Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][C@@H:25]([OH:27])[C@@H:24]([OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.CCO.O>[OH:28][C@@H:24]1[C@H:25]([OH:27])[CH2:26][N:22]([C:3]2[C:2]([C:33]3[CH:34]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2C[C@@H](O)[C@@H](O)C2)c(Br)c1
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2C[C@@H](O)[C@@H](O)C2)c(-c2cncnc2)c1

Procedure:
5-Bromo-6-((3S,4R)-3,4-dihydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 71.1, 60 mg, 0.13 mmol), pyrimidin-5-ylboronic acid (32.2 mg, 0.26 mmol), Pd(PPh3)2Cl2 (9.11 mg, 0.013 mmol) and Na2CO3 (55.0 mg, 0.519 mmol) were added to a MW vial and treated with a mixture of DME (551 μL), water (157 μL) and EtOH (79 μL). The vial was sealed, evacuated/purged with argon and subjected to MW irradiation at 125° C. for 10 min. The RM was diluted with DME (3 mL), treated with Si-Thiol (Silicycle, 1.44 mmol/g, 54.1 mg, 0.078 mmol), centrifuged, the supernatant was filtered and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative SFC (Column DEAP, isocratic 25% in 9 min.) to yield the title compound as a white amorphous solid. UPLC-MS (Condition 3) tR=0.83 min, m/z=462.1 [M+H]+, m/z=460.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.05 (dd, J=10.76, 4.16 Hz, 2H) 3.26 (dd, J=10.51, 4.89 Hz, 2H) 3.98 (t, J=3.91 Hz, 2H) 4.89 (br. s, 2H) 7.35 (d, J=8.56 Hz, 2H) 7.79-7.90 (m, 2H) 8.10 (d, J=2.20 Hz, 1H) 8.79 (d, J=2.20 Hz, 1H) 8.88 (s, 2H) 9.20 (s, 1H) 10.17 (s, 1H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][S:5][S:6][CH2:7][CH2:8][NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17].[CH2:19]1[C@@H:23]([CH2:24][CH2:25][CH2:26][CH2:27][C:28](O)=[O:29])[S:22][S:21][CH2:20]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[S:21]1[CH2:20][CH2:19][C@H:23]([CH2:24][CH2:25][CH2:26][CH2:27][C:28]([NH:2][CH2:3][CH2:4][S:5][S:6][CH2:7][CH2:8][NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])=[O:29])[S:22]1
Reactant: O=C(O)CCCC[C@@H]1CCSS1
Reactant: NCCSSCCNC(=O)c1ccccc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(CCCC[C@H]1CCSS1)NCCSSCCNC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 23.6 %

Procedure:
The HCl salt of N-(2-(2-(2-aminoethyl)-disulfanyl)-ethyl)-2-hydroxybenzamide (0.322 mmol) was taken up in DMF (5 mL) along with (R)-α-lipoic acid (TCI, 66 mg, 0.322 mmol) HATU (134 mg, 0.354 mmol) and DIEA (170 μL, 0.97 mmol). The resulting reaction mixture was stirred at room temperature for 4 h. It was then diluted with EtOAc (30 mL) and washed successively with water (3×5 mL) and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. Purification by chromatography (CH2Cl2) afforded (S)—N-(2-(2-(2-(5-(1,2-dithiolan-3-yl)pentanamido)ethyl)disulfanyl)ethyl)-2-hydroxybenzamide (35 mg, 24%). Mass calculated for C19H28N2O3S4: 460.1. found: [M+H]+=461.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:9]=[C:10]([F:15])[CH:11]=2)[O:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:47]C>C1COCC1.O>[ClH:47].[C:17]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:8]1[CH:9]=[C:10]([F:15])[CH:11]=[C:12]2[C:7]=1[O:6][C@@H:5]([CH2:4][NH2:1])[CH2:14][CH2:13]2
Reactant: CCl
Reactant: [N-]=[N+]=NC[C@H]1CCc2cc(F)cc(-c3ccccc3-c3ccccc3)c2O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cl
Product: NC[C@H]1CCc2cc(F)cc(-c3ccccc3-c3ccccc3)c2O1
Yield: 52 %

Procedure:
Treatment of (2R)-2-(azidomethyl)-8-(biphenyl-2-yl)-6-fluorochroman (0.85 g, 2.36 mmol) with polymer-bound triphenylphosphine (3 mmol/g, 1.02 g, 3.06 mmol) in THF (30 mL) and water (2 mL) according to the procedure described for Example Cl-Me provided 0.46 g (52%) of ((2R)-8-(biphenyl-2-yl)-6-fluorochroman-2-yl)methanamine hydrochloride as an off-white solid salt, mp 98° C.; MS (ESI) m/z 334.2 [M+H]+; [α]D25=−27.00° (c=1% SOLN, MeOH).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:14][C:15]1[CH:25]=[CH:24][C:18]2[N:19]=[C:20]([S:22][CH3:23])[O:21][C:17]=2[CH:16]=1.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:14][C:15]3[CH:25]=[CH:24][C:18]4[N:19]=[C:20]([S:22][CH3:23])[O:21][C:17]=4[CH:16]=3)[C:5]2=[N:6][CH:7]=1
Reactant: Fc1cnc2[nH]cnc2c1
Reactant: CSc1nc2ccc(CCl)cc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nc2ccc(Cn3cnc4cc(F)cnc43)cc2o1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
To a stirred solution of 6-fluoro-3H-imidazo[4,5-b]pyridine (502 mg, 3.66 mmol) from Step 2 of Example 70 in anhydrous DMF (10 mL) at 0° C. was added in one portion sodium hydride (60% dispersion in mineral oil, 220 mg, 5.49 mmol), and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added a solution of 6-(chloromethyl)-2-(methylthio)benzo[d]oxazole (858 mg, 4.03 mmol) from Step 3 of Example 56 in DMF (2 mL). The mixture was allowed to warm to rt and stir for a further 3 h. To the reaction mixture was added water and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed sequentially with water and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 30 to 50% ethyl acetate in petroleum ether to afford 6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]oxazole (698 mg, 61%) as a white solid. The regiochemistry of the alkylation was determined by 2-dimensional nuclear Overhauser effect (NOE) experiment. 1H NMR (300 MHz, DMSO-d6): δ 8.71 (s, 1H), 8.41 (s, 1H), 8.07 (d, J=6.9 Hz, 1H), 7.68 (s, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.35 (d, J=6.3 Hz, 1H), 5.59 (s, 2H), 2.73 (s, 3H); LCMS (ESI) m/z 315 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.Cl.[CH3:9][NH:10][CH3:11].[CH2:12]=O.[OH-].[Na+]>O>[CH3:9][N:10]([CH3:12])[CH2:11][CH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: CNC
Reactant: Cc1cnccn1
Reactant: C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)CCc1cnccn1
Temperature: 25 °C
Yield: 66.5 %

Procedure:
A mixture of 94.0 g (1.0 mole) of methylpyrazine and 83.9 g (1.03 mole) of dimethylamine hydrochloride was heated until it began refluxing. 131.3 g (40% aqueous solution) (1.75 mole) of formaldehyde was added over a period of two hours. The resulting brown viscous mass was refluxed for additional 2.5 hours. The mixture was cooled to room temperature. It was diluted with 250 ml of water, made basic with 10% sodium hydroxide solution and extracted with chloroform. After removing the chloroform the residue was distilled to give 100.6 g of β-dimethylaminoethylpyrazine, b.p. 116°-120° C. at 20 mm Hg.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13](ON=C(C1C=CC=CC=1)C#N)=[O:14])([CH3:11])([CH3:10])[CH3:9].Cl.[NH2:27][C@@:28]1([C:48]([OH:50])=[O:49])[C@H:33]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=2)[C@@H:32]([OH:44])[C@@H:31]2[C@H:29]1[C@H:30]2[C:45]([OH:47])=[O:46]>O1CCOCC1.O>[C:8]([O:12][C:13]([NH:27][C@@:28]1([C:48]([OH:50])=[O:49])[C@H:33]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=2)[C@@H:32]([OH:44])[C@@H:31]2[C@H:29]1[C@H:30]2[C:45]([OH:47])=[O:46])=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: N[C@]1(C(=O)O)[C@@H]2[C@@H](C(=O)O)[C@@H]2[C@H](O)[C@H]1OCc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@]1(C(=O)O)[C@@H]2[C@@H](C(=O)O)[C@@H]2[C@H](O)[C@H]1OCc1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Reaction time: 4.5 h
Yield: 91.8 %

Procedure:
Triethylamine (212.80 mL, 154.49 g, 1.53 mol) and 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (125.33 g, 508.90 mmol) are added sequentially to a suspension of (1S,2R,3S,4S,5R,6R)-2-amino-3-[(3,4-dichlorobenzyl)oxy]-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylic acid hydrochloride (140 g, 339 mmol) in 1,4-dioxane (203.56 mL), and water (0.6 mL/mmol-pure-LR, 203.56 mL), at ambient temperature. After 4.5 hours, add additional 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (25.07 g, 101.78 mmol) and triethylamine (23.64 mL, 17.17 g, 169.63 mmol) to the reaction and stir at 50° C. overnight. Cool to 23° C., dilute with water (500 mL), and wash with methyl tert-butyl ether (6×500 mL). Dilute the aqueous phase with 10% aq. HCl (300 mL; final pH=2) and extract with ethyl acetate (2×500 mL). The ethyl acetate extracts are dried over MgSO4 and concentrated in vacuo to yield the title compound (148.3 g, 92% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=O.S([O-])([O-])(=O)=O.[Mg+2].[Cl-].[C:25]([O:29][C:30](=[O:33])[CH2:31][Zn+])([CH3:28])([CH3:27])[CH3:26]>O1CCCC1.C(OCC)(=O)C>[CH2:16]([O:15][C:11](=[O:14])[CH:12]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2)[CH2:31][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:33])[CH3:17]
Reactant: CC(C)(C)OC(=O)C[Zn+]
Reactant: CCOC(=O)C=O
Reactant: Nc1ccc2[nH]ncc2c1
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(CC(=O)OC(C)(C)C)Nc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 65 %

Procedure:
To a solution/suspension of 5-aminoindazole (1.01 g, 7.6 mmol) in tetrahydrofuran (20 mL) was added ethyl glyoxylate solution (ca. 50% in toluene, 1.7 mL, 1.1 equiv) in one portion followed by magnesium sulfate (4.6 g). The mixture was stirred at room temperature overnight (23 h) and then filtered and concentrated in vacuo. The resulting crude imine intermediate (1.3 g, 6 mmol) was dried by azeotroping with anhydrous benzene and further dried under high vacuum. The residue was then dissolved in tetrahydrofuran (20 mL) and cooled at 0° C. A solution of 2-tert-butoxy-2-oxoethylzinc chloride (0.5 M in ether, 24 mL, 2 equiv) was then slowly added. After stirring at 0° C. for 1 h, the mixture was stored at 4° C. overnight. The mixture was then diluted with ethyl acetate and quenched with half-saturated ammonium chloride solution along with a minimum amount of 0.5 N HCl to dissolve the precipitated solids. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel, eluting with 10% methanol in methylene chloride, to afford the desired product (1.3 g, 65%) as a tan oil. 1H-NMR (400 MHz, CDCl3) δ 7.89 (1H, s), 7.40-7.27 (1H, m), 6.98-6.77 (2H, m), 4.42-4.35 (1H, m), 4.30-4.12 (3H, m), 2.80 (2H, d, J=4.4 Hz), 1.43 (9H, s), 1.27-1.17 (4H, m). Mass spec.: 356.24 (M+Na)+, 278.23 (M−tBu)+, tR=1.287 min.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.F[C:19](F)(F)C(O)=O.[NH:25]1[CH2:29][CH2:28][CH2:27][C@@H:26]1[C:30]1[O:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[O:31]1[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=[C:30]1[CH:26]1[CH2:19][CH2:27][CH2:28][CH2:29][N:25]1[C:15](=[O:17])/[CH:14]=[CH:13]/[C:8]1[CH:7]=[C:6]2[C:11](=[N:10][CH:9]=1)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]2
Reactant: O=C(O)C(F)(F)F
Reactant: c1ccc2oc([C@H]3CCCN3)nc2c1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCc2cc(/C=C/C(=O)N3CCCCC3c3nc4ccccc4o3)cnc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.4 %

Procedure:
A 16 mL vial flask was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (60 mg, 0.24 mmol), DMF (5.8 mL), 2-[(2R)-pyrrolidin-2-yl]-1,3-benzoxazole trifluoroacetate (0.31 mmol theory; which may be prepared as described in Step 3), DIPEA (96 μL, 0.58 mmol), DMAP (2.4 mg, 0.02 mmol) and EDAC (56 mg, 0.29 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was purified on preparative TLC (eluent: dichloromethane/MeOH, 95/5) and column chromatography (eluent: dichloromethane/MeOH, 98/2) to give the title compound (12 mg, 13%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[O:33][CH3:34].O1CCOCC1>CO.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[CH:3]=2)[CH:30]=[CH:31][C:32]=1[O:33][CH3:34]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(-c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3cc(C)nn23)cc1OC
Temperature: 110 °C
Yield: 35.8 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 60 mg, 0.174 mmol), 3,4-dimethoxyphenylboronic acid (41 mg, 0.226 mmol), and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10 mg, 13.6 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (0.58 mL of 1,4-dioxane and 0.29 mL of saturated aqueous NaHCO3) was prepared in a 10 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 10 minutes in a CEM microwave reactor. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC (45-45% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (27.8 mg, 36%). ESI-MS: m/z 447.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([N:12]([CH3:27])[C:13](=[O:26])[CH2:14][C:15]([N:17]([CH2:24][CH3:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:16])[C:3]=1[C:4]([O:6]C)=O.[O-]CC.[Na+].O.Cl>C(O)C>[CH3:25][CH2:24][N:17]([C:15]([C:14]1[C:13](=[O:26])[N:12]([CH3:27])[C:8]2[CH:9]=[CH:10][CH:11]=[C:2]([Cl:1])[C:3]=2[C:4]=1[OH:6])=[O:16])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCN(C(=O)CC(=O)N(C)c1cccc(Cl)c1C(=O)OC)c1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCN(C(=O)c1c(O)c2c(Cl)cccc2n(C)c1=O)c1ccccc1
Reaction time: 1 h
Yield: 79 %

Procedure:
To (9) (5 mmol) dissolved in dry ethanol (25 ml) at 5° C. was added sodium ethoxide (0.37 g, 5.2 mmol). The mixture was stirred at this temperature for 1 h, and then at room temperature under TLC control. After completion of the reaction (˜2-3 h) [if the reaction was not completed by this time, the mixture was further refluxed for an additional 1-2 h], water (100 ml) was slowly added followed by a drop-wise addition of 1.0 N hydrochloric acid (6 ml) with stirring. After 30 minutes at 5° C., the crystals were collected by filtration, washed with water, and dried at 40° C. under vacuum to give (1) in 79% yield with an assay of 98.6%.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:7][N:6]=[C:5]([CH:8]=[O:9])[CH:4]=1.[C:10](=O)([O-])[O-].[K+].[K+].CN(C=O)C.CI>O>[CH3:10][N:7]1[C:3]([S:2][CH3:1])=[CH:4][C:5]([CH:8]=[O:9])=[N:6]1
Reactant: CSc1cc(C=O)n[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CSc1cc(C=O)nn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
To a mixture of 5-(methylsulfanyl)-1H-pyrazole-3-carbaldehyde (10.0 g), potassium carbonate (9.70 g) and N,N′-dimethylformamide (60 mL) was slowly added methyl iodide (6.6 mL) at 0° C., and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (6.38 g, yield 58%) as yellow crystals from the fraction eluted with ethyl acetate-hexane (1:5, volume ratio). melting point 47-48° C. MS: 157 (MH+).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:12]([OH:17])[C@@H:13]([OH:16])[C:14]#[CH:15].CCN(CC)CC.N#N>C(#N)C.CCOC(C)=O.[Cu]I.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>[OH:16][C@H:13]([CH2:12][OH:17])[C:14]#[C:15][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccccc1I
Reactant: C#C[C@H](O)CO
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1C#C[C@H](O)CO
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 85.7 %

Procedure:
A solution of methyl 2-iodobenzoate (2.312 ml, 15.26 mmol), (2S)-3-butyne-1,2-diol (1.380 g, 16.03 mmol), and Et3N (10.64 ml, 76 mmol) in Acetonitrile (25.2 ml) was degassed with N2 for 10 min and treated with CuI (0.581 g, 3.05 mmol) and Pd(PPh3)4 (0.264 g, 0.229 mmol) and the reaction mixture was heated to 80° C. After 20 min, the reaction mixture was cooled to ambient temperature. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NH4Cl, water and brine. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate-hexanes 0-100%) to afford the title compound (2.88 g, 13.08 mmol, 86% yield) as a beige solid: Rt=0.54 min, ES+ MS: 221 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:13](Cl)=[O:14]>ClCCCl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([N:6]=[C:13]=[O:14])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)c1c(F)cccc1F
Solvent: ClCCCl
Product: O=C=NC(=O)c1c(F)cccc1F
Temperature: 100 °C
Reaction time: 8 h

Procedure:
0.27 g (1.7 mmol) of 2,6-difluorobenzamide and 0.22 g (1.9 mmol, 1.1 eq) of oxalyl chloride were added to 10 ml of 1,2-dichloroethane and then the mixture was stirred for 8 hours at 100° C. The reaction solution was cooled down to room temperature. The reaction solvent and excessive oxalyl chloride were removed by distillation under reduced pressure to obtain 2,6-difluorobenzoyl isocyanate in an oily state. 10 ml of fresh 1,2-dichloroethane and 0.40 g (1.7 mmol) of 2-bromo-5-chloro-4-cyano aniline were successively added thereto, reacted for 2 hours and filtered to obtain 0.54 g (Yield 76%) of the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].[CH2:8]([NH:20][C:21](N1C=CN=C1)=[O:22])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>CO>[CH2:8]([NH:20][C:21]([NH:1][C:2]([CH2:5][OH:6])([CH3:7])[CH2:3][OH:4])=[O:22])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CC(N)(CO)CO
Reactant: CCCCCCCCCCCCNC(=O)n1ccnc1
Solvent: CO
Product: CCCCCCCCCCCCNC(=O)NC(C)(CO)CO

Procedure:
The preparation was carried out, according to the same process described in Example 1, from 3.5 g of 2-amino-2-methyl-1,3-propanediol of corresponding formula R2 --NH--R3, where R2 denoted H and R3 denoted: ##STR7## and 7 g of 1-N-(dodecylaminocarbonyl)imidazole of corresponding formula (III), where R1 denoted C12H25, in 100 cm3 of methanol.
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:18])[CH2:13][O:14][C:15](=[O:17])[CH3:16])=[CH:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7].[CH3:19][C:20]([CH2:27][CH2:28][CH:29]=[C:30]([CH3:41])[CH2:31][O:32][C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[CH:21][CH2:22][CH2:23][C:24](=[O:26])[CH3:25]>>[CH3:7][C:6]([OH:8])([CH2:5][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:18])[CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:19]#[CH:20].[CH3:25][C:24]([OH:26])([CH2:23][CH2:22][CH:21]=[C:20]([CH3:19])[CH2:27][CH2:28][CH:29]=[C:30]([CH3:41])[CH2:31][O:32][C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:1]#[CH:2]
Reactant: CC(=O)CCC=C(C)CCC=C(C)COC(=O)c1ccccc1
Reactant: CC(=O)CCC=C(C)CCC=C(C)COC(C)=O
Product: C#CC(C)(O)CCC=C(C)CCC=C(C)COC(=O)c1ccccc1
Product: C#CC(C)(O)CCC=C(C)CCC=C(C)COC(C)=O

Procedure:
The procedure described in Example 9 was repeated except that 6,10-dimethyl-11-acetoxy-5,9-undecadien-2-on or 6,10-dimethyl-11-(benzoyl)oxy-5,9-undecadien-2-one as employed as a starting material to give 3,7,11-trimethyl-12-acetoxy-6,10-dodecadien-1-in-3-ol and 3,7,11-trimethyl-12-(benzoyl)oxy-6,10-dodecadien-1-in-3-ol.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22])[CH2:9][C:10]#[CH:11]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]#[C:10][CH2:9][CH2:8][N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22].[C:13]1(=[O:22])[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20](=[O:21])[NH:12]1
Reactant: Ic1ccccn1
Reactant: C#CCCN1C(=O)c2ccccc2C1=O
Product: O=C1NC(=O)c2ccccc21
Product: O=C1c2ccccc2C(=O)N1CCC#Cc1ccccn1

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-iodopyridine (453 mg, 2.21 mmol) and 2-(but-3-ynyl)isoindoline-1,3-dione (400 mg, 2.01 mmol, Example 189(B)). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 70:30) to yield 250 mg (0.90 mmol, 45%) of 2-(4-pyridin-2-yl)but-3-ynyl)isoindoline-1,3-dione as.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:7])[CH2:4][CH2:5][Cl:6].[C:8]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9]>>[Cl:6][CH2:5][CH2:4][CH:3]([OH:7])[CH2:2][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:13][CH:14]=1
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: OC(CCl)CCCl
Product: CC(C)(C)c1ccc(OCC(O)CCCl)cc1

Procedure:
Utilizing the procedure of Preparation 21, 1,4-dichloro-2-butanol was reacted with 4-t-butylphenol to give white title compound, m.p. 45°-47° C. Petroleum ether (30°-60° C.) was the recrystallizing solvent.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH2:9]([C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#N)[CH3:10].C[O-].[Na+].C(O)(=O)C>CO.O>[CH2:9]([C:11]1[CH:12]=[C:13]([C:14]2[NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[N:8]=2)[CH:16]=[CH:17][CH:18]=1)[CH3:10]
Reactant: Nc1ccccc1N
Reactant: CCc1cccc(C#N)c1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CCc1cccc(-c2nc3ccccc3[nH]2)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
2.2 g. of o-phenylenediamine and 3.1 g. of m-ethylbenzonitrile were dissolved in 30 ml. of methanol. To the solution was added 1.1 g. of sodium methoxide in methanol. The mixture was stirred at 60° C. for 2 hours, acidified with acetic acid, stirred again at 100° C. for additional 3 hours and poured in 100 ml. of water. The resulting crystals were filtered off, dried and recrystallized from ethyl acetate. 2.7 g. of the product (60% of theory) was obtained. The product was identical to that obtained in Example 23.