Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([Cl:9])[CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C(Cl)Cl.CC([O-])=O.[K+].Br[C:37]1[S:38][C:39]2[C:45]([C:46]3[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=3)=[C:44]([C@H:53]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])[C:54]([O:56][CH2:57][CH3:58])=[O:55])[C:43]([CH3:64])=[CH:42][C:40]=2[N:41]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].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>[C:60]([O:59][C@@H:53]([C:44]1[C:43]([CH3:64])=[CH:42][C:40]2[N:41]=[C:37]([C:2]3[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([Cl:9])[CH:3]=3)[S:38][C:39]=2[C:45]=1[C:46]1[CH:47]=[CH:48][C:49]([Cl:52])=[CH:50][CH:51]=1)[C:54]([O:56][CH2:57][CH3:58])=[O:55])([CH3:61])([CH3:62])[CH3:63]
Reactant: Cc1cnc(Cl)cc1Br
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cc(Cl)ncc3C)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A microwave vial was charged with 4-bromo-2-chloro-5-methylpyridine (199 mg, 0.96 mmol), Bis(pinacolato)diboron (252 mg, 0.99 mmol), PdCl2(dppf).CH2Cl2 (44 mg, 0.05 mmol), then KOAc (293 mg, 2.98 mmol). The vial was flushed with argon, diluted with dioxane (4 mL), sealed, then heated to 100° C. for 1 hour. The reaction mixture was allowed to cool to room temperature and then a portion of this cooled solution (0.7 mL, 0.17 mmol) was added to a vial that was charged with (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (80 mg, 0.16 mmol) and Pd(PPh3)4 (9 mg, 0.01 mmol). The mixture was diluted with dioxane (2.0 mL) and to this was added 2M aqueous K2CO3 (0.30 mL, 0.60 mmol). The vial was sealed, heated to 100° C. for 1 hour, and then allowed to cool to room temperature. The mixture was diluted with EtOAc, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (0-20% EtOAc/Hex gradient) to afford the desired product. LCMS-ESL': calc'd C28H29Cl2N2O3S: 543.1 (M+H+); Found: 543.2 (M+H+).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[C:12]([C:14]([C:16]2[CH:25]=[C:24]([CH3:26])[C:19]3[NH:20][C:21](=[O:23])[O:22][C:18]=3[CH:17]=2)=[O:15])[CH:11]=[CH:10][N:9]=1.CI>C1COCC1.CCOC(C)=O>[Cl:7][C:8]1[CH:13]=[C:12]([C:14]([C:16]2[CH:25]=[C:24]([CH3:26])[C:19]3[N:20]([CH3:1])[C:21](=[O:23])[O:22][C:18]=3[CH:17]=2)=[O:15])[CH:11]=[CH:10][N:9]=1
Reactant: CC(C)(C)[O-]
Reactant: Cc1cc(C(=O)c2ccnc(Cl)c2)cc2oc(=O)[nH]c12
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc(C(=O)c2ccnc(Cl)c2)cc2oc(=O)n(C)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
220 mg (1.94 mmol) potassium-tert-butoxide were added to 500 mg (1.73 mmol) 6-(2-chloro-pyridine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one in 10.0 mL THF and the mixture was stirred for 30 min at RT. Then 0.220 mL (3.46 mmol) methyl iodide were added and the mixture was stirred overnight at RT. The reaction mixture was diluted with EtOAc and washed several times with saturated sodium chloride solution. The organic phase was dried on magnesium sulphate, filtered and evaporated down i. vac. The residue was triturated with DIPE and suction filtered.
Reaction SMILES: [CH3:1]C1C=C(O)C=CC=1O.CC1C(C)=C(C=CC=1O)O.[CH3:20][C:21]1[C:22]([OH:30])=[C:23]([CH3:29])[C:24]([CH3:28])=[C:25]([CH:27]=1)[OH:26]>[O-2].[Cr+3].[O-2].[O-2].[Cr+3].CO>[CH3:20][C:21]1[C:22]([OH:30])=[C:23]([CH3:29])[C:24]([CH3:28])=[C:25]([OH:26])[C:27]=1[CH3:1]
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: Cc1cc(O)ccc1O
Agent: [Cr+3]
Agent: Cc1c(O)ccc(O)c1C
Agent: [O-2]
Solvent: CO
Product: Cc1c(C)c(O)c(C)c(C)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into an autoclave (inner volume: 9 ml, made of SUS 316, equipped with a manometer) were charged 0.115 g of methylhydroquinone, 3.268 g of methanol and 4.6 mg of chromium oxide (manufactured by High Purity Chemicals). The reaction was started by elevating the temperature up to 350° C. with sand bath. The pressure during the reaction was 18 MPa. After 2 hours, the autoclave was quickly cooled and the reaction solution was taken out from the autoclave when the temperature was cooled back to the room temperature. The measurement according to the process described above revealed that the conversion of methylhydroquinone was 17% by mole, the selectivity of dimethylhydroquinone was 74% by mole and the selectivity of trimethylhydroquinone was 2% by mole. No tetramethylhydroquinone was produced.
Reaction SMILES: [N:1]1([C:7](=[S:9])[NH2:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH:11]([CH3:18])[C:12](=O)[C:13]([F:16])([F:15])[F:14]>>[CH3:18][C:11]1[S:9][C:7]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:8][C:12]=1[C:13]([F:16])([F:15])[F:14]
Reactant: NC(=S)N1CCNCC1
Reactant: CC(Br)C(=O)C(F)(F)F
Product: Cc1sc(N2CCNCC2)nc1C(F)(F)F
Yield: 25 %

Procedure:
Prepared in analogy to example 49 (a) from 1-piperazinecarbothioamide and 3-bromo-1,1,1-trifluoro-2-butanone. The crude material was purified by chromatography (SiO2, methanol/dichloromethane) to yield the title compound as a white crystalline solid (yield 25%). MS (m/e): 252.1 (M+H+, 100%).
Reaction SMILES: Br[C:2]1[C:3]([O:9][CH3:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:11][CH:12]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Cl:8][C:6]1[CH:7]=[C:2]([NH:11][CH:12]2[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15]2)[C:3]([O:9][CH3:10])=[N:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: COc1ncc(Cl)cc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ncc(Cl)cc1NC1CN(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 96 h
Yield: 96.5 %

Procedure:
To a solution of 3-bromo-5-chloro-2-methoxypyridine (5.00 g, 33.7 mmol) in toluene (100 mL) was added tert-butyl 3-aminoazetidine-1-carboxylate (5.8 g, 18.5 mmol), Xantphos (650 mg, 1.12 mmol), Cs2CO3 (14.6 g, 44.9 mmol) and Pd2(dba)3 (514 mg, 0.562 mmol). The reaction mixture was stirred at 60° C. under nitrogen for 4 days. After cooling to RT, the reaction mixture was filtered, washed with ethyl acetate (100 mL), the organic layer washed with water (60 mL), brine (60 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (ethyl acetate/hexane) to obtain 5.6 g of tert-butyl 3-((5-chloro-2-methoxypyridin-3-yl)amino)azetidine-1-carboxylate as a white-yellow oil (80%): 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J=2.2 Hz, 1H), 6.36 (d, J=2.2 Hz, 1H), 4.52 (d, J=6.5 Hz, 1H), 4.24 (dd, J=8.9, 7.1 Hz, 2H), 4.05 (m, 1H), 3.89 (s, 3H), 3.70 (dd, J=9.1, 4.8 Hz, 2H), 1.37 (s, 9H); MS (ES) m/z 314 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]=O)=[C:6]([O:10][CH3:11])[C:5]([O:12][CH3:13])=[C:4]([O:14][CH3:15])[C:3]=1[O:16][CH3:17].CC1[C:24](/[CH:25]=[CH:26]/[C:27]([O:29][CH2:30][CH3:31])=[O:28])=C(OC)C(OC)=C(OC)C=1OC>>[CH3:1][C:2]1[C:7](/[CH:8]=[C:26](\[CH2:25][CH3:24])/[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:6]([O:10][CH3:11])[C:5]([O:12][CH3:13])=[C:4]([O:14][CH3:15])[C:3]=1[O:16][CH3:17]
Reactant: COc1c(C)c(C=O)c(OC)c(OC)c1OC
Reactant: CCOC(=O)/C=C/c1c(C)c(OC)c(OC)c(OC)c1OC
Product: CCOC(=O)/C(=C/c1c(C)c(OC)c(OC)c(OC)c1OC)CC

Procedure:
Compound 8c was prepared from 7 (0.437 g, 1.82 mmol) as described above for 8a to give 0.258 g (0.762 mmol, 42%) of the product as a colorless oil following flash chromatography (1:3 EtOAc:hexanes).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][O:56][C:57]1[CH:61]=[C:60]([C:62](O)=[O:63])[O:59][N:58]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:62]([C:60]2[O:59][N:58]=[C:57]([O:56][CH3:55])[CH:61]=2)=[O:63])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: COc1cc(C(=O)O)on1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)N2CCC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)on1
Yield: 24 %

Procedure:
The desired compound was prepared according to the procedure of Example A27 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 3-methoxyisoxazole-5-carboxylic acid as starting materials in 24% yield. LCMS for C29H30ClN8O4 (M+H)+: m/z=589.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:10]([C:11]([O:13]C)=[O:12])[S:9][CH2:8][C:7](=[O:15])[C:6]=2[CH:16]=1.[OH-].[K+].O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:10]([C:11]([OH:13])=[O:12])[S:9][CH2:8][C:7](=[O:15])[C:6]=2[CH:16]=1
Reactant: COC(=O)C1SCC(=O)c2cc(Cl)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C1CSC(C(=O)O)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
In methanol (100 ml) was suspended methyl 6-chloro-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylate (21.5 g) followed by addition of 2N-KOH (70 ml). The mixture was stirred at room temperature for one hour. The resulting reaction mixture was poured into water, acidified and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and the solvent was distilled off to give 6-chloro-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylic acid (18.8 g, yield 93%). Recrystallization from ethyl acetate gave colorless prisms.
Reaction SMILES: [C:1]1([NH:11][C:12](=[O:14])[CH3:13])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:15]Br>CC(O)=O>[Br:15][C:4]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:1]([NH:11][C:12](=[O:14])[CH3:13])=[CH:2][CH:3]=1
Reactant: BrBr
Reactant: CC(=O)Nc1cccc2c1CCCC2
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(Br)c2c1CCCC2
Temperature: 25 °C
Yield: 91.5 %

Procedure:
To a solution of compound 2A (2 g, 11 mmol) in AcOH (15 mL) cooled at 0° C. was added a solution of bromine (1.69 mL, 33 mmol) in AcOH (1.2 mL) slowly so that the reaction temperature was maintained below 17° C. After addition, the reaction mixture was stirred at rt until all the starting material was consumed (˜4 h). The reaction mixture was then poured into ice/water and the resulting suspension filtered. The collected solid was washed with H2O until the filtrate pH=6-7, and dried in a vacuum oven at 50° C. overnight to yield compound 2B (2.7 g) as an off-white solid.
Reaction SMILES: [OH:1][C:2]([CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)([CH3:4])[CH3:3].[H-].[Na+].C1COCC1.[F:18][C:19]([F:37])([F:36])[CH2:20][NH:21][C:22](=[O:35])[C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[C:26]([NH:32][CH3:33])=[CH:25][C:24]=1F>CCOC(C)=O>[F:18][C:19]([F:36])([F:37])[CH2:20][NH:21][C:22](=[O:35])[C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[C:26]([NH:32][CH3:33])=[CH:25][C:24]=1[N:8]1[CH2:9][CH2:10][CH:5]([C:2]([OH:1])([CH3:4])[CH3:3])[CH2:6][CH2:7]1
Reactant: CNc1cc(F)c(C(=O)NCC(F)(F)F)cc1[N+](=O)[O-]
Reactant: CC(C)(O)C1CCNCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNc1cc(N2CCC(C(C)(C)O)CC2)c(C(=O)NCC(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 0.17 h

Procedure:
A mixture of 4-(1-hydroxy-1-methyl-ethyl)-piperidine (24 mg, 0.17 mmol), NaH-suspension (50% in mineral oil, 8 mg, ˜0.17 mmol) and THF (1 mL) is stirred for 10 min. Then, N-(2,2,2-trifluoro-ethyl)-2-fluoro-4-methylamino-5-nitro-benzoic acid amide is added and it is stirred for 1.5 h. The mixture is diluted with EtOAc, washed with water, concentrated, dried and directly used in the next step.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:21])=[C:4]2[CH:10]=[CH:9][N:8]([Si](C(C)C)(C(C)C)C(C)C)[C:5]2=[N:6][CH:7]=1.OS(O)(=O)=O>CC(O)C>[Br:1][C:2]1[C:3]([Cl:21])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)c(Br)cnc21
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: Clc1c(Br)cnc2[nH]ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-4-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (10.1 g, ≈14.0 mmol; crude material prepared according to Tetrahedron Lett., 2004, 45, 2317-2319) in IPA (250 mL) at 0° C. was added 2N H2SO4 (25 mL) and the mixture was allowed to warm to RT and stirred overnight. IPA was evaporated at 35° C. and water was added to the residue and neutralized with 2N NaOH. The precipitate formed was filtered, washed with water followed by hexane, and dried under vacuum to yield the title compound as off-white solid. MS (ES+): m/z 233.01 (100) [MH+]; HPLC: tR=4.51 min (ZQ2000, polar—15 min).
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].[CH2:19]([CH:21]1[O:23][CH2:22]1)Cl>C1COCC1.CN(C=O)C>[O:23]1[CH2:22][CH:21]1[CH2:19][O:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: ClCC1CO1
Reactant: Oc1ccc2c(c1)ncn2-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: c1ccc(-n2cnc3cc(OCC4CO4)ccc32)cc1
Reaction time: 0.08 h

Procedure:
A solution of 5-hydroxy-1-phenylbenzimidazole (Example 14) (0.24 g, 1.14 mmol) 1:1 THF/DMF (5 mL) was added under nitrogen to a stirred suspension of sodium hydride (41 mg of a 60% dispersion in oil, 1.71 mmol). After 5 minutes, epichlorohydrin (98 μL, 1.26 mmol) was added, and the solution was refluxed for 4 hours. The cooled solution was partitioned between diethyl ether and water, and the extract was washed with 2N NaOH and worked up to give an oil which was chromatographed on silica gel. EtOAc/petroleum ether (1: 1) eluted foreruns, while EtOAc eluted the epoxide Example 34 (0.14 g, 46%): mp (EtOAc/petroleum ether) 96-97.5° C.
Reaction SMILES: CO[C:3]1[C:4]([CH2:8][CH2:9][CH2:10][SH:11])=[CH:5][S:6][CH:7]=1.O.S([O-])(O)(=O)=O.[Na+].C1(C)C=CC=CC=1>O>[S:11]1[CH2:10][CH2:9][CH2:8][C:4]2=[CH:5][S:6][CH:7]=[C:3]12
Reactant: COc1cscc1CCCS
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: c1scc2c1CCCS2
Temperature: 110 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
Into a 500 ml three-necked flask (reaction container) with thermometer, 2.47 g (13.1 mmol) of 3-(4-methoxythiophene-3-yl) propane-1-thiol represented by the chemical formula (III-B), 320 mg (2.32 mmol) of sodium hydrogen sulfate monohydrate and 100 ml of toluene were transferred and heated to 110° C., then stirred for a period of 8 hours. After the reaction was completed, 100 ml of water was added to separate the organic layer from the water layer. The organic layer was washed twice each with 100 ml of water, and then dried over anhydrous sodium sulfate. Then it was condensed under a reduced pressure, thereby obtaining a crude product. This crude product was purified using silica gel column chromatography to obtain 3,4-dihydro-2H-thieno[3,4-b]thiopyran (1.68 g, 10.8 mmol, 82.4%) represented by the formula (II-B) having properties shown below. The chemical reaction equation (XII-B) is shown below.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[OH:14][C:15]1[C:23]([OH:24])=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18].[CH3:25][C:26]([CH3:28])=O>FC(F)(F)C(O)=O>[OH:24][C:23]1[C:15]2[O:14][C:26]([CH3:28])([CH3:25])[O:18][C:17](=[O:19])[C:16]=2[CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)c1cccc(O)c1O
Reactant: CC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)OC(=O)c2cccc(O)c2O1
Temperature: 25 °C
Yield: 33.9 %

Procedure:
Trifluoroacetic acid anhydride (42.0 mL, 300 mmol) was added dropwise to a cooled (−5° C.) solution of 2,3-dihydroxybenzoic acid (8.30 g, 53.9 mmol) in trifluoroacetic acid (83 mL), with stirring. Acetone (14.0 mL, 190 mmol) was then added dropwise over 27 minutes, and the mixture stirred and allowed to warm gradually to room temperature over 16.5 hours. The volatiles were concentrated under vacuum, the residue was dissolved in ethyl acetate (100 mL), and the solution slowly added to a rapidly stirred saturated aqueous sodium bicarbonate solution (200 mL). After gas evolution ceased, the mixture was extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried over magnesium sulfate, filtered, concentrated, and purified by silica gel chromatography (ethyl acetate/heptane) to give 8-hydroxy-2,2-dimethyl-4H-1,3-benzodioxin-4-one (123a, 3.55 g, 34% yield) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[C:7]([OH:10])[C:6]([CH3:11])=[CH:5][C:3]=1[OH:4].C(OO)(C)(C)C.S(=O)(=O)(O)O>C(O)(=O)C>[CH3:1][C:2]1[C:3](=[O:4])[CH:5]=[C:6]([CH3:11])[C:7](=[O:10])[C:8]=1[CH3:9]
Reactant: Cc1cc(O)c(C)c(C)c1O
Agent: CC(C)(C)OO
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC1=CC(=O)C(C)=C(C)C1=O
Yield: 77.9 %

Procedure:
A solution of 15.2 g (100 mmol) of 2,3,5-trimethylhydroquinone in 150 ml of acetic acid and 16.1 g (125 mmol) of 70% by weight aqueous tert-butyl hydroperoxide were simultaneously added dropwise to a stirred solution of 0.68 g (2.0 mmol) of iron 5,14-dihydrodibenzo[b,i][5,9,14,18]tetraaza[14]annulene and 0.5 ml of concentrated sulfuric acid in 50 ml of acetic acid at 40° C. with cooling. The reaction mixture was then subjected to steam distillation. The distillate was extracted by shaking with methylene chloride. The organic phase was shaken with aqueous sodium bicarbonate solution and then with water, separated from the aqueous phase, dried over magnesium sulfate, filtered and concentrated to a yellow oil, which slowly solidifed. 11.7 g (78%) of 2,3,5-trimethyl-p-benzoquinone were obtained in the form of yellow oily crystals.
Reaction SMILES: [NH2:1][CH:2]([CH:14]([CH3:17])[CH2:15][CH3:16])[C:3]([NH:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[O:4].C(O)C.[S:21](=[O:25])(=[O:24])([OH:23])[OH:22]>C(O)(C)C>[S:21]([O:23][S:21]([OH:24])(=[O:23])=[O:22])([OH:22])(=[O:25])=[O:24].[NH2:1][CH:2]([CH:14]([CH3:17])[CH2:15][CH3:16])[C:3]([NH:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[O:4]
Reactant: O=S(=O)(O)O
Agent: CCC(C)C(N)C(=O)NCCN1CCOCC1
Solvent: CCO
Solvent: CC(C)O
Product: O=S(=O)(O)OS(=O)(=O)O

Procedure:
To a solution of 2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide free base (25 g, 0.103 mol) dissolved in absolute, anhydrous ethanol (250 mL, 10 vol) cooled in an ice-water bath was slowly added concentrated sulfuric acid (4 mL, 75 mmol) by dropwise addition. Precipitation immediately occurred causing stirring to stop. The ice-water bath was removed and the addition of ethanol (200 mL) and isopropanol (225 mL) was necessary to restart stirring. The remaining required sulfuric acid (7 mL, 131 mmol) was slowly added in an ethanol:isopropanol solution (2:1, 75 mL). An exotherm (20.8° C.-24.0° C.) was observed. The white slurry was allowed to stir overnight under positive nitrogen pressure. The mixture was then filtered washing with isopropanol (150 mL) and dried under high vacuum (35° C.-40° C.) to afford 33.6 g (75% yield) of 2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide Disulfate as a white solid. 1H NMR, LC-MS confirmed the identity and XRD pattern matches the small scale screen sample pattern.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[C:11]#[N:12].[N-:17]=[N+:18]=[N-:19].[Na+].[Cl-].[NH4+].C(O)(=O)C>CN(C=O)C.O>[NH:17]1[C:11]([C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH2:1])=[N:12][N:19]=[N:18]1
Reactant: N#Cc1ccccc1Sc1ccccc1N
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Nc1ccccc1Sc1ccccc1-c1nnn[nH]1
Reaction time: 5 h
Yield: 66.5 %

Procedure:
In 25 ml of DMF were suspended 2.4 g of 2-(2-aminophenylthio)benzonitrile (prepared in accordance with Reference Example 5, Step 4), 3.4 g of sodium azide and 1.7 g of ammonium chloride and the suspension was stirred at 110°-120° C. for 5 hours. After cooling, the reaction mixture was diluted with water, acidified with acetic acid and extracted with ethyl acetate. The extract was washed with water, dried and concentrated and the residue was crystallized from ethyl acetate and isopropyl ether to give 1.9 g of the title compound as white crystals, m.p. 153°-156° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9]/[CH2:10][OH:11])=[CH:4][CH:3]=1.O[C:19]1[CH:30]=[CH:29][C:22]([O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[C:21]([CH3:31])[CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](/[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:9]/[CH2:10][O:11][C:19]2[CH:30]=[CH:29][C:22]([O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[C:21]([CH3:31])[CH:20]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)COc1ccc(O)cc1C
Reactant: OC/C=C(\c1ccccc1)c1ccc(Br)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccccc2)c2ccc(Br)cc2)cc1C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
The above allyl alcohol (0.889 g, 3.0 mmol), methyl (4-hydroxy-2-methylphenoxy)acetate (0.770 g, 3.9 mmol; see below) and triphenylphosphine (1.30 g, 5 mmol) were dissolved in a mixture of anhydrous toluene (12 mL) and tetrahydrofuran (4 mL). The mixture was cooled to 0° C., kept under nitrogen and diisopropyl azodicarboxylate (0.85 g, 4.2 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 3 h and then at 25° C. for 16 h. The solvents were evaporated in vacuo and the residue was submitted to column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 98:2-90:10) affording methyl (E)-[4-[3-(4-bromophenyl)-3-phenylallyloxy]-2-methylphenoxy]acetate.