Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2](F)(F)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[F:13][C:14](S(O)(=O)=O)([F:16])[F:15].[C:21]1([O:27][CH3:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:28][O:27][C:21]1[CH:26]=[CH:25][C:2]([C:3]([C:24]2[CH:25]=[CH:26][C:21]([O:27][CH3:28])=[CH:22][CH:23]=2)([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:14]([F:16])([F:15])[F:13])=[CH:23][CH:22]=1
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: COc1ccccc1
Reactant: O=C(c1ccccc1)C(F)(F)F
Product: COc1ccc(C(c2ccccc2)(c2ccc(OC)cc2)C(F)(F)F)cc1
Reaction time: 0.17 h
Yield: 93.8 %

Procedure:
A mixture of 10.0 g. (0.057 mol) of trifluoroacetophenone, 10 g (0.07 mol) trifluoromethyl sulfonic acid, and 10 g (1.09 mol) anisole was stirred at room temperature for 24 hours. There was a slight initial exothermic reaction which subsided within 10 minutes. At the end of 24 hours, the mixture was transferred to a separatory funnel and the organic material was washed with water (3×100 ml), saturated sodium bicorbonate (3×50 ml), and water (2×50 ml). The organic phase was dried (magnesium sulfate) and the excess volatile reagents were removed in vacuo. The resulting non-volatile material was crystallized from aqueous methanol to give 19.9 g (94% yield) of the desired product: m.p. 120°-121° C.; IR (KBr) 1604 and 1510 (Ar); 1145 (C-F), 810 (parasubstituted phenyl), 740 and 690 cm-1 (monosubstituted phenyl); NMR δ3.93 (s, 6H), 6.8s (d, J=4 Hz, 4H), 7.10 (d, J=4 Hz, 4H), 7.28 (s, broad, 5H); mass spectrum m/e, 372 (parent ion), 303 (P-69 base peak), 288 (P-84), 273 (P-99), 226 (P-146), 195 (P-177), 180 (P-192), 165 (P-207), 107 (P-265) 88 (P-284), 77 (P-295). Analytical: calculated for C22H19O2F3 ; C., 70.97; H, 5.12; F, 15.32%. Found: C, 71.13; H, 5.16; F, 15.1%.
Reaction SMILES: [CH2:1]([S:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[CH:8]=[C:7]([C:15]([O:17]C2CCCC(=O)C=2)=O)[C:6]1=[O:25])[CH3:2].C(N(CC)CC)C.C[C:34]([CH3:38])([OH:37])[C:35]#N.[C:39](O)(=O)[CH2:40][C:41](CC(O)=O)(C(O)=O)[OH:42]>ClCCl>[CH2:1]([S:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[CH:8]=[C:7]([C:15]([C:35]2[C:41](=[O:42])[CH2:40][CH2:39][CH2:38][C:34]=2[OH:37])=[O:17])[C:6]1=[O:25])[CH3:2]
Reactant: CC(C)(O)C#N
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CCSCn1c(=O)c(C(=O)OC2=CC(=O)CCC2)cc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCSCn1c(=O)c(C(=O)C2=C(O)CCCC2=O)cc2cccnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.97 g (8.3 mmol) of 3-oxo-1-cyclohexenyl 1-(ethylthiomethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate was dissolved in dichloromethane (80 mL). 1.40 mL (10.0 mmol) of triethylamine and 0.77 g (9.1 mmol) of acetone cyanohydrin were added to the above solution, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was poured into an aqueous solution of citric acid, and the mixture was extracted with dichloromethane. The organic phase was washed with water, dried, and concentrated. The residue was purified by column chromatography (ethyl acetate:n-hexane=1:4), and thus 0.77 g of the title compound was obtained as pale orange-colored crystals (yield: 26%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[NH4+:12].[Cl-].C[Si]([C:18]#[N:19])(C)C>N>[NH2:12][C:8]([C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[F:11])([CH3:9])[C:18]#[N:19]
Reactant: C[Si](C)(C)C#N
Reactant: [NH4+]
Reactant: CC(=O)c1cc(Br)ccc1F
Agent: N
Agent: [Cl-]
Product: CC(N)(C#N)c1cc(Br)ccc1F
Temperature: 30 °C
Reaction time: 48 h

Procedure:
1-(5-Bromo-2-fluorophenyl)-1-ethanone ([CAS 198477-89-3], 65 g, 299.5 mmol) and NH4Cl (32 g, 599 mmol) were dissolved in NH3 (in MeOH, 600 mL). Trimethylsilyl cyanide ([CAS 7677-24-9], 100 g, 1008.6 mmol) was added to the above mixture on an ice bath. The reaction mixture was stirred for 2 days at 30° C. The mixture was evaporated under reduced pressure. The residue was extracted with CH2Cl2 (2×300 mL). The organic layer was collected, dried and evaporated to give the crude product, which was purified by flash column chromatography over silica gel (gradient eluent:ethyl acetate/petrol ether from 1/20 to 1/2). The product fraction was collected and evaporated to give I-11 (60 g, 82%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[C:19]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCN(C(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
18 ml (0.117 mol) of ethyl piperidine-4-carboxylate and 32.4 ml (0.2325 mol) of triethylamine were dissolved in 580 ml of toluene and treated with 18 ml (0.155 mol) of benzoyl chloride. The mixture was stirred at room temperature for 2 hrs., filtered and the solvent was evaporated. The residue was chromatographed on silica gel with ethyl acetate/hexane (1:3→1:1) as the eluent. 28.3 g (92%) of ethyl 1-benzoyl-4-piperidine-carboxylate were obtained as white crystal; m.p. 75°-78°.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([C:8]([N:10]2[CH2:16][CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]2=3)=[O:9])=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:26]=[CH:25][C:7]([C:8]([N:10]2[CH2:16][CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]2=3)=[O:9])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1CCc2ccccc2-c2ccccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(C(=O)N2CCc3ccccc3-c3ccccc32)cc1
Yield: 94.9 %

Procedure:
A solution of 0.15 g of 5-(4-nitrobenzoyl)-6,7-dihydro-5H-dibenz[b,d]azepine in 20 μl of ethanol-ethyl acetate and 10 mg of 10% palladium-on-carbon is hydrogenated under 35 pounds per square inch of hydrogen for 8 hr. The mixture is filtered through diatomaceous earth and the filtrate evaporated to give 0.13 g of product as a light yellow solid.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4:10].[CH3:11]CO[CH2:14][CH3:15]>>[CH-:1]1[CH:11]=[CH:4][CH:3]=[CH:2]1.[CH-:15]1[CH:14]=[CH:3][CH:2]=[CH:1]1.[Zr+2:10]
Reactant: [Zr+4]
Reactant: [Li]CCCC
Reactant: CCOCC
Agent: [Cl-]
Product: [Zr+2]
Product: c1cc[cH-]c1
Temperature: 40 °C
Reaction time: 6 h
Yield: 51 %

Procedure:
6.22 g (0.010 mol) of the dimethylsilyl ligand above were dissolved in 75 mL of ether, treated with 8.2 mL of butyllithium in hexanes (2.5 M, 0.021 mol), and stirred at 40° C. for 6 h. ZrCl4 (2.3 g, 0.010 mol) was added, and the mixture was stirred for 18 h. The resulting yellow precipitate was collected on a closed frit (5.5 g), and the filtrate evaporated to orange solids (3.3 g). The yellow precipitate was stirred in dichloromethane (150 mL), filtered, and solvent removed from the filtrate to give 3.8 g of zirconocene (51%, 60:40 rac:meso ratio). A 12:1 rac:meso sample (1.0 g) was obtained by slow evaporation of a dichloromethane/hexane solution of the zirconocene. 1H-NMR δ (CDCl3): (rac isomer) 7.6–7.7 (m, 3H), 7.4–7.55 (m, 7H), 7.08 (s, 1H), 6.6 (s, 1H), 3.2 (m, 1H), 2.6 (s, 3H), 2.4 (s, 3H), 1.58 (s, 9H), 1.56 (s, 9H), 1.3 (s, 3H), 1.18 (s, 3H), 1.1 (d, 3H), 0.95 (d, 3H).
Reaction SMILES: [C:1]1([C@H:7]([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:13]1([C:19]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@H:27]3[C@H:23]([CH2:24][NH:25][CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[C:29]1([C:19]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:27]3[C@H:23]([CH2:24][N:25]([C:8](=[O:10])[C@H:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH3:11])[CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: C[C@H](C(=O)O)c1ccccc1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](C(=O)N1C[C@@H]2C(=O)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1)c1ccccc1
Reaction time: 0.67 h
Yield: 57.3 %

Procedure:
N,N'-Carbonyldiimidazole (0.66 g) is added to a solution of (S)-2-phenylpropionic acid (0.62 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 40 minutes at +5° C. and a solution of (3aR,7aR)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (1.35 g) and triethylamine (0.57 cc) in dichloromethane (40 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with distilled water (2×50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.2-0.063 mm, diameter 1.8 cm, height 15 cm), eluting with ethyl acetate and collecting 15 cc fractions. The first fraction is concentrated to dryness under reduced pressure (2.7 kPa). (3aR,7aR)-7,7-diphenyl-2-[(S)-2-phenylpropionyl]-4-perhydroisoindolone (1 g) is obtained in the form of a white meringue. [α]D20 =-231° (c=1, methanol).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:14].[K+].Cl[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24]Cl)[CH:19]=1.O>CS(C)=O>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][O:14][C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:19]=1
Reactant: ClCc1cccc(CCl)c1
Reactant: Oc1ccccc1-c1ccccc1
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: c1ccc(-c2ccccc2OCc2cccc(COc3ccccc3-c3ccccc3)c2)cc1
Temperature: 35 °C
Yield: 95 %

Procedure:
A 100 mL 3-neck flask was equipped with a magnetic stirrer, a reflux condenser, a nitrogen blanket, and a heating mantle with a temperature controller and a thermocouple. The flask was charged with o-phenylphenol (6.83 grams, 0.04 moles), with KOH (2.63 grams, 0.04 moles), and with 25 mL of DMSO. The mixture was stirred at about 35° C. for about ¾ hour, then a solution of α,α′-dichloro-m-xylene (3.52 grams, 0.02 moles) in 5 mL of DMSO was added to the dark solution over about 25 minutes. After the addition, the reaction mixture was heated at 50° C. for about 3 hours, and then it was poured into about 400 mL of water. A sticky white solid separated. The mixture was slurried with about 75 mL of diethyl ether; the solids dissolved. The mixture was transferred to a separatory funnel, and the layers were separated. The aqueous layer was extracted with 2×75 mL of diethyl ether. The ether layers were combined and were washed with 1×75 mL of saturated aqueous sodium chloride solution, and then they were dried over anhydrous magnesium sulfate. After filtration, the ether was removed by rotary evaporation at a bath temperature of about 60° C./P=3.4 kPa to give 8.42 grams of clear, viscous brown oil. Yield=95%. Structure was confirmed by IR, GC/MS, and 1H- and 13C-NMR analyses.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si](O[C:27]1[C:32](/[CH:33]=[CH:34]\[C:35]2[CH:40]=[C:39]([O:41][CH3:42])[C:38]([O:43][CH3:44])=[C:37]([O:45][CH3:46])[CH:36]=2)=[CH:31]C=C(OCC)[C:28]=1[O:50][Si](C(C)(C)C)(C)C)(C(C)(C)C)(C)C.C(O)(=[O:60])C.O.[CH2:63]1[CH2:67][O:66][CH2:65][CH2:64]1>>[OH:50][C:28]1[C:64]([OH:60])=[C:65]([O:66][CH2:67][CH3:63])[CH:31]=[C:32](/[CH:33]=[CH:34]\[C:35]2[CH:36]=[C:37]([O:45][CH3:46])[C:38]([O:43][CH3:44])=[C:39]([O:41][CH3:42])[CH:40]=2)[CH:27]=1
Reactant: C1CCOC1
Reactant: CC(=O)O
Reactant: CCOc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)c(O[Si](C)(C)C(C)(C)C)c1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: CCOc1cc(/C=C\c2cc(OC)c(OC)c(OC)c2)cc(O)c1O
Temperature: 25 °C

Procedure:
Tetrabutylammonium fluoride (0.75 mL, 0.75 mmol, 1M in THF) was added to a solution of 36 (0.21 g, 0.375 mmol) and glacial acetic acid (43 μL, 0.75 mmol) in THF 7 mL at 0° C. The reaction mixture was allowed to warm to room temperature overnight, then cooled to 0° C. and water was added. The reaction mixture was extracted with TBME (3×) and the organic phase was dried (Na2SO4) and concentrated in vacuo. The residue was partitioned between CH3CN and cyclohexane and the CH3CN layer was separated and concentrated in vacuo to give the crude product. Purification by column chromatography (SiO2 1:1 EtOAc:cyclohexane) gave ZSB-81 (38 mg, 29%) as an 89:11 mixture of Z:E isomers:
Reaction SMILES: F[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[CH:4]=O.[NH2:11][NH2:12]>C1COCC1>[I:10][C:6]1[CH:7]=[CH:8][N:9]=[C:2]2[NH:11][N:12]=[CH:4][C:3]=12
Reactant: NN
Reactant: O=Cc1c(I)ccnc1F
Solvent: C1CCOC1
Product: Ic1ccnc2[nH]ncc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 2-fluoro-4-iodonicotinaldehyde (11.33 g, 45.1 mmol) in THF (200 mL) was added hydrazine (5.67ml, 181 mmol) dropwise. The resulting mixture was stirred at RT under a nitrogen atmosphere for 5 h. The reaction was concentrated, diluted with 10:1 acetone/MeOH and filtered through a pad of silica gel. Removed most of the solvent in vacuo, then diluted with some hexanes and filtered resulting solid. Dried to yield 4-iodo-1H-pyrazolo[3,4-b]pyridine as an off-white solid. MS m/z=246 [M+1]+. Calc'd for C6H4IN3: 245.02.
Reaction SMILES: C([N:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH:25](O)[CH2:26][CH3:27])(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[OH:30]>>[NH:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH2:25][C@@H:26]([OH:30])[CH3:27]
Reactant: CO
Reactant: CCC(O)c1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Product: C[C@H](O)Cc1ncc[nH]1

Procedure:
A solution of N-tritylimidazolylpropanol (S)-(6) (2.39 g, 6.51 mmol) in 80 ml methanol containing 4.3 ml glacial acetic acid (5%) was refluxed for about 12 hours. After that time, TLC indicated disappearance of the starting materials. The mixture was concentrated in vacuo and a white precipitate appeared upon addition of 50 ml of cold distilled water. The mixture was chilled, then filtered, and the white precipitate was washed with cold distilled water (10 ml). The filtrate was then evaporated twice, and the residual yellow oil redissolved in 50 ml dry methanol and passed through the weakly basic anion exchange resin (hydroxide form) IRA-68. The solution was then evaporated to yield a solid residue that could be recrystallized from a mixture of methanol and ethyl acetate. yield: 0.80 g, 98% of pure (S)-(7). m.p. 119-121° C.; 1H NMR (200 Mhz, CD3OD) δ6.96 (s, 2H, NCHCHN); 3.96 (m, 1H, CHCH3); 2.4-2.65 (ABX, 3JH-H=6.3 Hz, 3JHb-H=6.7 Hz, 3JHa-Hb=14.5 Hz, CH2); 0.87 (d, 3H, 3JH-H=6.3 Hz, CH3); 13C NMR (50 MHz, CD3OD) δ145.8 (s, CH2CNH); 121.2 (d, NCH═CHNH); 67.1 (d, CHOH); 38.4 (t, CH2); 23.1 (q, CH3); MS (CI): [M+1]+. 127
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]([CH3:16])([CH3:15])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[O:29])=[CH:26][N:25]=1.CC(N(C)C)=O>C(CC(C)(C)C)(C)C>[NH2:5][C:6]([CH3:16])([CH3:15])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:24]2[CH:32]=[CH:31][C:27]([C:28](=[O:29])[NH2:30])=[CH:26][N:25]=2)=[CH:10][CH:9]=1
Reactant: CC(C)(N)Cc1ccc(O)cc1
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)CC(C)(C)C
Solvent: CC(=O)N(C)C
Solvent: CC(=O)O
Product: CC(C)(N)Cc1ccc(Oc2ccc(C(N)=O)cn2)cc1
Temperature: 140 °C

Procedure:
A mixture of 4-(2-amino-2-methylpropyl)phenol acetic acid salt (45.06 g, 200 mmol), powdered K2CO3 (69.1 g, 500 mmol), 6-chloronicotinamide (31.32 g, 200 mmol), DMAC (622 mL) and iso-octane (70 mL) was slowly heated to reflux at 140° C. A water trap filled with iso-octane was used to collect water formed in the reaction, and reflux was maintained for 5.5 h. The mixture was allowed to cool to room temperature, and the solids were filtered and washed with EtOAc. The filtrate was concentrated in vacuo to 88.6 g of solid which was dissolved in EtOAc (500 mL). To this solution was added water (800 mL), 1N HCl (200 mL) and MeOH (50 mL). The pH of this mixture was adjusted to 7.2 with con. HCl, and the aqueous layer was separated and washed with methyl t-butyl ether (500 mL). The product was crystallized by addition of 10N NaOH (20 mL) which raised the pH to 11. This pH was maintained by addition of 10N NaOH as needed during the course of the crystallization (90 min). The product was filtered, washed with water and dried in vacuo at 45° C. to 53.11 g (93%) of white solid which was >98% pure by HPLC analysis: 1H NMR (300 MHz, DMSO-d6) NMR was consistent with the desired product.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)=[O:4].[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1>O1CCOCC1>[Br:11][C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[CH:10]=[CH:9][CH:8]=1
Reactant: c1c[nH]cn1
Reactant: O=C(CBr)c1cccc(Br)c1
Solvent: C1COCCO1
Product: O=C(Cn1ccnc1)c1cccc(Br)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of 2-bromo-1-(3-bromophenyl)ethanone (120 mg, 0.432 mmol) in dioxane (2 mL) was added imidazole (58.8 mg, 0.864 mmol) and the reaction mixture was stirred for 1 h at 80° C. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography using MeOH:CH2Cl2 (6:94) as eluent to give the sub-title compound in 68% yield (77.9 mg, 0.293 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([N:20]([CH2:34][CH3:35])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=O)[NH:28][CH:27]=1)=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:34]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[NH:12][C:11]2=[O:17])[NH:28][CH:27]=1)=[O:25])[CH3:35]
Reactant: O=C1Cc2c(cccc2-c2cccc(Br)c2)N1
Reactant: CCN(CC)CCNC(=O)c1c[nH]c(C=O)c1C
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1c[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(Br)c4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 71.7 %

Procedure:
To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72.0 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(3-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (93.5 mg, 72%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:13])[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl:14][C@@H:15]([CH2:19][CH3:20])[C:16](O)=[O:17].C(Cl)CCl>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:6]([O:5][CH2:4][C@H:3]([OH:13])[CH2:2][NH:1][C:16](=[O:17])[C@@H:15]([Cl:14])[CH2:19][CH3:20])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NC[C@@H](O)COCc1ccccc1
Reactant: CC[C@H](Cl)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC[C@H](Cl)C(=O)NC[C@@H](O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 5.9 %

Procedure:
Preparation of 886355 using modifications to Scheme 7 and Scheme 4: To a stirred solution of (R)-1-amino-3-(benzyloxy)propan-2-ol, Compound 22 in Scheme 7 (8.0 g, 44.1 mmol) in DMF (60 mL) was added (S)-2-chlorobutanoic acid (5.0 g, 40.8 mmol) followed by TEA (10.5 g. 103.8 mmol), DMAP (0.4 g, 3.3 mmol) and finally EDC (9.52 g, 49.7 mmol). The reaction mixture was stirred at rt for 5 d after which time the completed reaction was concentrated to a crude syrup. Purification over silica gel (Biotage, eluting with a gradient of 20-100% EtOAc in heptanes) followed by collection of the desired fractions, concentration and drying in vacuo provided (S)—N—((R)-3-(benzyloxy)-2-hydroxypropyl)-2-chlorobutanamide (683.5 mg, 2.392 mmol, 5.9% yield).
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[O:18])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.C(Cl)Cl.O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[O:2]=[C:3]1[NH:8][CH:7]=[C:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[O:18])=[CH:14][CH:15]=2)[CH:5]=[CH:4]1
Reactant: COc1ccc(Cc2ccc(NC(=O)Nc3ccc(C)cc3)cc2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(NC(=O)Nc2ccc(Cc3ccc(=O)[nH]c3)cc2)cc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A suspension of N-(4-(6-methoxy-pyridin-3-ylmethyl)-phenyl)-N′-(4-methyl-phenyl)-urea (Example 95; 0.28 g, 0.81 mmol) and trimethylsilyl-jodide (0.6 ml) in chloroform (10 ml) is stirred for 16 h at 60° C. Then CH2Cl2 (4 ml), water (10 ml) and saturated NaHCO3 solution (5 ml) is added and the suspension stirred vigorously. Filtration, washing with CH2Cl2 and water followed by column chromatography (SiO2; AcOEt/MeOH 9:1→4:1 MeOH) yields the title compound: 1H-NMR (DMSO-d6): 11.4 (s, HN), 8.52 (s, HN), 8.47 (s, HN), 7.33 (d, 2H), 7.29 (d, 2H), 7.25 (dd, 1H), 7.16 (s, 1H), 7.07 (d, 2H), 7.04 (d, 2H), 6.24 (d, 1H), 3.58 (s, 2H), 2.22 (s, 3H).
Reaction SMILES: B([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)(O)O.Br[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:4]2[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=2)[CH:15]=1
Reactant: Brc1cccnc1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(O)c1ccc(-c2cccnc2)cc1
Yield: 85.3 %

Procedure:
To a solution of 4-boronobenzoic acid (1.66 g, 10 mmol) and 3-bromopyridine (1.72 g, 11 mmol) in acetonitrile (40 mL) and water (40 mL), potassium carbonate (5.5 g, 40 mmol), bis(triphenylphosphine)palladium(II) chloride (400 mg, 0.37 mmol) were added. The mixture was degassed and purged withed nitrogen. The mixture was stirred under reflux for 24 h. Then the hot suspension was filtered and concentrated to half of the original volume and washed with dichloromethane. The aquatic phase was adjusted to pH=3 with hydrochloric acid (1 M) and filtrated, washed with water. The residue was dried in vacuum to obtain 1.7 g of white solid of 4-(pyridin-3-yl)benzoic acid. Yield: 85%. LC-MS (ESI) m/z: 200 (M+1)+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH2:6]1)=[O:4].[Cl:20][S:21](O)(=[O:23])=[O:22]>ClCCl>[CH3:17][O:16][C:11]1[CH:12]=[CH:13][C:14]([S:21]([Cl:20])(=[O:23])=[O:22])=[CH:15][C:10]=1[CH:7]1[CH2:8][CH2:9][N:5]([C:3](=[O:4])[C:2]([F:1])([F:18])[F:19])[CH2:6]1
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccccc1C1CCN(C(=O)C(F)(F)F)C1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)Cl)cc1C1CCN(C(=O)C(F)(F)F)C1
Temperature: -5 °C
Reaction time: 18 h
Yield: 90.8 %

Procedure:
1.7 g of 2,2,2-trifluoro-1-(3-(2-methoxyphenyl)pyrrolidin-1-yl)ethanone (6.22 mmol) were dissolved in 5 mL of dichloromethane and the solution was cooled to −5° C. At this temperature, 14.5 g of chlorosulfonic acid (124 mmol) were slowly added dropwise. Stirring was continued for 1 h at −5° C. and 18 h at room temperature. The reaction was then cooled to 0° C. and slowly added into 30 g of a water/ice mixture. The suspension was extracted 5 times with 100 mL of dichloromethane and the combined organic phases were washed twice with 5% aqueous sodium hydrogencarbonate solution. The organic layer was dried over sodium sulfate, filtered, and the solvent was evaporated to yield 2.1 g of the title compound as a yellowish solid (storage in the refrigerator under argon atmosphere).