Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]([N:11]2[CH:15]=[C:14]([C:16]3[C:17]4[CH:24]=[CH:23][NH:22][C:18]=4[N:19]=[CH:20][N:21]=3)[CH:13]=[N:12]2)[CH2:8][C:9]#[N:10])[CH2:3][CH2:2]1.[Cl:25][C:26]1[C:31]([CH3:32])=[C:30](Cl)[N:29]=[CH:28][N:27]=1.C(N(CC)C(C)C)(C)C.C(O)C>>[Cl:25][C:26]1[N:27]=[CH:28][N:29]=[C:30]([N:1]2[CH2:2][CH2:3][CH:4]([CH:7]([N:11]3[CH:15]=[C:14]([C:16]4[C:17]5[CH:24]=[CH:23][NH:22][C:18]=5[N:19]=[CH:20][N:21]=4)[CH:13]=[N:12]3)[CH2:8][C:9]#[N:10])[CH2:5][CH2:6]2)[C:31]=1[CH3:32]
Reactant: N#CCC(C1CCNCC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reactant: Cc1c(Cl)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1c(Cl)ncnc1N1CCC(C(CC#N)n2cc(-c3ncnc4[nH]ccc34)cn2)CC1
Yield: 44.3 %

Procedure:
A solution of 3-piperidin-4-yl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (0.20 g, 0.00062 mol), 4,6-dichloro-5-methylpyrimidine (0.11 g, 0.00067 mol) and N,N-diisopropylethylamine (130 microL, 0.00076 mol) in ethanol (2.0 mL, 0.034 mol) was heated to reflux for 1.2 hours, then the reaction was purified by preparative-LCMS (pH 10) to give 123 mg white solid (44% yield). LCMS (M+1): 448.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)=[O:4].[CH2:16]([NH:23][C:24]([NH:26][CH3:27])=[S:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(OCC)C>[CH2:16]([N:23]=[C:24]1[N:26]([CH3:27])[C:3]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=2)([OH:4])[CH2:2][S:25]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NS(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Reactant: CNC(=S)NCc1ccccc1
Solvent: CCOCC
Product: CN1C(=NCc2ccccc2)SCC1(O)c1ccc(Cl)c(S(N)(=O)=O)c1

Procedure:
4.7 g of 2-bromo-4'-chloro-3'-sulfamoylacetophenone and 2.7 g of 1-benzyl-3-methylthiourea were reacted as prescribed in Example 23 and the reaction mixture was introduced into 200 ml of diethyl ether while stirring. The hygroscopic crystals of the 2-benzylimino-4-(4-chloro-3-sulfamoylphenyl)-3-methyl-1,3-thiazolidine-4-ol-hydrobromide were rapidly filtered off, dissolved in 70 ml of water and converted into the end product according to the prescription of Example 28. Colorless solid body: decomposition beginning at 110° C, γC=N 1610 cm-1.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH:5]([N:8]=[N:9][C:10]1(Cl)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:7])[CH3:6].O>CO>[CH:5]([N:8]=[N:9][C:10]1([N:1]=[N+:2]=[N-:3])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:7])[CH3:6]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)N=NC1(Cl)CCCCC1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)N=NC1(N=[N+]=[N-])CCCCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 9.75 grams (0.15 moles) of sodium azide in 100 mls of 70% aqueous methanol in a 250 ml erlenmeyer flask cooled in an ice bath, was added 18.85 grams (0.1 moles) of 1-isopropylazo-1-chlorocyclohexane (from Example 3-2) over 15 minutes while holding the reaction temperature below 10° C. After the addition was complete the mixture was stirred an additional 20 minutes at room temperature, poured into 200 ml water and extracted into 100 ml of pentane. The pentane solution was washed successively with 50 ml portions of water and saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure on a rotating evaporator. The product was a yellow liquid and weighed 18.4 grams (94.4 % crude yield). It was not shock sensitive and its infrared spectrum was in agreement with the structure of 1-isopropylazo-1-azidocylohexane (strong azide band at 2100 cm-1).
Reaction SMILES: [S:1]([O:11][C@@H:12]1[C@H:16]([OH:17])[C@@H:15]([CH2:18][OH:19])[O:14][C@H:13]1[N:20]1[C:29]2[N:28]=[CH:27][N:26]=[C:24]([NH2:25])[C:23]=2[N:22]=[CH:21]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH3:30][O:31][C:32]1[CH:53]=[CH:52][C:35]([C:36](Cl)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)=[CH:34][CH:33]=1>N1C=CC=CC=1>[CH3:30][O:31][C:32]1[CH:53]=[CH:52][C:35]([C:36]([NH:25][C:24]2[C:23]3[N:22]=[CH:21][N:20]([C:29]=3[N:28]=[CH:27][N:26]=2)[C@@H:13]2[O:14][C@H:15]([CH2:18][O:19][C:36]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[C:35]3[CH:34]=[CH:33][C:32]([O:31][CH3:30])=[CH:53][CH:52]=3)[C@@H:16]([OH:17])[C@H:12]2[O:11][S:1]([C:4]2[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=2)(=[O:2])=[O:3])([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)=[CH:34][CH:33]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2[C@H](O)[C@@H](CO)O[C@H]2n2cnc3c(N)ncnc32)cc1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(Nc2ncnc3c2ncn3[C@@H]2O[C@H](COC(c3ccccc3)(c3ccc(OC)cc3)c3ccc(OC)cc3)[C@@H](O)[C@H]2OS(=O)(=O)c2ccc(C)cc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.4 %

Procedure:
2'-O-Tosyladenosine (Compound A1) (4.21 g, 10 mmol) and 4,4'-dimethoxytrityl chloride (7.45 g, 22 mmol) were added to anhydrous pyridine (50 ml), and stirred at room temperature for 20 hours. After ice cooling, 50% aqueous pyridine was added, the mixture was extracted with chloroform, and the organic layer was washed successively with aqueous sodium bicarbonate and water, and dried over magnesium sulfate. After distillating away the chloroform, the pyridine was removed by co-evaporation with toluene, and the residue was subjected to silica gel column chromatography eluant: toluene-ethyl acetate-triethylamine→(9:1:0.1) toluene-ethyl acetate-triethylamine-methanol (9:1:0.1:0.2)]. Fractions containing the desired substance were combined and concentrated to give Compound A2 (7.74 g, yield 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].Cl[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:19].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:21]([O:20][C:18]([N:14]1[C:13](=[O:16])[CH:12]=[CH:11][C:10]([C:4]2[CH:5]=[C:6]([Cl:9])[C:7]([CH3:8])=[C:2]([Cl:1])[CH:3]=2)=[N:15]1)=[O:19])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCOC(=O)Cl
Reactant: Cc1c(Cl)cc(-c2ccc(=O)[nH]n2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCOC(=O)n1nc(-c2cc(Cl)c(C)c(Cl)c2)ccc1=O
Yield: 31 %

Procedure:
A mixture of 2.55 g of 6-(3,5-dichloro-4-methylphenyl)-3-pyridazone, 1.43 g of butyl chloroformate, 1.75 g of potassium carbonate and 100 ml of acetonitrile was heated under reflux for 7.5 hours. After cooling the reaction mixture, the unreacted pyridazone and inorganic salts were removed by filtration and the solvent was distilled under reduced pressure from the filtrate. The residue was recrystallized from hexane, giving 1.1 g (31%) of the desired Compound No. 32, in the form of needles, whose melting point and spectroscopic data agreed completely with those of the compound obtained in Example 6.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[C:21]([Cu])#[N:22]>CC(N(C)C)=O.CCOC(C)=O>[N+:18]([C:3]1[CH:4]=[C:5]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:7][C:2]=1[C:21]#[N:22])([O-:20])=[O:19]
Reactant: N#C[Cu]
Reactant: O=[N+]([O-])c1cc(-c2ncccc2C(F)(F)F)ccc1Br
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(-c2ncccc2C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 4 h

Procedure:
To a solution of 2-(4-bromo-3-nitro-phenyl)-3-(trifluoromethyl)-pyridine (0.55 mmol) in DMA (4 mL) add CuCN (0.60 mmol). Stir the mixture 4 hours at 110° C. Cool to room temperature, dilute with 20 ml of EtOAc, and filter through celite pad. Wash the filtrated with brine, dry over Na2SO4, concentrate under vacuum, and purify by flash chromatography (1:1 hexanes/EtOAc) to give 2-nitro-4-(3-trifluoromethyl-pyridin-2-yl)-benzonitrile.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[N:8][N:7]=[N:6]1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:16][C:17]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:18]=1[NH2:19]>CN(C=O)C>[N:5]1([CH2:4][CH2:3][CH2:2][NH:19][C:18]2[CH:20]=[CH:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:17]=2[F:16])[CH:9]=[N:8][N:7]=[N:6]1
Reactant: Nc1ccc([N+](=O)[O-])cc1F
Reactant: ClCCCn1cnnn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(NCCCn2cnnn2)c(F)c1
Temperature: 25 °C
Yield: 14.1 %

Procedure:
To a mixture of 1-(3-chloropropyl)-1H-tetrazole (2.10 g, 14.33 mmol), cesium carbonate (4.66 g, 14.33 mmol) and a catalytic amount of KI in DMF (30 mL) in an ice bath was added 2-fluoro-4-nitroaniline (1.50 g, 9.61 mmol) in one portion. After the mixture was refluxed for 35 h, the mixture was cooled to rt and filtered. The filtrate was concentrated in vacuo. To the residue was added water (50 mL) and the resulting mixture was extracted with DCM (20 mL 2). The combined organic layers were washed with brine (20 mL×2) and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=2:1) to give the title compound as oil (0.36 g, 10%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10](=[O:15])[CH2:11][CH2:12][O:13][CH3:14])[C:7]([C:16]([F:19])([F:18])[F:17])=[CH:6][C:5]=1[NH2:20].[C:22](Cl)(Cl)=[O:23]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10](=[O:15])[CH2:11][CH2:12][O:13][CH3:14])[C:7]([C:16]([F:17])([F:19])[F:18])=[CH:6][C:5]=1[N:20]=[C:22]=[O:23]
Reactant: O=C(Cl)Cl
Reactant: COCCC(=O)c1cc(C(=O)OC)c(N)cc1C(F)(F)F
Solvent: Cc1ccccc1
Product: COCCC(=O)c1cc(C(=O)OC)c(N=C=O)cc1C(F)(F)F
Yield: 100 %

Procedure:
In a dried flask purged with argon, a solution of 2-amino-5-(3-methoxy-propionyl)-4-trifluoromethyl-benzoic acid methyl ester (154 mg, 0.504 mmol) in dry toluene (4.7 mL) was cooled to 0° C. and treated dropwise with a solution of phosgene in toluene (20%, 4.9 mL). A slow stream of phosgene was introduced and the reaction mixture was heated to reflux for 2 h. Argon was blown through the yellow solution and the solvent distilled off leaving the title compound (168 mg, 100%) as an oily residue, sufficiently pure for the next step. 1H-NMR (CDCl3, 360 MHz): 8.20 (s, 1H), 7.45 (s, 1H), 4.00 (s, 3H), 3.75 (t, J=8 Hz, 2H), 3.35 (s, 3H), 3.10 (t, J=8 Hz, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])O)[OH:8])[OH:6])=[O:4].[NH2:13][CH:14]([C:17]([OH:19])=[O:18])[CH2:15][OH:16]>[Ni]>[OH:12][CH2:11][CH:9]([NH:13][CH:14]([C:17]([OH:19])=[O:18])[CH2:15][OH:16])[CH:7]([OH:8])[CH:5]([OH:6])[CH:3]([OH:4])[CH2:2][OH:1]
Reactant: NC(CO)C(=O)O
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Ni]
Product: O=C(O)C(CO)NC(CO)C(O)C(O)C(O)CO

Procedure:
The product, obtained in the form of a resin, was made from D-fructose and DL-serine using Raney nickel as a catalyst and heating for 2 hours to 50° C. and for 3 hours to 70° C.
Reaction SMILES: [C-:1]#[N:2].[Na+].S(=O)(=O)(O)O.[Br:9][C:10]1[CH:26]=[C:25]([CH2:27]Cl)[CH:24]=[C:23]([Br:29])[C:11]=1[CH2:12][C:13]1[CH:14]=[C:15]([CH:20]([CH3:22])[CH3:21])[C:16](=[O:19])[NH:17][N:18]=1>CS(C)=O>[Br:9][C:10]1[CH:26]=[C:25]([CH2:27][C:1]#[N:2])[CH:24]=[C:23]([Br:29])[C:11]=1[CH2:12][C:13]1[CH:14]=[C:15]([CH:20]([CH3:22])[CH3:21])[C:16](=[O:19])[NH:17][N:18]=1
Reactant: [C-]#N
Reactant: CC(C)c1cc(Cc2c(Br)cc(CCl)cc2Br)n[nH]c1=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)c1cc(Cc2c(Br)cc(CC#N)cc2Br)n[nH]c1=O
Temperature: 40 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
A suspension of sodium cyanide (279 mg, 5.69 mmol) in dimethyl sulfoxide (2.0 mL) was treated with concentrated sulfuric acid (0.10 mL), 6-(2,6-dibromo-4-chloromethyl-benzyl)-4-isopropyl-pyridazin-3-one (62) (346 mg, 0.79 mmol) and an addition rinse of dimethyl sulfoxide (3.0 mL). The reaction was stirred at 25° C. for 5 min and at 40° C. for 1 h. At this time, the reaction was heated to 60° C. for 1 h and then was cooled to 25° C. The mixture was poured onto a mixture of ice and a saturated aqueous sodium bicarbonate solution (50 mL). This mixture was extracted into ethyl acetate (3×50 mL). The combined organics were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over magnesium sulfate, filtered and concentrated under vacuum. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1:2 hexanes/ethyl acetate) afforded [3,5-dibromo-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenyl]-acetonitrile (63) (227 mg, 67%) as a light orange solid; LRMS for C16H15Br2N3O (M+H) at m/z=424. Molecular Weight=425.1255; Exact Mass=422.9582
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[CH3:10][O:11][C:12](=[O:20])[C:13]([N+:18]#[C-:19])=[CH:14]N(C)C>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[CH3:10][O:11][C:12]([C:13]1[N:18]=[CH:19][N:5]([CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[F:1])[CH:14]=1)=[O:20]
Reactant: [C-]#[N+]C(=CN(C)C)C(=O)OC
Reactant: NCc1ccccc1F
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: COC(=O)c1cn(Cc2ccccc2F)cn1
Temperature: 25 °C

Procedure:
8 g of o-fluorobenzylamine and 6.6 g of 2-isocyano-3-dimethylaminoacrylic acid methyl ester are dissolved in 66 ml of xylene and heated under reflux for 3 hours while stirring. After cooling to room temperature, the whole is diluted with ethyl acetate and extracted by shaking twice with 50 ml of 2N hydrochloric acid each time and then with water. The aqueous phases are washed twice with 50 ml of ethyl acetate each time. All the aqueous phases are combined, rendered alkaline with concentrated ammonia and then extracted by shaking three times with 100 ml of dichloromethane each time. The extracts are combined, washed twice with water, dried over magnesium sulphate and concentrated to dryness by evaporation. The residue is dissolved in ethyl acetate, filtered over silica gel, concentrated and caused to crystallise by the addition of diethyl ether. 1-(o-fluorobenzyl)-imidazole-4-carboxylic acid methyl ester having a melting point of 87°-89° is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:14]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1ccc(O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1

Procedure:
1-(4-hydroxy-3-nitro-phenyl)-ethanone was treated with benzyl bromide in the presence of K2CO3 in DMF, and processed as reported in the synthesis of example 20a to obtain the crude product which was purified using flash chromatography (silica gel, 5% CH3CN in chloroform). Yield, 94%; mp, 132° C.; MS (CI): 300 (M++29), 272 (M++1), 91; analysis: C15H13NO4 requires, C, 66.42; H, 4.83; N, 5.16. found; C, 66.58; H, 4.52; N, 5.30%.
Reaction SMILES: [F-:1].[K+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11]>O1CCOCC1>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([F:1])(=[O:12])=[O:11]
Reactant: [F-]
Reactant: O=S(=O)(Cl)c1ccccc1F
Agent: [K+]
Solvent: C1COCCO1
Product: O=S(=O)(F)c1ccccc1F
Temperature: 25 °C
Yield: 73.7 %

Procedure:
Potassium fluoride (99%) (12 g, 216 mmol) was added to a solution of 2-fluoro-benzenesulfonyl chloride (10 g, 51 mmol) in 1, 4 dioxane (35 mL). The reaction mixture was refluxed for 24 hours, then cooled to room temperature and poured into ice water (200 mL). The ice water was extracted with chloroform (3×50 mL). The combined chloroform layers were dried (MgSO4), filtered, and concentrated to afford 2-fluoro-benzenesulfonyl fluoride (2a) as a colorless oil 6.7 g (74%). (M+H)+=177
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[OH:17])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:18]Br>C(=S)=S>[Br:18][CH:7]1[C:6]2[C:15](=[C:2]([OH:1])[CH:3]=[CH:4][CH:5]=2)[C:14](=[O:16])[C:13]2[C:12]([OH:17])=[CH:11][CH:10]=[CH:9][C:8]1=2
Reactant: O=C1c2c(O)cccc2Cc2cccc(O)c21
Reactant: BrBr
Solvent: S=C=S
Product: O=C1c2c(O)cccc2C(Br)c2cccc(O)c21
Temperature: 50 °C
Yield: 77.6 %

Procedure:
1,8-Dihydroxy-9-anthrone (17.3 g) was dissolved in carbon disulphide (1.25 liter) by heating, and the solution was treated dropwise with 18.5 g of bromine with stirring at 50° C. The solution was left stirring at that temperature overnight, then cooled to room temperature and concentrated to one tenth of its volume by removal of the solvent under reduced pressure. The yellow precipitate was filtered off, dried and recrystallised from a petroleum ether (boiling point 40°-60° C.)/chloroform mixture (1:1) to give 10-bromo-1,8-dihydroxy-9-anthrone (18.1 g, 77.5%), melting point 149°-151° C. (with decomposition). [Literature reference, O. E. Schultz and H.-H. Schultze-Mosgau, Arch. Pharm. (Weinheim. Ger.), 1965, 298, 273, gives melting point 148°-150° C. (with decomposition)].
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([NH:16][NH2:17])=O)=[N:4][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][N:7]=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](N)=[NH:24].C([O-])C.[Na+]>CN(C=O)C>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:5]2[N:4]=[C:3]([C:14]3[NH:24][C:23]([C:19]4[S:18][CH:22]=[CH:21][CH:20]=4)=[N:17][N:16]=3)[C:2]([NH2:1])=[N:7][CH:6]=2)[CH:9]=1
Reactant: N=C(N)c1cccs1
Reactant: NNC(=O)c1nc(-c2cccnc2)cnc1N
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncc(-c2cccnc2)nc1-c1nnc(-c2cccs2)[nH]1
Temperature: 160 °C
Yield: 42.1 %

Procedure:
3-amino-6-(3-pyridyl)pyrazine-2-carbohydrazide (40 mg, 0.173 mmoles), thiophene-2-carboxamidine (21.92 mg, 0.173 mmoles) and sodium ethanolate (11.82 mg, 0.173 mmoles) were added to a microwave vial. DMF (1 mL) was then added and the vial sealed and heated in the microwave at 160° C. for 40 minutes. The reaction mixture was filtered and purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound (23.4 mg, 31% Yield). 1H NMR (400.0 MHz, DMSO-d6) d 14.96 (s, 1H), 9.55 (s, 1H), 8.99 (s, 1H), 8.84 (d, J=6.1 Hz, 1H), 8.69 (dd, J=1.2, 4.9 Hz, 1H), 7.95 (s, 2H), 7.81 (d, J=3.0 Hz, 1H), 7.73-7.68 (m, 2H) and 7.22 (dd, J=3.8, 4.8 Hz, 1H) ppm; MS (ES+) 323.10
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]([N:8]1[CH:12]=[C:11]([NH:13][C:14](=[O:20])[CH:15]([NH2:19])[CH2:16][CH2:17][CH3:18])[N:10]=[CH:9]1)([CH3:7])[CH3:6].[OH:22][C@@H:23]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:24](O)=[O:25]>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]([N:8]1[CH:12]=[C:11]([NH:13][C:14](=[O:20])[CH:15]([NH:19][C:24](=[O:25])[CH:23]([OH:22])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:16][CH2:17][CH3:18])[N:10]=[CH:9]1)([CH3:6])[CH3:7]
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CC(=O)OC)cn1
Reactant: CC(C)(C)[C@H](O)C(=O)O
Product: CCCC(NC(=O)C(O)C(C)(C)C)C(=O)Nc1cn(C(C)(C)CC(=O)OC)cn1

Procedure:
3-[4-(2-Amino-pentanoylamino)-imidazol-1-yl]-3-methyl-butyric acid methyl ester was coupled with (S)-2-hydroxy-3,3-dimethyl-butyric acid to provide the title compound: C13 NMR (100 MHz, CDCl3) 13.9, 19.1, 26.3, 28.1, 35.2, 35.3, 47.1, 51.9, 52.7, 56.4, 79.9, 105.0, 131.0, 137.6, 169.3, 170.1, 173.1; MS m/z 411.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:55])[C:7]1[CH:15]=[C:14]([NH:16][C:17](=[O:54])[CH2:18][N:19]([CH2:45][CH2:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C:20](=[O:44])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:13]=[C:9]([C:10]([OH:12])=[O:11])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CN(C(O[N:69]1[C:74](=[O:75])[CH2:73][CH2:72][C:70]1=[O:71])=[N+](C)C)C.CCN(C(C)C)C(C)C>C1COCC1>[O:71]=[C:70]1[CH2:72][CH2:73][C:74](=[O:75])[N:69]1[O:11][C:10](=[O:12])[C:9]1[CH:8]=[C:7]([CH:15]=[C:14]([NH:16][C:17](=[O:54])[CH2:18][N:19]([CH2:45][CH2:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C:20](=[O:44])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])[CH:13]=1)[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:55]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)N(CCC(=O)OC(C)(C)C)CC(=O)Nc1cc(C(=O)O)cc(C(=O)OC(C)(C)C)c1
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)N(CCC(=O)OC(C)(C)C)CC(=O)Nc1cc(C(=O)ON2C(=O)CCC2=O)cc(C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Yield: 90 %

Procedure:
5-{2-[(2-tert-Butoxycarbonyl-ethyl)-(17-tert-butoxycarbonyl-heptadecanoyl)-amino]-acetylamino}-isophthalic acid mono-tert-butyl ester (214 mg) was dissolved in dry THF and TSTU (0.105 mg) and DIPEA (0.1 ml) was added. The mixture was stirred at room temperature under nitrogen. After 20 h the reaction mixture was concentrated. The residue was redissolved in EtOAc and filteret. The filtrate was extracted with 0.1 N HCl (2×) and brine (1×), dried (Na2SO4) and concentrated to give 5-{2-[(2-tert-Butoxycarbonyl-ethyl)-(17-tert-butoxycarbonyl-heptadecanoyl)-amino]-acetylamino}-isophthalic acid 1-tert-butyl ester 3-(2,5-dioxo-pyrrolidin-1-yl)ester as a yellow sirup in 90% yield (218 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N+:3]=1[O-:9].[CH3:10][CH:11]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:12][CH2:13][OH:14].[OH-].[Na+]>CS(C)=O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:14][CH2:13][CH2:12][CH:11]([CH3:10])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[N+:3]=1[O-:9]
Reactant: CC(CCO)CC(C)(C)C
Reactant: [O-][n+]1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(CCOc1cccc(Cl)[n+]1[O-])CC(C)(C)C

Procedure:
The 0.82 g (0.0050 moles) of 2,6-dichloropyridine N-oxide and 0.80 g (90%) (0.0050 moles) of 3,5,5-trimethyl-1-hexanol was reacted with 0.206 g (0.0050 moles) of ground sodium hydroxide in 8.2 ml of DMSO at 80° C. for 8.5 hours to give 2-chloro-6-(3,5,5-trimethylhexyloxy)pyridine N-oxide. It was reacted with 0.600 g (0.015 moles) of ground sodium hydroxide at 80° C. for 4 hours to give 1-hydroxy-6-(3,5,5-trimethy-hexyloxy) pyridine-2(1H)-one. After cooling, it was added 74 ml of water and was adjusted with 6N HCL to pH 3. The precipitate was filtered and washed with water to give 0.577 g (45%). It was recrystallized from ethyl acetate and hexanes: mp 130.5°-131° C.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[OH:20][CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]1>>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([N:24]3[CH2:25][CH2:26][CH2:27][CH:22]([CH2:21][OH:20])[CH2:23]3)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2]
Reactant: OCC1CCCNC1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)N3CCCC(CO)C3)s2)c(C)[nH]c1=O
Yield: 54.7 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 3-hydroxymethylpiperidine as described in Step 5, Example 24 to give the title compound as a solid (54.7% yield). LC/MS: RT 2.63 min; m/e 397 (M+H); 1H NMR (δ, ppm): 11.8 (1H, s), 7.6 (1H, d); 7.4 (1H, s); 7.24 (1H, d), 4.6 (1H, br s), 3.6 (21H, m), 3.2 (1H, m), 2.4 (2H, q), 2.36 (3H, s), 2.1 (1H, t), 1.8-1.4 (5H, m), 1.1 (3H, t), 0.94 (1H, m).