Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[N:5]2[CH:15]=[CH:16][N:17]=[C:4]2[N:3]=1.[SH:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([CH:28]2[CH2:30][CH2:29]2)=[O:27])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:14][C:12]1[NH:11][N:10]=[C:9]([NH:8][C:6]2[N:5]3[CH:15]=[CH:16][N:17]=[C:4]3[N:3]=[C:2]([S:18][C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26]([CH:28]4[CH2:29][CH2:30]4)=[O:27])=[CH:23][CH:24]=3)[CH:7]=2)[CH:13]=1
Reactant: Cc1cc(Nc2cc(Cl)nc3nccn23)n[nH]1
Reactant: O=C(Nc1ccc(S)cc1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Nc2cc(Sc3ccc(NC(=O)C4CC4)cc3)nc3nccn23)n[nH]1
Temperature: 190 °C

Procedure:
A mixture of (7-Chloro-imidazo[1,2-a]pyrimidin-5-yl)-(5-methyl-1H-pyrazol-3-yl)-amine (73 mg, 0.29 mmol), N-(4-mercaptophenyl)cyclopropanecarboxamide (170 mg, 0.88 mmol), potassium carbonate (81 mg, 0.58 mmol) in DMF (1 ml) was heated with microwave at 190° C. for 30 minutes. The reaction mixture was then purified by HPLC to give the title compound Example 10 as an off-white solid (110 mg). 1H NMR (400 MHz, DMSO) δ 10.54 (s, 1H) 8.26 (d, J=2.8 Hz, 1H) 7.97 (d, J=2.4 Hz, 1H) 7.79 (d, J=8.8 Hz, 2H) 7.57 (d, J=8.8 Hz, 2H) 6.89 (s, 1H) 5.82 (s, 1H) 2.20 (s, 3H) 1.81-1.85 (m, 1H) 0.84-0.86 (m, 4H). [M+H] calc'd for C20H19N7OS, 406; found, 406.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:10]([C:11]2[CH:15]=[CH:14][S:13][CH:12]=2)[CH2:9][N:8]([CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])[CH2:7]1)=[O:5])C.C1NCC2C1CC1C(C#N)=CSC=12>Cl>[C:18]1([CH:16]([N:8]2[CH2:9][CH:10]([C:11]3[CH:15]=[CH:14][S:13][CH:12]=3)[CH:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH3:17])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)C1CN(C(C)c2ccccc2)CC1c1ccsc1
Agent: Cl
Agent: N#Cc1csc2c1CC1CNCC21
Product: CC(c1ccccc1)N1CC(C(=O)O)C(c2ccsc2)C1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
The product from step b), diastereomer 1 (1.4 g, 4.3 mmol) was dissolved in 12 M HCl (10 mL) and was stirred at 80° C. for 12 hours. The reaction mix then was cooled to room temperature and evaporated to dryness to afford the subtitle compound. MS calculated for C17H19NO2S+H: 302, observed: 302.
Reaction SMILES: C([O-])=O.[NH4+].C([O:12][C:13]1[CH:39]=[CH:38][C:16]([C:17]([NH:19][CH2:20][C:21](=[O:37])[N:22]2[CH2:27][CH2:26][N:25]([C:28](=[O:36])[CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:24][CH2:23]2)=[O:18])=[CH:15][CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[OH:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([NH:19][CH2:20][C:21](=[O:37])[N:22]2[CH2:23][CH2:24][N:25]([C:28](=[O:36])[CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:26][CH2:27]2)=[O:18])=[CH:38][CH:39]=1
Reactant: O=C(NCC(=O)N1CCN(C(=O)Cc2ccccc2)CC1)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: O=C(NCC(=O)N1CCN(C(=O)Cc2ccccc2)CC1)c1ccc(O)cc1
Temperature: 75 °C
Yield: 70 %

Procedure:
Ammonium formate (107 mg, 1.6985 mmoles) was added to a mixture of 4-benzyloxy-N-[2-oxo-2-(4-phenylacetyl-piperazin-1-yl)-ethyl]-benzamide (80 mg, 0.17 mmol) in MeOH (15 mL). Pd/C (30 mg in 3 drops of water) was then added and the resulting mixture was refluxed at 75° C. for three hours. The reaction mixture was then filtered through a bed of celite under reduced pressure. The methanol was removed and EtOAc and water were added. The organic layer was extracted, washed with brine, dried over sodium sulphate and concentrated to afford 4-hydroxy-N-[2-oxo-2-(4-phenylacetyl-piperazin-1-yl)-ethyl]-benzamide in 70% yield. LC-MS purity 94.82%. 1H NMR (DMSO-D6): δ 10 (s, 1H), 8.3 (s, 1H), 7.7 (d, 2H), 7.3 (t, 2H), 7.2 (d, 2H), 6.8 (d, 2H), 4.1 (d, 2H), 3.8 (d, 2H), 3.5 (m, 8H).
Reaction SMILES: [CH3:1][C:2]([NH:4][CH:5]1[CH:10]([OH:11])[O:9][CH:8]([CH2:12][OH:13])[CH:7]([OH:14])[CH:6]1[OH:15])=[O:3].OO.[O:18]=[CH:19][C@@H:20]([C@H:22]([C@H:24]([C@@H:26]([CH2:28][OH:29])[OH:27])[OH:25])[OH:23])[OH:21]>>[C:2]([NH:4][C@@H:5]1[C@@H:6]([OH:15])[C@@H:7]([OH:14])[C@@H:8]([CH2:12][OH:13])[O:9][CH:10]1[OH:11])(=[O:3])[CH3:1].[O:18]=[CH:19][C@@H:20]([C@H:22]([C@H:24]([C@@H:26]([CH2:28][OH:29])[OH:27])[OH:25])[OH:23])[OH:21]
Reactant: CC(=O)NC1C(O)OC(CO)C(O)C1O
Agent: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Agent: OO
Product: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O

Procedure:
N-Acetylhexosamine dialdose may, for example, be manufactured by oxidation of the 6-position of N-acetylhexosamine either chemically or enzymatically. An example of the chemical oxidation is a Fenton method where oxidation is carried out with hydrogen peroxide in the presence of a ferrous salt while that of the enzymatic oxidation is an oxidation using galactose oxidase [EC 1.1.3.9; Cooper, et al.; The Journal of Biological Chemistry, volume 234, pages 445-448 (1959)]. Oxidation of N-acetyl-D-galactosamine with galactose oxidase gives N-acetylgalactosamine dialdose.
Reaction SMILES: C[Si](Cl)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[C:12]1([P:22]([C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:39]=[CH:38][CH:37]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[P:29](OCC)OCC)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.[OH-].[Na+]>O.C1COCC1>[C:12]1([P:22]([C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:39]=[CH:38][CH:37]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[PH2:29])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: CCOP(OCC)c1ccccc1P(c1cccc2ccccc12)c1cccc2ccccc12
Agent: C[Si](C)(C)Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: Pc1ccccc1P(c1cccc2ccccc12)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.5 %

Procedure:
Under a nitrogen atmosphere, 5.74 g (52.9 mmol) of trimethylsilyl chloride was added dropwise to a 75 mL THF suspension of 2.01 g (52.9 mmol) of lithium aluminum hydride at −30° C. over a period of 30 minutes, and after the dropwise addition, the whole was stirred at room temperature for 1.5 hours. Then, a 50 mL THF solution of 8.50 g (17.6 mmol) of diethyl 2-[di(1-naphthyl)phosphino]phenylphosphonite (7) was added dropwise at −30° C. over a period of 30 minutes and the whole was stirred at room temperature for 16 hours. Thereto was gradually added dropwise a 15 mL THF solution of 7.5 mL of water at 0° C. to 10° C., and then 30 mL of 1N sodium hydroxide aqueous solution was added. Under a nitrogen atmosphere, the organic layer was decanted and the solvent was removed by evaporation. The residue was dissolved in 30 mL of diethyl ether, and the solution was washed three times with 10 mL of water degassed beforehand and then, dried over anhydrous sodium sulfate. The drying agent was removed and the solvent was removed by evaporation to obtain the title compound (6.50 g, a white viscous solid). Yield 93.5%.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[C:25](#[N:27])[CH3:26]>>[N:27]1([CH2:2][CH2:3][O:4][C:5]2[CH:6]=[C:7]([C:11]3[C:15]4[S:16][CH:17]=[CH:18][C:14]=4[O:13][N:12]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:9][CH2:10][CH2:5][CH2:6][CH2:26][CH2:25]1
Reactant: CC#N
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1cc(OCCN2CCCCCC2)cc(-c2noc3ccsc23)c1

Procedure:
The title compound is prepared from 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, hexamethyleneimine and acetonitrile essentially as described above in example 40. Purity by LC/MS (APCI)=99%, [M+H]+=343.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:37])([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[C:17]([N:19]([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:20][CH2:21][CH3:22])[N:16]=[C:15]([C:27]([OH:29])=O)[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[F:47][C:48]1[CH:53]=[CH:52][C:51]([CH:54]([NH2:56])[CH3:55])=[CH:50][CH:49]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:30]([C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])([CH3:37])[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[C:17]([N:19]([S:23]([CH3:26])(=[O:24])=[O:25])[CH2:20][CH2:21][CH3:22])[N:16]=[C:15]([C:27]([NH:56][CH:54]([C:51]2[CH:52]=[CH:53][C:48]([F:47])=[CH:49][CH:50]=2)[CH3:55])=[O:29])[CH:14]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(N)c1ccc(F)cc1
Reactant: CCCN(c1cc(COCC(C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(C(=O)O)n1)S(C)(=O)=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCN(c1cc(COCC(C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(C(=O)NC(C)c2ccc(F)cc2)n1)S(C)(=O)=O
Reaction time: 0.67 h

Procedure:
To a solution of 4-({2-[(tert-butoxycarbonyl)amino]-2-methyl-3-phenylpropoxy}methyl)-6-[(methylsulfonyl)(propyl)amino]pyridine-2-carboxylic acid (10 mg, 0.019 mmol, intermediate VII) in DMF (0.5 mL) was added diisopropylethyl amine (0.05 mL, 0.028 mmol), [1-(4-fluorophenyl)ethyl]amine (0.008 mL, 0.056 mmol) and BOP reagent (10 mg, 0.022 mmol), and the reaction mixture was allowed to stand at rt for 40 min, purified by preparative HPLC (5->95% CH3CN/H2O, 0.1% added TFA, C18 PRO YMC 20×150 mm) to afford tert-butyl [1-benzyl-2-({2-({[1-(4-fluorophenyl)ethyl]amino}carbonyl)-6-[(methylsulfonyl)(propyl)amino]pyridin-4-yl}methoxy)-1-methylethyl]carbamate. Boc removal in HCl(g) saturated EtOAc and lyophilization from dioxane/water provided 4-[(2-amino-2-methyl-3-phenylpropoxy)methyl]-N-[1-(4-fluorophenyl)ethyl]-6-[(methylsulfonyl)(propyl)amino]pyridine-2-carboxamide as an hydrochloride white solid. 1H NMR (400 MHz, CD3OD) δ 8.61 (d, J=8.0 Hz, 1H), 7.97 (s, 1H), 7.65 (s, 1H), 7.46-7.41 (m, 2H), 7.38-7.25 (m, 3H), 7.24-7.19 (m, 2H), 7.11-7.03 (m, 2H), 5.30-5.20 (m, 1H), 4.75 (s, 2H), 4.03-3.94 (m, 2H), 3.51 (A of AB, d, J=10.4 Hz, 1H), 3.46 (B of AB, d, J=10.4 Hz, 1H), 3.11 (A of AB, d, J=13.6 Hz, 1H), 3.10 (s, 3H), 2.92 (B of AB, d, J=13.6 Hz, 1H), 1.64-1.54 (m, 2H), 1.62 (d, J=7.2 Hz, 3H), 1.29 (s, 3H), 0.92 (t, J=7.6 Hz, 3H). HRMS (ES, M+H) calcd. for C29H37FN4O4S: 557.2593, found: 557.2613.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[CH:20]([NH2:21])[C:19](=[O:22])[N:6]2[C:7]=1[C:8]([O:10][CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:9].[ClH:23].F[C:25]1[NH:26][CH:27]=[CH:28][N:29]=1.Cl>CN(C=O)C.C(#N)C.CO>[ClH:23].[NH:26]1[CH:27]=[CH:28][N:29]=[C:25]1[NH:21][CH:20]1[C:19](=[O:22])[N:6]2[C:7]([C:8]([O:10][CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:15])([CH3:16])[CH3:17])=[O:9])=[C:2]([CH3:1])[CH2:3][S:4][C@H:5]12
Reactant: Fc1ncc[nH]1
Reactant: CC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(N)[C@H]2SC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Solvent: CC#N
Product: CC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(Nc3ncc[nH]3)[C@H]2SC1

Procedure:
A solution of 0.18 g. of pivaloyloxymethyl 3-methyl-7-aminoceph-3-em-4-carboxylate (0.18 g.) and 2-fluoroimidazole hydrochloride (0.14 g.) in DMF (1 ml.) and acetonitrile (1 ml.) was heated at 50° for 7 hours. After evaporation the residue was chromatographed on silica gel using CH2Cl2 /MeOH 95:5 v/v as eluant. The oily product was treated with one equivalent of HCl in MeOH. The solution was evaporated and the residue was triturated with ether and filtered to give pivaloyloxymethyl 7-(imidazol-2-yl)amino-3-methylceph-3-em-4-carboxylate hydrochloride having the following n.m.r. in d6DMSO+CD3COOD: 1.2 (s, 9H); 2.1 (s, 3H); 3.6 (m, 2H); 5.25 (d, 1H); 5.7 (d, 1H); 5.85 (m, 2H); 7.05 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[C:16](O)(=[O:18])[CH3:17].C(OC(=O)C)(=O)C>O>[C:16]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14])(=[O:18])[CH3:17]
Reactant: CC(=O)O
Reactant: Nc1cc2nc[nH]c(=O)c2cc1[N+](=O)[O-]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Nc1cc2nc[nH]c(=O)c2cc1[N+](=O)[O-]
Yield: 76 %

Procedure:
A solution of 7-amino-6-nitro-3H-quinazolin-4-one (5.90 g, 28.6 mmol) [Leonard, N. J.; Morrice, A. G.; Sprecker, M. A.; J. Org. Chem., 1975, 40, 356-363] in a mixture of glacial acetic acid (300 mL) and acetic anhydride (100 mL) is heated under reflux for 6 h, and water (100 mL) is added. The solution is then concentrated to a small volume to give 7-acetamido-6-nitro-3H-quinazolin-4-one (5.37 g, 76%). 1H NMR (DMSO) δ10.51 (1H, brs), 8.57 (1H, s), 8.24 (1H, s), 7.97 (1H, s), 2.15 (3H, s).
Reaction SMILES: C([N:5]1[C:12](=O)[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6]1)CCC.C([C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1)#N>ClCCl>[CH3:27][O:26][C:24]([C:23]1[CH:28]=[CH:29][C:20]([C:12]2[N:11]3[C:7](=[N:8][C:9]4[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=43)[S:6][N:5]=2)=[CH:21][CH:22]=1)=[O:25]
Reactant: COC(=O)c1ccc(C#N)cc1
Reactant: CCCCn1sc2nc3ccccc3n2c1=O
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2nsc3nc4ccccc4n23)cc1
Yield: 43.1 %

Procedure:
A mixture of 2-butyl-1,2,4-thiadiazolo[4,5-a]benzimidazole-3(2H)-one (0.3 g, 1.2 mmole) and methyl 4-cyanobenzoate (0.41 g, 2.5 mmole) in 7 mL of dichloromethane was heated to reflux for 20 h. The precipitate was filtered and washed with dichloromethane to give 0.16 g (48%) of 3-[4-(methoxycarbonyl)phenyl]-1,2,4-thiadiazolo [4,5-a]benzimidazole as a white solid: mp 204-206° C.; 1H NMR (CDCl3) δ 8.33 (d, 2H), 7.98 (d, 2H), 7.83 (d, 1H), 7.49 (m, 2H), 7.20 (t, 1H), 4.02 (s, 3H) ppm; 13C NMR (CDCl3) δ165.96, 165.30, 151.08, 149.10, 133.16, 132.55, 130.24(2C), 128.69(3C), 125.34, 121.58, 119.96, 112.01, 52.56 ppm; IR (KBr) ν 1729, 1508, 1448, 1275, 733 cm-1 ; HRMS calcd for C16H11N3O2S, 309.0572 found 309.05719.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][CH3:19])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: COc1ccccc1/C=C/C(=O)O
Product: COc1ccccc1/C=C/C(=O)Nc1cnn(Cc2ccc(C(C)=O)o2)c1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(2-methoxy-phenyl)-acrylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:16](=[C:17]4[CH:24]=[CH:23][N:22]([CH3:25])[C:18]4=[CH:19][CH:20]=3)[O:15][CH:14]([OH:26])[CH2:13]2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].C[N+]1([O-])CCOCC1>ClCCl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:16](=[C:17]4[CH:24]=[CH:23][N:22]([CH3:25])[C:18]4=[CH:19][CH:20]=3)[O:15][C:14](=[O:26])[CH2:13]2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9]
Reactant: COc1cc(C2CC(O)Oc3c2ccc2c3ccn2C)cc(Br)c1OC
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: COc1cc(C2CC(=O)Oc3c2ccc2c3ccn2C)cc(Br)c1OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 20.6 %

Procedure:
To a mixture of 4-(3-bromo-4,5-dimethoxyphenyl)-2-hydroxy-7-methyl-pyrrolo[2,3-h]chroman (6 mg; 0.014 mmol), molecular sieves 4A° (20 mg) and 4-methylmorpholin-N-oxide (2 mg; 0.017 mmol ) in dichloromethane (0.5 ml) at 0° C. was added TPAP (0.4 mg). The mixture was stirred at this temperature for 0.5 h and at room temperature for 20 min. It was concentrated and passed through a bond-elute (hexane:ethyl acetate=9:1 and 4:1 as eluents), yielding the title compound (1.2 mg; 20%). 1H NMR (acetone-d6): 7.30 (d, J=3.1 Hz; 1H), 7.21 (dd, J=0.8, 8.4 Hz; 1H), 7.03 (d, J=2.0 Hz; 1H), 6.92 (d, J=8.4 Hz; 1H), 6.87 (dd, J=0.6, 2.1 Hz; 1H), 6.55 (dd, J=0.8, 3.1 Hz; 1H), 4.55 (t, J=5.9 Hz; 1H), 3.86, 3.84, 3.77 (s each, 9H), 3.24 (dd, J=6.4, 15.8 Hz; 1H), 3.13 (dd, J=5.9, 15.8 Hz; 1H).
Reaction SMILES: CN(C)CCNC(C1C2C(=C(C)C3N(C)C4C=CC(O)=C(CCC)C=4C=3C=2)C=CN=1)=O.[CH2:32]([O:34][C:35]([C:37]1[C:53]2[C:41](=[C:42]([CH3:59])[C:43]3[N:44]([CH3:58])[C:45]4[CH:46]=[CH:47][C:48]([OH:57])=[C:49]([CH2:54][CH:55]=[CH2:56])[C:50]=4[C:51]=3[CH:52]=2)[CH:40]=[CH:39][N:38]=1)=[O:36])[CH3:33]>C(O)C.[Pd]>[CH2:32]([O:34][C:35]([C:37]1[C:53]2[C:41](=[C:42]([CH3:59])[C:43]3[N:44]([CH3:58])[C:45]4[CH:46]=[CH:47][C:48]([OH:57])=[C:49]([CH2:54][CH2:55][CH3:56])[C:50]=4[C:51]=3[CH:52]=2)[CH:40]=[CH:39][N:38]=1)=[O:36])[CH3:33]
Reactant: C=CCc1c(O)ccc2c1c1cc3c(C(=O)OCC)nccc3c(C)c1n2C
Agent: [Pd]
Agent: CCCc1c(O)ccc2c1c1cc3c(C(=O)NCCN(C)C)nccc3c(C)c1n2C
Solvent: CCO
Product: CCCc1c(O)ccc2c1c1cc3c(C(=O)OCC)nccc3c(C)c1n2C
Yield: 51 %

Procedure:
1-[(2-Dimethylaminoethyl)aminocarbonyl]-5,6-dimethyl-9-hydroxy-10-propyl-6H-pyrido-[4,3-b]carbazole ##STR26## 0.7 g of 1-ethoxycarbonyl-5,6-dimethyl-9-hydroxy-10-allyl-6H-pyrido[4,3-b]carbazole is hydrogenated in 200 ml of ethanol in the presence of 0.3 g of 10% palladium-on-carbon at 40° C. under a hydrogen pressure of 1.105Pa for 30 minutes. Filtration is carried out, the catalyst is washed with ethanol and the combined filtrates are concentrated to dryness. The residue is chromatographed on silica using as eluant first dichloromethane and then a dichloromethane/ethanol mixture (98/2). 0.362 g of 1-ethoxycarbonyl-5,6-dimethyl-9-hydroxy-10-propyl-6H-pyrido[4,3-b]carbazole is obtained. Yield: 51%.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7](=[N:13][O:14][CH3:15])[C:8]([O:10]CC)=[O:9])[N:3]=1.[OH-].[Na+].Cl.[Cl-].[Na+]>>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7](=[N:13][O:14][CH3:15])[C:8]([OH:10])=[O:9])[N:3]=1
Reactant: CCOC(=O)C(=NOC)c1noc(N)n1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Product: CON=C(C(=O)O)c1noc(N)n1
Temperature: 25 °C
Yield: 92.1 %

Procedure:
Ethyl 2-(5-amino-1,2,4-oxadiazol-3-yl)-2-methoxyiminoacetate (syn isomer) (2.5 g) was added to 1 N aqueous sodium hydroxide (14 ml), and the solution was stirred at ambient temperature for an hour. The reaction mixture was adjusted to pH 1.8 with 10% hydrochloric acid, salted out with sodium chloride, and then extracted with a mixture of ethyl acetate and tetrahydrofuran. After drying over anhydrous magnesium sulfate, the extract was evaporated to dryness to give a residue, which was washed with diisopropyl ether to obtain 2-(5-amino-1,2,4-oxadiazol-3-yl)-2-methoxyiminoacetic acid (syn isomer) (2.0 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[C:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[C:4]([CH3:20])[N:3]=1.[NH2:21][C@@H:22]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:23][CH2:24][OH:25]>C(O)CCC>[NH2:1][C:2]1[N:7]=[C:6]([NH:21][C@@H:22]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:23][CH2:24][OH:25])[C:5]([C:9]#[C:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[C:4]([CH3:20])[N:3]=1
Reactant: CCCC[C@H](N)CCO
Reactant: Cc1nc(N)nc(Cl)c1C#CCNC(=O)OC(C)(C)C
Solvent: CCCCO
Product: CCCC[C@@H](CCO)Nc1nc(N)nc(C)c1C#CCNC(=O)OC(C)(C)C
Yield: 64.4 %

Procedure:
The product from step (vi) (200 mg) and the product from step (v) (177 mg) were combined in butan-1-ol (5 mL) and reacted in a CEM Microwave, at 120° C. for 1 h. The solvents were evaporated, and the crude product was purified by chromatography, eluting with 5% MeOH in EtOAc to afford the subtitle compound 170 mg.
Reaction SMILES: [SH:1][C:2]1[N:6]([CH3:7])[C:5]([C:8]([F:11])([F:10])[F:9])=[N:4][N:3]=1.[Cl:12][C:13](Cl)=[C:14]([Cl:17])[C:15]#[N:16].C(N(CC)CC)C>C(Cl)Cl>[CH3:7][N:6]1[C:5]([C:8]([F:9])([F:11])[F:10])=[N:4][N:3]=[C:2]1[S:1][C:13]([Cl:12])=[C:14]([Cl:17])[C:15]#[N:16]
Reactant: N#CC(Cl)=C(Cl)Cl
Reactant: Cn1c(S)nnc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(SC(Cl)=C(Cl)C#N)nnc1C(F)(F)F
Temperature: 25 °C
Yield: 25.8 %

Procedure:
To a stirred mixture of 3.5 g (0.0192 mole) 3-mercapto-4-methyl-5-trifluoromethyl-1,2,4-triazole (the product of Example 6) and 3.0 g (0.0192 mole) trichloro-acrylonitrile in methylene chloride, 1.94 g (0.0192 mole) triethylamine in methylene chloride were added dropwise. The reaction mixture was stirred at room temperature for several days. The reaction mixture was washed with water and then dried over magnesium sulfate. The organic phase was passed through a short silica gel (SiO2) column and stripped to give a thick oil which soon crystallized. The material was recrystallized from methylene chloride/hexane to give 1.5 g of the above-identified product as a light yellow solid, melting point 90°-94° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([S:16][C:17]2[S:18][C:19]([C:22]([O:24]CC)=[O:23])=[CH:20][N:21]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[Li+].[OH-].CO>C1COCC1>[CH3:1][C:2]1[C:3]([S:16][C:17]2[S:18][C:19]([C:22]([OH:24])=[O:23])=[CH:20][N:21]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: CCOC(=O)c1cnc(Sc2cc3c(cc2C)C(C)(C)CCC3(C)C)s1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2c(cc1Sc1ncc(C(=O)O)s1)C(C)(C)CCC2(C)C
Temperature: 50 °C
Yield: 77.1 %

Procedure:
To a solution of 0.183 g (0.47 mmol) of ethyl 2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthylthio)-5-thiazolecarboxylate (Compound 14) in 2.0 mL of THF was added 1.0 mL of LiOH (2.1N aqueous solution) and 1.0 mL of MeOH. The solution was heated at 50° C. for 1 h, cooled to room temperature and concentrated in vacuo. The residue was diluted with water, the aqueous layer acidified to pH=1 using 10% HCl and extracted with ether. The combined organic layers were washed with brine, dried (MgSO4), filtered, and the solvents removed in vacuo to give the title compound as a white solid (131 mg, 78%): PNMR (300 MHz, CD3OD) δ 1.28 (s, 6H), 1.32 (s, 6H), 1.73 (s, 4H), 2.40 (s, 3H), 7.42 (s, 1H), 7.63 (s, 1H), 8.12 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2)CC1
Yield: 85.5 %

Procedure:
A slurry of 4-(N-(t-butoxycarbonyl)piperidin-4-yl)oxy-1-nitrobenzene (15.1 g, 46.8 mmol) in absolute ethanol (500 mL) and methanol (200 mL) was purged with nitrogen, treated with 10% palladium on carbon (1.2 g, 50% water by wt.) and placed on a Parr Hydrogenator under 43 psi of hydrogen gas. The catalyst was removed by filtration. Solvent removal under reduced pressure gave a solid after drying. Purification by flash silica gel chromatography using a step gradient of 50 to 85% ethyl acetate in hexane gave 11.7 g of 4-(N-(t-butoxycarbonyl)piperidin-4-yl)oxybenzenamine, NMR (CDCl3, TMS) δ1.45 (s, 9), 1.7 (m, 2), 1.86 (m, 2), 3.25 (m, 2), 3.68 (m, 2), 4.25 (m, 1), 6.63 (m, 2), 6.76 (m, 2).
Reaction SMILES: [CH:1]1([CH:7]([N:10]2[C:14]3[CH:15]=[C:16]([F:20])[C:17]([F:19])=[CH:18][C:13]=3[N:12]=[C:11]2[C:21]2[C:22]([O:29][CH3:30])=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[CH2:8][OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O[C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][N:33]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH3:39][O:38][C:36](=[O:37])[C:35]1[CH:40]=[CH:41][C:32]([O:9][CH2:8][CH:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:10]2[C:14]3[CH:15]=[C:16]([F:20])[C:17]([F:19])=[CH:18][C:13]=3[N:12]=[C:11]2[C:21]2[C:22]([O:29][CH3:30])=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)=[N:33][CH:34]=1
Reactant: COc1ccc(-c2nc3cc(F)c(F)cc3n2C(CO)C2CCCCC2)c(OC)n1
Reactant: COC(=O)c1ccc(O)nc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Product: COC(=O)c1ccc(OCC(C2CCCCC2)n2c(-c3ccc(OC)nc3OC)nc3cc(F)c(F)cc32)nc1
Yield: 4 %

Procedure:
The title compound was prepared in analogy to Example 4, intermediate from 2-cyclohexyl-2-[2-(2,6-dimethoxy-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-ethanol and methyl 6-hydroxynicotinate (commercially available) and replacing di-ethyl azodicarboxylate by di-tert-butyl azodicarboxylate. The crude product was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 60:40) to give the desired compound as a white solid (4%). MS (Turbo Spray) m/z=553.4 [M+H].