Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]([C:11]1[CH:16]=[CH:15][C:14]([S:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][N:19]=2)=[CH:13][CH:12]=1)=O.CO.[BH4-].[Na+]>O>[CH2:1]([NH:8][CH2:9][C:11]1[CH:12]=[CH:13][C:14]([S:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][N:19]=2)=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(Sc2ccc(C=O)cc2)nc1
Reactant: NCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NC(=O)c1ccc(Sc2ccc(CNCc3ccccc3)cc2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.9 %

Procedure:
Combine benzylamine (17 mg, 0.16 mmol), 6-(4-formyl-phenylsulfanyl)-nicotinamide (40 mg, 0.16 mmol), 3 Å molecular sieves (0.1 g), and methanol (3 mL) and stir overnight at room temperature. Filter off the sieves then add sodium borohydride (25 mg, 0.64 mmol) to the reaction and stirred at room temperature for 1 hour. Pour the reaction into water then extract with ethyl acetate (3×10 mL). The combined ethyl acetate extracts were dried over sodium chloride/magnesium sulfate, filtered, and concentrated on a rotary evaporator to yield the crude product (50 mg). The crude product was purified by flash column chromatography on silica gel eluting with 10% aqueous ammonium hydroxide in ethanol and chloroform to yield 6-[4-(benzylamino-methyl)-phenylsulfanyl]-nicotinamide, (24 mg): m/z=349.99 (M+1); 1H NMR (MeOD, 300.00 MHz): (8.84 (dd, 1H, J=2.3, 1.0 Hz), 8.02 (dd, 1H, J=8.6, 2.3 Hz), 7.66-7.49 (m, 4H), 7.66-7.49 (m, 4H), 7.42-7.34 (m, 5H), 6.99-6.92 (m, 1H), 3.88-3.77 (m, 4H). HPLC=99% (5.82 minutes (5/95 to 95/5 ACN/(0.1% TFA in water) over 10 minutes, Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nM.
Reaction SMILES: C(O)CCCCCCCO.FC1C(F)=CC=CC=1CBr.[F:21][C:22]1[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:23]=1[CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][OH:34].FC1C(F)=CC=CC=1COCCCCCCCC(O)=O.Cl.Cl.[CH2:62]([O:69][C:70](=[O:78])[CH2:71][C@@H:72]([NH2:77])[CH2:73][N:74]([CH3:76])[CH3:75])[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1>>[CH2:62]([O:69][C:70](=[O:78])[CH2:71][C@@H:72]([NH:77][C:33](=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][O:25][CH2:24][C:23]1[CH:35]=[CH:36][CH:37]=[C:38]([F:39])[C:22]=1[F:21])[CH2:73][N:74]([CH3:75])[CH3:76])[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1
Reactant: OCCCCCCCCOCc1cccc(F)c1F
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Agent: Cl
Agent: Fc1cccc(CBr)c1F
Agent: O=C(O)CCCCCCCOCc1cccc(F)c1F
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCOCc1cccc(F)c1F

Procedure:
The title compound, m/e=415.5 ([M+H]+), was produced in analogy with intermediate 1, steps 1 to 4. Thus, 1,8-octanediol was alkylated in step 1 with 2,3-difluorobenzyl bromide, leading to 8-(2,3-difluoro-benzyloxy)-octan-1-ol, which was oxidized in step 2 to 8-(2,3-difluoro-benzyloxy)-octanoic acid. This was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-3-[8-(2,3-difluoro-benzyloxy)-octanoylamino]-4-dimethylamino-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: [C:1]1([N:7]2C(=O)C3=CNC4C=CC=CC=4C3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([F:33])=[C:29]([F:32])[CH:30]=2)[N:25]=[CH:24][C:23]=1[C:34]([O:36]CC)=O.C1(NN)C=CC=CC=1>>[F:33][C:28]1[C:29]([F:32])=[CH:30][C:31]2[C:22]3[C:23]([C:34](=[O:36])[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)=[CH:24][NH:25][C:26]=2[CH:27]=1
Reactant: O=c1c2c[nH]c3ccccc3c-2nn1-c1ccccc1
Reactant: CCOC(=O)c1cnc2cc(F)c(F)cc2c1Cl
Solvent: NNc1ccccc1
Product: O=c1c2c[nH]c3cc(F)c(F)cc3c-2nn1-c1ccccc1

Procedure:
The title compound was prepared following the procedure described in Step 3 for the synthesis of 4a, using 3c and phenyl hydrazine. 1H NMR (DMSO-d6) δ (ppm): 7.18 (1H, t, J=7.82 Hz), 7.43 (2H, dd, J=8.30, 7.33 Hz), 7.75 (1H, dd, J=11.22, 7.32 Hz), 8.18, 3H, m), 8.90 (1H, s). m/z 298.2 (MH+).
Reaction SMILES: [CH3:1][C@H:2]([NH:7][C:8]([C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[C:27]4[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=4)[N:21]([CH3:29])[N:20]=3)[N:17]=2)[N:12](COCC[Si](C)(C)C)[CH:11]=1)=[O:9])[C:3]([CH3:6])([CH3:5])[CH3:4].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[CH3:1][C@H:2]([NH:7][C:8]([C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[C:27]4[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=4)[N:21]([CH3:29])[N:20]=3)[N:17]=2)[NH:12][CH:11]=1)=[O:9])[C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: C[C@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C(C)(C)C
Solvent: NCCN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
In a round-bottomed flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1,2,2-trimethyl-propyl)-amide (102 mg, 0.194 mmol) was dissolved in dichloromethane (0.9 ml) and trifluoroacetic acid (0.6 ml, 7.8 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was dissolved in dichloromethane (0.9 ml) and ethylenediamine (0.8 ml, 11.7 mmol) was added. The yellow solution was stirred at room temperature for 1 h then quenched with water and diluted with ethyl acetate. The suspension was filtered, washed with hot water and ethyl acetate and dried under high vacuum to provide 52 mg (64%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1,2,2-trimethyl-propyl)-amide as a light yellow powder. MS: (M+H)+=395; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.38 (br. s., 1H), 9.08 (s, 1H), 8.44 (s, 1H), 8.40 (dd, J=9.1, 5.3 Hz, 1H), 8.03 (d, J=9.8 Hz, 1H), 7.69 (dd, J=9.8, 1.9 Hz, 1H), 7.20 (td, J=9.1, 2.3 Hz, 1H), 4.15 (s, 3H), 4.09-4.19 (m, 1H), 1.26 (d, J=6.8 Hz, 3H), 0.93 (s, 9H).
Reaction SMILES: [CH2:1]([C:4]1([CH3:17])[CH2:12][C:11]2[C:6](=[C:7]([Cl:15])[C:8]([Cl:14])=[C:9]([OH:13])[CH:10]=2)[C:5]1=[O:16])[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]([O:28]CC)=[O:27].[OH-].[Na+]>CN(C=O)C.O>[O:16]=[C:5]1[C:6]2[C:11](=[CH:10][C:9]([O:13][CH2:25][C:26]([OH:28])=[O:27])=[C:8]([Cl:14])[C:7]=2[Cl:15])[CH2:12][C:4]1([CH2:1][CH:2]=[CH2:3])[CH3:17]
Reactant: CCOC(=O)CBr
Reactant: C=CCC1(C)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCC1(C)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 55 °C

Procedure:
A stirred mixture of 2-allyl-2-methyl-5-hydroxy-6,7-dichloro-1-indanone (3.4 g, 0.0126 mole), potassium carbonate (4.2 g.) and ethyl bromoacetate (4.8 g.) in DMF (40 ml.) is warmed at 55° C. in an inert atmosphere, then treated with water (40 ml.) and 10N sodium hydroxide (2 ml.) and heated on a steam bath for one hour, poured into water (300 ml.), acidified and extracted with ether. The ether extract is washed with water, dried over magnesium sulfate and the solvent evaporated to leave a tan oil which is purified by chromatography over silica affording 2.0 g. of (1-oxo-2-allyl-2-methyl-6,7-dichloro-5-indanyloxy)acetic acid as a tan oil.
Reaction SMILES: C=[C:2]1[CH2:7][O:6][C:5]2([CH2:12][CH2:11][CH:10]([N:13]3[C:18](=[O:19])[C:17]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]5[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=5)=[CH:23][CH:22]=4)=[C:16]([CH2:35][CH2:36][CH3:37])[N:15]4[N:38]=[CH:39][N:40]=[C:14]34)[CH2:9][CH2:8]2)[O:4][CH2:3]1.I([O-])(=O)(=O)=[O:42].[Na+].CC(C)=O.C(#N)C>[Os](=O)(=O)(=O)=O.O.C(OCC)(=O)C>[OH:42][CH:2]1[CH2:3][O:4][C:5]2([CH2:8][CH2:9][CH:10]([N:13]3[C:18](=[O:19])[C:17]([CH2:20][C:21]4[CH:22]=[CH:23][C:24]([C:27]5[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=5)=[CH:25][CH:26]=4)=[C:16]([CH2:35][CH2:36][CH3:37])[N:15]4[N:38]=[CH:39][N:40]=[C:14]34)[CH2:11][CH2:12]2)[O:6][CH2:7]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=C1COC2(CCC(n3c(=O)c(Cc4ccc(-c5ccccc5C#N)cc4)c(CCC)n4ncnc34)CC2)OC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCC(O)CO3)c2ncnn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To a mixture of 4′-{[4-(3-methylidene-1,5-dioxaspiro[5.5]undec-9-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (2.0 g), sodium periodate (4.1 g), acetone (40 mL), acetonitrile (40 mL) and water (40 mL) was added osmium tetraoxide (1.48 g, 7% immobilized catalyst) at 0° C., and the mixture was stirred at room temperature for 8 hr. Sodium periodate (1.6 g) and osmium tetraoxide (0.60 g, 7% immobilized catalyst) were added, and the mixture was further stirred at room temperature for 16 hr. Ethyl acetate and water were added to the reaction mixture, the precipitate was filtered off, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL) and methanol (20 mL), sodium tetrahydroborate (0.29 g) was added, and the mixture was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture. After evaporation of the solvent under reduced pressure, the residue was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.5 g, 73%).
Reaction SMILES: FC(F)(F)C(N[C@@H]1C2C(=CC=C(OC)C=2)C(=O)C1)=O.[CH2:20]([O:23][C@H:24]1[C:32]2[C:27](=[CH:28][C:29]([O:33][CH:34]([CH3:36])[CH3:35])=[CH:30][CH:31]=2)[C@@H:26]([NH2:37])[CH2:25]1)[CH:21]=[CH2:22].[C:38]([O:42][C:43](=[O:56])[NH:44][C@H:45]([CH:53]1[CH2:55][O:54]1)[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([CH3:41])([CH3:40])[CH3:39].Cl([O-])(=O)(=O)=O.[Li+].[Cl-].[Na+].O.C([O-])(O)=O.[Na+]>CC#N>[CH2:20]([O:23][C@H:24]1[C:32]2[C:27](=[CH:28][C:29]([O:33][CH:34]([CH3:35])[CH3:36])=[CH:30][CH:31]=2)[C@@H:26]([NH:37][CH2:55][C@@H:53]([OH:54])[C@@H:45]([NH:44][C:43](=[O:56])[O:42][C:38]([CH3:40])([CH3:39])[CH3:41])[CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:25]1)[CH:21]=[CH2:22]
Reactant: C=CCO[C@@H]1C[C@H](N)c2cc(OC(C)C)ccc21
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C1CO1
Agent: COc1ccc2c(c1)[C@@H](NC(=O)C(F)(F)F)CC2=O
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CC#N
Solvent: O
Product: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)c2cc(OC(C)C)ccc21
Yield: 44.3 %

Procedure:
Step AW (1): A solution of (1S,3R)-3-(allyloxy)-6-isopropoxy-2,3-dihydro-1H-inden-1-amine (1.3 g, 5.3 mmol), (S)-(1-oxiranyl-2-phenylethyl)-carbamic acid tert-butyl ester (1.7 g, 6.5 mmol), and lithium perchlorate (2.8 g, 26.3 mmol) in 40 mL CH3CN was stirred at 50° C. for 18 h. The mixture was poured into brine/NaHCO3 solution, extracted with EtOAc (200 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified using silica-gel column chromatography (30-80% EtOAc/Hexane) to afford 1.2 g (45% yield) of tert-butyl (2S,3R)-4-((1S,3R)-3-(allyloxy)-6-isopropoxy-2,3-dihydro-1H-inden-1-ylamino)-3-hydroxy-1-phenylbutan-2-ylcarbamate. LC-MS (M+H)+=511.25. 1H NMR (300 MHz, CDCl3) δ 1.2-1.4 (m, 15H) 2.5-2.7 (m, 1H) 2.7-2.9 (m, 2H) 3.0-3.1 (m, 2H) 3.5-3.7 (m, 1H) 3.7-3.9 (m, 1H) 4.0-4.1 (m, 2H) 4.2-4.3 (m, 1H) 4.5-4.7 (m, 2H) 4.7-4.8 (m, 1H) 5.1-5.3 (m, 2H) 5.8-6.0 (m, 1H) 6.8-6.9 (m, 1H) 7.0-7.3 (m, 7H).
Reaction SMILES: C[Li].[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]2[O:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][C:12]2=[O:25])[CH:7]=[CH:8][C:9]=1[Cl:10].I[CH2:27]I.O>C(OCC)C.C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]2[O:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:13][C:12]32[O:25][CH2:27]3)[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: ICI
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(=O)C1
Agent: [Li]C
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C2(CO2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 18.9 %

Procedure:
A solution (3 M, 0.56 mL) of methyllithium in diethyl ether was added to a solution of tert-butyl (7RS)-7-(3,4-dichlorophenyl)-6-oxo-1,4-oxazepane-4-carboxylate (300 mg) and diiodomethane (335 mg) in THF (3 mL), and the mixture was stirred at 0° C. for 30 min, and at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and HPLC to give the title compound (59 mg).
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[CH:5]=1.C([Li])CCC.Cl[C:18]([O:20][CH3:21])=[O:19]>C1COCC1.C(=O)(O)[O-].[Na+]>[CH3:21][O:20][C:18](=[O:19])[C:2]#[C:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[CH:5]=1
Reactant: COC(=O)Cl
Reactant: Fc1cccc(C=C(Br)Br)c1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C#Cc1cccc(F)c1
Yield: 110.3 %

Procedure:
To a stirred solution of 1-(2,2-dibromo-vinyl)-3-fluoro-benzene (23.8 g) in anhydrous THF (350 ml) cooled to −78° was added dropwise over 30 minutes, n-butyllithium (2.2 eq, 1.6M in hexanes). The mixture was stirred for a further 30 minutes at −78° before methyl chloroformate (11.6 g, 9.5 ml) was added and the resultant mixture allowed to warm to 0° for 1 hour before being diluted with 1:1 saturated aqueous sodium bicarbonate:ammonium chloride (100 ml) and extracted into ether (2×100 ml). The combined organic extract was washed with brine (25 ml), dried (Na2SO4) and evaporated to dryness to give the title compound as a brown oil (16.7 g, 100%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Br:13]Br>C(Cl)Cl>[Br:13][C:6]1[CH:5]=[C:4]([O:3][C:2]([F:11])([F:12])[F:1])[CH:9]=[CH:8][C:7]=1[OH:10]
Reactant: BrBr
Reactant: Oc1ccc(OC(F)(F)F)cc1
Solvent: ClCCl
Product: Oc1ccc(OC(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 20 h
Yield: 56.4 %

Procedure:
A solution of 1.78 g (10.0 mmol) of 4-trifluoromethoxyphenol in 5 mL of CH2Cl2 at 0° C. was treated with a solution of 2.20 g (14.0 mmol) of bromine in 5 mL of CH2Cl2. The cooling bath was removed and the resulting mixture was stirred at rt for 20 h. The reaction quenched with 5% aqueous Na2S2O3 and the resulting mixture was partitioned between 150 mL of ether and 150 mL of H2O. The layers were separated; the organic layer was dried over MgSO4 and concentrated in vacuo. Flash chromatography on 125 g of silica gel using 9:1 v/v hexanes/CH2Cl2 as the eluant afforded 1.45 g (56%) of the title compound as an oil. 1H NMR (500 MHz, CDCl3): δ 5.50 (s, 1H), 7.02 (d, J=9.0, 1H), 7.12 (dd, J=9.0, 2.0, 1H), 7.37 (d, J=2.0, 1H).
Reaction SMILES: [CH3:1][N:2]([S:23]([C:26]1[S:27][CH:28]=[CH:29][N:30]=1)(=[O:25])=[O:24])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18](OCC)=[O:19])[CH2:15][N:16]=1)=[CH:8]2.[BH4-].[Li+]>O1CCCC1.CO.C(OCC)(=O)C.Cl>[OH:19][CH2:18][CH2:17][CH:14]1[S:13][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][CH:5]=[CH:4][C:3]=3[N:2]([CH3:1])[S:23]([C:26]2[S:27][CH:28]=[CH:29][N:30]=2)(=[O:24])=[O:25])=[N:16][CH2:15]1
Reactant: CCOC(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4nccs4)c3[nH]2)S1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(c1cccc2cc(C3=NCC(CCO)S3)[nH]c12)S(=O)(=O)c1nccs1
Temperature: 0 °C
Reaction time: 2 h
Yield: 13.7 %

Procedure:
Ethyl (2-{7-[methyl(1,3-thiazol-2-ylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (200 mg) was dissolved in a mixed solvent of tetrahydrofuran (5 mL) and methanol (5 mL), and the mixture was cooled to 0° C. Lithium borohydride (20 mg) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (100 mL) and 1N hydrochloric acid (50 mL). The organic layer was dried over sodium sulfate, and filtrated, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (25 mg, yield 14%) as a pale-yellow solid. MS: 423 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C:9]1([CH3:15])[CH3:14])=O)(C)(C)C.CCN(CC)CC.[CH3:23][S:24](Cl)(=[O:26])=[O:25].O>C(Cl)Cl>[CH3:14][C:9]1([CH3:15])[NH:8][CH2:13][CH2:12][N:11]([S:24]([CH3:23])(=[O:26])=[O:25])[CH2:10]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1(C)C
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C)CN(S(C)(=O)=O)CCN1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2,2-dimethylpiperazine-1-carboxylic acid tert-butyl ester (1.0 g, 4.60 mmol) and NEt3 (1.3 mL, 9.34 mmol) in DCM (11 mL) was cooled to 0° C. before the drop wise addition of a solution of methanesulfonyl chloride (580 mg, 5.00 mmol) in DCM (2 mL). The resulting mixture was warmed to r.t. and allowed to stir for 30 min before H2O was added. The organic phase was dried (phase separator) and concentrated in vacuo. The resulting residue was dissolved in DCM (10 mL) and TFA (2 mL) was added. The resulting mixture was allowed to stir at r.t. for 30 min then concentrated in vacuo. The resulting residue was partitioned between DCM and sat. aq. NaHCO3 and the aqueous phase was loaded onto an Isolute® SCX-2 cartridge which was washed with H2O and MeOH. The product was eluted with 2M NH3/MeOH affording the title compound (800 mg, 90%). LCMS (method A): RT 0.29 min [M+H]+ 193.3
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([N+:16]([O-])=O)=[CH:15][C:9]=2[S:8][CH:7]=1)[CH3:2].[Sn](Cl)Cl.Cl>C(O)C>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([NH2:16])=[CH:15][C:9]=2[S:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)CC1=CSc2cc([N+](=O)[O-])ccc2N1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: CCOC(=O)CC1=CSc2cc(N)ccc2N1
Temperature: 100 °C
Yield: 45.9 %

Procedure:
A solution of (7-nitro-4H-benzo[1,4]thiazin-3-yl)-acetic acid ethyl ester (5.8 g, 20.7 mmol) in ethanol (90 mL) was treated with tin (II) chloride and 1.0 M aqueous hydrochloric acid solution (3 mL). The reaction mixture was heated at 100° C. for 3 h. The suspension was allowed to cool and was concentrated in vacuo. The crude material was suspended in ethyl acetate (90 mL) and treated with 6.0 M aqueous sodium hydroxide solution (90 mL). The resulting precipitate was filtered. The filter cake was thoroughly washed with ethyl acetate, the filtrated was washed with saturated aqueous brine solution, and concentrated in vacuo. The crude oil was purified by flash column chromatography (Merck silica gel 60, 40-63 μm, ethyl acetate/hexanes) to afford the desired product, (7-amino-4H-benzo[1,4]thiazin-3-yl)-acetic acid ethyl ester (2.38 g, 9.51 mmol, 46%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.21 (t, 3H, J=7.1 Hz), 3.30 (s, 2H), 3.43 (bs, 2H), 4.08 (q, 2H, J=7.1 Hz), 4.52 (s, 1H), 6.39 (dd, 1H, J1=8.3 Hz, J2=2.7 Hz), 6.46 (d, 1H, J=2.3 Hz), 6.62 (d, 1H, J=7.6 Hz), 10.38 (bs, 1H). LC-MS (ESI) calcd for C12H14N2O2S [M+H+] 251.08, found 251.23 [M+H+].
Reaction SMILES: [C@@H:1]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4](O)[C@H:2]1[OH:3].C(Cl)(=O)C(C)(C)C.CS(Cl)(=O)=O.C[O-].[Na+].[BH4-].[Na+].Cl>N1C=CC=CC=1.C(O)C.CC(C)=O.O>[C@@H:1]1([N:10]2[CH:11]=[N:12][C:13]3[C:19]2=[N:18][CH:17]=[N:16][C:14]=3[NH2:15])[O:9][C@H:6]([CH2:7][OH:8])[CH2:4][C@@H:2]1[OH:3]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: CC(C)(C)C(=O)Cl
Agent: CS(=O)(=O)Cl
Agent: C[O-]
Solvent: c1ccncc1
Solvent: O
Solvent: CC(C)=O
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)C[C@@H]1O
Temperature: -15 °C
Reaction time: 1.5 h

Procedure:
Adenosine (5.0 g, 18.7 mmol) was suspended in dry pyridine (50 ml) and colled to -15° C. To the suspension was added pivaloyl chloride (7.0 ml, 56.8 mmol), and the mixture was first stirred at -15° C. for 1.5 hour, and then at 0° C. for 2 hours. Methanesulfonyl chloride (4.3 ml, 55.6 mmol) was added dropwise to the reaction mixture under ice cooling. The mixture was stirred at room temperature for 3 hours, then cooled with ice again. A small amount of water was added and stirred for 30 minutes. The reaction mixture was extracted with chloroform-ether. The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with water, and dried over magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated in vacuo to dryness to give amorphous substances. The remaining pyridine was removed by repeated co-evaporation with toluene. The residue was dissolved in methanol (150 ml), cooled to -15° C., after which sodium methoxide (8.1 g, 150 mmol) and sodium borohydride (2.5 g, 66.1 mmol) were added. The mixture was first stirred at room temperature for 14 hours and then at 50° C. for 3 hours. After ice cooling, a small amount of acetone was added to the reaction mixture to decompose an excess of NaBH4. Concentrated hydrochloric acid was gradually added to neutralize the solution. Ethanol was added to the mixture, which was then concentrated under reduced pressure to remove water completely. The residue was suspended in chloroform-methanol and applied to a silica gel column (250 g). Elution with chloroform-methanol (8:1→5:1) gave compound A'3 as oils, which were then crystallized from ethanol-ether. Yield: 2.7 g (57%).
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([I:14])[CH:9]=2)=[N:5][CH:4]=1)=O.Cl.NO.C([N:20](CC)CC)C.C(=O)(O)[O-].[Na+].[Cl-].ClC1N(C)C=C[N+]=1C>ClCCl.O>[C:1]([C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([I:14])[CH:9]=2)=[N:5][CH:4]=1)#[N:20]
Reactant: CCN(CC)CC
Reactant: O=Cc1cnc(-c2cccc(I)c2)o1
Agent: Cl
Agent: Cn1cc[n+](C)c1Cl
Agent: NO
Solvent: O
Solvent: ClCCl
Product: N#Cc1cnc(-c2cccc(I)c2)o1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 69.3 %

Procedure:
5-Formyl-2-(3-iodophenyl)-1,3-oxazole (200 mg, 0.668 mmol) obtained in Step 1 was dissolved in dichloromethane (8 mL), and the mixture was stirred at room temperature for 3.5 hours after adding hydroxylamine hydrochloride (56.0 mg, 0.803 mmol) and triethylamine (0.112 mL, 0.803 mmol). A saturated aqueous sodium bicarbonate solution was added to the mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane (10 mL), cooled to 0° C., and stirred at 0° C. for 1 hour after adding 2-chloro-1,3-dimethylimidazolium chloride (136 mg, 0.802 mmol) and triethylamine (0.224 mL, 1.61 mmol). Thereafter, water was added to the mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was then purified by silica gel column chromatography to give 5-cyano-2-(3-iodophenyl)-1,3-oxazole (137 mg, 70%).