Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([CH2:8][C:9](=[O:11])[O-:10])[CH2:3][N+:4]([CH3:7])([CH3:6])[CH3:5].N[C@H](C(O)=O)CCCCN>N1C=CC=CC=1C([O-])=O.N1C=CC=CC=1C([O-])=O.N1C=CC=CC=1C([O-])=O.[Cr+3]>[OH:1][CH:2]([CH2:8][C:9](=[O:10])[O-:11])[CH2:3][N+:4]([CH3:7])([CH3:5])[CH3:6]
Reactant: C[N+](C)(C)C[C@H](O)CC(=O)[O-]
Agent: [Cr+3]
Agent: NCCCC[C@H](N)C(=O)O
Agent: O=C([O-])c1ccccn1
Product: C[N+](C)(C)CC(O)CC(=O)[O-]

Procedure:
This experiment was conducted on a commercial 1,500 sow farrow-to-wean operation in central Kansas and used 599 sows (PIC Line C22). Experimental treatments were arranged in a 2×2 factorial with main effects of added L-carnitine (0 or 50 ppm) and chromium tris-picolinate (0 or 200 ppb). Sows were started on test on the first day of breeding. Each sow remained on the same treatment through gestation, lactation, and through a second gestation period (2 parities). During gestation, all sows were fed a grain sorghum-soybean meal-based diet formulated to contain 0.65% lysine, 0.83% Ca, and 0.76% P. In lactation, all sows were fed a grain sorghum-soybean meal based diet formulated to contain 1.10% lysine, 0.90% Ca, and 0.80% P (Table 3). Dietary treatments were provided via a corn-based top dress fed at 30 g/d. The top dress was formulated to provide 90 mg/d and 250 mg/d carnitine in gestation and lactation, respectively. Chromium tris-picolinate was provided at 360 mcg/d and 1,000 mcg/d during gestation and lactation, respectively. These inclusions were calculated to provide 50 mg/kg carnitine (CarniFeed, Lonza Inc., NJ) and 200 mcg/kg chromium (Chromapure, Lonza Inc., NJ) when sows were fed 4 lb/d of the gestation diet and 11 lb/d of the lactation diet. The top dress was added to the top of the feed box between meals in order to be consumed with the rest of the diet. The top dress was color-coded (1% dyed corncobs) by treatment to assure proper distribution of experimental treatments.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:12])[N:8]=[C:7]2[OH:13].[H-].[Na+].[Br-].[Li+].Br[CH2:19][CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>COCCOC.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:12])[N:8]([CH2:19][CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:27])([CH3:29])[CH3:28])([CH3:24])[CH3:25])[C:7]2=[O:13]
Reactant: Oc1nc(Cl)nc2c(Br)cccc12
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: [Br-]
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)OCCCn1c(Cl)nc2c(Br)cccc2c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43.6 %

Procedure:
To a solution of 8-bromo-2-chloroquinazolin-4(3H)-one (407c; 0.110 g, 0.424 mmol) in 2 mL DME and 0.5 mL DMF in an ice/water bath was added sodium hydride (60% in mineral oil; Aldrich; 0.019 g, 0.466 mmol). After 10 min, lithium bromide (Aldrich; 0.074 g, 0.848 mmol) was added and the reaction was warmed to RT. After 15 min, (3-bromopropoxy)-tert-butyldimethylsilane (0.108 mL, 0.466 mmol) was added. After 30 min, the reaction was placed in a 60° C. oil bath and heated over the weekend. The reaction was partitioned between water and EtOAc. The aq layer was extracted 2× EtOAc and The combined organic layers were washed with water 2 times, satd aq NaCl once, and the organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography using 0-20% EtOAc/hexane. The product-containing fractions were concentrated to afford 8-bromo-3-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-chloroquinazolin-4(3H)-one (0.080 g, 0.185 mmol, 43% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 8.21 (1H, dd, J=7.9, 1.3 Hz), 8.02 (1H, dd, J=7.8, 1.4 Hz), 7.34 (1H, t, J=7.8 Hz), 4.38-4.50 (2H, m), 3.78 (2H, t, J=5.8 Hz), 1.96-2.05 (2H, m), 0.89 (9H, s), 0.03-0.08 (6H, m). m/z (ESI, +ve ion) 431.0/433.0/435.0 (M+H)+.
Reaction SMILES: CC([Si](C)(C)[O:6][C@H:7]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C:9](=[CH:10][C:11](=[O:34])[C@@H:12]3[C@@H:21]2[CH2:20][CH2:19][C@@:17]2([CH3:18])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[O:26][CH2:27][CH2:28][CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:8]1)(C)C.O1CCCC1.C(O)(=O)C.[Cl-].[Na+]>O>[OH:6][C@H:7]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C:9](=[CH:10][C:11](=[O:34])[C@@H:12]3[C@@H:21]2[CH2:20][CH2:19][C@@:17]2([CH3:18])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[O:26][CH2:27][CH2:28][CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:8]1
Reactant: CC(C)(C)CCCO[C@H]1CC[C@H]2[C@@H]3C(=O)C=C4C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)CCCO[C@H]1CC[C@H]2[C@@H]3C(=O)C=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
A mixture of 1 part of 3β-{[(1,1-dimethylethyl)dimethylsilyl] oxy}-17β-[(4,4-dimethylpentyl)oxy]androst-5-en-7-one, 22 parts of tetrahydrofuran, 10 parts of acetic acid, and 5 parts of water is heated at approximately 60° under reflux for 48 hours, then poured into 200 parts of water. Approximately 15 parts of sodium chloride is stirred into the resultant mixture. The solid which precipitates is isolated by filtration, washed on the filter with water, dried in air, and finally taken up in 1,1'-oxybisethane. Solvent is thereupon removed by vacuum distillation; and the residue is chromatographed on silicic acid, using benzene and mixtures thereof with increasing amounts of ethyl acetate as developing solvent. Eluates are selected via thin layer chromatography which, upon evaporation of solvent and recrystallization of the residues from a mixture of 2-propanone and hexane, afford 3β-hydroxy-17β-[(4,4-dimethylpentyl)oxy]androst-5-en-7-one melting at 203°-205°. The product has the formula ##STR10##
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[N:10]=[C:11]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:12]([C:16]2[CH:17]=[CH:18][C:19](=[O:25])[N:20]([CH:22]([CH3:24])[CH3:23])[N:21]=2)=[N:13][C:14]=1Br.[C:32]([C:34]1[N:38]([CH3:39])[CH:37]=[N:36][CH:35]=1)#[CH:33].O>C1COCC1.[Cu]I.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>[NH2:8][C:9]1[N:10]=[C:11]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:12]([C:16]2[CH:17]=[CH:18][C:19](=[O:25])[N:20]([CH:22]([CH3:24])[CH3:23])[N:21]=2)=[N:13][C:14]=1[C:33]#[C:32][C:34]1[N:38]([CH3:39])[CH:37]=[N:36][CH:35]=1
Reactant: C#Cc1cncn1C
Reactant: CC(C)n1nc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)n1nc(-c2nc(C#Cc3cncn3C)c(N)nc2-c2ccccc2)ccc1=O
Yield: 84.5 %

Procedure:
In the presence of copper(I) iodide (3.7 mg) and dichlorobis(triphenylphosphine)palladium(II) (13.7 mg), triethylamine (0.0596 ml) was dropwise added to a mixture of 6-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (150 mg) and 5-ethynyl-1-methyl-1H-imidazole (45.4 mg) in THF (1.5 ml) at 50° C. The mixture was refluxed for 2 hours. Water was added to the reaction mixture to give a solid. The solid was purified by column chromatography on silica gel eluting with a mixture of MeOH and EtOAc (2:98 v/v) to give 6-{5-amino-6-[(1-methyl-1H-imidazol-5-yl)ethynyl]-3-phenyl-2-pyrazinyl}-2-isopropyl-3(2H)-pyridazinone as a solid (135 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3I)[N:9]([CH2:17][C:18]([O:20]CC)=[O:19])[C:8]=2[CH3:23])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:31]1[CH:36]=[N:35][CH:34]=[CH:33][N:32]=1)CCC.C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+]>C1(C)C=CC=CC=1.O.[Pd].CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[C:31]3[CH:36]=[N:35][CH:34]=[CH:33][N:32]=3)[N:9]([CH2:17][C:18]([OH:20])=[O:19])[C:8]=2[CH3:23])=[CH:24][CH:25]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: CCOC(=O)Cn1c(C)c(Oc2ccc(Cl)cc2)c2c(I)cccc21
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: Cc1c(Oc2ccc(Cl)cc2)c2c(-c3cnccn3)cccc2n1CC(=O)O
Temperature: 90 °C
Reaction time: 20 h

Procedure:
The product from step (i) (250 mg), 2-(tributylstannyl)-pyrazine (260 mg), Pd (dba)2 (30 mg) and triphenyl-arsine (210 mg) were dissolved in toluene (4 ml) and heated at 90° C. for 20 h. The reaction was cooled to RT, methanol (10 ml) added, followed by 1M aqueous sodium hydroxide (2 ml) and stirred for 20 h. The mixture was diluted with water, extracted with EtOAc, washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified using reverse phase preparative chromatography (eluent MeCN/NH3(aq)) to give the title compound. Yield 30 mg.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C@@H:19]1[CH2:23][C@@H:22]([N:24]([CH3:26])[CH3:25])[CH2:21][C@H:20]1[C:27]([OH:29])=O.Cl.[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([CH:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)=[C:36]([C@@H:38]([NH:40][C:41](=[O:43])[CH3:42])[CH3:39])[CH:37]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.O>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([CH:44]2[CH2:45][CH2:46][N:47]([C:27]([C@@H:20]3[CH2:21][C@H:22]([N:24]([CH3:25])[CH3:26])[CH2:23][C@H:19]3[C:13]3[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=3[F:11])=[O:29])[CH2:48][CH2:49]2)=[C:36]([C@@H:38]([NH:40][C:41](=[O:43])[CH3:42])[CH3:39])[CH:37]=1
Reactant: CC(=O)N[C@@H](C)c1cc(Cl)ccc1C1CCNCC1
Reactant: CN(C)[C@H]1C[C@@H](C(=O)O)[C@H](c2ccc(F)cc2F)C1
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: O
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](C)c1cc(Cl)ccc1C1CCN(C(=O)[C@@H]2C[C@H](N(C)C)C[C@H]2c2ccc(F)cc2F)CC1
Reaction time: 18 h

Procedure:
N,N-diisopropylethylamine (82.4 μL, 0.473 mmol) was added to a stirred suspension of (1R,2R,4R)-2-(2,4-difluorophenyl)-4-(dimethylamino)cyclopentanecarboxylic acid hydrochloride (48.2 mg, 0.158 mmol, prepared essentially as described in EXAMPLE 44), N-[(1S)-1-(5-chloro-2-piperidin-4-ylphenyl)ethyl]acetamide hydrochloride (50 mg, 0.158 mmol), and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (72.0 mg, 0.189 mmol) in N,N-dimethylformamide (1.5 mL) at ambient temperature. After approximately 18 h, the reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification of the crude residue by preparative reversed phase high pressure liquid chromatography on YMC Pack Pro C18 phase (gradient elution; 0–100% acetonitrile/water as eluent, 0.1% TFA modifier) afforded the title compound as a buff white solid (m/z (ES) 532 (MH+).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[C:9](=[O:20])[CH2:8]1)(=[O:3])[CH3:2]>C(Cl)Cl.FC(F)(F)C(O)=O>[C:1]([O:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][C:9](=[O:20])[CH2:8]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCC1CCN(C(=O)OC(C)(C)C)C(=O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)OCCC1CCNC(=O)C1
Reaction time: 1 h

Procedure:
The product from Step C is dissolved in 2:1 methylene chloride and trifluoroacetic acid. The reaction is stirred for 1 h, and evaporated, giving the title compound.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[OH:23][C:24]1[N:25]=[N:26][CH:27]=[CH:28][CH:29]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:25]4[C:24](=[O:23])[CH:29]=[CH:28][CH:27]=[N:26]4)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: Oc1cccnn1
Reactant: O=C(NCc1cn(-c2ccc(I)cc2)cn1)c1ccc(Cl)s1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: O=C(NCc1cn(-c2ccc(-n3ncccc3=O)cc2)cn1)c1ccc(Cl)s1
Temperature: 130 °C
Yield: 15.8 %

Procedure:
A mixture of 5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 1-6 prepared in Example 1 (100 mg, 0.23 mmol), 3-hydroxypyridazine (43 mg, 0.45 mmol), 8-hydroxyquinoline (15 mg, 0.10 mmol) and K2CO3 (123 mg, 0.89 mmol) in DMSO (1 mL) was degassed before being charged with CuI (19 mg, 0.10 mmol). The mixture in a sealed tube was heated at 130° C. overnight. The mixture was then purified by HPLC to give the title compound (15 mg). MS 412.0 and 414.0 (M+H, Cl pattern).
Reaction SMILES: [Na].[C:2]([OH:9])(=[O:8])/[CH:3]=[CH:4]\[C:5]([OH:7])=O.[CH3:10][C:11]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH2:12]>>[C:5]1(=[O:7])[O:9][C:2](=[O:8])[CH:3]=[CH:4]1.[CH3:12][C:11]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH2:10]
Reactant: O=C(O)/C=C\C(=O)O
Agent: C=C(C)CC(C)(C)C
Agent: [Na]
Product: O=C1C=CC(=O)O1

Procedure:
Type B is the sodium salt of a copolymer of maleic acid and 2,4,4-trimethylpent-1-ene obtained by hydrolysis of a copolymer of maleic anhydride and 2,4,4-trimethylpent-1-ene. Latter copolymer is obtainable in accordance with Example 3 of EP-A 9169. Instead of isolating the unhydrolyzed copolymer by spray drying as in Example 3 of EP-A 9169, 325 parts of water are added to the suspension and excess diisobutene is distilled off by steam distillation (bath temperature 80° C.). When an internal temperature of 98° C. is reached, steam is passed in for a further 1 h. Following the addition of a further 220 parts of water and 200 parts of 50% strength by weight sodium hydroxide solution, the mixture is stirred at 100° C. until a virtually clear aqueous solution is obtained (about 4 h). The solids content is then adjusted to 25% using water. The pH of the solution is 10. The K value of the copolymer (determined in accordance with Fikentscher as a 1% strength by weight solution in dimethylformamide) is in the range of 30-40.
Reaction SMILES: CO[C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]=[N+:12]=[N-:13])=[CH:6][C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[Na+].Cl.[CH3:24][O:25][C:26](=[O:33])[C@H:27]([CH2:29][CH2:30][S:31][CH3:32])[NH2:28].Cl.COC(=O)[C@H](CCSC)NC(=O)C1C=CC(N)=CC=1C1C=CC=CC=1>CO>[CH3:24][O:25][C:26](=[O:33])[C@H:27]([CH2:29][CH2:30][S:31][CH3:32])[NH:28][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]=[N+:12]=[N-:13])=[CH:6][C:5]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: COC(=O)c1ccc(CN=[N+]=[N-])cc1-c1ccccc1
Agent: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CN=[N+]=[N-])cc1-c1ccccc1

Procedure:
The desired compound was prepared by saponification of the product of Example 332A using sodium hydroxide in refluxing aqueous methanol, followed by coupling of the resulting acid with methionine methyl ester hydrochloride using the procedure of step C in the preparation of compound 8.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][OH:5].C(N(C(C)C)CC)(C)C.Cl[C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[C:6]1([CH:3]2[CH2:4][O:5][C:22](=[O:24])[NH:1][CH2:2]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NCC(CO)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NCC(c2ccccc2)CO1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A cooled (0° C.) solution of 3-amino-2-phenylpropan-1-ol (245 mg, 1.62 mmol) in CH2Cl2 (10 mL) was treated with diisopropylethylamine (1.65 mL, 9.72 mmol) and triphosgene (241 mg, 0.81 mmol), under an atmosphere of nitrogen. The reaction was stirred at 0° C. for an additional 2 h. The reaction was quenched with sat. NaHCO3 (2 mL) and then extracted with EtOAc (3×40 mL). The combined organic extracts were washed with brine (30 mL), dried (MgSO4), filtered and concentrated to afford the title compound as a colorless oil. LCMS=178.2 (M+1)+.
Reaction SMILES: [CH2:1]([Li])CCC.[Br:6][C:7]1[CH:8]=[C:9]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[C:11]1([CH2:13][CH2:12]1)[C:10]2=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[Br:6][C:7]1[CH:8]=[C:9]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[C:11]1([CH2:13][CH2:12]1)[C:10]2=[CH2:1]
Reactant: CC1(C)Oc2ccc(Br)cc2C(=O)C12CC2
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1c2cc(Br)ccc2OC(C)(C)C12CC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a suspension of methyl(triphenyl)phosphonium bromide (20.8 g, 58.2 mmol) in tetrahydrofuran (168 ml) was added n-butyllithium (2.69 M solution in hexane, 21.6 ml, 58.2 mmol) under dry ice-acetone bath cooling and argon atmosphere. The mixture was stirred for 1 hour at 0° C. To the mixture was added 6-bromo-2,2-dimethyl-4H-spiro[chromene-3,1′-cyclopropan]-4-one (8.18 g, 29 mmol). The mixture was stirred for 1 hour at 0° C. The reaction was quenched by adding water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by silicagel column chromatography (hexane/ethyl acetate=20:1-10:1) to afford 6-bromo-2,2-dimethyl-4-methylene-4H-spiro[chromene-3,1′-cyclopropane] (7.69 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:54])[CH2:7][CH:6]([O:8][C:9]([CH2:11][CH2:12][N:13]2[C:20](=[O:21])[N:19]([CH2:22][CH2:23][C:24]([O:26][CH:27]3[CH2:32][C:31]([CH3:34])([CH3:33])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]3)=[O:25])[C:17](=[O:18])[N:16]([CH2:37][CH2:38][C:39]([O:41][CH:42]3[CH2:47][C:46]([CH3:49])([CH3:48])[NH:45][C:44]([CH3:51])([CH3:50])[CH2:43]3)=[O:40])[C:14]2=[O:15])=[O:10])[CH2:5][C:4]([CH3:53])([CH3:52])[NH:3]1>C(OC(=O)C)(=O)C.C(OCC)C.C(Cl)Cl>[C:6]([N:3]1[C:2]([CH3:54])([CH3:1])[CH2:7][CH:6]([O:8][C:9]([CH2:11][CH2:12][N:13]2[C:14](=[O:15])[N:16]([CH2:37][CH2:38][C:39]([O:41][CH:42]3[CH2:43][C:44]([CH3:51])([CH3:50])[N:45]([C:9](=[O:10])[CH3:11])[C:46]([CH3:49])([CH3:48])[CH2:47]3)=[O:40])[C:17](=[O:18])[N:19]([CH2:22][CH2:23][C:24]([O:26][CH:27]3[CH2:32][C:31]([CH3:33])([CH3:34])[N:30]([C:24](=[O:25])[CH3:23])[C:29]([CH3:35])([CH3:36])[CH2:28]3)=[O:25])[C:20]2=[O:21])=[O:10])[CH2:5][C:4]1([CH3:53])[CH3:52])(=[O:8])[CH3:5]
Reactant: CC1(C)CC(OC(=O)CCn2c(=O)n(CCC(=O)OC3CC(C)(C)NC(C)(C)C3)c(=O)n(CCC(=O)OC3CC(C)(C)NC(C)(C)C3)c2=O)CC(C)(C)N1
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)N1C(C)(C)CC(OC(=O)CCn2c(=O)n(CCC(=O)OC3CC(C)(C)N(C(C)=O)C(C)(C)C3)c(=O)n(CCC(=O)OC3CC(C)(C)N(C(C)=O)C(C)(C)C3)c2=O)CC1(C)C
Temperature: 95 °C

Procedure:
12 g of 1,3,5-tris-[2-(2,2,6,6-tetramethyl-piperidin-4-yl-oxycarbonyl)-ethyl]-isocyanuric acid (m.p. 153°-155° C.) were suspended in 120 ml of acetic anhydride, and the suspension was heated at 95° C. for 26 hours. The acetic anhydride was then distilled off as completely as possible, in a water-jet vacuum, from the clear solution formed; the residue was dissolved in 200 ml of diethyl ether/methylene chloride (9:1), the solution was washed twice with water, three times with saturated sodium hydrogen carbonate solution, and finally again twice with water. The organic phase was dried over sodium sulphate, the solvent was distilled off in vacuo, and the residue was recrystallised from diethyl ether/acetonitrile (98:2) to obtain pure 1,3,5-tris-[2-(1-acetyl-2,2,6,6-tetramethyl-piperidin-4-yl-oxycarbonyl)-ethyl]-isocyanuric acid, m.p. 126.5°-128° C.
Reaction SMILES: [O:1]=[C:2]([CH2:8][C:9](=O)[CH3:10])[C:3]([O:5]CC)=[O:4].Cl.[NH2:13]O>Cl>[CH3:10][C:9]1[CH:8]=[C:2]([C:3]([OH:5])=[O:4])[O:1][N:13]=1
Reactant: CCOC(=O)C(=O)CC(C)=O
Reactant: NO
Agent: Cl
Product: Cc1cc(C(=O)O)on1
Reaction time: 7 h
Yield: 58.7 %

Procedure:
Concentrated HCl (450 ml) was added to ethyl 2,4-dioxovalerate ( 177.8 g, 1.1 mol ) followed by hydroxylamine hydrochloride (103.7 g, 1.68 mol). The reaction mixture was stirred for 7 hours, then allowed to stand for 60 hours. The solvent was removed in vacuo and the residue was chilled on ice. A solid formed which was collected by filtration and washed with cold water. The solid was dissolved in THF (11), the solution was filtered and the solvent was removed in vacuo. The residue was slurried with ethyl acetate (200 ml) and the solid collected by filtration. Concentration of filtrate to approximately 30 ml afforded a second crop of the product. The two crops were combined and recrystallized from methanol to afford 82.1 g (58%) of 3-methylisoxazole-5-carboxylic acid, m.p. 209°-211° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([CH2:16][OH:17])[C@H:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([CH:16]=[O:17])[C@H:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1C=O
Reaction time: 0.5 h

Procedure:
(3S,4S)-1-Benzyloxycarbonyl-3-(tert-butoxycarbonyl)amino-4-hydroxymethylpyrrolidine (1.00 g, 2.85 mmol) was dissolved in dichloromethane (40 mL). Under cooling with ice, Dess Martin reagent (1.42 g, 3.42 mmol) was added thereto, and the resultant mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. Under cooling, 5% aqueous sodium thiosulfate solution (50 mL) was added thereto, followed by stirring for 0.5 hours. The aqueous layer was extracted with dichloromethane (30 mL×1), and the organic layer was washed sequentially by a 0.05 mol/L aqueous sodium hydroxide solution (60 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, to thereby yield the title compound as a colorless oily substance (0.90 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][CH2:6]2.CS[C:13]1[S:14][CH2:15][CH2:16][N:17]=1.C1C2C(=CC=CC=2)C=CC=1S(O)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([C:13]1[S:14][CH2:15][CH2:16][N:17]=1)[CH2:6]2
Reactant: CSC1=NCCS1
Reactant: Clc1cccc2c1CNC2
Agent: O=S(=O)(O)c1ccc2ccccc2c1
Solvent: ClCCl
Product: Clc1cccc2c1CN(C1=NCCS1)C2
Temperature: 150 °C

Procedure:
A mixture of 4-chloroisoindoline (700 mg), 2-methylthio-2-thiazoline (600 mg), and β-naphthylsulfonic acid (35 mg) was heated at 150° C. for 30 minutes. The product was cooled, dissolved in methylene chloride, washed with water, the organic layer dried over anhydrous potassium carbonate, filtered, and solvent removed from the filtrate under reduced pressure. The residue was chromatographed on silica gel packed in methylene chloride/2% methanol/ammonia, eluting with methylene chloride/2% methanol, to give 4-chloro-2-(thiazolin-2-yl)isoindoline, a compound of Formula (IA), m.p. 167°-169° C.