Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:26])(=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]CC.C(O)(=O)CCCCCCCCCCCCCCCCCCC>>[C:1]([OH:26])(=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: CCCCCCCCCCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)O

Procedure:
Mixed with 120 kg of isopropyl alcohol was 100 kg of behenic acid (trade name Edenor C22-85R), manufacture by Henkel Co., dissolved at 50° C. and filtered employing a 10 μm filter. Thereafter, the temperature was lowered to 30° C. and recrystallization was performed. The cooling rate during recrystallization was controlled to be 3° C./hour. The resulting crystals were subjected to centrifugal filtration, were washed with 100 kg of isopropyl alcohol, and subsequently dried. The resulting crystals then underwent esterification. Subsequently, GC-FID was performed, resulting in a silver behenate proportion of 99 percent and a lignoceric acid proportion of 0.5 percent, and an arachidic acid proportion of 0.5 percent as other products.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8](SC)[CH:7]=[CH:6]2.CO.[CH2:17]1COCC1.O[O:23][S:24]([O-:26])=O.[K+]>O>[CH3:17][S:24]([C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=1)(=[O:26])=[O:23]
Reactant: C1CCOC1
Reactant: COc1ccc2nc(SC)ccc2c1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc2nc(S(C)(=O)=O)ccc2c1

Procedure:
A solution of 6-methoxy-2-methylsulfanyl-quinoline (1.0 g, 5 mmoles) in 100 mL 1:1 MeOH/THF was treated with a solution of 5 g OXONE™ in 50 mL water and stirred for 2–3 hours until the oxidation is complete. The mixture is poured into water and extracted with EtOAc. The organic phase is dried and evaporated to yield 2-methanesulfonyl-6-methoxy-quinoline as a crystalline white product.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH:10]2[CH2:27][CH:26]3[N:12]([C:13](=[O:33])[N:14]([CH3:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][CH:21]4[C:23]([C:29]([OH:31])=O)([NH:24][C:25]3=[O:28])[CH2:22]4)[CH2:11]2)[CH:6]=[C:5]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:4]=1.CCN=C=NCCCN(C)C.[CH:51]1([S:54]([NH2:57])(=[O:56])=[O:55])[CH2:53][CH2:52]1.C1CCN2C(=NCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH:10]2[CH2:27][CH:26]3[N:12]([C:13](=[O:33])[N:14]([CH3:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][CH:21]4[C:23]([C:29]([NH:57][S:54]([CH:51]5[CH2:53][CH2:52]5)(=[O:56])=[O:55])=[O:31])([NH:24][C:25]3=[O:28])[CH2:22]4)[CH2:11]2)[CH:6]=[C:5]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:4]=1
Reactant: COc1nc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)N3C2)cc(-c2ccccc2)n1
Reactant: NS(=O)(=O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1nc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCCCCN(C)C(=O)N3C2)cc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.6 %

Procedure:
Compound 1i (78 mg, 0.146 mmol) and EDAC (34 mg, 0.175 mmol) were dissolved in DCM (3 ml). The reaction mixture was stirred at room temperature for 1 h (LC-MS indicated presence of the intermediate). Cyclopropane sulphonic amide (20 mg, 0.161 mmol) and DBU (46 μl, 0.307 mmol) were added and the reaction mixture was stirred at RT for 3.5 h. Citric acid (5%) was added and the organic layer was separated and washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified by preparative HPLC which gave the pure title compound (50 mg, 54%), (M+H)+639).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])(=[O:5])=[O:4].O(C)[Na].[CH2:22]([CH:24]1[O:26][CH2:25]1)Cl>>[CH2:22]([N:2]([CH3:1])[S:3]([C:6]([F:17])([F:18])[C:7]([F:15])([F:16])[C:8]([F:13])([F:14])[C:9]([F:10])([F:12])[F:11])(=[O:5])=[O:4])[CH:24]1[O:26][CH2:25]1
Reactant: ClCC1CO1
Reactant: CNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CO[Na]
Product: CN(CC1CO1)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
N-Methylperfluorobutanesulfonamide (MeFBSA, 313 g, 1.0 mol; preparation described in U.S. Pat. No. 6,664,354, Savu et al., Example 1, Part A) was added to a stirred mixture of 220 g NaOCH3 (1.02 mol; 25% NaOMe in MeOH). The solvent was removed under vacuum (pot temperature about 80° C.; 50 mm Hg). The resulting paste was dissolved in 250 mL THF and treated with 473 g (5.11 mol) epichlorohydrin and stirred at reflux for 4 hr. GLC analysis showed complete conversion of MeFBSA. The slurry was cooled, washed with water (300 mL) and the resulting lower layer was taken up in methylene chloride, rewashed with water (300 mL), and dried over MgSO4. The product was stripped and one-plate distilled to a main cut of MeFBSG as a colorless liquid (260.8 g, bp 95-105° C./0.3 mmHg).
Reaction SMILES: [C:1]1([C@@H:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:20]3=[CH:19][CH:18]=[CH:17][C:16]=5[OH:23])=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:25][C:26]#[N:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]1([C@@H:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16]([O:23][CH2:25][C:26]#[N:27])=[CH:17][CH:18]=[CH:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1cccc2c1c1cccc3c1n2[C@@H](c1ccccc1)CO3
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCOc1cccc2c1c1cccc3c1n2[C@@H](c1ccccc1)CO3
Temperature: 70 °C
Reaction time: 4 h
Yield: 62.2 %

Procedure:
A mixture of (S)-(+)-1-Phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-ol (0.161 g, 0.534 mmol), bromoacetonitrile (0.074 mL, 1.07 mmol), potassium carbonate (0.148 g, 1.07 mmol), and DMF (2 mL) is stirred at 70° C. for 4 h. Additional bromoacetonitrile (0.074 mL) and potassium carbonate (0.074 g) are then added and the mixture is stirred overnight. Bromoacetonitrile and potassium carbonate (0.074 mL and 0.074 g, respectively) are then added and the temperature is increased to 90° C. The mixture is heated at that temperature for 5.5 h and then allowed to cool and stir overnight, after which the mixture is partitioned between ethyl acetate, aq. ammonium chloride, and brine. The organic layers are dried over magnesium sulfate, concentrated, and the residue is chromatographed on silica gel gel (40 mL) using first CH2Cl2/hexane (1:1) to elute unreacted starting material, and then ethyl acetate/CH2Cl2/hexane (5:45:50) to give 0.113 g of (S)-(+)-2-[(1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]acetonitrile.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:20][C:21](=O)[CH:22]([CH3:24])[CH3:23]>C(O)C>[CH:22]([C:21]1[N:1]=[C:2]2[C:7]([O:8][CH2:9][C:10]3([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:12][CH2:11]3)=[CH:6][CH:5]=[CH:4][N:3]2[CH:20]=1)([CH3:24])[CH3:23]
Reactant: CC(C)C(=O)CBr
Reactant: Nc1ncccc1OCC1(c2ccccc2)CC1
Solvent: CCO
Product: CC(C)c1cn2cccc(OCC3(c4ccccc4)CC3)c2n1
Yield: 75.9 %

Procedure:
A stirred mixture of 2-amino-3-[(1-phenylcyclopropyl)methoxy]pyridine (0.84 g, 3.50 mmol, see example 23), 1-bromo-3-methyl-2-butanone (0.69 g, 4.2 mmol) and molecular sieves (4.2 g, type 4 Å, beads, 8–12 mesh) in anhydrous ethanol (10 mL) was refluxed for 24 h under argon. The molecular sieves were filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in a 1:1 (v/v) mixture of saturated aq sodium bicarbonate and water (20 mL) and then extracted with ethyl acetate (3×40 mL). The organic extracts were combined, washed with water (2×5 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo to yield the crude product. Purification by dry column (600 mL funnel filled with 300 mL of silica gel 10–40μ, Sigma cat. S-6628) eluted with a mixture of ethyl acetate-hexanes (1:3 v/v, containing 0.5% v/v isopropylamine) yielded 0.814 g (76% yield) of 2-isopropyl-8-[(1-phenyl-cyclopropyl)methoxy]imidazo[1,2-α]pyridine as a free base (Rf=0.60 in ethyl acetate-hexanes, 1:1 v/v, containing 0.5% v/v isopropylamine). A stirred solution of the free amine (0.755 g, 2.46 mmol) in anhydrous diethyl ether (10 mL) was treated with ethereal hydrogen chloride (50 mL) to form the hydrochloride salt. After 1 h, the solvent was decanted and the title compound was isolated as a solid (0.844 g, quantitative). 1H-NMR (300 MHz, CDCl3) δ 15.59 (br s, 1H, +NH), 8.36 (m, 1H, Ar), 7.85 (d, 1H, Ar), 7.63 (d, 2H, Ar), 7.24 (m, 2H, Ar), 7.13 (m, 1H, Ar), 7.01 (t, 1H, Ar), 6.74 (d, 1H, Ar), 4.29 (s, 2H, CH20), 3.64 (m, 1H, CH), 1.40 (d, 6H, 2CH3), 1.12 (m, 4H, CH2CH2); 13C-NMR (75 MHz, CDCl3, APT) δ 145.64 (+), 144.89 (+), 142.33 (+), 133.36 (+), 130.04 (−), 128.27 (−), 126.78 (−), 120.09 (−), 116.68 (−), 110.31 (−), 109.82 (−), 77.99 (+), 25.51 (−), 25.45 (+), 21.99 (−), 11.45 (+); LRMS-ES m/z: MH+ 307.3.
Reaction SMILES: [CH2:1]([NH:8][C:9]([N:11]1[C@H:16]2[CH2:17][N:18]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33](F)[N:32]=3)[C:19](=[O:29])[C@H:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[N:15]2[C:14](=[O:38])[CH2:13][N:12]1[CH2:39][CH:40]=[CH2:41])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1C(=O)CCC1.[NH:49]1[CH2:52][CH:51]([N:53]2[CH2:58][CH2:57][N:56]([CH2:59][CH3:60])[CH2:55][CH2:54]2)[CH2:50]1.C(C1C=CC=CC=1)C1C=CC=CC=1>O>[CH2:1]([NH:8][C:9]([N:11]1[C@H:16]2[CH2:17][N:18]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([N:49]4[CH2:52][CH:51]([N:53]5[CH2:58][CH2:57][N:56]([CH2:59][CH3:60])[CH2:55][CH2:54]5)[CH2:50]4)[N:32]=3)[C:19](=[O:29])[C@H:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[N:15]2[C:14](=[O:38])[CH2:13][N:12]1[CH2:39][CH:40]=[CH2:41])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCN1CC(=O)N2[C@@H](Cc3ccc(O)cc3)C(=O)N(Cc3cccc(F)n3)C[C@@H]2N1C(=O)NCc1ccccc1
Reactant: CCN1CCN(C2CNC2)CC1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: c1ccc(Cc2ccccc2)cc1
Product: C=CCN1CC(=O)N2[C@@H](Cc3ccc(O)cc3)C(=O)N(Cc3cccc(N4CC(N5CCN(CC)CC5)C4)n3)C[C@@H]2N1C(=O)NCc1ccccc1
Yield: 36.8 %

Procedure:
To a mixed solution of (6S,9aS)-N-benzyl-8-((6-fluoropyridin-2-yl)methyl)-6-((4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide (30.0 mg, 0.0537 mmol) described in Production Example 2-4 and NMP (2.0 mL) was added a mixture (45.0 mg) of 1-(azetidin-3-yl)-4-ethylpiperazine and benzylbenzene described in Production Example 1-3-2 at room temperature. The resultant mixture was irradiated with a microwave at 140° C. for 8 hours. Water was added to the reaction mixture, the resultant solution was extracted with ethyl acetate, and an organic layer was washed with saturated brine. An organic layer was dried over anhydrous magnesium sulfate and then filtrated. The solvent was evaporated under a reduced pressure, the resultant residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=20:1), and was then further purified by NH silica gel thin-layer chromatography (ethyl acetate). The resultant product was further purified by silica gel thin-layer chromatography (methanol) and was then filtrated using a NH silica gel to give the title compound (14.0 mg, yield: 37%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([CH3:13])[C:11](=[O:14])[CH2:10][CH:9]1[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]([O-])([O-])=O.[K+].[K+].CI>CN(C)C=O.Cl>[CH3:18][O:16][C:15]([CH:9]1[CH2:10][C:11](=[O:14])[CH:12]([CH3:13])[N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:17]
Reactant: CC1C(=O)CC(C(=O)O)N1C(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C1CC(=O)C(C)N1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3.0 g of crude 5-methyl-4-oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester in 25 mL of N,N-dimethylformamide was added 1.2 g (8.7 mmol) of K2CO3, and 1.2 mL (19.3 mmol) of methyl iodide. The mixture was stirred at 80° C. for 20 min, cooled to ambient temperature, then diluted with 125 mL of 0.2M HCl(aq.). This was extracted with diethyl ether (3×20 mL), then the combined ether layers were extracted with water (1×20 mL), and brine (1×20 mL), dried over MgSO4, filtered, and concentrated to an oil. The product was purified via silica gel chromatography, eluting with 20% ethyl acetate/hexanes to give the 2,5-cis isomer. The 2,5-trans isomer eluted slightly faster than the desired cis isomer. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.30 (d, J=7.1 Hz, 3H) 1.40 (m, 9H) 2.59 (dd, J=19.2, 3.2 Hz, 1H) 3.12 (dd, J=18.3, 11.2 Hz, 1H) 3.66 (s, 3H) 3.92 (q, J=6.8 Hz, 1H) 4.63 (dd, J=10.7, 3.6 Hz, 1H), NOE observed between H-2 and H-5, not observed in the corresponding trans isomer; MS (ESI) m/z=256 (M−H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([C:9](Cl)=[O:10])=[CH:6][S:7][CH:8]=1)[CH3:2].[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([S:20][S:21][C:22]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:23]=2[NH2:24])=[C:17]([CH:19]=1)[NH2:18].C(N([CH2:35][CH3:36])CC)C>C(Cl)Cl>[Cl:29][C:26]1[CH:27]=[CH:28][C:22]([S:21][S:20][C:16]2[CH:15]=[CH:14][C:13]([Cl:12])=[CH:19][C:17]=2[NH:18][C:9]([C:5]2[C:4]([O:3][CH2:35][CH3:36])=[CH:8][S:7][CH:6]=2)=[O:10])=[C:23]([CH:25]=1)[NH:24][C:9]([C:5]1[C:4]([O:3][CH2:1][CH3:2])=[CH:8][S:7][CH:6]=1)=[O:10]
Reactant: Nc1cc(Cl)ccc1SSc1ccc(Cl)cc1N
Reactant: CCOc1cscc1C(=O)Cl
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cscc1C(=O)Nc1cc(Cl)ccc1SSc1ccc(Cl)cc1NC(=O)c1cscc1OCC

Procedure:
A 6.60 g. portion of 4-ethoxy-3-thiophenecarbonyl chloride in 50 ml of methylene chloride is added dropwise to a solution of 5.48 g. of 2,2'-(dithio)bis[5-chloroaniline] and 3.54 g. of triethylamine in 100 ml of methylene chloride as in Example 14. After filtration through magnesium silicate, the filtrate was concentrated to dryness and the residue was recrystallized from methylene chloride:petroleum ether to give 2',2"'-(dithio)-bis[5'-chloro-4-ethoxy-3-thiophenecarboxanilide] as yellow crystals, m.p. 179°-181° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH2:10][O:11][Si:12]([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:6][CH:7]=1.[C:29]([CH2:33][C:34](OC)=[O:35])(=O)[CH2:30][CH3:31].O>C1CCCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Si:12]([O:11][CH2:10][CH2:9][O:8][C:5]1[N:6]=[C:7]2[C:2](=[CH:3][CH:4]=1)[NH:1][C:29]([CH2:30][CH3:31])=[CH:33][C:34]2=[O:35])([C:25]([CH3:28])([CH3:27])[CH3:26])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCC(=O)CC(=O)OC
Reactant: CC(C)(C)[Si](OCCOc1ccc(N)cn1)(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCCCC1
Product: CCc1cc(=O)c2nc(OCCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc2[nH]1
Temperature: 260 °C
Yield: 51.4 %

Procedure:
A solution of compound C (89.5 g), methyl propionylacetate (32.8 g) and p-toluenesulphonic acid (1.0 g) in cyclohexane (900 ml) was heated under reflux with azeotropic removal of water for 20 hours. Volatile material was then removed from the reaction mixture by evaporation and the residue was dissolved in ethyl acetate (1 l). The solution was washed with saturated sodium hydrogen carbonate solution (500 ml), water (500 ml), saturated sodium chloride solution (500 ml), and then dried (MgSO4). The solvent was removed by evaporation and the residue dissolved in a eutectic mixture of 26.5% v/v diphenyl and 73.5% v/v diphenyl oxide (750 ml). The solution was heated to 260° C. and the temperature maintained for 30 minutes. The solution was cooled and diluted with hexane (1 l) to give 6-[2-(t-butyldiphenylsilyl)oxyethoxy]-2-ethyl-1,5-naphthyridin-4(1H)-one (D) (55.4 g), as a white solid, m.p. 209°-210° C.; NMR (d6 -DMSO): 1.1(s,9H), 1.35(t,3H), 2.8(q,2H), 4.15(t,2H), 4.65(t,2H), 6.3(br s,1H), 7.25(d,1H), 7.5-7.6(m,7H), 7.65-7.8(m,4H), 8.1(d,1H).
Reaction SMILES: O1C=CC(N(C[C@@H]2OC(=O)N(C3C=CC(N4[CH2:33][CH2:32][CH:31]=[CH:30][CH2:29]4)=C(F)C=3)C2)[C:7]([O:9][CH2:10][C:11](Cl)(Cl)Cl)=[O:8])=N1.N1C=CC=C[CH:36]=1>ClCCl>[C:7]([O:9][CH2:10][CH3:11])(=[O:8])[CH3:36].[CH3:33][CH2:32][CH2:31][CH:30]([CH3:29])[CH3:36]
Reactant: c1ccncc1
Reactant: O=C1O[C@@H](CN(C(=O)OCC(Cl)(Cl)Cl)c2ccon2)CN1c1ccc(N2CC=CCC2)c(F)c1
Solvent: ClCCl
Product: CCCC(C)C
Product: CCOC(C)=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60 %

Procedure:
To a stirred solution of 5(R)-[N-isoxazol-3-yl-N-(2,2,2-trichloroethyloxycarbonyl)-aminomethyl]-3-[3-fluoro-4-(1,2,5,6-tetrahydropyrid yl)phenyl]oxazolidin-2-one (228 mg, 0.4 mM) in dry dichloromethane (5 ml) at 0–4° C., was added pyridine (158 mg, 2.0 mM) followed by dropwise addition of a solution of (S)-(+)-2,3,0-isopropylideneglycinoyl chloride (EP 0 413 401 A2; 200 mg, 1.2 mM) in dichloromethane (1 ml). The solution was stirred at 0–4° C. for 10 min. and then allowed to warm to ambient temperature. The reaction mixture was washed with water and brine, dried over sodium sulfate and evaporated to a gum. The title compound was isolated by MPLC (60% ethyl acetate/isohexane) and was obtained as a crisp foam on evaporation (158 mg, 60%).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].Cl[Si](C)(C)C.Br[C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1/[C:14](=[CH:22]/[C:23]1[NH:24][CH:25]=[CH:26][C:27]=1[O:28][CH3:29])/[C:15](=[O:21])[NH:16]2>CN(C=O)C.C(N(CC)CC)C>[OH:5][CH2:1][CH2:2][C:3]#[C:4][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1/[C:14](=[CH:22]/[C:23]1[NH:24][CH:25]=[CH:26][C:27]=1[O:28][CH3:29])/[C:15](=[O:21])[NH:16]2
Reactant: C#CCCO
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCCO)c21
Temperature: 70 °C

Procedure:
Using Method I above, 3-butyn-1-ol (40 mg, 0.57 mmol) (Aldrich) was dissolved, under argon, in 3 mL DMF and 2 mL triethylamine, and to this solution was added chlorotrimethylsilane (0.13 mL, 1 mmol). The reaction was stirred at room temperature for 1 h, at which time (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (110 mg, 0.38 mmol) (Starting Material 1 supra) was added and the solution was degassed for 15 min by bubbling argon through the solution. (Ph3P)2PdCl2 (13 mg) and Cul (7 mg) were added and the reaction was heated at 70° C. for 14 h. The reaction mixture was then poured into 25 mL 1N HCl and the yellow precipitate was filtered off. The product was purified via flash column chromatography to obtain (Z)-1,3-dihydro-4-(4-hydroxy-1-butynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one as a yellow powder. (Yield 35 mg, 30%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][CH:8]([C:10]1[N:11]=[CH:12][S:13][C:14]=1[C:15](OCC)=[O:16])[CH3:9].O.CCOC(C)=O>C1COCC1>[CH3:7][CH:8]([C:10]1[N:11]=[CH:12][S:13][C:14]=1[CH2:15][OH:16])[CH3:9]
Reactant: CCOC(=O)c1scnc1C(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1ncsc1CO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83.6 %

Procedure:
To a 0° C. mixture of lithium aluminum hydride (300 mg, 7.9 mmol) in anhydrous THF (10 mL) was slowly added a solution of ethyl 4-(propan-2-yl)-1,3-thiazole-5-carboxylate (1.06 g, 6.1 mmol) in anhydrous THF (10 mL). The reaction mixture was stirred at room temperature for 1.5 hours. After cooling to 0° C., water (20 mL) and EtOAc (40 mL) were added. The mixture was stirred for 30 minutes. The solid material was removed by filtration. The organic layer was recovered. The aqueous layer was extracted with EtOAc (2×20 mL). The combined organic extracts were dried over MgSO4, filtered, evaporated, and dried in vacuo, affording [4-(propan-2-yl)-1,3-thiazol-5-yl]methanol (802 mg, 96% yield). The product was used without further purification.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:10]([OH:13])([CH3:12])[CH3:11])[CH:7]=[N:8][CH:9]=1.I[CH3:15].O>CN(C)C=O>[Br:3][C:4]1[CH:9]=[N:8][CH:7]=[C:6]([C:10]([O:13][CH3:15])([CH3:11])[CH3:12])[CH:5]=1
Reactant: CI
Reactant: CC(C)(O)c1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(C)(C)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of sodium hydride (60% dispersion in mineral oil, 46 mg, 1.2 mmol) in N,N-dimethylformamide (4.6 mL) at 0° C. was added a solution of the title compound from Example 22 Step C (100 mg, 0.463 mmol) in N,N-dimethylformamide (4.6 mL). After warming to room temperature and stirring for 1 hour, the solution was cooled back to 0° C. and iodomethane (35 μl, 0.56 mmol) was added. After stirring overnight, the reaction was poured into water and extracted with ethyl acetate. The organic extracts were combined, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure to afford the title compound: LCMS m/z 232.97 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][CH:22]([CH3:32])[CH2:23][CH:24]([C:26]1[N:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[NH2:25]>CCCCCCC.C(O)C.CC(O)C>[CH3:21][CH:22]([CH3:32])[CH2:23][C@@H:24]([NH:25][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[C:26]1[N:27]=[N:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)CC(N)c1cccnn1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Solvent: CCCCCCC
Solvent: CC(C)O
Solvent: CCO
Product: CC(C)C[C@@H](NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)c1cccnn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and 3-methyl-1-(pyridazin-3-yl)butan-1-amine (Example 321 a) as starting materials. The product was isolated by chiral chromatography on Reprosil Chiral NR using a mixture of heptane, ethanol and 2-propanol as eluent. The (+)-enantiomer was isolated. MS (EI): m/e=432.5 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:5][O:6][CH3:7])[CH2:3][OH:4].N1C=CN=C1.C(N(CC)CC)C.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>CN(C)C=O.O>[CH3:1][C:2]([CH3:8])([CH2:3][O:4][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:5][O:6][CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COCC(C)(C)CO
Agent: c1c[nH]cn1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCC(C)(C)CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
1 g of 2,2-dimethyl-3-methoxy-1-propanol was admixed with 10 ml of N,N-dimethyl formamide, and 0.29 g of imidazole was added thereto. The mixture was cooled in ice-water bath, and 1.65 ml of triethyl amine was added thereto. After stirring for 5 minutes, 1.65 g of tert-butyldimethylsilyl chloride in 10 ml of N,N-dimethyl formamide was slowly added to the reaction mixture, and the mixture was stirred in ice-water bath for further 4 hours. The reaction mixture was diluted with 10 ml of water, and extracted twice with 20 ml of dichloromethane for each time. The combined dichloromethane extract was dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated to dryness to give 1.78 g of concentrate of 2,2-dimethyl-1-methoxy-3-[(tert-butyldimethylsilyl)oxy]-propane. The crude product was purified by column chromatography using petroleum ether as eluent, to give colorless pure compound.