 7.34-7.40 (t, 2H, J=3.21 Hz), 7.56 (s, 1H), 7.61 (s, 1H), 7.71 (s, 1H), 7.73 (s, 1H), 7.97-8.01 (m, 2H), 8.46-8.48 (m, 1H), 8.67 (s, 1H). LCMS: (ES+) m/z=554.2 (M+H).: Column-Ascentis Express C18 (5×2.1 mm-2.7 μm) Mphase A: 2% ACN-98% H2O-10 mM NH4COOH Mphase B: 98% ACN-2% H2O-10 mM NH4COOH
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:14][C:15]1[CH:16]=[C:17]([CH2:18][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH3:13])=[C:6]([CH:12]=2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)c1cc(O)ccc1C
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCc2cccc(Cl)c2)ccc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 103.7 %

Procedure:
A suspension of ethyl 5-hydroxy-2-methylbenzoate (39.06 g, 217 mmol), 3-chlorobenzyl bromide (31.3 ml, 238 mmol) and potassium carbonate (44.9 g, 325 mmol) in N,N-dimethylformamide (1000 ml) was stirred at room temperature for 18 hours. The reaction was then filtered, diluted with ethyl acetate (2 L), washed with water (2 L then 3×1 L) and brine (1 L), filtered through a hydrophobic frit and concentrated to give the title compound as a dark yellow oil (68.61 g) which was used without further purification. MS (ES+) [C17H1735ClO3+H]+ 305. 1H-NMR (400 MHz, d6-DMSO) δ 1.31 (3H, t, J 7.2), 2.42 (3H, s), 4.28 (2H, q, J 7.2), 5.14 (2H, 2), 7.13-7.16 (1H, m), 7.19-7.23 (1H, m), 7.33-7.45 (4H, m), 7.54-7.55 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:14]O)[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[C:7](=[O:12])[C:6]=2[CH:13]=1.S(Cl)([Cl:18])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][Cl:18])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[C:7](=[O:12])[C:6]=2[CH:13]=1
Reactant: O=S(Cl)Cl
Reactant: CC1(C)Oc2c(CO)cc(Cl)cc2C1=O
Product: CC1(C)Oc2c(CCl)cc(Cl)cc2C1=O

Procedure:
A solution of 5-chloro-7-(hydroxymethyl)-2,2-dimethylbenzofuran-3(2H)-one (656) (278 mg, 1.23 mmol) in neat thionyl chloride (5 mL) was stirred at room temperature for 48 hours. The reaction was concentrated to obtain 5-chloro-7-(chloromethyl)-2,2-dimethylbenzofuran-3(2H)-one (657) as a brown/grey solid.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:25])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]2[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=O)[CH:11]=[CH:12][CH:13]=1.[CH3:26][NH:27][NH2:28]>CO>[ClH:1].[CH3:2][N:3]([CH3:25])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:14]2[N:27]([CH3:26])[N:28]=[C:16]3[C:17]4[C:22]([CH2:23][CH:15]23)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:11]=[CH:12][CH:13]=1
Reactant: CNN
Reactant: CN(C)CCCOc1cccc(C=C2Cc3ccccc3C2=O)c1
Agent: Cl
Solvent: CO
Product: CN(C)CCCOc1cccc(C2C3Cc4ccccc4C3=NN2C)c1
Yield: 10.8 %

Procedure:
A stirred solution of 8.6 g (0.024 mole) of 2-[[3-[3-(dimethylamino)propoxy]phenyl]methylene]-2,3-dihydro-1H-inden-1-one hydrochloride from part B and 1.3 g (0.028 mole) of methyl hydrazine in 50 ml of methanol is heated at reflux for 2 hours. After cooling, the solvent is evaporated to give 1.0 g of an amber oily residue.
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][C:16]#[CH:17])=[CH:11][CH:12]=2)[C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=2)=[N:6][C:5]1=O)([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>C1C=CC=CC=1>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][C:16]#[CH:17])=[CH:11][CH:12]=2)[C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=2)=[N:6][C:5]1=[S:37])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2C(C)C
Solvent: c1ccccc1
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=S)n2C(C)C
Temperature: 70 °C

Procedure:
A suspension of 50 mg (0.139 mmol) 1-isopropyl-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazoline-2-one and 56 mg (0.139 mmol) Lawesson's reagent in 2 ml benzene is heated to 70° C. overnight. The reaction mixture is extracted (water/di-chloromethane) and the organic layer is dried and evaporated.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH2:11]([O:13][CH:14]=[CH:15][C:16](Cl)=[O:17])[CH3:12]>C(OCC)C>[C:5]([C:4]1[CH:3]=[C:2]([CH:10]=[CH:9][CH:8]=1)[NH:1][C:16](=[O:17])[CH:15]=[CH:14][O:13][CH2:11][CH3:12])([OH:7])=[O:6]
Reactant: CCOC=CC(=O)Cl
Reactant: Nc1cccc(C(=O)O)c1
Solvent: CCOCC
Product: CCOC=CC(=O)Nc1cccc(C(=O)O)c1
Temperature: 40 °C

Procedure:
100 Grams of m-aminobenzoic acid was suspended in 1 liter of diethyl ether, and at a room temperature with stirring 44.6 g of β-ethoxyacrylic chloride was added dropwise. Then the reaction mixture was heated at 40° C. for 5 hours. After the reaction was completed, the precipitated matter was collected by filtration and washed with water three times, and dried, and recrystallized from methanol to obtain 60 g of m-carboxy-N-(β-ethoxyacryloyl)aniline. Colorless cotton-like crystals. Melting point: 200.5°-202° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([OH:9])[N:3]=1.CC#N.[CH3:13][N:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15](Cl)=[S:16]>C(Cl)Cl>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([C:15](=[S:16])[N:14]([CH3:13])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4](=[O:9])[N:3]=1
Reactant: Nc1nc(O)ncc1F
Reactant: CN(C(=S)Cl)c1ccccc1
Solvent: ClCCl
Solvent: CC#N
Product: CN(C(=S)n1cc(F)c(N)nc1=O)c1ccccc1
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 37.1 %

Procedure:
A 25 mL screw-top vial was charged with 4-amino-5-fluoropyrimidin-2-ol (100.1 mg, 0.775 mmol), CH3CN (3 mL) and BSA (0.284 mL, 1.162 mmol). The resulting mixture was then agitated on a rotary shaker at 65° C. for 90 min. After cooling to room temperature, methyl(phenyl)carbamothioic chloride (157.6 mg, 0.849 mmol) was added, and the reaction mixture was agitated on a rotary shaker at 65° C. for 16 h. After cooling to room temperature, the reaction mixture was diluted with CH2Cl2 (100 mL) and washed with satd aq NaCl solution (50 mL×2). The organic layer was then dried over Na2SO4, filtered, and concentrated in vacuo to afford a green oil. This crude material was then purified by normal phase chromatography (gradient, 0 to 35% MeOH/CH2Cl2) to provide 4-amino-5-fluoro-N-methyl-2-oxo-N-phenylpyrimidine-1(2H)-carbothioamide (80.1 mg, 37%) as a 90% pure beige/green solid: mp 192-196° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J=6.7 Hz, 1H), 7.83 (s, 1H), 7.66 (s, 1H), 7.38 (m, 2H), 7.34-7.26 (m, 3H), 3.71 (s, 3H); ESIMS m/z 279 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:34](=[CH:35][CH:36]=3)[CH2:33][C@:23]3([C:31]5[C:26](=[N:27][CH:28]=[CH:29][CH:30]=5)[NH:25][C:24]3=[O:32])[CH2:22]4)=[O:17])[C:13](=[O:37])[C:12]([CH3:39])([CH3:38])[C:11](=O)[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[BH3-]C#[N:43].[Na+]>CO.O.C([O-])(O)=O.[Na+]>[NH2:43][C@@H:11]1[CH2:10][C@@H:9]([C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=2)[N:14]([CH2:15][C:16]([NH:18][C:19]2[CH:20]=[C:21]3[C:34](=[CH:35][CH:36]=2)[CH2:33][C@:23]2([C:31]4[C:26](=[N:27][CH:28]=[CH:29][CH:30]=4)[NH:25][C:24]2=[O:32])[CH2:22]3)=[O:17])[C:13](=[O:37])[C:12]1([CH3:38])[CH3:39]
Reactant: [BH3-]C#N
Reactant: CC1(C)C(=O)C[C@@H](c2cc(F)cc(F)c2)N(CC(=O)Nc2ccc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1(C)C(=O)N(CC(=O)Nc2ccc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)[C@H](c2cc(F)cc(F)c2)C[C@H]1N
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 2-[(6S)-6-(3,5-difluorophenyl)-3,3-dimethyl-2,4-dioxopiperidin-1-yl]-N-[(2R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]acetamide (380 mg, 0.698 mmol, described in Example 7) and NH4OAc (571 mg, 7.41 mmol) in CH3OH (2 mL) was stirred at ambient temperature for 20 min. NaCNBH3 (498 mg, 7.92 mmol) was added and stirring was continued at ambient temperature for 12 h. The reaction mixture was diluted with H2O (40 mL) and aqueous NaHCO3 (70 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:CH3OH—100:0 to 80:20, to give 2-[(4R,6S)-4-amino-6-(3,5-difluorophenyl)-3,3-dimethyl-2-oxopiperidin-1-yl]-N-[(2R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]acetamide, which eluted first, and 2-[(4S,6S)-4-amino-6-(3,5-difluorophenyl)-3,3-dimethyl-2-oxopiperidin-1-yl]-N-[(2R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]acetamide, which eluted second, the title compound. MS: m/z=546 (M+1). HRMS: m/z=546.2287; calculated m/z=546.2311 for C30H30F2N5O3.
Reaction SMILES: Br[C:2]1[C:3](=[O:15])[N:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([CH3:8])=[CH:6][N:7]=1.[F:16][C:17]([F:26])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:18][NH2:19].C(OCC)(=O)C>C1(C)C=CC=CC=1>[F:16][C:17]([F:26])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:18][NH:19][C:2]1[C:3](=[O:15])[N:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([CH3:8])=[CH:6][N:7]=1
Reactant: CCOC(=O)Cn1c(C)cnc(Br)c1=O
Reactant: NCC(F)(F)c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)Cn1c(C)cnc(NCC(F)(F)c2ccccc2)c1=O
Temperature: 25 °C
Yield: 75.6 %

Procedure:
To a stirred suspension of 3-bromo-1-(ethoxycarbonylmethyl)-6-methylpyrazinone (750 mg, 2.75 mmol), as prepared in step 5 of Example 2, in toluene (30 mL) was added 2,2-difluoro-2-phenylethylamine (900 mg, 5.75 mmol), as prepared in the preceding step. The mixture was refluxed for two days under nitrogen. The solution was allowed to cool to room temperature, and ethyl acetate (50 mL) was added. The diluted reaction mixture was washed with 10% HCl (2×20 mL) and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with 10% citric acid (50 mL), brine, and dried over Na2SO4. After evaporating the solvent, the solid was collected and washed with 15% ethyl acetate in hexane to give the title compound as an off-white solid (730 mg, 76%). 1H NMR (400 MHz, CDCl3) δ 7.54 (m, 2H), 7.43 (m, 3H), 6.67 (s, 1H ), 6.14 (s(br), 1H), 4.70 (s, 2H), 4.24 (q, 2H, J=7.1 Hz), 4.09 (td, 2 H, J=14.3, 6.5 Hz), 2.11 (s, 3H), 1.29 (t, 3H, J=7.1 Hz).
Reaction SMILES: [Br-].[NH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:34]=[CH:35][CH:36]=1)[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:4].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[S:47]1[CH:51]=[CH:50][C:49]([CH:52]=O)=[CH:48]1>C1(C)C=CC=CC=1>[S:47]1[CH:51]=[CH:50][C:49](/[CH:52]=[CH:14]\[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:7]2[CH:6]=[C:5]([C:3]([NH2:2])=[O:4])[CH:36]=[CH:35][CH:34]=2)=[CH:48]1
Reactant: O=Cc1ccsc1
Reactant: NC(=O)c1cccc(OCCCCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: NC(=O)c1cccc(OCCCCC/C=C\c2ccsc2)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
To a stirred suspension of 6-[3-(aminocarbonyl)phenoxy]hexyl(triphenyl)phosphonium bromide (2.0 g, 3.55 mmol, 1.2 equiv.) in anhydrous toluene (28 ml) was added a solution of potassium bis(trimethylsilyl)amide (0.5M; 7.1 ml, 3.55 mmol, 1.2 equiv.) in toluene, slowly, dropwise over a period of 15 min at 0° C., under N2. The dark orange solution was stirred for another 20 min at 0° C. and cool—d to −78° C., when thiophene-3-carboxaldehyde was instantly added, and the temperature was left to rise—from −78° C. to r.t. The light yellow mixture was stirred at r.t. for 16 h. The reaction mixture was quenched with saturated aqueous NH4Cl (20 ml) and the solvent was evaporated under reduced pressure. The residue was taken-up in CH2Cl2 and H2O, the organic phase was separated, washed with brine and dried (Na2SO4). The solved was evaporated under reduced pressure and the residue was purified by column chromatography on silica eluting with EtOAc/hexane (10%-50% gradient) to give the desired compound as an off-white solid (300 mg, 35%), mp 71-73° C. By 1H NMR analysis it consisted of a mixture of Z:E (90:10). HPLC-MS (method 1): m/z 316 [M+H]+, Rt=4.62 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][NH2:16])[CH2:11][CH:12]=1>CO.[OH-].[OH-].[Pd+2]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][NH2:16])[CH2:9][CH2:8]1
Reactant: NCCCN1CC=C(c2ccccn2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: NCCCN1CCC(c2ccccn2)CC1
Reaction time: 10 h
Yield: 92 %

Procedure:
To a solution of 3-(3',6'-Dihydro-2'-H-[2,4']bipyridinyl-1'-yl)-propylamine (3.48 g crude, 15.9 mmol) in MeOH (40 mL), was added 1.0 g of Pearlman's catalyst. The suspension was hydrogenated under 120 psi for 10 h after which the reaction mixture was filtered thro' a pad of celite and the solvent was removed. The residue was purified by column chromatography over silica gel using CH2Cl2 /methanol/2M NH3 in MeOH (90:8:4 to 90:40:40) as the eluting system. The product was obtained as a pale yellow oil (3.21 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:29]#[N:30])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH:25]([F:27])[F:26])[C:17]([O:19]C(C)(C)C)=[O:18])[C:10](=[O:28])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:29]#[N:30])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH:25]([F:27])[F:26])[C:17]([OH:19])=[O:18])[C:10](=[O:28])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC(F)F)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cn(C(CC(F)F)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
114 mg (260 μmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4,4-difluorobutanoate (racemate) in 8 ml of dichloromethane and 400 μl (5.20 mmol) of TFA were reacted according to General Method 6A. Yield: 99 mg (91% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:14]([OH:16])=O)[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[NH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][C:31]=1[Cl:38]>>[Cl:38][C:31]1[CH:32]=[C:33]([C:34]#[N:35])[CH:36]=[CH:37][C:30]=1[NH:29][C:14](=[O:16])[CH:13]([N:12]1[C:11]2[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=2[N:9]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: N#Cc1ccc(N)c(Cl)c1
Product: N#Cc1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(Cl)c1
Yield: 62 %

Procedure:
The title compound was prepared in analogy to example 22, int. d) from [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid and 4-amino-3-chlorobenzonitrile to give the desired compound as a white solid (62%). MS (ES+): M−H: 539.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][Si](C(C)(C)C)(C)C)=[CH:12][C:11]=2[N:24]2[C:32](=[O:33])[C:31]3[CH:30]=[C:29]4[CH:34]=[CH:35][CH:36]=[CH:37][C:28]4=[CH:27][C:26]=3[C:25]2=[O:38])=[O:8])=[CH:5][CH:4]=1.O1CCOCC1.Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=2[N:24]2[C:25](=[O:38])[C:26]3[CH:27]=[C:28]4[CH:37]=[CH:36][CH:35]=[CH:34][C:29]4=[CH:30][C:31]=3[C:32]2=[O:33])=[O:8])=[CH:39][CH:40]=1
Reactant: COc1ccc(C(=O)Nc2ccc(O[Si](C)(C)C(C)(C)C)cc2N2C(=O)c3cc4ccccc4cc3C2=O)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc(C(=O)Nc2ccc(O)cc2N2C(=O)c3cc4ccccc4cc3C2=O)cc1
Reaction time: 6 h
Yield: 63.8 %

Procedure:
A solution of N-(4-methoxybenzoyl)-2-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-4-(tert-butyldimethylsiloxy)benzeneamine (48.6 mg, 0.088 mmol) in 2:1 dioxane:methanol (6 mL) was treated with 12 M aqueous hydrochloric acid (0.010 mL). After 6 h, the mixture was concentrated in vacuo and the residue purified by flash chromatography (silica gel; ethyl acetate/hexanes) to yield 24.6 mg (64%) of the title compound.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24]Br)[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].[C:27]([O-:34])(=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].[Na+]>CC(C)=O>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24][O:34][C:27](=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Reactant: CCCCCC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCCC(=O)OCC(=O)O[C@H]1[C@@H](CC)C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21C
Yield: 77.5 %

Procedure:
In 150 ml of 50% aqueous acetone are dissolved 5.0 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one and 2.5 g of sodium n-hexanoate and the solution is refluxed for 6 hours. The solvent is distilled off under reduced pressure and the residue is extracted with 300 ml of ethyl acetate. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue is subjected to column chromatography. Following passage of 750 ml of diisopropyl ether-n-hexane (9:1), elution is carried out with 1000 ml of a 1:1 mixture of the same solvents. The eluate is evaporated under reduced pressure to remove the solvent, giving 4.2 g of the above-identified compound as a light-yellow viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:6]=[CH:7][CH:8]=[C:9]2[CH:13]=[CH:12][NH:11][C:10]=12>CC(O)=O.[Fe]>[NH:11]1[C:10]2=[C:5]([O:4][C:3]3[CH:14]=[CH:15][C:16]([NH2:18])=[CH:17][C:2]=3[F:1])[N:6]=[CH:7][CH:8]=[C:9]2[CH:13]=[CH:12]1
Reactant: O=[N+]([O-])c1ccc(Oc2nccc3cc[nH]c23)c(F)c1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1ccc(Oc2nccc3cc[nH]c23)c(F)c1
Reaction time: 0.17 h
Yield: 99.4 %

Procedure:
To a solution of 260 (100 mg, 0.36 mmol) in AcOH (4 mL) at 90° C., was added iron powder (102 mg, 2.1 mmol). The reaction mixture was vigorously stirred for 10 min, cooled, filtered through a Celite pad and concentrated. The residue was purified by flash column chromatography, eluent EtOAc/hexane (1:1), to afford title compound 261 (87 mg, 99% yield) as an off-white solid. MS (m/z): 244.1 (M+H) (found).