Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[N+:10]([O-])([OH:12])=[O:11].O>C(O)(=O)C>[OH:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=[N+]([O-])O
Reactant: O=Cc1ccccc1O
Solvent: O
Solvent: CC(=O)O
Product: O=Cc1cccc([N+](=O)[O-])c1O
Temperature: 25 °C
Yield: 26.3 %

Procedure:
To a solution of 2-hydroxybenzaldehyde (5.0 g, 41 mmol) in acetic acid (50 mL) at 0° C. was added nitric acid (65%, 4 g) dropwise. The reaction mixture was slowly warmed to room temperature for 2 hours and then heated at 40° C. for another 5 hours. The resulting mixture was poured into ice (75 g) and water (500 g). The precipitates were filtrated and purified by silica gel chromatography to afford the product 2-hydroxy-3-nitrobenzaldehyde (1.8 g, yield 26%). 1H NMR (400 MHz, CDCl3) δ ppm 11.44 (s, 1H), 10.42 (s, 1H), 8.34-8.37 (dd, 1H, J=2.0 Hz, 8.4 Hz), 8.10-8.13 (dd, 1H, J=2.0 Hz, 7.6 Hz), 7.12-7.16 (t, 1H, J=8.0 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([O-])=[O:8].[Na+].C(Cl)(=O)C(Cl)=O.C[N:20](C=O)C.N>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([NH2:20])=[O:8]
Reactant: CN(C)C=O
Reactant: O=C([O-])c1cc(Br)cnc1Cl
Agent: N
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Product: NC(=O)c1cc(Br)cnc1Cl
Temperature: 23 °C
Reaction time: 1 h
Yield: 427.3 %

Procedure:
Sodium 5-bromo-2-chloronicotinate (229 mg, 0.798 mmol) was suspended in CH2Cl2 (7.9 mL). Oxalyl chloride (0.084 ml, 0.957 mmol) was added followed by DMF (0.002 mL, 0.080 mmol) and the reaction mixture was stirred at 23° C. for 1 h. The solvent was removed by evaporation and the intermediate residue was dried under vacuum for 90 minutes. The crude acid chloride was suspended in CH3CN (7.9 mL) and NH3 (7M in MeOH, 0.125 mL, 0.877 mmol) was added and the reaction mixture was stirred at ambient temperature for 16 h. The solvent was removed by evaporation and the residue was partitioned between EtOAc (20 mL) and H2O (20 mL). The EtOAc layer was removed and the aqueous layer was extracted with EtOAc (3×25 mL). The combined organics were washed with brine, dried over MgSO4 and concentrated. The resulting solid was triturated with cold CH2Cl2 to provide the desired product as a tan powder (80.5 mg, 43%). 1H NMR (CDCl3) δ 6.08 (s, 1H), 6.66 (s, 1H), 8.36 (d, 1H, J=2.54 Hz), 8.54 (d, 1H, J=2.54 Hz).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:18][C@H:17]2[C@H:13]([N:14]=[C:15]([N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[S:16]2)[C@@H:12]([OH:28])[C@@H:11]1[OH:29])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+]>CN(C=O)C>[CH2:6]([O:29][C@@H:11]1[C@@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[O:18][C@H:17]2[C@H:13]([N:14]=[C:15]([N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[S:16]2)[C@H:12]1[O:28][CH2:11][CH:10]=[CH2:9])[CH:4]=[CH2:5]
Reactant: CN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H]2S1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCO[C@@H]1[C@H]2N=C(N(C)C(=O)OC(C)(C)C)S[C@H]2O[C@H](CO[Si](C)(C)C(C)(C)C)[C@H]1OCC=C
Temperature: 15 °C
Reaction time: 1.5 h
Yield: 155.2 %

Procedure:
A solution of 26 (35 g, 78 mmol) (Prepared according to the synthesis of Example 3, step 4) in DMF (250 mL) was treated with NaH (70%, 8 g, 233 mmol) at 5° C. for 30 min, then Allyl-Br (28 g, 233 mmol) was added slowly. After stirring for 1.5 hours at 15° C., the reaction was quenched by H2O (300 mL), extracted with ethyl acetate (3×200 mL). The organic layers were collected, washed with brine (5×100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by a silica gel column, eluted with 5%˜10% ethyl acetate in petroleum ether to afford the title compound (32 g, 78%) as a yellow oil; (ES, m/z) [M+H]+ 529.1; 1H NMR (300 MHz, CDCl3) δ 6.07 (d, J=6.3 Hz, 1H), 5.85-6.05 (m, 2H), 5.15-5.38 (m, 4H), 4.22-4.30 (m, 4H), 4.02-4.07 (m, 2H), 3.76-3.78 (m, 2H), 3.60-3.62 (m, 1H), 3.48-3.52 (m, 1H), 3.31 (s, 3H), 1.55 (s, 9H), 0.93 (s, 9H), 0.08 (s, 6H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([C:21]([N:23]1[CH2:29][CH2:28][CH2:27][N:26]([CH:30]2[CH2:33][CH2:32][CH2:31]2)[CH2:25][CH2:24]1)=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)=O)(C)(C)C>CCO.Cl.O1CCOCC1>[CH:30]1([N:26]2[CH2:27][CH2:28][CH2:29][N:23]([C:21]([C@@:9]3([CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=4)[CH2:10][CH2:11][CH2:12][NH:8]3)=[O:22])[CH2:24][CH2:25]2)[CH2:31][CH2:32][CH2:33]1
Reactant: CC(C)(C)OC(=O)N1CCCC1(Cc1cccc(F)c1)C(=O)N1CCCN(C2CCC2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: O=C(N1CCCN(C2CCC2)CC1)[C@@]1(Cc2cccc(F)c2)CCCN1
Yield: 54.3 %

Procedure:
A solution of 2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-2-(3-fluoro-benzyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (40.0 mg) in EtOH (5.0 mL) and 4 M HCl in dioxane (2.0 mL) was stirred for 10 h. The mixture was concentrated and the residue diluted with CH2Cl2 and treated with Et3N. The mixture was washed with water and concentrated to yield title compound (17 mg, 54%). MS (ESI): mass calcd. for C26H38FN3O3, 359.60; m/z found, 360.3 [M+H]+. 1H NMR (CDCl3): 7.23-6.84 (m, 4H), 3.87-3.40 (m, 4H), 3.15-3.0 (m, 1H), 2.97-2.71 (m, 4H), 2.68-2.40 (m, 4H), 2.10-1.98 (m, 3H), 1.93-1.54 (m, 9H).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([CH3:7])([CH3:6])[CH3:5].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][N:11]=1>C(O)C>[Br:16][C:13]1[CH:14]=[CH:15][C:10]2[N:11]([CH:2]=[C:3]([C:4]([CH3:7])([CH3:6])[CH3:5])[N:9]=2)[CH:12]=1
Reactant: CC(C)(C)C(=O)CBr
Reactant: Nc1ccc(Br)cn1
Solvent: CCO
Product: CC(C)(C)c1cn2cc(Br)ccc2n1
Temperature: 25 °C
Yield: 81.5 %

Procedure:
1-bromopinacolone (178 mg) was dissolved in 2.0 ml of ethanol, 156 mg of 2-amino-5-bromopyridine was added, and the mixture was stirred all night by heating under reflux. After cooled down to room temperature, the solvents were distilled outunder reduced pressure, ethyl acetate followed by saturated sodium hydrogen carbonate aqueous solution were added. Organic layer was dried with anhydrous sodium sulfate, and the solvents were distilled outunder reduced pressure. The obtained residues were purified by preparative thin-layer silicagel chromatography (hexane:ethyl acetate=75 :25) to obtain 186 mg of the above compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.C(O)(C)C.[CH2:17]([NH2:20])[CH2:18][CH3:19]>O>[CH3:12][O:11][C:4]1[N:3]=[C:2]([NH:20][CH2:17][CH2:18][CH3:19])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: CCCN
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Solvent: CC(C)O
Solvent: O
Product: CCCNc1nc(OC)ccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 98 %

Procedure:
Into a stirred and cooled (water bath) mixture of 188.6 g (1 mole) of 2-chloro-6-methoxy-3-nitropyridine and 200 ml of isopropanol, 141.9 g (2.4 mole) of n-propylamine are added drop by drop in the course of about 3 hours at a maximum temperature of 25° C. Stirring is continued overnight and then 1000 ml of water are added; the precipitated product is filtered off by suction, washed with water and then dried. The product obtained thereby is intensively yellow colored with a melting point of 69°-70° C. in a yield of 98% of theory.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10](Br)[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:24])=[O:5])[CH3:2].C[C:26]([N:28](C)C)=O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[C-]#N.[Zn+2].[C-]#N.[Zn]>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([C:26]#[N:28])[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2nc(-c3cccc(OC)c3)sc2c1O
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCOC(=O)c1nc(C#N)c2nc(-c3cccc(OC)c3)sc2c1O
Temperature: 120 °C
Reaction time: 4.5 h

Procedure:
A mixture of 4-bromo-7-hydroxy-2-(3-methoxy-phenyl)-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (197 mg, 0.48 mmole), tris(dibenzylideneacetone)-dipalladium(0)(22 mg, 0.02 mmole), 1,1′-bis(diphenylphosphino)ferrocene (27 mg, 0.04 mmole), zinc cyanide (27 mg, 0.29 mmole) and zinc (4 mg, 0.06 mmole) in dimethylacetamide (968 μl) was stirred at 120° C. for 4.5 h before it was cooled to room temperature, partitioned between ethyl acetate and water, filtered. The filtrate washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of methanol and dichloromethane to give the title compound as a yellow solid (32 mg). MS: (+) m/z 356.24 (M+1), MS: (−) m/z 354.24 (M−1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:25][C:26]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[C:27]=1[CH2:28]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:25][C:26]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[C:27]=1[CH2:28][O:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C)c1CO
Reactant: N#CCc1cccc(O)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cccc(C)c1COc1cccc(CC#N)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-(3-Hydroxyphenyl)acetonitrile (Step A, 5 g, 37 mmol) and diisopropyl azodicarboxylate (DIAD, 3.38 g, 16.7 mmol) in dry THF (20 ml) was added drop wise to a solution of 2,6-Dimethylbenzyl alcohol (2.25 g, 16.5 mmol) and triphenylphosphine (TPP, 4.3 g, 16.4 mmol) in THF (30 ml) at 0° C. under argon. The reaction mixture was stirred at room temperature for 16 hours or until all the starting material is consumed. Silica gel (25 g) was added to the mixture, solvents were removed under reduced pressure, loaded on silica gel column and eluted with methylene chloride:hexane (1:1) to give light yellow crystalline solid.
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].[NH2:5][C:6](=[O:37])[C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[O:18][CH2:19][C:20]([OH:22])=[O:21])[N:11]([CH2:23][C:24]2[CH:25]=[C:26]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:27]=[CH:28][CH:29]=2)[C:10]=1[CH3:36])=[O:8].[Na].C([O-])(O)=O.[Na+]>CN(C)C=O>[CH:2]([O:22][C:20](=[O:21])[CH2:19][O:18][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[C:9]([C:7](=[O:8])[C:6]([NH2:5])=[O:37])=[C:10]([CH3:36])[N:11]2[CH2:23][C:24]1[CH:25]=[C:26]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:27]=[CH:28][CH:29]=1)([CH3:4])[CH3:3]
Reactant: Cc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cccc2n1Cc1cccc(-c2ccccc2)c1
Reactant: CC(C)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)C(N)=O)c2c(OCC(=O)OC(C)C)cccc2n1Cc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a flask containing 15 ml of dimethylformamide was added with stirring 0.11 ml of 2-bromopropane and 500 mg. of ((3-(2-amino-1,2-dioxoethyl)-1-((1,1'-biphenyl)-3-ylmethyl)-2-methyl-1H-indol-4-yl)oxy)acetic acid, sodium salt. The reaction mixture was stirred at room temperature overnight. The reaction was incomplete. Thereafter, 180 mg of KI was added and the mixture was heated. After 24 hours the reaction mixture was poured into 50 ml of saturated NaHCO3 and extracted with ethyl acetate. The EtOAc solution was washed with water, dried over Na2SO4, and concentrated at reduced pressure. The title compound was then crystallized from EtOAc/hexane.
Reaction SMILES: [NH:1]([C:34]([O:36][CH2:37][CH:38]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44]2[C:39]1=[CH:40][CH:41]=[CH:42][CH:43]=2)=[O:35])[C@H:2]([C:14]([N:16]([CH3:33])[C@H:17]([C:25]([NH:27][C@H:28]([C:30]([OH:32])=[O:31])[CH3:29])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:3][C:4](=[O:13])[O:5]CC1C=CC=CC=1.[H][H]>[Pd].CO>[NH:1]([C:34]([O:36][CH2:37][CH:38]1[C:39]2[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:45]2[C:50]1=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:35])[C@H:2]([C:14]([N:16]([CH3:33])[C@H:17]([C:25]([NH:27][C@H:28]([C:30]([OH:32])=[O:31])[CH3:29])=[O:26])[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:15])[CH2:3][C:4](=[O:5])[OH:13]
Reactant: [H][H]
Reactant: C[C@H](NC(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: [Pd]
Solvent: CO
Product: C[C@H](NC(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@H](CC(=O)O)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Fmoc-Asp(OBn)-MePhe-Ala-pip (Compound SP453) (7.44 g, 10.0 mmol) and 20% palladium on active carbon (1.49 g, 2.8 mmol) were added to methanol (50 ml) under a nitrogen atmosphere, the atmosphere in the reaction vessel was replaced with hydrogen gas, and the mixture was stirred at room temperature for 5 hours. The reaction solution was filtered through celite, and the organic layer was concentrated under reduced pressure to afford Fmoc-Asp-MePhe-Ala-pip (Compound SP454) (5.69 g, 86%).
Reaction SMILES: [NH2:1][C:2]([CH3:18])([CH2:5][N:6]1[N:10]=[C:9]2[C:11]([CH3:17])=[CH:12][C:13]([Br:16])=[C:14]([F:15])[C:8]2=[N:7]1)[C:3]#[N:4].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[S:26])=[CH:23][CH:22]=1>>[Br:16][C:13]1[CH:12]=[C:11]([CH3:17])[C:9]2=[N:10][N:6]([CH2:5][C:2]([NH:1][C:25](=[S:26])[C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:29][CH:28]=3)([C:3]#[N:4])[CH3:18])[N:7]=[C:8]2[C:14]=1[F:15]
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: Cc1cc(Br)c(F)c2nn(CC(C)(N)C#N)nc12
Product: Cc1cc(Br)c(F)c2nn(CC(C)(C#N)NC(=S)c3ccc(C(F)(F)F)cc3)nc12

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(5-bromo-4-fluoro-7-methyl-2H-benzotriazol-2-yl)-2-methylpropionitrile (120 mg, described in Example 50) and 4-trifluoromethylthiobenzoyl chloride (0.09 mL), the title compound was isolated as a white solid (175 mg, 88%). Rf=0.65 (1:1 EA/heptane). MS (ES): M/Z [M+H]=516. NMR: (400 MHz, DMSO-d6): 1.75 (s, 3H), 2.41 (s, 3H), 5.41 (d, J=13.3 Hz, 1H), 5.56 (d, J=13.3 Hz, 1H), 7.45 (dd, J=5.9, 1.1 Hz, 1H), 7.85-7.90 (m, 4H), 8.90 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −122.4 (d, J=5.3 Hz, 1F), −42.0 (s, 3F).
Reaction SMILES: [C:1]([O:4][CH:5]([C:8]1[C:13]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=1)[CH2:6][F:7])(=[O:3])[CH3:2].C1([O:24][C:25](=O)[NH:26][C:27]2[N:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[N:28]=2)C=CC=CC=1>C(#N)C>[C:1]([O:4][CH:5]([C:8]1[C:13]([S:14]([NH:17][C:25]([NH:26][C:27]2[N:28]=[C:29]([O:35][CH3:36])[CH:30]=[C:31]([O:33][CH3:34])[N:32]=2)=[O:24])(=[O:15])=[O:16])=[CH:12][CH:11]=[CH:10][N:9]=1)[CH2:6][F:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(CF)c1ncccc1S(N)(=O)=O
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Solvent: CC#N
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2cccnc2C(CF)OC(C)=O)n1

Procedure:
To a solution of 2-(1-acetoxy-2-fluoroethyl)-3-pyridinesulfonamide (2.10 g) and phenyl(4,6-dimethoxypyrimidin-2-yl)carbamate (1.49 g) in 50 ml acetonitrile is added dropwise 0.7 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU) at 15° C. After stirring for 2 hours the resultant solution is extracted with methylene chloride and 5% hydrochloric acid. The organic phase is dried over magnesium sulfate, filtered and evaporated to yield the subject compound.
Reaction SMILES: O[C:2]([CH3:17])([CH3:16])[C:3]#[C:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)=[O:6].C(NCC)C.C([OH:25])C>>[CH3:16][C:2]1([CH3:17])[C:3](=[O:25])[CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[O:6]1
Reactant: CC(C)(O)C#CC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CCO
Solvent: CCNCC
Product: CC1(C)OC(c2ccc([N+](=O)[O-])cc2)=CC1=O
Reaction time: 1.5 h
Yield: 92 %

Procedure:
To a stirred solution of 4-hydroxy-4-methyl-1-(4-nitrophenyl)pent-2-yn-1-one (1.74 g, 7.46 mmol, 1 eq) in ethanol (30 mL), a solution of diethylamine (778 mg, 7.46 mmol, 1 eq) in EtOH (5 mL) was added dropwise at RT. The reaction mixture was then stirred for additional 90 min. The ethanol was removed, and the mixture was then diluted with EtOAc (100 mL). The combined organic layers were washed with water (50 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford 2,2-dimethyl-5-(4-nitrophenyl)furan-3(2H)-one (1.6 g, 92%) which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1.[OH-].[NH4+:13]>>[Br:1][C:2]1[C:10]2[C:9]([NH2:13])=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1
Reactant: Clc1ncnc2scc(Br)c12
Reactant: [NH4+]
Agent: [OH-]
Product: Nc1ncnc2scc(Br)c12
Temperature: 90 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
A suspension of 5-bromo-4-chlorothieno[2,3-d]pyrimidine (1 g, 4.01 mmol) in concentrated aqueous ammonium hydroxide (150 mL, 3852 mmol) was stirred overnight at 90° C. in a sealed vessel. The reaction was allowed to cool to room temperature and filtered. The white solid in the filter was air dried to afford 5-bromothieno[2,3-d]pyrimidin-4-amine (796 mg). LC/MS (ES) m/z=387.1 [M+H]+.
Reaction SMILES: C(C1C2N=C(C3C=CC(F)=CC=3)C=CC=2N=C(N)N=1)C.[O:21]1[CH2:26][CH2:25][CH2:24][O:23][CH:22]1[CH2:27][CH2:28][Mg]Br.[Cl:31][C:32]1[N:33]=[C:34](Cl)[C:35]2[N:41]=[C:40]([C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=3)[CH:39]=[CH:38][C:36]=2[N:37]=1>>[Cl:31][C:32]1[N:33]=[C:34]([CH2:28][CH2:27][CH:22]2[O:23][CH2:24][CH2:25][CH2:26][O:21]2)[C:35]2[N:41]=[C:40]([C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=3)[CH:39]=[CH:38][C:36]=2[N:37]=1
Reactant: Br[Mg]CCC1OCCCO1
Reactant: Fc1ccc(-c2ccc3nc(Cl)nc(Cl)c3n2)cc1
Agent: CCc1nc(N)nc2ccc(-c3ccc(F)cc3)nc12
Product: Fc1ccc(-c2ccc3nc(Cl)nc(CCC4OCCCO4)c3n2)cc1

Procedure:
The procedure for the synthesis of 4-ethyl-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidin-2-ylamine was repeated, except for the use of (1,3-dioxan-2-ylethyl)magnesium bromide instead of ethylmagnesium bromide and 2,4-Dichloro-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidine (see WO2006135993) instead of N-[4-chloro-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidin-2-yl]-acetamide. The resulting title compound was characterised as follows: MS (m/z) 374.0 [M+H]+; HPLC Rt=4.46 minutes (Method A).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.C(OO)(=[O:18])C.C(O)(C)C>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][C:7]1[CH:8]=[N+:9]([O-:18])[CH:10]=[CH:11][CH:12]=1
Reactant: CC(=O)OO
Reactant: COc1cccc(Oc2cccnc2)c1
Solvent: CC(C)O
Solvent: CC(=O)O
Product: COc1cccc(Oc2ccc[n+]([O-])c2)c1
Temperature: 35 °C
Reaction time: 16 h

Procedure:
A solution of 68 g of 3-(3-methoxyphenoxy)pyridine in 100 ml of glacial acetic acid is treated with 75 g of 40% peracetic acid in acetic acid. The mixture is stirred 16 hours at 35° C. and then is refluxed 1 hour. The mixture is cooled, 100 ml isopropanol added, and the mixture is concentrated at reduced pressure. The oily residue is dissolved in 500 ml of dichloromethane and is washed with excess cold 25% sodium hydroxide solution. The organic layer is concentrated to yield 3-(3-methoxyphenoxy)pyridine 1-oxide, m.p. 75°-77° C.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[N:15]=[N:16][N:17]([CH2:19][C:20]([O:22]C)=[O:21])[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[N:15]=[N:16][N:17]([CH2:19][C:20]([OH:22])=[O:21])[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2]
Reactant: COC(=O)Cn1cc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)nn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N1c2ccc(-c3cn(CC(=O)O)nn3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 50 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of methyl {4-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]-1H-1,2,3-triazol-1-yl}acetate (for a preparation, see Intermediate 75) (250 mg, 0.582 mmol) in methanol (5 mL) was added a 2M NaOH aqueous solution (0.873 mL, 1.746 mmol). The reaction mixture was stirred at 50° C. for 1 hour, then cooled to room temperature and concentrated in vacuo. The residue was partitioned between AcOEt and a 2M NaOH aqueous solution. The layers were separated and the organic phase was further extracted with a 2M NaOH aqueous solution. The combined aqueous layers were acidified to pH=3 using a 2M HCl aqueous solution. then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over a Na2SO4 cartridge and concentrated in vacuo to give {4-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]-1H-1,2,3-triazol-1-yl}acetic acid (245 mg, 0.566 mmol, 97%) as a white solid.
Reaction SMILES: [OH:1][CH:2]([CH:6]([NH:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:23]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=O.[CH3:34][NH2:35]>>[OH:1][CH:2]([C:3]([NH:35][CH3:34])=[O:5])[CH:6]([NH:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[N:23]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1ccc(-c2ccccc2)n1
Product: CNC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1ccc(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.3 by reacting 2-hydroxy-4-phenyl-3-(2-(3-phenyl-1H-pyrazol-1-yl)nicotinamido)butanoic acid with methylamine; ESI-MS [M+H]+: 456.2
Reaction SMILES: [O:1]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)[C@H:2]1[O:10][C@@H:9]([CH3:11])[C@@H:7]([OH:8])[C@@H:5]([OH:6])[C@@H:3]1[OH:4].[CH2:21]([Sn](=O)CCCC)CCC>CO>[CH3:21][O:6][C@@H:5]1[C@H:7]([OH:8])[C@H:9]([CH3:11])[O:10][C@H:2]([O:1][C:12]2[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=2)[C@H:3]1[OH:4]
Reactant: C[C@@H]1O[C@H](Oc2ccc([N+](=O)[O-])cc2)[C@@H](O)[C@H](O)[C@@H]1O
Reactant: CCCC[Sn](=O)CCCC
Solvent: CO
Product: CO[C@H]1[C@H](O)[C@@H](Oc2ccc([N+](=O)[O-])cc2)O[C@@H](C)[C@H]1O
Temperature: 70 °C
Reaction time: 40 h
Yield: 60.8 %

Procedure:
6 g (21 mmol) of p-nitrophenyl β-L-fucopyranoside in 300 ml of absol. methanol are treated with 7.84 g (31.5 mmol) of dibutyl tin oxide and heated under reflux for 2 h. The mixture is then concentrated, and the residue is dried and then taken up in 300 ml of DMF. After addition of 15.7 ml of methyl iodide, the batch is stirred at 70° C. for 40 h. The solvent is removed under reduced pressure and the residue is taken up in 300 ml of dichloromethane. The suspension is filtered, and the solution that remains is concentrated again and subjected to flash chromatography (dichloromethane/methanol 99:1). The concentration gives 3.82 g (61%) of the target product.