Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[H-].[Na+].[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[S:16](Cl)(=[O:18])=[O:17]>O1CCCC1>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:16]([C:12]1[S:11][CH:15]=[CH:14][CH:13]=1)(=[O:18])=[O:17]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(NS(=O)(=O)c2cccs2)c1Br
Temperature: 2.5 °C
Reaction time: 0.08 h

Procedure:
A solution of 5-amino-4-bromo-3-methylisoxazole (177 mg, 1.0 mmol) in dry tetrahydrofuran (THF, 2 ml) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 90 mg, 2.2 mmol) in dry THF (1 ml) at 0-5° C. After stirring at 0-5° C. for 5 min., the reaction was stirred at room temperature for 10 min to complete the reaction. The reaction mixture was re-cooled to 0° C. and thiophene-2-sulfonyl chloride (200 mg, 1.1 mmol) dissolved in dry THF (2 ml) was added dropwise. Stirring was continued for 1 h; during this period the reaction mixture slowly attained ambient temperature. THF was removed under reduced pressure. The residue was dissolved in water (10 ml), the pH was adjusted to 10-11 by adding 5 N sodium hydroxide solution, and was extracted with ethyl acetate (3×10 ml) to remove the neutral impurities. The aqueous layer was acidified with concentrated HCl (pH 2-3) and extracted with methylene chloride (3×10 ml). The combined organic layers was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give N-(4-bromo-3-methyl-5-isoxazolyl)thiophene-2-sulfonamide. The pure material was obtained by recrystallization using hexanes/ethyl acetate (110 mg, 34% yield), m.p. 125-127° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:9]#[C:10][Si](C)(C)C)[C:5]([NH2:8])=[N:6][CH:7]=1.BrC1C(N)=NC=C(Br)N=1.C([Si](C)(C)C)#C.[H-].[Na+].[S:32](Cl)([C:35]1[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=1)(=[O:34])=[O:33]>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:10][N:8]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)C#Cc1nc(Br)cnc1N
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: C#C[Si](C)(C)C
Agent: Nc1ncc(Br)nc1Br
Agent: [H-]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(Br)cnc32)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52 %

Procedure:
To a solution of 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (3.00 g, 11.1 mmol, prepared using A from 3,5-dibromopyrazin-2-amine with ethynyltrimethylsilane) in DMF (60 mL) at about 0° C. was added 60 wt % NaH (0.577 g, 14.4 mmol) in three portions. After about 15 min, TsCl (2.75 g, 14.4 mmol) was added and the mixture was allowed to warm slowly to rt. After about 16 h, the mixture was poured into ice-cold water (120 mL) and the precipitate was collected by vacuum filtration. The crude solid was dissolved in DCM (15 mL) and purified by silica gel chromatography eluting with DCM to give 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.16 g, 52%): LC/MS (Table 2, Method c) Rt=1.58 min; MS m/z: 352 (M+H)+.
Reaction SMILES: OC1C=C(C2N=C3C=CC(I)=CN3C=2)C=CC=1.[Br:18][CH2:19][CH2:20][OH:21].N1C=CN=C1.[C:27]([Si:31]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)Cl)([CH3:30])([CH3:29])[CH3:28].[Cl-].[Na+]>CN(C)C=O>[Br:18][CH2:19][CH2:20][O:21][Si:31]([C:27]([CH3:30])([CH3:29])[CH3:28])([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCCBr
Agent: Oc1cccc(-c2cn3cc(I)ccc3n2)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCBr)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
Precipitates were filtered and recovered from the resulting mixture, sufficiently washed with water, and dried under reduced pressure, to obtain 927 mg (corresponding to 2.76 mmol) of 2-(3′-hydroxyphenyl)-6-iodoimidazo[1,2-a]pyridine (FIG. 2-8, Step 2). Separately, 2.50 g (corresponding to 20.0 mmol) of 2-bromoethanol and 2.72 g (corresponding to 40.0 mmol) of imidazole were dissolved in 10 mL of dimethylformamide, and cooled to 0° C. Then, 5.50 g (corresponding to 20.0 mmol) of t-butyldiphenylchlorosilane was added thereto. After the reaction mixture was stirred at room temperature for 18 hours, a saturated sodium chloride solution was added, and extracted three times with ethyl acetate. The combined ethyl acetate layers were dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=10/1) to obtain 7.04 g (corresponding to 19.4 mmol) of 1-bromo-2-(t-butyldiphenylsiloxy)ethane (FIG. 2-8, Step 3).
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].N1C=CN=C1.[C:10]([Si:14]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)Cl)([CH3:13])([CH3:12])[CH3:11]>ClCCl>[Br:1][CH2:2][CH2:3][O:4][Si:14]([C:10]([CH3:13])([CH3:12])[CH3:11])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCCBr
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](OCCBr)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 82.6 %

Procedure:
To a stirred solution of 2-bromoethanol (25 g, 200 mmol) and imidazole (41 g, 600 mmol) in dichloromethane (300 mL) was added tert-butyldiphenylchlorosilane (55 mL, 210 mmol) at room temperature and the mixture was stirred for 24 h. The resulting mixture was poured into ice-water, extracted with dichloromethane (2×250 mL), washed with brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, hexanes) afforded (2-bromo-ethoxy)-tert-butyl-diphenyl-silane (60 g, 83%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B2OCC(C)(C)CO2)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.Br[C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[C:22]#[N:23]>COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>[F:1][C:2]1[CH:3]=[C:4]([C:20]2[C:21]([C:22]#[N:23])=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: N#Cc1ccccc1Br
Reactant: CC1(C)COB(c2cc(F)cc([N+](=O)[O-])c2)OC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: N#Cc1ccccc1-c1cc(F)cc([N+](=O)[O-])c1
Temperature: 90 °C
Yield: 72.1 %

Procedure:
A mixture of 2-(3-fluoro-5-nitrophenyl)-5,5-dimethyl-[1,3,2]dioxaborinane (15 g, 59 mmol) and 2-bromobenzonitrile (12.4 g, 68.2 mmol) in 1,2-dimethoxyethane (125 mL) and 2 M aqueous sodium carbonate (50 mL) was degassed with nitrogen for 30 min then treated with tetrakis-(triphenylphosphine)palladium(0) (2.06 g, 1.8 mmol). The reaction was then heated at 90° C. for 16 h, cooled to ambient temperature and partitioned between ethyl acetate and water. The organics were washed with brine, dried over anhydrous magnesium sulfate, filtered and pre-adsorbed onto silica gel. Purification by dry flash chromatography on silica gel, eluting with isohexane (containing 1% methanol) on a gradient of ethyl acetate (10-40%) afforded 3′-fluoro-5′-nitrobiphenyl-2-carbonitrile as a cream-coloured solid (10.3 g, 72%): δH (400 MHz, CDCl3) 7.54-7.61 (2H, m), 7.65 (1H, ddd, J 8, 2 and 2), 7.74 (1H, ddd, J 8, 8 and 2), 7.84 (1H, dd, J 8 and 2), 8.03 (1H, ddd, J 8, 8 and 2), 8.22-8.24 (1H, m).
Reaction SMILES: [CH:1]1([C:7]([CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH:11]=O)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[Na]>>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:11][CH2:10][CH:9]([C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:8])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:29][CH2:28]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=CCC(C(=O)C1CCCCC1)c1ccccc1
Agent: [Na]
Product: COc1ccccc1N1CCN(CCC(C(=O)C2CCCCC2)c2ccccc2)CC1
Yield: 79.4 %

Procedure:
Following the procedures described in the Example 1, Step C, the reaction of 3-cyclohexanecarbonyl-3-phenylpropionaldehyde (1.39 mmol) and 2-methoxyphenylpiperazine (1.39 mmol) with sodium triacetoxyboranehydride (1.80 mmol) gave pure product 1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)propyl]piperazine (464 mg) in 79% yield. The oxalate salt was prepared as described above.
Reaction SMILES: [C:1]([S:4][CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[C:13]3[NH:17][C:16]([C:18]([C:58]4[CH:63]=[CH:62][CH:61]=[C:60]([CH2:64][S:65][C:66](=[O:68])[CH3:67])[CH:59]=4)=[C:19]4[N:57]=[C:22]([C:23]([C:46]5[CH:51]=[CH:50][CH:49]=[C:48]([CH2:52][S:53][C:54](=[O:56])[CH3:55])[CH:47]=5)=[C:24]5[NH:45][C:27](=[C:28]([C:34]6[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][S:41][C:42](=[O:44])[CH3:43])[CH:35]=6)[C:29]6[CH:30]=[CH:31][C:32]=2[N:33]=6)[CH:26]=[CH:25]5)[CH:21]=[CH:20]4)=[CH:15][CH:14]=3)[CH:9]=[CH:10][CH:11]=1)(=[O:3])[CH3:2].[Zn:69](OC(C)=O)OC(C)=O.O.O.O>C(Cl)(Cl)Cl.CO>[Zn+2:69].[C:66]([S:65][CH2:64][C:60]1[CH:59]=[C:58]([C:18]2[C:16]3[NH:17][C:13]([C:12]([C:8]4[CH:9]=[CH:10][CH:11]=[C:6]([CH2:5][S:4][C:1](=[O:3])[CH3:2])[CH:7]=4)=[C:32]4[N:33]=[C:29]([C:28]([C:34]5[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][S:41][C:42](=[O:44])[CH3:43])[CH:35]=5)=[C:27]5[NH:45][C:24](=[C:23]([C:46]6[CH:51]=[CH:50][CH:49]=[C:48]([CH2:52][S:53][C:54](=[O:56])[CH3:55])[CH:47]=6)[C:22]6[CH:21]=[CH:20][C:19]=2[N:57]=6)[CH:25]=[CH:26]5)[CH:30]=[CH:31]4)=[CH:14][CH:15]=3)[CH:63]=[CH:62][CH:61]=1)(=[O:68])[CH3:67]
Reactant: CC(=O)O[Zn]OC(C)=O
Agent: CC(=O)SCc1cccc(-c2c3nc(c(-c4cccc(CSC(C)=O)c4)c4ccc([nH]4)c(-c4cccc(CSC(C)=O)c4)c4nc(c(-c5cccc(CSC(C)=O)c5)c5ccc2[nH]5)C=C4)C=C3)c1
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: [Zn+2]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 16.2 mg of 29 (16.7 μmol) in 20 mL of CHCl3 and a solution of 80.0 mg of Zn(OAc)2.2H2O (365 μmol) in 5 mL of methanol were combined and stirred at ambient temperature. After 2 h the metalation was completed (checked by fluorescence excitation spectroscopy) and 40 mL of H2O was added. The phases were separated and the organic layer was washed three times with 5% NaHCO3 and dried (Na2SO4). The solvents were removed under reduced pressure. Column chromatography over flash silica gel with CH2Cl2/hexanes (4:1) gave the title compound as a purple solid in quantitative yield. IR (neat): {tilde over (v)}=2922 (w, CH), 2849 (w, CH), 1690 (s, CO), 1655 (m, arom. C═C), 1600 (w, arom. C═C), 1478 (w), 1420 (w), 1338 (w), 1208 (m), 1131 (m), 1067 (w), 1002 (m), 955 (w), 932 (w), 794 (m), 717 (m); 1H NMR (300.5 MHz, CDCl3): δ=2.30 (s, 12H, CH3), 4.31 (s, 8H, CH2), 7.62–7.69 (m, 8H, ArH), 8.05–8.13 (m, 8H, ArH), 8.92 (s, 8H, β-pyrrole); LD-MS calcd av mass 1028.15 (C56H44N4O4S4Zn), obsd 1028.8, 986.6 [M+-COCH3], 954.7 [M+-SCOCH3], 911.3 [M+-SCOCH3—COCH3], 880.4 [M+-2 SCOCH3], 838.8 [M+-2 SCOCH3—COCH3], 805.3 [M+-3 SCOCH3]; λabs (toluene) 424, 550, 589 nm; λem (toluene) 597, 647 nm.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[CH3:18])[NH2:14]>CO.O>[NH2:10][C:11]1[CH:12]=[C:13]([NH:14][C:2]2[N:7]=[C:6]([NH:14][C:13]3[CH:15]=[CH:16][C:17]([CH3:18])=[C:11]([NH2:10])[CH:12]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:15]=[CH:16][C:17]=1[CH3:18]
Reactant: Cc1ccc(N)cc1N
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: O
Solvent: CO
Product: Cc1ccc(Nc2ncc(F)c(Nc3ccc(C)c(N)c3)n2)cc1N
Temperature: 70 °C

Procedure:
2,4-Dichloro-5-fluoropyrimidine (50 mg, 0.30 mmol) was dissolved in a mixture of MeOH (1 ml) and H2O (0.1 ml). 3-amino-4-methylaniline (146 mg, 1.2 mmol) was added and the mixture was refluxed for 20 hours (70° C. oil-bath temperature). The mixture was cooled to 22° C., concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHCl3-Acetone, 2:1) to give N2,N4-bis(3-amino-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 8.11 (d, 1H, J=5.1 Hz), 7.98 (bs, 1H) (7.68 (dd, 1H, J=2.4, 8.1 Hz), 7.40-7.55 (m, 4H), 2.43 (s, 3H), 2.42 (s, 3H); LCMS: purity: 95.0%; MS (m/e): 338.66 (M+, 70).
Reaction SMILES: [CH:1](=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[CH:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2)[CH3:2].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1(=O)NC(=O)CC1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:2][CH:1]=[C:3]1[C:4]2[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=2[CH:6]=[CH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2
Reactant: O=C1CCC(=O)N1Br
Reactant: CC=C1c2ccccc2C=Cc2ccccc21
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCC=C1c2ccccc2C=Cc2ccccc21

Procedure:
To 2.8 g (12.8 mmol) of 5-ethylidene-5H-dibenzo [a,d]cycloheptene dissolved in 150 ml of carbon tetrachloride is added 1 equivalent of dry N-bromosuccinimide and a few milligrams of benzoylperoxide. The mixture is warmed and lightened with a 150 W lamp and after a few minutes the reaction is finished as indicated by succinimide floating at the surface. The mixture is cooled, filtered and evaporated to dryness. NMR indicates an almost quantitative yield. The compound is used as such, without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1.Cl[C:20](=[O:25])[C:21]([O:23][CH3:24])=[O:22].CCCCCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:24][O:23][C:21](=[O:22])[C:20]([N:12]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[C:8](=[O:11])[CH2:9][CH3:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:25]
Reactant: COC(=O)C(=O)Cl
Reactant: CCC(=O)c1ccc(Cl)cc1Nc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCC(=O)c1ccc(Cl)cc1N(C(=O)C(=O)OC)c1ccccc1
Temperature: 110 °C
Yield: 87.6 %

Procedure:
To a solution of 1-(4-chloro-2-phenylamino-phenyl)-propan-1-one (13.0 g, 50.2 mmol) in toluene (150 mL) was added methyl chlorooxoacetate (42.86 g, 350.0 mmol) at room temperature under nitrogen. The reaction mixture was heated at reflux at 110° C. for 16 hr. Completion of the reaction was monitored by silica TLC (mobile phase; hexane:ethyl acetate=1:1; Rf=0.5). The reaction mixture was concentrated under vacuum to afford 15.2 g (87.6% crude yield) of N-(5-chloro-2-propionyl-phenyl)-N-phenyl-oxalamic acid methyl ester. The crude product was used in the next step without further purification.
Reaction SMILES: C([O:9][C:10]1[CH:11]=[C:12]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:13][N:14]([C:20]1[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=1)[N:15]1[CH:19]=[N:18][N:17]=[CH:16]1)(=O)C1C=CC=CC=1.[OH-].[Na+]>CO>[F:31][C:30]1[CH:29]=[CH:28][C:12]([CH2:13][N:14]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)[N:15]2[CH:16]=[N:17][N:18]=[CH:19]2)=[CH:11][C:10]=1[OH:9]
Reactant: N#Cc1ccc(N(Cc2ccc(F)c(OC(=O)c3ccccc3)c2)n2cnnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc(N(Cc2ccc(F)c(O)c2)n2cnnc2)cc1
Yield: 66.3 %

Procedure:
To a solution of 4-[(3-benzoyloxy-4-fluorobenzyl)(4-cyanophenyl)amino]-4H-[1,2,4]triazole (0.958 g, 2.32 mmol) in MeOH (10 mL) was added NaOH (0.25 g, 6.25 mmol), and the solution heated to reflux for 5 minutes and then concentrated in vacuo. Water (10 mL) was added and the milky suspension was neutralised (pH 7-8) with 2N HCl. The white precipitate was filtered off, washed with a small amount of water (5 mL) and dried under high vacuum to give STX488 as a white solid (0.476 g, 66%); δH (400 MHz, DMSO-d6) 4.95 (s, 2H), 6.70 (ddd, J=11.4, 8.4, 2.4, 1H), 6.75 (AA′BB′, 2H), 6.84 (dd, J=8.4, 2.4, 1H), 7.06 (dd, J=11.3, 8.4, 1H), 7.76 (AA′BB′, 2H), 8.75 (s, 2H), 9.90 (s, 1H—exchanges with D2O); LRMS (FAB+) m/z (rel. intensity) 310.1 (100, [M+H]+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][CH2:9][CH2:10][NH2:11].F[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20]>C1COCC1.C(OCC)(=O)C>[CH3:7][O:8][CH2:9][CH2:10][NH:11][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20]
Reactant: COCCN
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCNc1ccccc1[N+](=O)[O-]
Reaction time: 24 h

Procedure:
Potassium carbonate (4.15 g) and 2-methoxyethylamine (1.3 ml) were added to a solution of 1-fluoro-2-nitrobenzene (1.56 ml) in dry THF (20 ml). The mixture was stirred at 23° for 24 h, then it was diluted with ethyl acetate, washed with a saturated ammonium chloride solution (100 ml), 10% sodium hydroxide solution (100 ml) and brine (100 ml), dried and concentrated in vacuo. The residue was purified by flash chromatography (eluting with CH-EA 3:1) to give the title compound as an orange oil (2.55 g). T.l.c. CH-EA (2:1), Rf 0.51.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=1>O>[C:5]([NH:8][C:9]1[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc(N)c1
Solvent: O
Product: CC(=O)Nc1cccc(C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Acetic anhydride (176 mL) was added slowly to a stirred mixture of 103.2 mL of m-toluidine in 300 mL of water. After complete addition, the mixture was stirred for 4 hours at room temperature. The mixture was cooled in an ice bath, then extracted with diethyl ether. The ether extract was dried over anhydrous sodium sulfate, filtered, and the filtrate evaporated under reduced pressure to leave an oily residue which solidified. The solid was collected, washed with water, then dissolved in diethyl ether. The etheral solution was dried over anhydrous sodium sulfate, filtered, and the filtrate evaporated under reduced pressure to yield 3-acetamidotoluene as a solid, mp 59°-61° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33]([C:41]([OH:43])=O)=[CH:34][N:35]2[CH:38]([CH3:40])[CH3:39])=[CH:31][CH:30]=1.[NH2:44][C:45]1[S:46][CH:47]=[CH:48][N:49]=1>C(Cl)Cl>[S:46]1[CH:47]=[CH:48][N:49]=[C:45]1[NH:44][C:41]([C:33]1[C:32]2[C:36](=[CH:37][C:29]([Cl:28])=[CH:30][CH:31]=2)[N:35]([CH:38]([CH3:39])[CH3:40])[CH:34]=1)=[O:43]
Reactant: CC(C)n1cc(C(=O)O)c2ccc(Cl)cc21
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)n1cc(C(=O)Nc2nccs2)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 36.6 %

Procedure:
A solution of triphenylphosphine (179 mg, 0.68 mmol) in methylene chloride (3 mL) cooled to 0° C. was treated with N-bromosuccinimide (122 mg, 0.68 mmol). This solution was stirred at 0° C. for 15 min. At this time, the reaction was treated with 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (125 mg, 0.53 mmol). This solution was stirred at 0° C. for 5 min and then was allowed to warm to 25° C. where it was stirred for 30 min. The reaction was then treated with 2-amino-thiazole (121 mg, 1.21 mmol) and was stirred at 25° C. for 3 d. At this time, the reaction was partitioned between water (30 mL) and ethyl acetate (30 mL). The organic layer was separated and then washed with a 1N aqueous hydrochloric acid solution (1×20 mL), a saturated aqueous sodium bicarbonate solution (1×20 mL), water (1×20 mL), and a saturated aqueous sodium chloride solution (1×20 mL). The organic layer was then dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) afforded 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid thiazol-2-ylamide (62 mg, 37%) as a pink solid: mp 202-204° C.; EI-HRMS m/e calcd for C17H16ClN3O (M+) 319.0546, found 319.0547.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:28])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[CH:14][C:13]=2[Cl:27])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].[CH2:29]([OH:34])[CH:30]=[CH:31][C:32]#[CH:33]>>[Cl:27][C:13]1[CH:14]=[C:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[CH:16]=[CH:17][C:12]=1[C:10]([C:8]1[CH:9]=[C:4]([N:1]2[CH:33]=[C:32]([CH:31]=[CH:30][CH2:29][OH:34])[N:3]=[N:2]2)[CH:5]=[CH:6][C:7]=1[CH3:28])=[O:11]
Reactant: Cc1ccc(N=[N+]=[N-])cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: C#CC=CCO
Product: Cc1ccc(-n2cc(C=CCO)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 116, using compound 434 (0.15 mmol) and pent-2-en-4-yn-1-ol (0.30 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 30:70 to 50:50 as the eluent to afford the title compound as yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:23])[C@H:4]([CH2:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[NH2:22])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[OH-].[Na+]>CC(OC)(C)C>[C:9]([O:8][C:6]([NH:5][C@H:4]([C:3]([OH:23])=[O:2])[CH2:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[NH2:22])=[O:7])([CH3:12])([CH3:10])[CH3:11]
Reactant: COC(=O)[C@H](CSc1ccc(Br)cc1N)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CSc1ccc(Br)cc1N)C(=O)O
Reaction time: 33 h
Yield: 99.9 %

Procedure:
1.65 g (3.99 mmol) of N-tert-butoxycarbonyl-3-(2-amino-4-bromophenylthio)-L-alanine methyl ester (98%) was dissolved in 65 ml TBME and emulsified in 240 ml buffer solution (0.1M sodium chloride; 20 mM sodium phosphate pH 7.5) under vigorous stirring. 0.75 ml Alcalase 2.4 L [a subtilisin Carlsberg from Novo Nordisk] was added and the pH maintained at 7.5 under vigorous stirring by the controlled addition (pH-static) of 1.0N sodium hydroxide solution. After 33 h, 4.23 ml of 1.0N sodium hydroxide solution was consumed and the conversion degree was >99% (HPLC analysis). The reaction mixture was acidified to pH 2 with 32% hydrochloric acid, filtered over Decalite. After phase separation the aqueous phase was extracted with 3×275 ml ethyl acetate. The combined organic phases were dried on anhydrous sodium sulfate and evaporated. The residue was dissolved in dichloromethane, evaporated and dried at HV to give 1.56 g N-tert-butoxycarbonyl-3-(2-amino-4-bromophenylthio)-L-alanine as a pale yellow solid (yield: 99.8%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:13][CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-])=O)[CH:18]=3)[N:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C>CO.C(OCC)(=O)C.[Pd]>[NH2:23][C:19]1[CH:18]=[C:17]([C:15]2[N:16]=[C:12]([NH:11][S:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)(=[O:10])=[O:9])[S:13][CH:14]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2nc(-c3cccc([N+](=O)[O-])c3)cs2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3cccc(N)c3)cs2)cc1
Yield: 79.7 %

Procedure:
A solution of 1.5 g of 4-methyl-N-[4-(3-nitro-phenyl)-thiazol-2-yl]-benzenesulfonamide in 150 ml of methanol and 70 ml of ethyl acetate was hydrogenated at room temperature after the addition of 0.15 g of palladium on active charcoal (10%). The catalyst was filtered off and the filtrate was concentrated. Crystallization from ethyl acetate/hexane (1:1) yielded 1.1 g of N-[4-(3-amino-phenyl)-thiazol-2-yl]-4-methyl-benzenesulfonamide as a colorless solid.