Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([C:12]1[S:16][C:15]([CH2:17][NH:18][C:19](=[O:39])[C@H:20]([CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:21][C:22]([O:24][CH3:25])=[O:23])=[CH:14][CH:13]=1)[CH2:3][O:4][Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].C(N(C(C)C)CC)(C)C.[N+:49]([C:52]1[CH:57]=[CH:56][C:55]([S:58](Cl)(=[O:60])=[O:59])=[CH:54][CH:53]=1)([O-:51])=[O:50]>ClCCl>[Si:5]([O:4][CH2:3][C@H:2]([C:12]1[S:16][C:15]([CH2:17][NH:18][C:19](=[O:39])[C@H:20]([CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:21][C:22]([O:24][CH3:25])=[O:23])=[CH:14][CH:13]=1)[NH:1][S:58]([C:55]1[CH:54]=[CH:53][C:52]([N+:49]([O-:51])=[O:50])=[CH:57][CH:56]=1)(=[O:59])=[O:60])([C:8]([CH3:9])([CH3:10])[CH3:11])([CH3:7])[CH3:6]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)N[C@H](C(=O)NCc1ccc([C@H](N)CO[Si](C)(C)C(C)(C)C)s1)C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)NCc1ccc([C@@H](CO[Si](C)(C)C(C)(C)C)NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)s1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of N-({5-[(1R)-1-amino-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl]-thiophen-2-yl}methyl)-Nα-(methoxycarbonyl)-β-phenyl-L-phenylalaninamide (125 mg, 0.220 mmol) in dichloromethane (4.4 mL) was treated with diisopropylethylamine (0.046 mL, 0.264 mmol) and solid p-nitrobenzensulfonyl chloride (59 mg, 0.264 mmol) and the mixture was stirred at room temperature for 18 hours, quenched with saturated NaHCO3 (0.5 mL), diluted with DCM, washed with sat. NaHCO3, dried over MgSO4, filtered and concentrated. The crude was purified on silica gel 10%-50% ethyl acetate in hexane to provide the title compound. 1H NMR (CD3)2CO) δ 8.39 (2H), 8.05 (2H), 7.67 (1H), 7.41 (5H), 7.30-7.15 (6H), 6.65 (1H), 6.42 (1H), 6.30 (1H), 5.10 (1H), 4.72 (1H), 4.50 (1H), 4.23 (1H), 4.13 (1H), 3.82 (2H), 3.49 (3H), 0.84 (9H), 0.01 (6H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.Br[C:11]1[N:16]=[C:15]([CH3:17])[N:14]=[C:13]([NH:18][C:19]2[S:20][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][N:23]=2)[CH:12]=1.CCN(C(C)C)C(C)C>C(O)CCC>[OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:11]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]([NH:18][C:19]3[S:20][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][N:23]=3)[CH:12]=2)[CH2:6][CH2:5]1
Reactant: OCCN1CCNCC1
Reactant: COC(=O)c1cnc(Nc2cc(Br)nc(C)n2)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COC(=O)c1cnc(Nc2cc(N3CCN(CCO)CC3)nc(C)n2)s1
Temperature: 25 °C
Yield: 83.8 %

Procedure:
1-(2-hydroxyethyl)piperazine (Compound 3) (65 g, 0.5 mol), methyl 2-(6-bromo-2-methylpyrimidin-4-ylamino)thiazole-5-formate (Compound 11) (32.9 g, 0.1 mol), n-butanol (280 mL) and DIPEA (28.3 g, 0.2 mol) were mixed in reaction flask and reacted by refluxing for 8 h. Cooled down to room temperature and crystals precipitated overnight. After air pump filtration the cake was rinsed by n-butanol and dried to give target Compound 6 (31.7 g, yield: 83.8%).
Reaction SMILES: [Cl-].[OH:2][CH2:3][CH2:4][C@@H:5]([C:7]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:11](=[O:19])[C:10]2=[C:20]([CH3:23])[CH:21]=[CH:22][N:9]2[N:8]=1)[NH3+:6].[Br:24][C:25]1[C:33]2[C:32](Cl)=[N:31][CH:30]=[N:29][C:28]=2[N:27]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:26]=1.[F-].[Cs+].C(N(CC)C(C)C)(C)C>C(O)(C)(C)C>[Br:24][C:25]1[C:33]2[C:32]([NH:6][C@H:5]([C:7]3[N:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:11](=[O:19])[C:10]4=[C:20]([CH3:23])[CH:21]=[CH:22][N:9]4[N:8]=3)[CH2:4][CH2:3][OH:2])=[N:31][CH:30]=[N:29][C:28]=2[N:27]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:26]=1
Reactant: Cc1ccn2nc([C@@H]([NH3+])CCO)n(-c3ccccc3)c(=O)c12
Reactant: C[Si](C)(C)CCOCn1cc(Br)c2c(Cl)ncnc21
Agent: [Cl-]
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: Cc1ccn2nc([C@H](CCO)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 96 h
Yield: 58.6 %

Procedure:
(S)-3-Hydroxy-1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)propan-1-aminium chloride (228 mg, 0.68 mmol) was treated with 5-bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (495 mg, 1.36 mmol), cesium fluoride (41 mg, 0.27 mmol) and N,N-diisopropylethylamine (1.60 ml, 9.19 mmol) in tert-butanol (5.0 ml) according to Preparation 13 but stirring the reaction mixture at 100° C. during 96 h. The residue was purified using SP1® Purification System (0% to 100%, hexane-ethyl acetate) to give 249 mg (57% yield) of the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14]1[C:15]([NH2:20])=[CH:16][CH:17]=[CH:18][CH:19]=1)([CH3:3])[CH3:2]>C(#N)C>[CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:2])[CH3:3])[C:5]=1[N:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]=[C:1]1[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:12])[CH3:11]
Reactant: CC(C)c1cccc(C(C)C)c1Nc1ccccc1N
Solvent: CC#N
Product: CC(C)c1cccc(C(C)C)c1-n1c(-c2ccccc2)nc2ccccc21
Temperature: 25 °C
Yield: 59.9 %

Procedure:
N1-(2,6-diisopropylphenyl)benzene-1,2-diamine (8.5 g, 32 mmol) and benzldehyde (3 g, 28.8 mmol) were reacted in acetonitrile (100 ml) under reflux for 3 hours. The reaction mixture was cooled to room temperature. Ferric chloride (0.05 g, 0.28 mmol) was added. The reaction mixture was heated up again to reflux overnight. Air was bubbled through the reaction while reflux. The solvent was evaporated. The residue was dissolved in dichloromethane (200 mL) and ran through a short silica gel plug. The crude product was purified by column chromatography using dichloromethane to 3% of ethyl acetate in dichloromethane. 3.4 g of desired product was obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:10]=1[Cl:11])=[O:5])C.[OH-].[Li+].O>CO>[Cl:11][C:10]1[N:9]([CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnn(C2CCOCC2)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cnn(C2CCOCC2)c1Cl
Temperature: 80 °C
Yield: 99.1 %

Procedure:
5-Chloro-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (2.194 g (98%), 8.31 mmol) was dissolved in methanol (12.5 mL). Lithium hydroxide (0.274 g, 11.44 mmol) and water (12.5 mL) were added and the mixture was heated at 80° C. for 1 hour. After cooling to room temperature, the mixture was concentrated to remove the methanol. Tetrahydrofuran was added to the residue and removed in vacuo to ensure complete removal of the methanol. The aqueous residue was treated with 6N HCl (1.88 mL) resulting in the precipitation of a thick milky solid. The solid was collected by filtration, washed with water and dried under high vacuum with heat to give 5-chloro-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-4-carboxylic acid (1.900 g, 99%). Mass spectrum: m/z: 231.30 (M+H).
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[CH3:11][CH:12]1[NH:16][N:15]=[CH:14][CH2:13]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([N:16]2[CH:12]([CH3:11])[CH2:13][CH:14]=[N:15]2)=[O:9])[CH:4]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: CC1CC=NN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC1CC=NN1C(=O)c1cccnc1

Procedure:
Hydrochloride of nicotinic acid chloride (4 g) was suspended in 20 ml of chloroform followed by addition of a mixture of 1.7 g of 5-methyl-2-pyrazoline and 4 g of triethylamine, washing with water and concentration. The product was purified by chromatography on a silica gel column (chloroform/methanol=100/1). Yield; 3.4 g.
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.C[Si]([N-][Si](C)(C)C)(C)C.C1(C)C=CC=CC=1.CC(C)C(C1C=C([C:45]#[N:46])C=CC=1)=O.C([C:50]1[CH:51]=[C:52](/[C:56](/[CH:62]([CH3:64])[CH3:63])=[CH:57]\[C:58]([O:60][CH3:61])=[O:59])[CH:53]=[CH:54][CH:55]=1)#N.C(C1C=C(/C(/C(C)C)=C/C(OC)=O)C=CC=1)#N>O1CCCC1>[C:45]([C:51]1[CH:50]=[CH:55][CH:54]=[CH:53][C:52]=1/[C:56](/[CH:62]([CH3:63])[CH3:64])=[CH:57]\[C:58]([O:60][CH3:61])=[O:59])#[N:46]
Reactant: COC(=O)/C=C(\c1cccc(C#N)c1)C(C)C
Reactant: CC(C)C(=O)c1cccc(C#N)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: COC(=O)/C=C(/c1cccc(C#N)c1)C(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)/C=C(\c1ccccc1C#N)C(C)C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of bis(2,2,2-trifluoromethyl)(methoxy carbonylmethyl)phosphonate (0.38 ml, 1.8 mmol) in 2.5 ml anhydrous tetrahydrofuran was added a solution of 18-Crown-6 (1.9 g, 7.5 mmol) in 2.5 ml anhydrous tetrahydrofuran. The reaction mixture was cooled to −78° C. under argon to which was added a solution of 0.5M bis(trimethylsilyl)amide in toluene (3.6 ml, 1.8 mmol). The reaction was stirred at −78° C. for 15 minutes to which was added a solution of 3-(2-methylpropanoyl)benzenecarbonitrile in 2.5 ml anhydrous tetrahydrofuran. The reaction was allowed to warm to room temperature and stirred for 48 hours. The reaction was quenched by the addition of 20 ml of a saturated ammonium chloride solution followed by extraction with 2×25 ml diethyl ether. Combined organic layers were washed with 2×25 ml water, 2×25 ml saturated brine solution, dried over magnesium sulfate, filtered and concentrated to give a 9:1 mixture of methyl (2Z)-3-(3-cyanophenyl)-4-methylpent-2-enoate and methyl (2E)-3-(3-cyanophenyl)-4-methylpent-2-enoate (420 mg, 120%) as a clear oil which was sufficiently pure to use without further purification. ES-MS (M+H+): 230.1.
Reaction SMILES: Cl[C:2]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1)([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)[CH2:3][CH2:4][CH3:5].[OH:23][N:24]=[C:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([CH:2]([O:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH2:3][CH2:4][CH2:5][N:28]2[CH2:29][CH2:30][C:25](=[N:24][OH:23])[CH2:26][CH2:27]2)=[CH:14][CH:15]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CCCC(Cl)(OC1CCCCO1)c1ccc(C(C)(C)C)cc1
Reactant: ON=C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)c1ccc(C(CCCN2CCC(=NO)CC2)OC2CCCCO2)cc1

Procedure:
58.4 g of 1-chloro 1-(4-tertbutylphenyl) 1-tetrahydro pyranyloxy butane in 200 ml ethanol are heated to reflux under stirring with 20 g 4-hydroxyimino piperidine and 20 g sodium carbonate. After 20 hours reflux, the solution is concentrated to dryness then taken up with water, extracted with dried methylene chloride and concentrated to dryness under vacuum 70.5 g of pure compound are thus produced. It is recrystallized from methanol to recover 40 g of a solid having a melting point of 150°-151° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:12][C:13]([F:24])([F:23])[C:14]1[C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[NH:16][N:15]=1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:16]2[C:17]3[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=3[C:14]([C:13]([F:12])([F:24])[F:23])=[N:15]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1

Procedure:
The title compound was prepared from 4-bromophenyl methyl sulfone and 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole using a similar procedure to that described for Example 7.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[N:13][CH:14]=[CH:15][C:10]=3[C:9]3[CH:16]=[N:17][C:18]([NH:20][C:21]4[N:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]5)=[CH:23][CH:22]=4)=[CH:19][C:8]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([N:7]2[C:11]3[CH:12]=[N:13][CH:14]=[CH:15][C:10]=3[C:9]3[CH:16]=[N:17][C:18]([NH:20][C:21]4[CH:22]=[CH:23][C:24]([N:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[CH:25][N:26]=4)=[CH:19][C:8]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3cc4c(cn3)c3ccncc3n4-c3ccccc3)nc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(-n2c3cnccc3c3cnc(Nc4ccc(N5CCNCC5)cn4)cc32)cc1

Procedure:
A solution of crude compound 372 in DCM (8 mL) was treated with trifluoroacetic acid (2.0 mL, 27 mmol) at room temperature for 2 h. After the volatiles were removed, the residue was subjected to reverse phase preparative HPLC (acetonitrile/H2O containing 0.1% TFA each, 40 min from 10 to 40%). Lyophilization provided compound 370 (12 mg) as a yellow solid (TFA salt). 1H NMR (500 MHz, CD3OD) δ ppm 9.46 (1 H, s), 8.80 (1 H, d, J=0.7 Hz), 8.65 (1 H, d, J=5.6 Hz), 8.53 (1 H, d, J=5.6 Hz), 8.05 (1 H, d, J=2.9 Hz), 7.90 (1 H, dd, J=9.3, 2.9 Hz), 7.77-7.83 (2 H, m), 7.68-7.76 (3 H, m), 7.24 (1 H, d, J=9.3 Hz), 7.14 (1 H, s), 3.46-3.53 (4 H, m), 3.40-3.46 (4 H, m). LCMS-ESI (POS), M/Z, M+1. Found 422.2.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)=[O:4].S(Cl)([Cl:16])=O>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([Cl:16])=[O:13])=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Reactant: O=S(Cl)Cl
Product: COC(=O)c1ccc(C(=O)Cl)nc1
Temperature: 25 °C

Procedure:
To 5-(Methoxycarbonyl)pyridine-2-carboxylic acid (Maybridge, 1.0 g, 5.52 mmol) was added thionyl chloride (Aldrich, 25 mL) and this reaction mixture was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the intermediate 5-(methoxycarbonyl)pyridine-2-carboxylic acid chloride as a tan solid which was used without further purification.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][C@@H:6]1Br)(=[O:3])[CH3:2].[Cl:20][C:21]1[C:26]([CH3:27])=[CH:25][C:24]([OH:28])=[C:23]([C:29]2[O:33][N:32]=[CH:31][CH:30]=2)[CH:22]=1.C1(C)C=CC=CC=1>[Cl-].[Zn+2].[Cl-].[N-]1C=CN=C1.[Ag+].C(#N)C>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][C@H:6]1[O:28][C:24]1[CH:25]=[C:26]([CH3:27])[C:21]([Cl:20])=[CH:22][C:23]=1[C:29]1[O:33][N:32]=[CH:31][CH:30]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Reactant: Cc1cc(O)c(-c2ccno2)cc1Cl
Agent: [Ag+]
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cc(C)c(Cl)cc1-c1ccno1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 10 %

Procedure:
A mixture of 0.8 g (5.87 mmol) of zinc chloride, 2 g of 13× molecular sieve, 2 g (5.6 mmol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide, 1 g (4.77 mmol) of 4-chloro-2-(5-isoxazolyl)-5-methylphenol, 1 g (5.7 mmol) of silver imidazolate, 5 ml of toluene and 5 ml of acetonitrile is prepared. The mixture is kept stirred at 80° C. for 90 minutes and then cooled and filtered. The residual solid is rinsed on the filter with methanol and the combined filtrates are concentrated under reduced pressure. The crude product obtained is purified by chromatography on silica gel, elution being carried out using a dichloromethane/ethyl acetate mixture (9/1; v/v). The pure fraction is crystallized from ethyl ether. The expected compound is thus obtained in the form of a white solid with a yield of 10%.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([C:22]#[C:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C:31]([O:33]C)=[O:32])=[CH:26][CH:25]=2)[CH:11]=[C:12]2[C:17]=1[O:16][C:15]([CH3:19])([CH3:18])[CH2:14][C:13]2([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].Cl>C(O)C.O1CCCC1.O>[C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([C:22]#[C:23][C:24]2[CH:25]=[CH:26][C:27]([CH2:30][C:31]([OH:33])=[O:32])=[CH:28][CH:29]=2)[CH:11]=[C:12]2[C:17]=1[O:16][C:15]([CH3:18])([CH3:19])[CH2:14][C:13]2([CH3:21])[CH3:20])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)Cc1ccc(C#Cc2cc(C(=O)OC(C)(C)C)c3c(c2)C(C)(C)CC(C)(C)O3)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)c1cc(C#Cc2ccc(CC(=O)O)cc2)cc2c1OC(C)(C)CC2(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.2 %

Procedure:
A solution of 6-(4-methoxycarbonylmethyl-phenylethynyl)-2,2,4,4-tetramethyl-chroman-8-carboxylic acid tert-butyl ester (Intermediate 53, 0.014 g, 0.03 mmol) in ethanol (0.3 mL), tetrahydrofuran (0.3 mL) and water (0.3 mL) was treated with 1N lithium hydroxide (0.12 mL, 0.12 mmol) and the resulting reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was neutralized with 2N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a yellow oil (0.012 g, 88%).
Reaction SMILES: [C:1]([O:4][CH:5]1[O:19][C@H:18]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:9][C:10](=[O:12])[CH3:11])[C@H:6]1[NH2:7])(=[O:3])[CH3:2].[I:25][C:26]1[C:31]([CH2:32][CH3:33])=[C:30]([I:34])[CH:29]=[C:28]([I:35])[C:27]=1[C:36]1[CH:41]=[CH:40][C:39]([C:42](Cl)=[O:43])=[C:38]([N+:45]([O-:47])=[O:46])[CH:37]=1>>[N+:45]([C:38]1[CH:37]=[C:36]([C:27]2[C:28]([I:35])=[CH:29][C:30]([I:34])=[C:31]([CH2:32][CH3:33])[C:26]=2[I:25])[CH:41]=[CH:40][C:39]=1[C:42]([C:5]1([O:19][C@H:18]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:9][C:10](=[O:12])[CH3:11])[C@H:6]1[NH2:7])[O:4][C:1](=[O:3])[CH3:2])=[O:43])([O-:47])=[O:46]
Reactant: CCc1c(I)cc(I)c(-c2ccc(C(=O)Cl)c([N+](=O)[O-])c2)c1I
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](N)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CCc1c(I)cc(I)c(-c2ccc(C(=O)C3(OC(C)=O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3N)c([N+](=O)[O-])c2)c1I

Procedure:
1,3,4,6-tetra-O-acetyl-D-glucosamine (9) is reacted with 2′, 4′, 6′-triiodo-3′-ethyl-3-nitrobiphenyl-4-carbonyl chloride (14) to yield 2-nitro-4-(3′-ethyl-2′, 4′, 6′-triiodophenyl)-benzoyl-1,3,4,6-tetra-O-acetyl-D-glucosamine (15).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].C([O:13][C:14](=O)[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=2)[CH:19]=1)=O)(C)(C)C>C1(C)C(C)=CC=CC=1>[CH3:30][C:26]1[CH:25]=[C:24]([C:20]2[CH:19]=[C:18]([C:16]3[CH2:15][C:14](=[O:13])[NH:8][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=4[N:7]=3)[CH:23]=[CH:22][CH:21]=2)[CH:29]=[CH:28][N:27]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Reactant: Nc1ccccc1N
Solvent: Cc1ccccc1C
Product: Cc1cc(-c2cccc(C3=Nc4ccccc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from commercially available 1,2-phenylendiamine (108 mg, 1.0 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (311 mg, 1.0 mmol) in xylene (20 ml) under reflux conditions for 2 h according to the general procedure M. Obtained as an off-white solid (230 mg, 70%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:17]=1)[C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.[CH3:41][NH:42][O:43][CH3:44]>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:10]=[C:11]([C:12](=[O:14])[N:42]([O:43][CH3:44])[CH3:41])[CH:15]=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:17]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1cc(C(=O)O)cc(S(C)(=O)=O)c1
Reactant: CNOC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CON(C)C(=O)c1cc(NC(=O)OC(C)(C)C)cc(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.4 %

Procedure:
3-Tert-butoxycarbonylamino-5-(methylsulfonyl)-benzoic acid (850 mg; 2.695 mmol) was diluted in 30 ml of THF, 1,1′-carbonyldiimidazole (1.3 g; 8.086 mmol) and triethylamine (0.818 ml; 5.661 mmol) were added. The reaction mixture was stirred at room temperature for 30 min., then, N,O-dimethylhydroxylamine (0.329 g; 0.005 mol) was added. The reaction mixture was refluxed overnight. Then, it was concentrated in vacuo. The crude was diluted with dichloromethane and to washed with a saturated sodium bicarbonate solution. The organic phase was separated, dried on MgSO4 and concentrated in vacuo. The crude was treated with isopropyl ether/ethyl acetate 2/1. The precipitate formed was filtered and dried in vacuo. 460 mg (1.25 mmol; 46% yield) of [3-methanesulfonyl-5-(methoxy-methyl-carbamoyl)-phenyl]-carbamic acid tert-butyl ester were obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.C([N:17]=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[OH-].[NH4+]>C1COCC1>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH2:17])=[O:5]
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)c1cc([N+](=O)[O-])ccc1N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 2-amino-5-nitro-benzoic acid (12.9 g, 81.9 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDCl) (17.3 g, 90.1 mmol), 1-hydroxybenzotriazole hydrate (HOBt) (12.2 g, 90.1 mmol) in THF (200 mL) was added 4-methylmorpholine (NMM) (9.91 mL, 90.1 mmol). After 10 minutes, ammonium hydroxide (50% v/v, 50 mL) was added. The mixture was stirred at room temperature under nitrogen for 17 hours. Solvent was removed under reduced pressure. Water was added. The solid separated was filtered, washed with aqueous NaHCO3 solution, and with water, and dried in air, to afford 2-amino-5-nitro-benzamide as a yellow solid. Yield: 9.88 g (66%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](I)[CH:9]=1)(=[O:3])[CH3:2].[F:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:31]2[CH:32]=[N:33][C:28]([F:27])=[CH:29][CH:30]=2)[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc(I)c1
Reactant: OB(O)c1ccc(F)nc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc(-c2ccc(F)nc2)c1
Yield: 55 %

Procedure:
By carrying out the operation analogously to example 3, starting from 3-iodophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation I, and 6-fluoro-3-pyridineboronic acid, the expected product is obtained in the form of a white powder with a yield of 55%.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]([CH3:16])[C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[C:4]([Cl:17])[CH:3]=1.[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C(Cl)Cl.C1COCC1>[Br:1][C:2]1[CH:15]=[C:14]([CH3:16])[C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23][O:18]3)=[CH:11][N:12]=2)=[C:4]([Cl:17])[CH:3]=1
Reactant: Cc1cc(Br)cc(Cl)c1Oc1ccc(O)cn1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(Br)cc(Cl)c1Oc1ccc(OC2CCCCO2)cn1
Temperature: 25 °C
Reaction time: 95 h

Procedure:
To a solution of 6-(4-bromo-2-chloro-6-methylphenoxy)pyridin-3-ol (5.00 g) in CH2Cl2-THF (70 mL, 5:2) were added 3,4-dihydro-2H-pyran (4.35 mL) and PPTS (200 mg) at room temperature. After stirring at room temperature for 95 hours, the solvent was removed under reduced pressure. To the residue was added saturated aqueous NaHCO3, and extracted with AcOEt. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=4/1 to 1/1) to give 2-(4-bromo-2-chloro-6-methyl-phenoxy)-5-(tetrahydro-2H-pyran-2-yloxy)pyridine as a yellow oil (6.30 g).