Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:18]([OH:21])(=[O:20])=[O:19])[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([S:14]([OH:17])(=[O:16])=[O:15])[C:12]=2[CH:13]=1)([O-])=O.S(=O)(=O)(O)O.C([O-])=O.[Na+]>[Pd].O>[NH2:1][C:4]1[CH:5]=[C:6]([S:18]([OH:21])(=[O:20])=[O:19])[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([S:14]([OH:17])(=[O:16])=[O:15])[C:12]=2[CH:13]=1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)O)c2cccc(S(=O)(=O)O)c2c1
Agent: [Pd]
Agent: O=C[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: Nc1cc(S(=O)(=O)O)c2cccc(S(=O)(=O)O)c2c1
Reaction time: 20 h

Procedure:
A solution of 20.6 parts of the magnesium salt of 3-nitronaphthalene-1,5-disulphonic acid and 5.5 parts of sulphuric acid in 160 parts of water is reacted with 20.4 parts of sodium formate and 1.24 parts (dry weight) of 3% palladium-on-carbon catalyst according to the procedure of Example 1. After 22 hours a further 10 parts of sodium formate are added and stirring under reflux is continued for an additional period of 20 hours. The mixture is cooled and filtered and the filter cake is washed with dilute sulphuric acid until only the catalyst remains on the filter. Analysis of the combined filtrates by ultraviolet spectroscopy and by titration of an aliquot with sodium nitrite solution indicates that the theoretical yield (17.6 parts) of 3-aminonaphthalene-1,5-disulphonic acid has been formed.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[N:8]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([Cl:16])=[CH:11][C:10]=2[Cl:17])[N:7]=[C:6]([C:18]#[N:19])[C:5]=1[S:20]C#N>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O.C(Cl)(Cl)Cl>[NH2:3][C:4]1[N:8]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([Cl:16])=[CH:11][C:10]=2[Cl:17])[N:7]=[C:6]([C:18]#[N:19])[C:5]=1[S:20][S:20][C:5]1[C:6]([C:18]#[N:19])=[N:7][N:8]([C:9]2[C:10]([Cl:17])=[CH:11][C:12]([Cl:16])=[CH:13][C:14]=2[Cl:15])[C:4]=1[NH2:3]
Reactant: N#CSc1c(C#N)nn(-c2c(Cl)cc(Cl)cc2Cl)c1N
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: N#Cc1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N)c1SSc1c(C#N)nn(-c2c(Cl)cc(Cl)cc2Cl)c1N
Temperature: 25 °C
Reaction time: 3.1 h
Yield: 93.5 %

Procedure:
Benzyltriethylammonium chloride (0.32 g, 0.0014 mole) and a solution of NaOH (6.0 g, 0.15 mol) in water (20 cc) were added with stirring to a suspension of 5-amino-3-cyano-4-thiocyanato-1-(2,4,6-trichlorophenyl)-1H-pyrazole (16.2 g, 0.047 mol) in CHCl3 (180 cc). The resulting mixture was stirred under laboratory atmosphere, at ambient temperature, for 3.1 hours, at the end of which time a TLC of a reaction aliquot portion showed that the reaction was complete. The yellow-coloured solid product was separated off by filtration, was washed with water, and was then dissolved in ethyl acetate, the solution being subjected to an extraction with water (2×200 ml) and to a dehydration over MgSO4. A dehydration in a vacuum oven at a temperature of 70° to 75° C. for approximately 16 hours gave 4,4'-dithiobis[5-amino-3-cyano-1-(2,4,6-trichlorophenyl)-1H-pyrazole] (14.0 g, 93.5%) in the form of a yellow-coloured solid substance.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:10][C:5]=2[O:4][C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[CH2:28]([O:27][C:25]([NH:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:10][C:5]=2[O:4][C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:26])[CH3:29]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)c1oc2cc(OCc3ccccc3)ccc2c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: CCOC(=O)Nc1c(C(=O)OCC)oc2cc(OCc3ccccc3)ccc12
Yield: 82.3 %

Procedure:
A mixture of 40 g (0.13 mol) of ethyl 3-amino-6-(phenylmethoxy)benzofuran-2-carboxylate, 18 ml (0.19 mol) of ethyl chloroformate and 51 g (0.37 mol) of potassium carbonate in 400 ml of benzene is heated at reflux for 18 hours and is then cooled and filtered and the filtrate is concentrated under reduced pressure. 41 g of product are obtained by recrystallization of the residue from diisopropyl ether.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH:8]([Br:10])[Br:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].ClC1C=CC=CC=1.[Br:20]Br.[OH-].[Na+]>O>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([Br:20])([Br:9])[Br:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: BrBr
Reactant: O=[N+]([O-])c1ccc(C(Br)Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccc(C(Br)(Br)Br)cc1
Yield: 86 %

Procedure:
A solution of 100 parts of p-nitrobenzal bromide in 1,000 parts of chlorobenzene is stirred with a solution of 80 parts of bromine plus 160 parts of 50% sodium hydroxide in 1,000 parts of water at 50° C for 10 hours. The bottom layer is separated and evaporated to dryness to give 110 parts (86% yield) of p-nitrobenzotribromide, m.p. 66°-70° C.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C1C=C([C:17]23[CH2:26][CH:21]([O:22][C:23]2([CH3:25])[CH3:24])[N:20]([CH3:27])[CH2:19][CH2:18]3)C=CC=1>CC(C)=O>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:17]1([C:23]([CH3:25])([CH3:24])[OH:22])[CH2:26][CH2:21][N:20]([CH3:27])[CH2:19][CH2:18]1
Reactant: COc1ccccc1
Reactant: CN1CCC2(c3cccc(C(F)(F)F)c3)CC1OC2(C)C
Solvent: CC(C)=O
Product: COc1ccccc1C1(C(C)(C)O)CCN(C)CC1

Procedure:
4-(2'-Methoxyphenyl)-α,α,1-trimethyl-4-piperidinemethanol was prepared from anisole by the procedure described in Example 3 except that acetone was used in place of cyclopentanone in the preparation of III; m.p. 110°-111°; NMR (in CDCl3): τ2.6-3.1 (m, 4H); 6.2 (s, 3H); 6.7-8.5 (m, 9H); 7.9 (s, 3H) and 8.9 (broad s, 6H). Anal. Calcd. for C16H25NO2 : C, 72.96; H, 9.57; N, 5.32. Found: C, 73.02; H, 9.56; N, 5.41.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH3:37])[CH:28]4[CH2:31][CH:30]([CH2:32][CH2:33][C:34]([OH:36])=O)[CH2:29]4)[CH2:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.C(N(CC)C(C)C)(C)C.[C:53]([C:57]1[CH:58]=[C:59]([NH2:64])[C:60]([NH2:63])=[CH:61][CH:62]=1)([CH3:56])([CH3:55])[CH3:54].CN(C)C=O>>[NH2:64][C:59]1[CH:58]=[C:57]([C:53]([CH3:55])([CH3:54])[CH3:56])[CH:62]=[CH:61][C:60]=1[NH:63][C:34](=[O:36])[CH2:33][CH2:32][CH:30]1[CH2:29][CH:28]([N:27]([CH2:26][C@@H:18]2[C@@H:19]3[C@@H:20]([O:21][C:22]([CH3:25])([CH3:24])[O:23]3)[C@H:16]([N:13]3[C:9]4[N:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:5][C:4]5[CH:38]=[CH:39][C:40]([O:42][CH3:43])=[CH:41][C:3]=5[O:2][CH3:1])[C:8]=4[CH:15]=[CH:14]3)[CH2:17]2)[CH3:37])[CH2:31]1
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCC(=O)O)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCC(=O)Nc4ccc(C(C)(C)C)cc4N)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
N,N,N′,N′-Tetramethyl-0-(7-azabenzotriazol-1-yl}uronium Hexafluorophosphate (0.44 g, 1.2 mmol) added to a solution of 3-(3-((((3aR,4R,6R,6aS)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)propanoic acid (460 mg, 0.77 mmol) and N,N-Diisopropylethylamine (0.44 mL, 2.6 mmol) and 4-tert-butylbenzene-1,2-diamine (0.15 g, 0.93 mmol) in N,N-Dimethylformamide (5 mL, 60 mmol). The reaction was stirred overnight at RT, partially concentrated to ca. 2 mls and then NaHCO3 (saturated) was added. The mixture was extracted with EtOAc (3×) and the combined organics were dried with MgSO4 and concentrated. Purified by flash chromatography (DCM/7N NH3 in MeOH 95:5) to yield a solid (0.24 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([F:18])=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([O:21]C)=[O:20])[NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>>[CH2:1]([O:8][C:9]1[C:17]([F:18])=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([OH:21])=[O:20])[NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc2c(OCc3ccccc3)c(F)ccc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc2c(OCc3ccccc3)c(F)ccc2[nH]1
Temperature: 85 °C
Yield: 99 %

Procedure:
Compound 1-3a was added to a solution of aqueous 2 N NaOH. The suspension was stirred at 80-90° C. until the reaction mixture became clear and was then held at reflux for 1-2 h. The solution was cooled and acidified with aqueous 3 N HCl, then the resulting precipitate was collected by filtration, washed with water, and dried under vacuum over P2O5 to provide the product (1-4a) in 99% yield. 1H NMR (CDCl3-d, 300 MHz) δ (ppm) 5.31 (s, 2H), 7.06-7.18 (m, 3H), 7.30-7.42 (m, 3H), 7.47-7.50 (m, 2H), 11.93 (bs, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18](O)=[O:19])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4].ON1C2N=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.ClC(Cl)C.[CH2:50]([NH:57][CH:58]1[C:67]2[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=2)[CH2:61][CH2:60][CH:59]1[CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[C:71]([O:75][CH3:76])[CH:70]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CN(C)C1C=CN=CC=1.ClCCl.CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18](=[O:19])[N:57]([CH2:50][C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)[CH:58]3[C:67]4[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=4)[CH2:61][CH2:60][CH:59]3[CH2:68][C:69]3[CH:74]=[CH:73][CH:72]=[C:71]([O:75][CH3:76])[CH:70]=3)[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: COc1cccc(CC2CCc3ccccc3C2NCc2ccccc2)c1
Reactant: COC(=O)c1cccc(-c2cccc(CC(=O)O)c2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1cccc(-c2cccc(CC(=O)N(Cc3ccccc3)C3c4ccccc4CCC3Cc3cccc(OC)c3)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.6 %

Procedure:
3′-Carboxymethyl-biphenyl-3-carboxylic acid methyl ester (77 mg) is combined with 76 mg 1-hydroxy-7-azabenzotriazole, 234 mg polymer-bound DCC, and 4 mg 4-dimethylaminopyridine in 4 ml 3:1 dichloroethane:DMF. The slurry is shaken 30 minutes at ambient temperature before adding 100 mg Benzyl-[2-(3-methoxy-benzyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-amine (prepared in a similar fashion to Preparation C). The mixture is shaken at ambient temperature 18 hours. The resin is filtered off and washed with dichloromethane and methanol. The solvent is evaporated to give a yellow oil. The oil is dissolved in dichloromethane, the insoluble material is filtered off, and the filtrate is separated by radial chromatography (4 mm plate, 3:1 hexanes:ethyl acetate). Product fractions are combined and evaporated to give 76 mg of the title compound as a colorless oil, 42%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)[C:5]2=[CH:4][N:3]=1.[NH2:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH2:21]1.C(N(CC)CC)C>CC(O)C>[C:29]([O:28][C:27](=[O:33])[NH:26][CH:23]1[CH2:22][CH2:21][CH:20]([NH:19][C:2]2[N:7]=[C:6]3[NH:8][N:9]=[C:10]([C:11]4[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=4)[C:5]3=[CH:4][N:3]=2)[CH2:25][CH2:24]1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: CSc1nccc(-c2n[nH]c3nc(Cl)ncc23)n1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CSc1nccc(-c2n[nH]c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)n1

Procedure:
To a solution of 6-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (from Example 7 supra) (2.5 g, 9.0 mmol) in 2-propanol (100 mL) was added trans-tert-butyl 4-aminocyclohexylcarbamate (2.2 g, 9.9 mmol) followed by triethylamine (1.0 g, 9.9 mmol). The reaction mixture was stirred and heated at reflux for 15 hours. The solvent was then removed under reduced pressure. The residue was extracted with dichloromethane (200 mL) and washed with water (3×25 mL), dried over anhydrous sodium sulfate, filtered and concentrated to afford {4-[3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester. (Yield 2.5 g, 61.0%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([CH:6]1[CH2:11][CH:10]([CH3:12])[CH2:9][CH2:8][C:7]1=O)=O.[C:14]([CH2:16][C:17]([NH2:19])=[O:18])#[N:15].N1CCCCC1>C(O)C>[C:14]([C:16]1[C:17](=[O:18])[NH:19][C:4]([CH2:3][O:2][CH3:1])=[C:6]2[C:7]=1[CH2:8][CH2:9][CH:10]([CH3:12])[CH2:11]2)#[N:15]
Reactant: N#CCC(N)=O
Reactant: COCC(=O)C1CC(C)CCC1=O
Solvent: C1CCNCC1
Solvent: CCO
Product: COCc1[nH]c(=O)c(C#N)c2c1CC(C)CC2
Yield: 32.3 %

Procedure:
3.7 g of the crude 2-methoxyacetyl-4-methylcyclohexanone, 1.68 g of cyanoacetamide and 1 ml of piperidine were mixed with 50 ml of ethanol and the obtained reaction mixture was heated under reflux for four hours. The crystals thus formed were filtered and purified to give 1.5 g of 4-cyano-2,3,5,6,7,8-hexahydro-1-methoxymethyl-7-methyl-3-oxoisoquinoline. m.p.: 205°-208° C. NMRδTMSDMSO-d6 :1.01 (3H, d), 1.2-2.0 (4H, m), 2.5-2.6 (1H, m), 2.7-2.9 (2H, m), 3.28 (3H, s), 4.32 (2H, s) and 11.86 (1H, s).
Reaction SMILES: S(Cl)(Cl)=O.[O:5]1[C:9]([CH2:10]O)=[CH:8][N:7]=[CH:6]1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.[Na+].C([O-])(=O)C.[K+]>C(O)CCC.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH2:10][C:9]2[O:5][CH:6]=[N:7][CH:8]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=S([O-])c1ccc(Cl)cc1
Reactant: OCc1cnco1
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: O=S(Cl)Cl
Solvent: CCCCO
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Cc1cnco1)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
Thionyl chloride (188 μl, 2.57 mmol) was added to a chloroform (10 ml) solution of oxazol-5-ylmethanol (85 mg, 0.858 mmol). The resulting mixture was stirred at 50° C. for 1.5 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue thus obtained was dissolved in butanol (10 ml). To the resulting solution were added sodium 4-chlorobenzenesulfinate (170 mg, 0.858 mmol), potassium acetate (252 mg, 2.57 mmol) and tetrabutylammonium iodide (15 mg), followed by stirring at 70° C. for 3 days. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue. The mixture was washed successively with water and brine and then, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to flash chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate (=1:1) fraction was concentrated under reduced pressure, whereby the title compound (81 mg, 37%) was obtained as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:20]Br.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:14][CH:15]=2)[C:10]([Br:20])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccc2c1cnn2Cc1ccccc1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccc2c1c(Br)nn2Cc1ccccc1
Temperature: 80 °C
Yield: 99.3 %

Procedure:
To a solution of 1-benzyl-4-nitro-1H-indazole (350 mg, 1.38 mmol) in acetic acid (5 mL), in a reaction vial was added bromine (265 mg, 1.66 mmol). The reaction vial was sealed and heated to 80° C., with magnetic stirring, for 2 hours. The mixture was allowed to cool. Saturated aqueous sodium bicarbonate solution was added (sufficient for the mixture to reach pH 8). The resulting solids were collected by filtration and washed with water. The material was dried under vacuum to give 1-benzyl-3-bromo-4-nitro-1H-indazole (455 mg).
Reaction SMILES: [C:1]([Si:5]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[O:6][CH2:7][C:8]([NH:12][C:13]([C:15]1[N:19]2[CH:20]=[CH:21][CH:22]=[C:23]([O:24][CH2:25][C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])[C:18]2=[N:17][C:16]=1[CH3:34])=[O:14])([C:10]#[N:11])[CH3:9])([CH3:4])([CH3:3])[CH3:2].C[Sn]([N:51]=[N+:52]=[N-:53])(C)C.Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.CO>[C:1]([Si:5]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[O:6][CH2:7][C:8]([NH:12][C:13]([C:15]1[N:19]2[CH:20]=[CH:21][CH:22]=[C:23]([O:24][CH2:25][C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])[C:18]2=[N:17][C:16]=1[CH3:34])=[O:14])([C:10]1[N:51]=[N:52][NH:53][N:11]=1)[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(C)(C#N)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1nn[nH]n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.2 %

Procedure:
To a solution of 300 mg of N-(1-{[tert-butyl (diphenyl)silyl]oxy}-2-cyanopropan-2-yl)-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide in 6 ml of toluene was added 240 mg of trimethyltin azide, followed by stirring for 4 hours under heating to reflux. The reaction mixture was left to be cooled to room temperature, and 10 ml of methanol and 10 ml of 1 M hydrochloric acid were then added thereto, followed by stirring at room temperature for 2 hours. The reaction mixture was neutralized by the addition of 1 M sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 292 mg of N-[1-{[tert-butyl (diphenyl)silyl]oxy}-2-(2H-tetrazol-5-yl)propan-2-yl]-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: C(N(CC)CC)C.CS(C)=O.[OH:12][CH2:13][CH2:14][CH2:15][C:16]1[N:17]=[C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:40])[C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=4)=[CH:28][CH:27]=3)=[CH:20][N:19]2[C:41]=1[CH3:42]>O>[CH3:42][C:41]1[N:19]2[CH:20]=[C:21]([NH:24][C:25](=[O:40])[C:26]3[CH:27]=[CH:28][C:29]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=4)=[CH:30][CH:31]=3)[CH:22]=[CH:23][C:18]2=[N:17][C:16]=1[CH2:15][CH2:14][CH:13]=[O:12]
Reactant: Cc1c(CCCO)nc2ccc(NC(=O)c3ccc(OCc4ccccn4)cc3)cn12
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(CCC=O)nc2ccc(NC(=O)c3ccc(OCc4ccccn4)cc3)cn12
Reaction time: 11 h
Yield: 54.3 %

Procedure:
Triethylamine (87.9 μL) and sulfur trioxide-pyridine complex (46.3 mg) were added to a DMSO solution (3 mL) of the compound (20.0 mg) obtained in Example 14, at room temperature. After stirred for 11 hours, the reaction liquid was poured into saturated saline water, and extracted with chloroform. The organic layer was dried with sodium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel chromatography (methanol/chloroform=1/25 to 1/8) to obtain N-[3-methyl-2-(3-oxopropyl)imidazo[1,2-a]pyridin-6-yl]-4-(pyridin-2-ylmethoxy)benzamide (10.8 mg).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[CH3:14][C@@H:15]1[CH2:19][O:18][C:17](=[O:20])[NH:16]1.C(=O)([O-])[O-].[K+].[K+].CNCCNC>[Cu]I.O.C1(C)C=CC=CC=1>[CH3:13][O:12][C:4]1[CH:3]=[C:2]([N:16]2[C@H:15]([CH3:14])[CH2:19][O:18][C:17]2=[O:20])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: C[C@@H]1COC(=O)N1
Reactant: COC(=O)c1ccc(Br)cc1OC
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(N2C(=O)OC[C@H]2C)cc1OC

Procedure:
To a mixture of methyl 4-bromo-2-methoxybenzoate (5.8 mL), (R)-4-methyloxazolidin-2-one (2 g) described in Preparation Example 25, potassium carbonate (2.8 g) and copper (I) iodide (760 mg) were added toluene (10 mL) and N,N′-dimethylethylenediamine (880 μL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give methyl (R)-2-methoxy-4-(4-methyl-2-oxooxazolidin-3-yl)benzoate (2.1 g). Methyl (R)-2-methoxy-4-(4-methyl-2-oxooxazolidin-3-yl)benzoate (2.1 g) was dissolved in methanol (8 mL) and tetrahydrofuran (8 mL), 1N aqueous sodium hydroxide solution (16 mL) was added, and the mixture was stirred at room temperature for 3 hr. 1N hydrochloric acid (16 mL) was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The title compound (2.2 g) was obtained.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([O:9][C:10](=[O:31])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]([C:24]1[CH:29]=[C:28]([OH:30])[CH:27]=[CH:26][N:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[CH3:8].I[CH2:33][CH2:34][CH3:35].CCOC(C)=O>CN(C=O)C.[Cl-].[Na+].O>[CH2:7]([O:9][C:10](=[O:31])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]([C:24]1[CH:29]=[C:28]([O:30][CH2:33][CH2:34][CH3:35])[CH:27]=[CH:26][N:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[CH3:8]
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(O)ccn1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1ccnc(N(CCCCCCC(=O)OCC)c2ccccn2)c1
Temperature: 70 °C
Reaction time: 17 h
Yield: 72.6 %

Procedure:
K2CO3 (21 mg, 0.15 mmol) was added to II (31 mg, 0.10 mmol) in DMF (2 mL) at rt under Ar(g). After 15 min iodopropane (11 μL, 0.11 mmol) was added and the reaction was stirred at 70° C. for 17 h. Brine (50 mL) and EtOAc (25 mL) were added, then the phases were separated, and the aqueous phase was extracted with EtOAc (25 mL). The organic phases were combined then dried over MgSO4, filtered, and subsequently evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with hexane/EtOAc (70:30) to furnish III as a colourless oil (28 mg, 80%).
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([I:23])[CH:20]=[CH:19][C:15]=3[C:16](O)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.Cl.C[O:26][C:27](=[O:38])[C@@H:28]([NH2:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Br:36])[CH:31]=1>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([I:23])[CH:20]=[CH:19][C:15]=3[C:16]([NH:37][C@@H:28]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([Br:36])[CH:31]=3)[C:27]([OH:26])=[O:38])=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12
Reactant: COC(=O)[C@@H](N)Cc1cccc(Br)c1
Agent: Cl
Product: O=C(N[C@@H](Cc1cccc(Br)c1)C(=O)O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoic acid was coupled to (S)-2-amino-3-(3-bromo-phenyl)-propionic acid methyl ester hydrochloride as in EXAMPLE 1, Part C. The methyl ester was hydrolyzed as in EXAMPLE 2, Part E, to afford the title compound. HPLC: RT=9.91 min. MS (ESI−): mass calcd. for C22H16BrIN4O5S2, 687.3; m/z found, 686 [M−H]−. 1H NMR (400 MHz, DMSO-d6): 13.05 (s, 1H), 11.77 (s, 1H), 9.03 (d, J=7.8, 1H), 8.45-8.35 (m, 2H), 7.92-7.86 (m, 1H), 7.82 (d, J=1.5, 1H), 7.53-7.51 (br m, 1H), 7.47-7.38 (m, 2H), 7.36-7.34 (m, 1H), 7.31-7.19 (m, 2H), 4.65-4.54 (m, 1H), 3.19 (dd, J=14.0, 4.7, 1H), 3.00 (dd, J=13.7, 10.8, 1H).