Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[CH2:6]([O:8][C:9]([C:11](=[CH:16][C:17]1[O:18][C:19]([CH3:22])=[CH:20][CH:21]=1)[CH2:12][C:13](O)=O)=[O:10])[CH3:7]>C(OC(=O)C)(=O)C.ClCCl>[C:1]([O:4][C:13]1[C:21]2[CH:20]=[C:19]([CH3:22])[O:18][C:17]=2[CH:16]=[C:11]([C:9]([O:8][CH2:6][CH3:7])=[O:10])[CH:12]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=Cc1ccc(C)o1)CC(=O)O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1cc(OC(C)=O)c2cc(C)oc2c1
Yield: 50 %

Procedure:
Sodium acetate (30 g, 0.36 mol) was added under vigorous stirring to a solution of 3-(ethoxycarbonyl)-4-(5-methyl-2-furyl)but-3-enoic acid (45 g, 0.19 mol) in 250 mL of acetic anhydride. The reaction mixture was refluxed for 2 h and evaporated in vacuum (˜20 mmHg) at 70° C. until the solvent distillation ceased. The obtained crude product was suspended in 500 mL of dichloromethane. The suspension was filtered. The solid was washed with 200 mL of dichloromethane. The combined solutions were washed with 200 mL of a saturated aqueous solution of NaHCO3 and evaporated in vacuum to dryness. The obtained crude product was chromatographed on a layer of silica gel (200×150 mm) with hexane/ethyl acetate mixture, 3:1 as eluent to give 25 g (95 mmol, 51%) of desired compound as a yellow solid.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([N:14]([CH3:27])[C:15]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[F:26])=[O:16])[CH2:11][CH:12]=[CH2:13])(C(C)(C)C)(C)C.Cl>CO>[F:26][C:20]1[C:21]([F:25])=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][NH:17][C:15](=[O:16])[N:14]([C@@H:10]([CH2:11][CH:12]=[CH2:13])[CH2:9][OH:8])[CH3:27]
Reactant: C=CC[C@@H](CO[Si](C)(C)C(C)(C)C)N(C)C(=O)NCc1cccc(F)c1F
Agent: Cl
Solvent: CO
Product: C=CC[C@@H](CO)N(C)C(=O)NCc1cccc(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.7 %

Procedure:
To a solution of (S)-1-(1-(tert-butyldimethylsilyloxy)pent-4-en-2-yl)-3-(2,3-difluorobenzyl)-1-methylurea (3.45 g, 8.65 mmol) in MeOH (60 mL) was added HCl (4 N in dioxane, 11.0 mL). The resulting solution was stirred at RT for 30 min. The mixture was concentrated and re-dissolved in EtOAc. The organic mixture was washed with saturated NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give (S)-3-(2,3-difluorobenzyl)-1-(1-hydroxypent-4-en-2-yl)-1-methylurea (2.5 g, quant.) as a white solid, which was used without further purification. LRMS (M+H+) m/z 285.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:29])=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@@H:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:7]2.[CH3:30][N:31]([CH3:35])[C:32](Cl)=[O:33]>>[Cl:29][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:32](=[O:33])[N:31]([CH3:35])[CH3:30])=[C:10]2[C:6]=1[CH2:7][N:8]([C@@H:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:15])=[O:16])[C:9]2=[O:11]
Reactant: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3c(Cl)ccc(N)c3C2=O)ccc1OC
Reactant: CN(C)C(=O)Cl
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3c(Cl)ccc(NC(=O)N(C)C)c3C2=O)ccc1OC
Temperature: 100 °C
Yield: 70 %

Procedure:
To (1S)-7-amino-4-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-2,3-dihydro-isoindol-1-one (800 mg, 1.82 mmol) was added dimethylcarbamyl chloride (3 ml). The mixture was heated at 100° C. for 20 hrs. The reaction mixture was cooled to room temperature and extracted with water (50 ml) and EtOAc (50 ml). The organic layer washed with water (50 ml), brine (25 ml), dried over Na2SO4 and concentrated. The resulted oil was purified by chromatography to give (1S)-3-{7-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-1,1-dimethyl-urea as a white solid (600 mg, 70% yield): mp, 205-207° C.; 1H NMR (CDCl3) δ 1.47 (t, J=7.0 Hz, 3H, OCH2CH3), 2.94 (s, 3H, CH3), 3.11 (s, 6H, N(CH3)2), 3.72 (dd, J=5, 15 Hz, 1H, CHHSO2), 3.88 (s, 3H, CH3), 4.05-4.22 (m, 4H, CHHSO2+CHHN+OCH2CH3), 4.40 (d, J=10 Hz, 1H, CHHN), 5.73-5.79 (m, 1H, NCH), 6.86-6.96 (m, 3H, Ar), 7.36 (d, J=9 Hz, 1H, Ar), 8.35 (d, J=9 Hz, 1H, Ar), 9.77 (s, 1H, NHCO); 13C NMR (CDCl3) δ 14.68, 36.27, 41.51, 46.96, 51.47, 55.73, 55.97, 64.64, 111.64, 111.67, 112.28, 118.20, 118.54, 119.31, 120.08, 129.13, 133.24, 138.58, 138.77, 148.94, 149.88, 155.01, 169.72. Anal Calcd for C23H28ClN3O6S: C, 54.32; H, 5.65; N, 8.12. Found: C, 54.16; H, 5.42; N, 7.82.
Reaction SMILES: CS(O[CH2:6][C:7]1[C:8]([Br:13])=[N:9][CH:10]=[CH:11][CH:12]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1.O>C(O)C>[Br:13][C:8]1[C:7]([CH2:6][N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: c1c[nH]cn1
Reactant: CS(=O)(=O)OCc1cccnc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Brc1ncccc1Cn1ccnc1
Temperature: 50 °C
Yield: 63.5 %

Procedure:
To a solution of (2-bromo-3-pyridyl)methyl methanesulfonate (2.5 g, 9.39 mmol) in ethanol (46.97 mL) at room temperature, potassium carbonate (2.62 g) and 1H-imidazole (1.31 g) are added. The mixture is stirred at 50° C. A thick sort of emulsion is formed and 10 mL of ethanol is added and the kind of emulsion is stirred at 50° C. overnight. Water is added until all solids are dissolved. Then, it is concentrated under reduced pressure and the residue is diluted with ethyl acetate and washed with sodium bicarbonate (saturated aqueous solution). Organic layer is decanted, dried over magnesium sulfate and solvent evaporated in vacuo. Crude material is purified by normal phase Isco chromatography using as eluent dichloromethane and methanol (98/2 to 90/10) to yield 1.42 g of the title compound. MS (m/z): 238, 240 (M+1, M+3).
Reaction SMILES: Cl([O-])=O.[Na+].[OH2:5].P([O-])(O)(O)=O.[Na+].[Br:12][C:13]1[CH:18]=[C:17]([C:19]2([CH:22]=[O:23])[CH2:21][CH2:20]2)[CH:16]=[CH:15][N:14]=1.CC(=CC)C>O.C(O)(C)(C)C>[Br:12][C:13]1[CH:18]=[C:17]([C:19]2([C:22]([OH:5])=[O:23])[CH2:20][CH2:21]2)[CH:16]=[CH:15][N:14]=1
Reactant: O=CC1(c2ccnc(Br)c2)CC1
Reactant: O
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Product: O=C(O)C1(c2ccnc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of sodium chlorite (368 mg, 3.26 mmol) and sodium dihydrogen phosphate monohydrate (449 mg, 3.26 mmol) in 5 mL of water is added dropwise to a solution of crude 1-(2-bromo-pyridin-4-yl)-cyclopropanecarbaldehyde (566 mg, 2.50 mmol) and 2-methyl-2-butene (1.73 mL, 16.3 mmol) in tert-butanol (12 mL), and the resulting reaction mixture is stirred at room temperature. After 18 hours, the mixture is concentrated in vacuo, acidified to pH 2 with 1M aqueous solution of HCl, diluted with brine (25 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers are dried over Na2SO4, filtered and concentrated to afford crude 1-(2-bromo-pyridin-4-yl)-cyclopropanecarboxylic acid, which is used without purification.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=2)[CH:17]=[CH:16][C:15]=1[S:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:39])[CH3:38])=[CH:32][CH:31]=1>C(O)C>[CH3:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][O:20][C:18]1[CH:17]=[CH:16][C:15]([S:29][C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:39])[CH3:38])=[CH:32][CH:31]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: CC(=O)Nc1ccc(Sc2ccc(OCc3cccc(C)c3)cc2N)cc1
Solvent: CCO
Product: CC(=O)Nc1ccc(Sc2ccc(OCc3cccc(C)c3)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 1d (18 mg, 0.085 mmol) was reacted in ethanol (1 mL) with the product from Example 120a (32 mg, 0.085 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (14 mg, 26%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J=7.35 Hz, 3H) 1.62-1.93 (m, 2 H) 2.02 (s, 3 H) 2.31 (s, 3 H) 2.99 (t, J=7.35 Hz, 2 H) 5.11 (s, 2 H) 6.30 (d, J=6.99 Hz, 1 H) 6.97-7.33 (m, 8 H) 7.34-7.50 (m, 3 H) 7.80 (d, J=8.82 Hz, 1 H) 8.36 (d, J=6.99 Hz, 1 H) 8.97 (d, J=8.82 Hz, 1 H) 9.97 (s, 1 H) 11.01 (s, 1 H) 14.36 (s, 1 H); MS (ESI+) m/z 549 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C@:9]1([CH3:32])[C@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@@H:12]([CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:11][C:10]1=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([O:8][C@:9]1([CH3:32])[C@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@@H:12]([CH2:22][O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[O:11][CH:10]1[OH:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@]1(OCc2ccccc2)C(=O)O[C@H](COCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[C@]1(OCc2ccccc2)C(O)O[C@H](COCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -65 °C
Reaction time: 0.25 h
Yield: 103.1 %

Procedure:
To a solution of (3R,4R,5R)-3,4-Bis(benzyloxy)-5-(benzyloxymethyl)-3-methyl-dihydrofuran-2(3H)-one (250 mmol) in toluene (625 mL) cooled to −70° C. was added dropwise a 1.5 M solution of Dibal in Toluene (250 mL, 375 mmol) at such a rate so that the reaction temperature does not go above −65° C. The reaction was further stirred at −65° C. for 15 mins (TLC analysis showed completion of reaction, 25% ethyl acetate in hexanes). The excess Dibal was destroyed by adding acetone (40 mL) to the reaction mixture while maintaining the temperature below −60° C. The reaction was diluted with cold 2.5 N HCl (300 mL), water (475 mL) and allowed to warm to 0° C. The reaction was extracted with ethyl acetate (625 mL). The organic layer was separated and washed with brine (500 mL), dried over MgSO4, filtered and the filtrate was concentrated in vacuum to dryness to furnish (3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxymethyl)-3-methyl-tetrahydrofuran-2-ol (112 g) as an oil, which was used in the next step without further purification.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2[N:13]=[CH:14][CH:15]=[CH:16][C:11]=2N=N1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][O:35][C@@H:34]([C:38]([OH:40])=O)[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(C(C)C)CC)(C)C.N1CCCC1>ClCCl>[N:13]1([C:38]([C@@H:34]2[O:35][CH2:36][CH2:37][N:32]([C:30]([O:29][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:31])[CH2:33]2)=[O:40])[CH2:14][CH2:15][CH2:16][CH2:11]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](C(=O)O)C1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCNC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCO[C@@H](C(=O)N2CCCC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.7 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluronium hexafluorophosphate (HATU) (1.47 g, 4.3 mmol) was added to a solution of (R)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (1 g, 4.3 mmol) and diisopropylethylamine (1.11 g, 8.6 mmol) in anhydrous dichloromethane (20 mL) at room temperature. Pyrrolidine (0.45 mL, 5.62 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. The mixture was partitioned between water and dichloromethane. The organics were dried over sodium sulfate and concentrated under reduced pressure and the resulting residue was purified via column chromatography (100-200 mesh silica gel, 0-0.5% methanol in dichloromethane) to afford (R)-tert-butyl 2-(pyrrolidine-1-carbonyl)morpholine-4-carboxylate (0.62 g).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:14][CH2:13][CH2:12]1.Cl.C([O-])([O-])=O.[K+].[K+]>CCO>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:14][CH2:13][CH2:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C1CNC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(N2CCC2)cc1
Yield: 11 %

Procedure:
1-Fluoro-4-nitrobenzene (5.0 g, 35.5 mmol) was added to a suspension of azetidine.HCl (3.98 g, 42.55 mmol) and K2CO3 (7.34 g, 53.19 mmol) in EtOH (100 mL) at r.t., and the reaction was stirred at 40° C. overnight. The reaction mixture was filtered and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=10:1) to give compound 700 mg (11%) of the title compound as a yellow solid. [M+H] Calc'd for C9H10N2O2, 180. Found, 180.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]([CH3:15])[C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[N:7][C:6]2=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]([CH3:15])[C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[N:7][C:6]2=[S:32]
Reactant: COc1cc2c(=O)nc(-c3ccccc3)n(C)c2cc1OC
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COc1cc2c(=S)nc(-c3ccccc3)n(C)c2cc1OC
Reaction time: 2 h

Procedure:
1.50 g (5.06 mmol) 6,7-Dimethoxy-1-methyl-2-phenyl-1H-quinazolin-4-one and) 2.00 g (4.94 mmol) Lawesson's reagent (C14H14O2P2S4, Fluka) were dissolved in 20 ml toluene. The reaction mixture was boiled for 2 h. After evaporation the residue was further purified by column chromatography with silica, eluent dichloromethane/acetone 95/5.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]([CH3:7])[CH3:6].C([O-])([O-])=O.[Cs+].[Cs+].[Cl:14][C:15]1[CH:16]=[C:17]([C:22]2[N:27]=[C:26]([N:28]3[CH2:32][CH2:31][CH2:30][CH:29]3[CH3:33])[N:25]=[C:24]([N:34]3[CH2:39][CH2:38][N:37]([C:40]4[N:45]=[CH:44][C:43]([OH:46])=[CH:42][C:41]=4[CH3:47])[CH2:36][CH2:35]3)[CH:23]=2)[CH:18]=[CH:19][C:20]=1[F:21].[Na+].[I-]>CN(C=O)C>[Cl:14][C:15]1[CH:16]=[C:17]([C:22]2[N:27]=[C:26]([N:28]3[CH2:32][CH2:31][CH2:30][CH:29]3[CH3:33])[N:25]=[C:24]([N:34]3[CH2:35][CH2:36][N:37]([C:40]4[N:45]=[CH:44][C:43]([O:46][CH2:3][CH2:4][N:5]([CH3:7])[CH3:6])=[CH:42][C:41]=4[CH3:47])[CH2:38][CH2:39]3)[CH:23]=2)[CH:18]=[CH:19][C:20]=1[F:21]
Reactant: CN(C)CCCl
Reactant: Cc1cc(O)cnc1N1CCN(c2cc(-c3ccc(F)c(Cl)c3)nc(N3CCCC3C)n2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(OCCN(C)C)cnc1N1CCN(c2cc(-c3ccc(F)c(Cl)c3)nc(N3CCCC3C)n2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cooled mixture of (2-chloro-ethyl)-dimethyl-amine hydrochloride (116 mg, 0.81 mmol) in DMF, add Cs2CO3 (526 mg, 1.62 mmol) and stir at 0° C. for 30 min. Add 6-{4-[6-(3-chloro-4-fluoro-phenyl)-2-(2-methyl-pyrrolidin-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-5-methyl-pyridin-3-ol (78 mg, 0.16 mmol) and NaI (29 mg, 0.16 mmol). Stir the mixture at room temperature for 1 h and then for 2 h at 45° C. Partition between EtOAc and water. Wash with brine, dry the solution (Na2SO4), and concentrate under reduced pressure. Purify the residue by flash column chromatography eluting with DCM:MeOH:NH4OH (90:10:1) to afford the title compound. 1H NMR (300 MHz, CDCl3): δ1.29 (t, 3H, J=6.3 Hz, CH3); 1.69 (m, 1H, CH2CH2); 1.91 (m, 1H, CH2CH2); 2.05 (m, 2H, CH2CH2); 2.32 (s, 3H, Ar—CH3); 2.33 (s, 6H, N(CH3)2); 2.71 (t, J=5.7 Hz, 2H); 3.13 (m, 4H); 3.64 (m, 4H); 3.80 (m, 4H); 4.06 (t, J=5.7 Hz, 2H); 4.34 (m, 1H); 6.25 (s, 1H, Ar—H); 7.10 (d, J=2.7 Hz, 1H); 7.18 (m, 1H); 7.89 (m, 2H); 8.04 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:39])[CH2:37][CH3:38])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36](=[O:39])[CH2:37][CH3:38])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:11])=[CH:13][CH:14]=1
Reactant: CCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: CCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)CC2)c1

Procedure:
Example 57 was prepared from bis(4-chlorophenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propanamide according to the procedures described in Scheme 10: ESMS m/e: 552.2 (M+H)+.
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:35])[C:11]2[CH:10]=[C:9]([CH:12]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:13])[S:8][C:7]=2[C:6]([CH3:34])([CH3:33])[CH2:5][CH2:4]1.[CH:36]([CH:38]=[CH:39][C:40]([CH3:47])=[CH:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=O.CO.O>C1OCCC1>[CH3:47][C:40]([CH:39]=[CH:38][CH:36]=[C:12]([C:9]1[S:8][C:7]2[C:6]([CH3:33])([CH3:34])[CH2:5][CH2:4][C:3]([CH3:2])([CH3:35])[C:11]=2[CH:10]=1)[CH3:13])=[CH:41][C:42]([O:44][CH2:45][CH3:46])=[O:43]
Reactant: CCOC(=O)C=C(C)C=CC=O
Reactant: CC(c1cc2c(s1)C(C)(C)CCC2(C)C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCOC(=O)C=C(C)C=CC=C(C)c1cc2c(s1)C(C)(C)CCC2(C)C
Yield: 83.3 %

Procedure:
4.50 g of [1-(4,5,6,7-tetrahydro-4,4,7,7-tetramethylbenzo[b]thien-2-yl)ethyl]triphenylphosphonium bromide and 1.3 g of ethyl 5-formyl-3-methylpenta-2,4-dienoate are dissolved in 70 ml of butylene oxide and the solution is heated at reflux for 2 hours. The cooled mixture is poured into a methanol/water mixture (6:4) and extracted several times with hexane. The hexane phase is washed three times with water, dried and evaporated. After filtration of the crude product over silica gel (eluting agent hexane/ether 9:1), there are obtained 2.4 g of ethyl 3-methyl-7-(4,5,6,7-tetrahydro-4,4,7,7-tetramethylbenzo[b]thien-2-yl)-2,4,6-octatrienoate as a pale yellowish oil.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)=[CH:10][C:9]=2[O:23][CH3:24])[CH:5]=[CH:4][CH:3]=1.[CH3:25]OC1C=C(C2OC3C=CC=CC=3N=2)C=CC=1B1OC(C)(C)C(C)(C)O1.BrC1C=CC=C(C)N=1>>[CH3:24][O:23][C:9]1[CH:10]=[C:11]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH:12]=[CH:13][C:8]=1[C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:25])[N:7]=1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1-c1cccc(Br)n1
Agent: Cc1cccc(Br)n1
Product: COc1cc(-c2nc3ccccc3o2)ccc1-c1cccc(C)n1

Procedure:
Utilizing the general procedure outlined in the synthesis of 2-[4-(6-bromopyridin-2-yl)-3-methoxyphenyl]-1,3-benzoxazole, 2-[3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzoxazole (200 mg, 0.57 mmol) was reacted with 2-bromo-6-methylpyridine (65 μL, 0.57 mmol) to afford the desired 2-[3-methoxy-4-(6-methylpyridin-2-yl)phenyl]-1,3-benzoxazole as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 7.96–7.95 (m, 2H), 7.89 (s, 1H), 7.82–7.79 (m, 1H), 7.67–7.60 (m, 3H), 7.39–7.36 (m, 2H), 7.14–7.12 (m, 1H), 4.00 (s, 3H), 2.65 (s, 3H). MS (ESI) 317 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15]C)=[O:14])=[CH:11][C:10]([C:17]([C:19]3[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=3)=[O:18])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]([C:17]([C:19]3[CH:20]=[N:21][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:23][CH:24]=3)=[O:18])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(C(=O)c2ccc(C(F)(F)F)nc2)nn1-c1ncccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(c1ccc(C(F)(F)F)nc1)c1cc(C(=O)O)n(-c2ncccc2Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
29 mg (0.07 mmol) of methyl 1-(3-chloropyridin-2-yl)-3-{[6-(trifluoromethyl)pyridin-3-yl]carbonyl}-1H-pyrazole-5-carboxylate were dissolved in 2 ml of ethanol, 4 mg (0.1 mmol) of 2N aqueous sodium hydroxide solution were added and the mixture was stirred at RT for 30 min. The solvent was distilled off under reduced pressure, the residue was taken up in water and the mixture was extracted once with methyl tert-butyl ether. The aqueous phase was then acidified with 2N hydrochloric acid and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated.
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[CH3:17][S:18][C:19](SC)=[N:20][C:21]#[N:22]>N1C=CC=CC=1>[C:21]([N:20]=[C:19]([S:18][CH3:17])[NH:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:14])([CH3:15])[C@H:3]1[OH:16])#[N:22]
Reactant: CSC(=NC#N)SC
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Solvent: c1ccncc1
Product: CSC(=NC#N)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Yield: 75 %

Procedure:
A solution of (3S,4R)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (15.00 g) and dimethyl N-cyanoimidodithiocarbonate [(CH3S)2C=N--CN] (10.05 g) in pyridine (75 ml) was stirred at 80° C. for 10 hours, and then concentrated in vacuo. The residue was dissolved in ethyl acetate, and washed with 5% hydrochloric acid, brine, saturated aqueous sodium bicarbonate solution and brine, successively. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was subjected to column chromatography on silica gel (300 g) and eluted with a mixture of chloroform and methanol (20:1). The fractions containing the object compound were combined and concentrated in vacuo to give (3S,4R)-4-(3-cyano-2-methyl-1-isothioureido)-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (16.3 g).
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].[C:6]([CH:14](Br)[CH:15]([CH3:26])[C:16]([N:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20]([OH:22])=[O:21])=[O:17])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C>[C:1]([S:3][CH:14]([C:6](=[O:13])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH:15]([CH3:26])[C:16]([N:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20]([OH:22])=[O:21])=[O:17])(=[O:4])[CH3:2]
Reactant: CC(C(=O)N1CCC[C@H]1C(=O)O)C(Br)C(=O)c1ccccc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CCO
Product: CC(=O)SC(C(=O)c1ccccc1)C(C)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 18 h

Procedure:
To a suspension of 0.47 g of potassium thioacetate in 10 ml. of ethanol is added 1.25 g. of 1-(3-benzoyl-3-bromo-2-methylpropionyl)-L-proline (Example 11, 3-bromo derivative of isomer A). The mixture is stirred for 18 hours, the solvent is removed in vacuo and the residue is partitioned between dichloromethane and water. The organic layer is washed with water, then sodium chloride solution and dried over magnesium sulfate. The solvent is removed in vacuo giving a yellow glass which is dissolved in 10 ml. of ethanol. A 0.47 g. portion of potassium thioacetate is added and the above procedure is repeated giving a yellow glass. This glass is purified by chromatography on a silica gel column with ethyl acetate-hexane-acetic acid (75:25:2) giving 0.28 g. of the desired product as a yellow glass.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)[C:9]([N:11]1[CH2:15][CH2:14][CH:13]2[N:16]([C:32]([CH:34]3[CH2:36][CH2:35]3)=[O:33])[CH2:17][CH:18]([C:19](=[O:31])[NH:20][CH:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][CH2:23][CH2:22]3)[CH:12]12)=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:21]1([NH:20][C:19]([CH:18]2[CH2:17][N:16]([C:32]([CH:34]3[CH2:35][CH2:36]3)=[O:33])[CH:13]3[CH2:14][CH2:15][N:11]([C:9](=[O:10])[CH:8]([NH2:7])[CH:37]4[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]4)[CH:12]23)=[O:31])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)NC(C(=O)N1CCC2C1C(C(=O)NC1CCCc3ccccc31)CN2C(=O)C1CC1)C1CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(C(=O)N1CCC2C1C(C(=O)NC1CCCc3ccccc31)CN2C(=O)C1CC1)C1CCCCC1
Reaction time: 2 h
Yield: 93.6 %

Procedure:
A solution of 46 (430 mg, 0.72 mmol) in DCM (10 mL) was cooled to 0° C. and treated with TFA (4 mL).). After 2 h, the solution was concentrated, diluted with DCM and washed successively with saturated aqueous NaHCO3, and brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 47 (332 mg) as a white foam that was used without further purification. Mass spectrum, m/z [493.7] (M+H)+.