Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[C:23]4[CH:24]=[CH:25][C:26]([C:28]5[N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH:30]=[CH:31][CH:32]=5)=[CH:27][C:22]=4[C:21]([CH3:41])([CH3:40])[O:20][CH:19]3[CH3:42])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.ClS([N:47]=[C:48]=O)(=O)=O>>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[C:23]4[CH:24]=[CH:25][C:26]([C:28]5[N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:30]([C:48]#[N:47])=[CH:31][CH:32]=5)=[CH:27][C:22]=4[C:21]([CH3:41])([CH3:40])[O:20][CH:19]3[CH3:42])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC1OC(C)(C)c2cc(-c3cccn3C(=O)OC(C)(C)C)ccc2N1C(=O)OCC1c2ccccc2-c2ccccc21
Product: CC1OC(C)(C)c2cc(-c3ccc(C#N)n3C(=O)OC(C)(C)C)ccc2N1C(=O)OCC1c2ccccc2-c2ccccc21
Yield: 64.6 %

Procedure:
Using the procedure for Example 18, the title compound (0.8 g, 65%) was prepared from 9H-fluoren-9-ylmethyl-6-[1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl]-2,4,4-trimethyl-2H-3,1-benzoxazine-1(4H)carboxylate (1.2 g, 2.1 mmol) and chlorosulfonyl isocyanate (0.28 mL, 3.1 mmol). A white solid: mp 135-136° C.; 1H-NMR (DMSO-d6) δ 7.90 (t, 2H, J=6.7 Hz), 7.64 (d, 1H, J=7.5 Hz), 7.59 (d, 1H, J=7.1 Hz), 7.40 (td, 2H, J=7.2, 2.0 Hz), 7.31-7.34 (m, 3H), 7.29 (d, 1H, J=1.2 Hz), 7.04-7.09 (m, 2H), 6.44 (d, 1H, J=3.57 Hz), 5.30 (q, 1H, J=5.6 Hz), 4.86 (dd, 1H, J=10.7, 5.2 Hz), 4.64 (dd, 1H, J=10.8, 5.2 Hz), 4.33 (t, 1H, J=4.7 Hz). 1.50 (s, 3H), 1.30 (s, 9H), 1.20 (s, 3H), 1.03 (d, 3H, J=5.6 Hz); MS (ESI) m/z 590 [M+H]+.
Reaction SMILES: [C:1](=[O:23])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.[NH2:24][CH2:25][CH2:26][S:27]([O-:29])=[O:28].[Na+].OC1C=CC(NC(=O)C)=CC=1.O>C(#N)C>[C:10]([NH:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][C:1]([NH:24][CH2:25][CH2:26][S:27]([OH:29])=[O:28])=[O:23])=[CH:8][CH:7]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)Nc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Reactant: NCCS(=O)[O-]
Agent: CC(=O)Nc1ccc(O)cc1
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(=O)Nc1ccc(OC(=O)NCCS(=O)O)cc1

Procedure:
Title compound 11a was prepared according to the General Method for the Reaction of Alkali Metal Salts of Amino Acid Derivatives with 4-Acetamidophenyl 4-Nitrophenyl Carbonate (3). A solution of 410 mg (3.20 mmol) of sodium 2-aminoethanesulfinate (5) in approximately one (1) mL of degassed water was reacted with a solution of 4-acetamidophenyl 4-nitrophenyl carbonate (3) (1.01 g, 3.19 mmol) in 10 mL of acetonitrile (MeCN). After work-up procedures, the aqueous layer was lyophilized off to afford 910 mg (˜quantitative yield) of the crude 2-((4-acetamidophenoxy)carbonylamino)ethanesulfinic acid (11a) which was used directly and without further isolation or purification procedures in the next step. The material thus obtained was contaminated with some sodium chloride (NaCl) and/or other sodium salts. 1H NMR (300 MHz, D2O): δ 7.22 (d, J=9.0 Hz, 2H), 6.93 (d, J=9.0 Hz, 2H), 3.31 (t, J=6.6 Hz, 2H), 2.42 (t, J=6.6 Hz, 2H), 1.96 (s, 3H). LC/MS (ESI): m/z=287.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH2:11][CH3:12])[C:9]#[N:10].[CH2:13](N)[CH2:14][NH2:15]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:9]1[NH:15][CH2:14][CH2:13][N:10]=1)[CH2:11][CH3:12]
Reactant: NCCN
Reactant: CCC(C#N)c1ccccc1F
Product: CCC(C1=NCCN1)c1ccccc1F

Procedure:
rac-2-[1-(2-Fluoro-phenyl)-propyl]-4,5-dihydro-1H-imidazole was prepared from rac-2-(2-fluoro-phenyl)-butyronitrile and ethylene diamine in analogy to Example 19 b): light yellow powder; MS (ISP): 207.0 ((M+H)+.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH2:9])=[CH:4][C:3]=1[OH:10].[C:11]1(=O)[O:16][C:14](=[O:15])[C:13]2[CH2:17][CH2:18][CH2:19][CH2:20][C:12]1=2>C(O)(=O)C>[Cl:1][C:2]1[C:3]([OH:10])=[CH:4][C:5]([N:9]2[C:14](=[O:15])[C:13]3[CH2:17][CH2:18][CH2:19][CH2:20][C:12]=3[C:11]2=[O:16])=[C:6]([F:8])[CH:7]=1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: Nc1cc(O)c(Cl)cc1F
Solvent: CC(=O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc(O)c(Cl)cc1F
Temperature: 25 °C
Yield: 34.3 %

Procedure:
2-Chloro-4-fluoro-5-aminophenol (6.6 g) and 3,4,5,6-tetrahydrophthalic anhydride (6 g) were dissolved in acetic acid (20 ml) and refluxed for 2 hours. The resultant mixture was allowed to cool to room temperature and poured into ice-water, followed by extraction with ether. The ether extract was washed with a saturated sodium hydrogen carbonate solution and water in this order, dried over anhydrous magnesium sulfate was concentrated. The residue was purified by silica gel chromatography to obtain 4.0 g of N-(4-chloro-2-fluoro-5-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide. M.P., 151° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:31][O:32][CH2:33][C:34](Cl)=[O:35]>C1COCC1.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH:30][C:34](=[O:35])[CH2:33][O:32][CH3:31])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:17])([F:18])[F:19])=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1ccc(-c2c(-c3cccc(F)c3)nn3cc(C(F)(F)F)ccc23)cc1
Reactant: COCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COCC(=O)NS(=O)(=O)c1ccc(-c2c(-c3cccc(F)c3)nn3cc(C(F)(F)F)ccc23)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-[2-(3-fluoro-phenyl)-6-trifluoromethyl-pyrazolo[1,5-a]pyridin-3-yl]-benzenesulfonamide (0.15 g 0.35 mmol) in dry THF (3 ml) was added N,N-(diisopropyl)aminomethylpolystyrene (Argonaut Technologies) (0.25 g 0.9 mmol), 4-dimethylaminopyridine (Aldrich) (0.03 g 0.25 mmol) and methoxyacetyl chloride (Aldrich) (0.09 g 0.8 mmol) and the mixture was shaken at room temperature for 18 hr. Tris-(2-aminoethyl)amine polystyrene (Argonaut Technologies) (0.5 g 1.7 mmol) was added and shaking continued for 6 hr. The resins were filtered, washed with dichloromethane (5 ml) and the solvents were removed. The residue was purified by SPE chromatography eluting with cyclohexane:ethyl acetate (5:1 then 2:1) to give the title compound as a white solid. (0.07 g, 40%).
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[N:6]=1.[CH3:16][C:17]1[C:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[C:20]([CH3:34])[O:19][N:18]=1.C(N=C(N(C)C)N(C)C)(C)(C)C>N1C=CC=CC=1>[CH3:16][C:17]1[C:21]([CH2:22][O:23][C:24]2[CH:25]=[CH:26][C:27]([S:30]([N:4]([CH2:3][CH:2]([CH3:15])[CH3:1])[C:5]3[CH:10]=[CH:9][N:8]=[C:7]([C:11]([F:12])([F:14])[F:13])[N:6]=3)(=[O:32])=[O:31])=[CH:28][CH:29]=2)=[C:20]([CH3:34])[O:19][N:18]=1
Reactant: CC(C)CNc1ccnc(C(F)(F)F)n1
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: c1ccncc1
Product: Cc1noc(C)c1COc1ccc(S(=O)(=O)N(CC(C)C)c2ccnc(C(F)(F)F)n2)cc1
Temperature: 100 °C

Procedure:
To a solution of N-(2-methylpropyl)-2-(trifluoromethyl)-4-pyrimidinamine (100 mg, 0.456 mmol) and 4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}benzenesulfonyl chloride (151 mg, 0.502 mmol) in pyridine (1 mL) was added 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (0.092 mL, 0.456 mmol). The reaction vessel was sealed and heated by microwaves to 100° C. for 30 minutes. The solvent was evaporated in vacuo to give the crude product, which was purified by solid phase extraction (SPE) using an aminopropyl (NH2) cartridge then a sulphonic acid (SCX) cartridge (both eluted with methanol). The appropriate fractions were combined and dried under a stream of nitrogen to give the crude product which was further purified by mass directed autoprep (formic acid modifier) to give the title product, 19.8 mg. LCMS (2 min, formic) Rt 1.32 min, m/z (ES+) 485 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH2:26]([NH2:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C(N(CC)CC)C.Cl>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:34][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:20]
Reactant: CCCCCCCCN
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCCCCCNC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.2 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), octylamine (0.460 g, 3.56 mmol), triethylamine (0.310 g, 3.06 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (50 ml), and the mixture was extracted with ethyl acetate (50 ml×3 portions). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting crude product was recrystallized from ether to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-octyl-3,4,5,6-tetrahydrophthalamide as white crystals (0.410 g, 30.2% yield).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:14][C:15]#[N:16]>>[Br:1][C:2]1[O:6][C:5](/[CH:7]=[C:14](/[C:13]2[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:11]([O:10][CH3:9])[CH:12]=2)\[C:15]#[N:16])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)o1
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C(C#N)=C/c2ccc(Br)o2)cc1OC
Yield: 83.6 %

Procedure:
5-Bromo-2-furaldehyde (350 mg) was condensed with 3,4-dimethoxybenzyl cyanide (354 mg) through Method A (production step 2), to thereby yield the target product (yield: 558 mg, 84%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])O.[Na+].I[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH:26][S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[S:36]([CH3:39])(=[O:38])=[O:37])(=[O:29])=[O:28])[CH:24]=2)[N:19](C(OC(C)(C)C)=O)[N:18]=1.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([NH:26][S:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[S:36]([CH3:39])(=[O:38])=[O:37])(=[O:28])=[O:29])[CH:24]=3)[NH:19][N:18]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3cccc(Br)c3)c2c1
Temperature: 20 °C
Yield: 69.4 %

Procedure:
N-[3-(3-Bromophenyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide can be obtained in the follow way: 1.6 g of (3-bromophenyl)boronic acid, 8.7 ml of a saturated aqueous sodium hydrogencarbonate solution and 0.11 g of tetrakis(triphenylphosphine)palladium[0] are added successively to a suspension, maintained under an atmosphere of argon, of 2.3 g of tert-butyl 3-iodo-5-(2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate in 90 ml of dimethylformamide. The reaction mixture is refluxed for 5 hours. After cooling to a temperature in the region of 20° C., the reaction mixture is hydrolyzed with 200 ml of water and extracted with 200 ml and then 100 ml of ethyl acetate. The pooled organic extracts are dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The brown oil thus obtained is purified by chromatography on a silica column (particle size 63-200 μm), eluting with a dichloromethane/methanol (99/1 by volume) mixture. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 1.4 g of N-[3-(3-bromophenyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide are obtained in the form of a yellow lac. This product is repurified by chromatography on a silica column (particle size 63-200 μm), with pure dichloromethane as eluent. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 0.73 g of N-[3-(3-bromophenyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide are obtained in the form of a white foam melting at 104° C.
Reaction SMILES: [CH3:1][CH:2]1[O:6][CH2:5][S:4][C:3]1=[N:7][OH:8].[CH3:9][N:10]([S:14][S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11](F)=[O:12].C(N(CC)CC)C>O1CCOCC1>[CH3:9][N:10]([S:14][S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11]([O:8][N:7]=[C:3]1[CH:2]([CH3:1])[O:6][CH2:5][S:4]1)=[O:12]
Reactant: CC1OCSC1=NO
Reactant: CN(SSc1ccccc1)C(=O)F
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC1OCSC1=NOC(=O)N(C)SSc1ccccc1

Procedure:
4-[[O-[N-Methyl-N-(phenylthiosulfenyl)carbamoyl]oximino]]-5-methyl-1,3-oxathiolane was prepared by the procedure described in Example I by reacting 5.0 g (0.0375 m) of 5-methyl-4-oximino-1,3-oxathiolane, 8.15 g (0.0375 m) of N-methyl-N-(phenylthiosulfenyl) carbamoyl fluoride and 3.79 g (0.0375 m) of triethylamine in 100 ml of dioxane. The crude residual oil was purified using silica gel column to yield 3.5 g of an oil.
Reaction SMILES: [CH2:1]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH3:5].OC(C(O)(C)C)(C)C.[Li]CCCC.[B:24]([O:33][CH:34]([CH3:36])[CH3:35])([O:29][CH:30]([CH3:32])[CH3:31])OC(C)C>C1COCC1.CCCCCC>[CH3:36][C:34]1([CH3:35])[C:30]([CH3:31])([CH3:32])[O:29][B:24]([C:8]2[S:7][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:10][CH:9]=2)[O:33]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCCCc1cccs1
Agent: CC(C)(O)C(C)(C)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCc1ccc(B2OC(C)(C)C(C)(C)O2)s1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 81.7 %

Procedure:
To a cooled (−78° C.) mixture of 2-n-pentylthiophene (5.0 g, 32.1 mmol) and pinacol (11.5 g, 97.23 mmol) in anhydrous THF (60 mL) was added dropwise to a solution of n-BuLi (22.3 mL, 35.6 mmol) in hexane. The mixture was stirred at −78° C. for 10 minute. The reaction mixture was then brought to 0° C. and stirred for 1 h before cooling to −78° C. before the addition of triisopropyl borate (7.3 g, 38.9 mmol) in THF (24 mL) using a dropping funnel. The mixture was slowly brought to room temperature while stirring overnight. The crude product was purified by flash chromatography (silica gel. eluent: hexane/EA) 10:1) to afford a reddish brown liquid 7.35 g (81.0%).
Reaction SMILES: [H-].[Na+].[C:3](Cl)(=[O:5])[CH3:4].[F:7][C:8]1[CH:29]=[CH:28][C:11]([NH:12][C:13]2[CH:14]=[C:15]([CH:24]=[CH:25][C:26]=2[CH3:27])[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])=[CH:10][CH:9]=1.Cl>C(OCC)(=O)C.CN(C)C=O>[C:16]([C:15]1[CH:24]=[CH:25][C:26]([CH3:27])=[C:13]([N:12]([C:11]2[CH:10]=[CH:9][C:8]([F:7])=[CH:29][CH:28]=2)[C:3](=[O:5])[CH3:4])[CH:14]=1)(=[O:17])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1ccc(C(=O)c2ccccc2)cc1Nc1ccc(F)cc1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)N(c1ccc(F)cc1)c1cc(C(=O)c2ccccc2)ccc1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
60% sodium hydride 79 mg and acetyl chloride 0.14 mL were added to N,N-dimethylformamide 5.0 mL solution of 3-(4-fluoroanilino)-4-methylbenzophenone 0.50 g under ice cooling sequentially, and it was stirred at room temperature for 4 hours. After the reaction mixture was cooled to ice temperature,60% sodium hydride 79 mg and acetyl chloride 0.14 mL were added sequentially, and it was stirred at room temperature for 5 hours and 30 minutes. Ethyl acetate and 1.0 mol/L hydrochloric acid were added to the reaction mixture. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with 1.0 mol/L hydrochloric acid and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Fuji SILYSIA Chemical Ltd., PSQ100B(spherical type), eluent; hexane:ethyl acetate=2:1] to give N-(5-benzoyl-2-methylphenyl)-N-(4-fluorophenyl)acetamide 82 mg of orange oil.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:11])[CH2:9][CH3:10].Cl.[NH2:14][CH:15]1[C:27](=[O:28])[C:26]2[C:18](=[CH:19][C:20]3[CH2:24][CH2:23][O:22][C:21]=3[CH:25]=2)[CH2:17][CH2:16]1>C(Cl)Cl>[O:28]=[C:27]1[C:26]2[C:18](=[CH:19][C:20]3[CH2:24][CH2:23][O:22][C:21]=3[CH:25]=2)[CH2:17][CH2:16][CH:15]1[NH:14][C:8](=[O:11])[CH2:9][CH3:10]
Reactant: CCC(=O)Cl
Reactant: NC1CCc2cc3c(cc2C1=O)OCC3
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)NC1CCc2cc3c(cc2C1=O)OCC3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
23 ml of triethylamine and 5.7 ml of propionyl chloride are added in succession to 17 g of dl-7-amino- 2,3,6,7-tetrahydro-5H-naphtho[2,3-b]furan-8-one hydrochloride suspended in 170 ml of methylene chloride. After 2 hours' stirring at room temperature, the reaction mixture is washed with water, decanted and concentrated to dryness. 20 g of the desired compound are obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4]1.[NH2:9][C:10]1[C:11]([C:18]([NH:20][C:21](=N)SC)=[O:19])=[N:12][C:13]([Cl:17])=[C:14]([NH2:16])[N:15]=1>CC(O)C>[NH:8]1[C:3]2([CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:2][NH:1]/[C:21]/1=[N:20]/[C:18]([C:11]1[C:10]([NH2:9])=[N:15][C:14]([NH2:16])=[C:13]([Cl:17])[N:12]=1)=[O:19]
Reactant: NCC1(N)CCCC1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Solvent: CC(C)O
Product: Nc1nc(N)c(C(=O)/N=C2/NCC3(CCCC3)N2)nc1Cl
Temperature: 70 °C

Procedure:
A solution of crude 1-aminomethyl-cyclopentylamine (Intermediate J) (80 mg, 0.70 mmol) in propan-2-ol (1.0 ml) is added to a suspension of 1-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-2-methyl-isothiourea (Intermediate A) (208 mg, 0.54 mmol) in propan-2-ol (1.08 ml) and heated at 70° C. for 2 days. After cooling to room temperature, the reaction mixture is filtered under vacuum, and the solid is rinsed with MeOH. The filtrate is concentrated in vacuo to afford a bright yellow residue which is loaded onto a SCX-2 cartridge and eluted with 33% NH3 (4 drops) in MeOH (5 ml×2). The methanolic ammonia fractions are combined and concentrated in vacuo. Purification using mass directed preparative LCMS eluting with 95% Water+0.1% NH3: 5% Acetonitrile to affords the title compound; [M+H]+ 310.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:15]/[OH:16])/[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[N:6]=1.Br[C:18]([CH3:29])([CH3:28])[C:19]([O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:15][O:16][C:18]([C:19]([O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[O:20])([CH3:29])[CH3:28])[C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[N:6]=1
Reactant: CC(C)(C)OC(=O)/C(=N\O)c1csc(N)n1
Reactant: CC(C)(Br)C(=O)OCC[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(=NOC(C)(C)C(=O)OCC[Si](C)(C)C)c1csc(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.3 %

Procedure:
24.9 g (102 mmol) of t-butyl 2-(2-amino-4-thiazolyl)-2-(Z)-hydroxyimino-acetate are dissolved in 400 ml of dimethylformamide. After the addition of 54.7 g (205 mmol) of 2-(trimethylsilyl)ethyl 2-bromo-2-methylpropionate, followed by 56.6 g (410 mmol) of finely ground potassium carbonate, the mixture is stirred at 25° C. for 4 hours in a nitrogen atmosphere. After the addition of 3 l of water, the mixture is extracted with 1.5 l of ethyl acetate. The organic phase is washed twice with 1.5 l of water. The aqueous phase is extracted with 1.5 l of ethyl acetate. The combined ethyl acetate solutions are dried over sodium sulphate and evaporated to dryness. The product is purified by flash chromatography on silica gel [hexane/ethyl acetate (2:1)] and crystallized from methanol/water. There are obtained 28.6 g (65.3%) of t-butyl 2-(2-amino-4-thiazolyl)-2-[(1-(2-(trimethylsilyl)ethoxycarbonyl)-1-methylethoxy]imino]-acetate of melting point 83° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl.[S:9](Cl)([Cl:12])(=[O:11])=[O:10]>O1CCOCC1.C(#N)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:9]([Cl:12])(=[O:11])=[O:10])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: O=S(=O)(Cl)Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: CN1CCN(S(=O)(=O)Cl)CC1
Temperature: 25 °C
Yield: 44 %

Procedure:
To a solution of N-methylpiperazine (1.48 mL, 13.3 mmol) in dioxane (6.7 mL) cooled to 0° C. was added 4N hydrochloric acid in dioxane (10 mL). The reaction was very exothermic, and the mixture was stirred until the reaction cooled to room temperature. The solvent was removed under reduced pressure and chased with ether (2×). The solid obtained was taken up in acetonitrile (7 mL) and sulfuryl chloride (3.53 mL, 3.3 equiv) was added. The mixture was warmed at relux for 24 hours and the product removed by filtration and washed with 1:1 acetonitrile/ether (100 mL). This crude material was recrystallized from hot methanol and acetonitrile to afford 4-methylpiperazin-1-ylsulfonyl chloride (1.36 g, 44%) as a white crystalline solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)O1.Br[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:21]([Br:27])=[CH:20][N:19]=1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>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.CCO>[Br:27][C:21]1[CH:22]=[C:23]([N+:24]([O-:26])=[O:25])[C:18]([C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)=[N:19][CH:20]=1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: O=[N+]([O-])c1cc(Br)cnc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=[N+]([O-])c1cc(Br)cnc1-c1ccc(O)cc1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (300 mg, 1.36 mmol), 2,5-dibromo-3-nitropyridine (383 mg, 1.36 mmol), tetrakis(triphenylphosphine)palladium (31 mg, 0.027 mmol), Na2CO3 (4.3 mL, 2 M aqueous), 4.3 mL toluene, and 2.1 mL EtOH was vigorously stirred at 55° C. for 2 h. After cooling to rt, the volatiles were removed under reduced pressure and the residue was purified with silica chromatography (EtOAc in hexane, 5% to 35%) to afford 4-(5-bromo-3-nitropyridin-2-yl)phenol as a yellow wax (285 mg, 71%). MS (ESI) m/z [M+H]+295, 297.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][CH:5]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C(O)(=O)C.[B-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: C1CCNC1
Agent: CC(=O)O[B-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-formyl-benzoic acid methyl ester (10 g), pyrrolidine (5.6 mL), and acetic acid (3.5 mL) in DCM (200 mL) was treated with sodium triacetoxyborohyride (20.65 g) and stirred at rt for 16 hours. The reaction mixture was then quenched with 3N NaOH (70 mL). The organic layer was dried over sodium sulfate and concentrated to yield the titled compound without purification.