Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].O1CCOCC1.[C:8]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:28])=[CH:23][N:22]=3)=[CH:18][CH:19]=2)[C@H:14]([NH:35]C(=O)OC(C)(C)C)[CH2:13][C@@H:12]1[CH3:43])(=[O:10])[CH3:9].CO>C(Cl)Cl>[ClH:1].[NH2:35][C@H:14]1[C:15]2[C:20](=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:28])=[CH:23][N:22]=3)[CH:16]=2)[N:11]([C:8](=[O:10])[CH3:9])[C@@H:12]([CH3:43])[CH2:13]1
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)N4CCOCC4)cn3)cc2[C@H](NC(=O)OC(C)(C)C)C[C@@H]1C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)N4CCOCC4)cn3)cc2[C@H](N)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 92 %

Procedure:
4M hydrochloric acid in 1,4-dioxane (10.11 ml, 40.4 mmol) was added to tert-butyl ((2S,4R)-1-acetyl-2-methyl-6-(5-(morpholine-4-carbonyl)pyridin-2-yl)-1,2,3,4-tetrahydroquinolin-4-yl)carbamate (for a preparation, see Intermediate 64) (2 g, 4.04 mmol) at room temperature, followed by MeOH (10 mL) and DCM (10 mL) and the mixture stirred at room temperature for 2 mins. The mixture was concentrated in vacuo to give 1-((2S,4R)-4-amino-2-methyl-6-(5-(morpholine-4-carbonyl)pyridin-2-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone hydrochloride (1.60 g, 3.71 mmol, 92% yield).
Reaction SMILES: [NH3:1].[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[N:11]2[N:12]=[C:13]([S:16][CH2:17][C:18]([O:20]CC)=O)[CH:14]=[CH:15][C:10]2=[N:9][N:8]=1>>[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[N:11]2[N:12]=[C:13]([S:16][CH2:17][C:18]([NH2:1])=[O:20])[CH:14]=[CH:15][C:10]2=[N:9][N:8]=1
Reactant: CCOC(=O)CSc1ccc2nnc(-c3cccs3)n2n1
Reactant: N
Product: NC(=O)CSc1ccc2nnc(-c3cccs3)n2n1
Temperature: 92.5 °C
Reaction time: 8 h

Procedure:
Ethanolic ammonia (5 mL) was added to intermediate ethyl 2-((3-(thiophen-2-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thio)acetate (60 mg, 0.188 mmol), the reaction vessel sealed and the mixture stirred overnight at 90-95° C. The mixture was then evaporated to dryness, the solid residue was filtered, washed 3 times with EtOH, and dried to give the desired 2-((3-(thiophen-2-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thio)acetamide.
Reaction SMILES: [CH3:1][S:2][C:3]([NH2:13])=[N:4][CH2:5][CH2:6][CH2:7][C@H:8]([NH2:12])[C:9]([OH:11])=[O:10].C(OC(NCCC[C@H](C(O)=O)N)=O)C1C=CC=CC=1>>[CH3:1][S:2][C:3]([NH:4][CH2:5][CH2:6][CH2:7][C@@H:8]([NH2:12])[C:9]([OH:11])=[O:10])=[NH:13]
Reactant: CSC(N)=NCCC[C@H](N)C(=O)O
Agent: N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Product: CSC(=N)NCCC[C@@H](N)C(=O)O

Procedure:
S-Methyl-D-thiocitrulline was prepared as described for S-methyl-L-thiocitrulline (Example I) except that the starting material was Nδ -(benzyloxycarbonyl)-D-ornithine (Sigma Chemicals, Inc.).
Reaction SMILES: [CH3:1][N:2]([CH2:26][C:27](=[O:33])[N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)[CH:3]1[CH2:8][CH2:7][CH:6]([O:9][C:10]2[C:21]3[C:20]4[C@@H:19]([CH2:22][CH2:23][C:24]#[N:25])[CH2:18][CH2:17][C:16]=4[S:15][C:14]=3[N:13]=[CH:12][N:11]=2)[CH2:5][CH2:4]1.[OH:34][Li].O.OO>CO>[CH3:1][N:2]([CH2:26][C:27](=[O:33])[N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)[CH:3]1[CH2:4][CH2:5][CH:6]([O:9][C:10]2[C:21]3[C:20]4[C@@H:19]([CH2:22][CH2:23][C:24]([NH2:25])=[O:34])[CH2:18][CH2:17][C:16]=4[S:15][C:14]=3[N:13]=[CH:12][N:11]=2)[CH2:7][CH2:8]1
Reactant: [Li]O
Reactant: CN(CC(=O)N1CCCC1)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CCC#N)CC4)CC1
Agent: OO
Solvent: CO
Solvent: O
Product: CN(CC(=O)N1CCCC1)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CCC(N)=O)CC4)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
A 25-mL round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was charged with a solution of 3-[(3S)-12-[(4-[methyl[2-oxo-2-(pyrrolidin-1-yl)ethyl]amino]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]propanenitrile (80 mg, 0.17 mmol, 1.00 equiv) in methanol (5 mL) and cooled to 0° C. Then LiOH.H2O (22 mg, 0.52 mmol, 3.00 equiv) and H2O2 (30%, 0.3 mL) were added at 0° C. and the resulting solution was stirred for 2 h at the same temperature. The reaction was quenched by the addition of saturated aqueous Na2SO3 and extracted DCM. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by preparative HPLC under the following conditions (SHIMADZU): column: SunFire Prep C18, 19*150 mm 5 um; mobile phase: water with 0.05% NH4HCO3 and CH3CN (6.0% CH3CN up to 50.0% in 16 min); flow rate: 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the desired 3-[(3S)-12-[(4-[methyl[2-oxo-2-(pyrrolidin-1-yl)ethyl]amino]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]propanamide (82.5 mg) as a white solid. MS (ES): m/z 486 [M+H]+; 1H NMR (400 MHz, CD3OD): δ 8.47 (1H, s), 5.32-5.22 (1H, m), 3.58 (2H, t), 3.45 (2H, t), 3.35 (2H, s), 3.20-3.09 (1H, m), 3.03-2.95 (1H, m), 2.73-2.65 (2H, m), 2.37 (3H, s), 2.33-2.19 (5H, m), 2.03-1.88 (6H, m), 1.66 (2H, m), 1.69-1.52 (4H, m).
Reaction SMILES: [O:1]1[C:7]2C=C[CH:10]=[CH:11][C:6]=2[C:5](=O)[NH:4][C:3](=[O:13])C1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][CH2:23][CH2:24][Cl:25].O1CCOCC1.[ClH:32]>CC(C)=O.P(Cl)(Cl)(Cl)=O>[Cl:32][C:5]1[N:4]([CH2:21][CH2:22][CH2:23][CH2:24][Cl:25])[C:3](=[O:13])[CH:10]=[C:11]2[O:1][CH2:7][C:6]=12
Reactant: ClCCCCBr
Reactant: O=C1COc2ccccc2C(=O)N1
Reactant: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: O=c1cc2c(c(Cl)n1CCCCCl)CO2
Temperature: 100 °C
Reaction time: 25 h
Yield: 45 %

Procedure:
5.0 g of 2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione was dissolved in 100 ml of acetone, 7.8 g (2 equivalents) of potassium carbonate and 6.5 ml (2 equivalents) of 1-bromo-4-chlorobutane were added, and the mixture heated and refluxed for 8 hours. The resultant mixture was allowed to cool, then filtered. The filtrate was concentrated and the residue obtained was dissolved in 50 ml of phosphorus oxychloride. Further, 20 ml of 4N hydrochloride dioxane-solution was added and the mixture stirred at 100° C. for 25 hours. The phosphorus oxychloride was distilled off and a 10% aqueous sodium hydroxide solution added under ice cooling. The mixture was extracted with methylene chloride, then was washed with a saturated aqueous solution of potassium bicarbonate and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off and the crude product obtained was purified by silica gel column chromatograph (hexane:ethyl acetate=6:1) to obtain 4.4 g of the above-identified compound (yield 45%).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[S:3]([O:6][C:7]1[NH:11][N:10]=[C:9]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[CH:13]=2)[CH:8]=1)(=[O:5])=[O:4].O[CH:27]([C:29]1[CH:46]=[CH:45][C:32]([C:33]([NH:35][CH2:36][CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[O:34])=[CH:31][CH:30]=1)[CH3:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[CH3:23][O:22][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C:9]1[CH:8]=[C:7]([O:6][S:3]([C:2]([F:1])([F:24])[F:25])(=[O:5])=[O:4])[N:11]([CH:27]([C:29]3[CH:46]=[CH:45][C:32]([C:33]([NH:35][CH2:36][CH2:37][C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])=[O:34])=[CH:31][CH:30]=3)[CH3:28])[N:10]=1)[CH:21]=[CH:20]2
Reactant: COc1ccc2cc(-c3cc(OS(=O)(=O)C(F)(F)F)[nH]n3)ccc2c1
Reactant: CC(O)c1ccc(C(=O)NCCC(=O)OC(C)(C)C)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc2cc(-c3cc(OS(=O)(=O)C(F)(F)F)n(C(C)c4ccc(C(=O)NCCC(=O)OC(C)(C)C)cc4)n3)ccc2c1
Reaction time: 2 h
Yield: 30.8 %

Procedure:
3-(6-Methoxy-2-naphthyl)-1H-pyrazol-5-yl trifluoromethanesulfonate (1.36 g, 3.65 mmol), tert-butyl N-[4-(1-hydroxyethyl)benzoyl]-β-alaninate (1.2 g, 4.02 mmol), and triphenylphosphine (1.44 g, 5.48 mmol) were suspended in DCM (25 ml). Diisopropyl azodicarboxylate (0.87 ml, 4.38 mmol) was added slowly. The mixture was stirred for 2 hr and then concentrated to ˜10 ml. This residue was chromatographed (SiO2, 25-30% ethyl acetate gradient) to give 0.727 g of tert-butyl N-{4-[1-(3-(6-methoxy-2-naphthyl)-5-{[(trifluoromethyl)sulfonyl]oxy}-1H-pyrazol-1-yl)ethyl]benzoyl}-β-alaninate, NMR (500 MHz, CDCl3) δ: 1.45 (s, 9H); 2.01 (d, J=7.1 Hz, 3H); 2.53 (t, J=5.9 Hz, 2H); 3.67 (q, J=5.9 Hz, 2H); 3.94 (s, 3H); 5.56 (q, J=7.1 Hz, 1H); 6.54 (s, 1H); 6.78 (br, 1H); 7.16 (br, 1H); 7.17 (dd, J=2.6 Hz, 9 Hz, 1H); 7.41 (d, J=8.4 Hz, 2H); 7.74 (d, J=8.4 Hz, 2H); 7.78 (d, J=8.4 Hz, 1H); 7.79 (d, J=8.5 Hz, 1H); 7.93 (dd, J=1.8 Hz, 8.5 Hz, 1H); 8.14 (d, J=1.6 Hz, 1H). MS C31H32F3N3O7S Cald: 647.19; Obsd (M+Na): 670.02 and 1.165 g of tert-butyl N-{4-[1-(5-(6-methoxy-2-naphthyl)-3-{[(trifluoromethyl)sulfonyl]oxy}-1H-pyrazol-1-yl)ethyl]benzoyl}-β-alaninate. NMR (500 MHz, CDCl3) δ: 1.46 (s, 9H); 1.85 (d, J=7.1 Hz, 3H); 2.55 (t, J=5.8 Hz, 2H); 3.68 (q, J=5.8 Hz, 2H); 3.95 (s, 3H): 5.52 (q, J=7.1 Hz, 1H); 6.23 (s, 1H); 6.85 (br, 1H); 7.16 (d, J=2.6 Hz, 1H); 7.21 (dd, J=2.6 Hz, 8.7 Hz, 1H); 7.22 (d, J=8.4 Hz, 2H); 7.24 (dd, J=1.5 Hz, 8.4 Hz, 1H); 7.62 (d, J=1.5 Hz, 1H); 7.67 (d, J=8.7 Hz, 1H); 7.71 (d, J=8.3 Hz, 2H); 7.76 (d, J=8.4 Hz, 1H). MS C31H32F3N3O7S Cald: 647.19; Obsd (M+Na): 670.20.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[OH:7][CH:8]1[CH:12]([C:13]([NH2:15])=O)[CH2:11][N:10]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9]1.ClCCl.O>O1CCCC1>[OH:7][CH:8]1[CH:12]([CH2:13][NH2:15])[CH2:11][N:10]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9]1
Reactant: NC(=O)C1CN(Cc2ccccc2)CC1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: NCC1CN(Cc2ccccc2)CC1O
Yield: 90.7 %

Procedure:
In a dry flask was place 1.34 g (35.0 mmol) of lithium aluminum hydride in 20 ml dry tetrahydrofuran cooled to -5° C. To this suspension was added dropwise 2.58 g (11.7 mmol) of 3-hydroxy-4-aminocarbonyl-1-phenylmethyl pyrrolidine. After completion of addition the suspension was warmed 2 hours under reflux, cooled. It was successively added 35 ml dichloromethane, 50 ml tetrahydrofuran and 2.3 ml water. The suspension was passed through a celite pad. The solvent removed to give 2.19 g (90.8%) of title compound as an oil.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[I:11][C:12]1[C:20]2[C:19]([NH2:21])=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]([CH2:22][C:23]2[S:27][C:26]([CH3:28])=[N:25][CH:24]=2)[N:13]=1.[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][O:38][C:39]2[CH:44]=[CH:43][N:42]3[C:45]([C:48](OCC)=[O:49])=[CH:46][N:47]=[C:41]3[CH:40]=2)[CH2:32][CH2:31]1>C1COCC1.O>[I:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[NH:21][C:48]([C:45]2[N:42]3[CH:43]=[CH:44][C:39]([O:38][CH2:37][CH2:36][N:33]4[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]4)=[CH:40][C:41]3=[N:47][CH:46]=2)=[O:49])[N:14]([CH2:22][C:23]2[S:27][C:26]([CH3:28])=[N:25][CH:24]=2)[N:13]=1
Reactant: Cc1ncc(Cn2nc(I)c3c(N)cccc32)s1
Reactant: CCOC(=O)c1cnc2cc(OCCN3CCN(C)CC3)ccn12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ncc(Cn2nc(I)c3c(NC(=O)c4cnc5cc(OCCN6CCN(C)CC6)ccn45)cccc32)s1
Temperature: 25 °C
Yield: 16.4 %

Procedure:
Lithium bis(trimethylsilyl)amide (1.0 M in THF, 0.24 mL) was added dropwise at ambient temperature and under a nitrogen atmosphere to a solution of 3-iodo-1-((2-methylthiazol-5-yl)methyl)-1H-indazol-4-amine (40 mg, 0.108 mmol) in anhydrous THF (3 mL). The resulting brown mixture was added via syringe to a cooled (ice-water bath) solution of ethyl 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (Preparation D; 35.9 mg, 0.108 mmol) in anhydrous THF (3 mL). The reaction mixture was allowed to warm to ambient temperature overnight. The reaction mixture was diluted with water, and extracted multiple times with dichloromethane. The dichloromethane extracts were dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by preparative thin-layer chromatography (silica, 7 N ammonia/MeOH:MeOH:DCM in a 3:7:90 ratio as eluent) to afford the product (11.6 mg) as a tan solid. MS (ES+APCI) m/z=657 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[C@H:10]([C:21]([OH:23])=[O:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.Cl[CH2:30]Cl.C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:30][O:22][C:21]([C@H:10]1[C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:12][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1)=[O:23]
Reactant: O=C(O)[C@@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Reactant: ClCCl
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
(3S,4S)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carboxylic acid (CAS RN: 907184-53-6) (35.7 g, 0.102 mol) were dissolved in methanol (350 mL) and at ambient temperature treated with sulfuric acid 97% (10.9 mL). The reaction mixture was stirred at 60° C. for 18 h. At 0° C. dichloro methane (500 mL) was added followed by aqueous sodium carbonate 10% (500 mL) (final pH 11) under vigorous stirring. The phases were separated. The aqueous phase was washed with dichloro methane, the combined organic phases with water and brine and then dried on sodium sulfate. After filtration and evaporation of the solvent the title product was obtained as a yellow oil (36.3 g, 98%) which was directly used in the next step. ES-MS m/e: 365.3 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:19]>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][O:15][CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCC1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 18 h

Procedure:
To a suspension of lithium aluminium hydride (1.41 g) in THF (15 mL) at 0° C. was added piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester as a solution in THF (10 mL) and the mixture stirred at room temperature for 3 h. The reaction was cooled to 0° C. and quenched by addition of aqueous ammonium chloride and the mixture filtered through celite. The filtrate was diluted with ethyl acetate, washed with water, separated and dried (MgSO4). The solvent was evaporated to give 3-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (1.25 g). To a solution of this alcohol (422 mg) in THF (8 mL) was added sodium hydride (94 mg; 60% dispersion in mineral oil). After 15 min iodomethane (0.49 mL) was added and the reaction stirred for 18 h. The mixture was then diluted with ethyl acetate and washed sequentially with water, brine, separated and dried (MgSO4). The solvent was evaporated and the residue purified by flash chromatography to give 3-methoxymethyl-piperidine-1-carboxylic acid tert-butyl ester (414 mg). To a solution of 3-methoxymethyl-piperidine-1-carboxylic acid tert-butyl ester (204 mg) in DCM (3 mL) was added 2M hydrogen chloride in diethyl ether and the mixture stirred for 18 h. The solvent was evaporated to give the desired amine (168 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=1)([O-])=O.[H-].[Na+].[CH3:15]I.CO.[CH:19](Cl)(Cl)Cl>C1COCC1.CO.[Pd]>[CH3:19][N:8]1[C:7]2[CH:11]=[CH:12][C:4]([NH2:1])=[CH:5][C:6]=2[N:10]=[CH:9]1.[CH3:15][N:10]1[C:6]2[CH:5]=[C:4]([NH2:1])[CH:12]=[CH:11][C:7]=2[N:8]=[CH:9]1
Reactant: ClC(Cl)Cl
Reactant: O=[N+]([O-])c1ccc2nc[nH]c2c1
Reactant: CI
Agent: [Pd]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1cnc2cc(N)ccc21
Product: Cn1cnc2ccc(N)cc21
Reaction time: 12 h
Yield: 11 %
Yield: 21 %

Procedure:
A solution of 5-nitrobenzimidazole (3.0 g, 18.4 mmol) in 100 ml of THF was stirred with NaH (2.7 g, 36.8 mmol) for 0.5 h at 25° C. To the solution was added methyl iodide (2.0 ml, 20.3 mmol) and resulting mixture was stirred for 12 h. The reaction mixture was concentrated in vacuo to provide an oil, which was dissolved in 200 ml of MeOH and stirred with 0.3 g of 10% Pd/C under H2 for 12 h. The reaction mixture was filtered and concentrated in vacuo, yielding a dark oily residue which was subjected to column chromatography (3% MeOH/CHCl3) to provide 0.69 g (3.9 mmol, 21%) of 1-methyl-5-aminobenzimidazole and 0.36 g (2.0 mmol, 11%) of 3-methyl-5-aminobenzimidazole.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:21]=[C:11]3[NH:12][C:13](=[O:20])[C:14]4[C:19]([N:10]3[N:9]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:5]=[CH:6][CH:7]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].C(N(CC)CC)C>C(#N)C>[O:20]=[C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]2[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:22](=[O:24])[CH3:23])[CH:7]=[CH:6][CH:5]=3)[CH:21]=[C:11]2[NH:12]1
Reactant: Nc1cccc(-c2cc3[nH]c(=O)c4ccccc4n3n2)c1
Reactant: CC(=O)OC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc(-c2cc3[nH]c(=O)c4ccccc4n3n2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of EXAMPLE 12 (0.04 g, 0.1 mmol) and acetic anhydride (0.02 mL, 1.5 mmol) in acetonitrile was treated with triethylamine (0.1 mL, 0.8 mmol). The mixture was stirred overnight at ambient temperature and filtered to provide the title compound. 1H NMR (DMSO-d6) δ 12.27 (s, 1H), 10.04 (s, 1H), 8.11-8.20 (m, 3H), 7.87-7.95 (m, 1H), 7.58-7.66 (m, 2H), 7.48-7.56 (m, 1H), 7.38 (t, J=7.8 Hz, 1H), 6.27 (s, 1H), 2.06-2.12 (m, 3H).
Reaction SMILES: [CH:1]1([CH2:4][C:5](=O)[CH3:6])[CH2:3][CH2:2]1.[CH3:8][C:9]([S:12]([NH2:14])=[O:13])([CH3:11])[CH3:10]>C1COCC1>[CH:1]1([CH2:4]/[C:5](=[N:14]/[S:12]([C:9]([CH3:11])([CH3:10])[CH3:8])=[O:13])/[CH3:6])[CH2:3][CH2:2]1
Reactant: CC(C)(C)S(N)=O
Reactant: CC(=O)CC1CC1
Solvent: C1CCOC1
Product: C/C(CC1CC1)=N\S(=O)C(C)(C)C
Temperature: 25 °C

Procedure:
A 25 mL round bottomed flask was charged with Ti(OEt)4 (technical grade, 0.37 mL, 1.4 mmol) and 1-cyclopropylpropan-2-one (79.0 mg, 0.81 mmol) in THF (1.45 mL), under an argon atmosphere. Then 2-methylpropane-2-sulfinamide (88.7 mg, 0.73 mmol) was added and the reaction mixture was heated to reflux overnight. After cooling to room temperature the reaction mixture was poured onto brine (1.7 mL), with rapid stirring. The resulting suspension was filtered through a pad of celite. The filtrate was concentrated under reduced pressure to afford crude 2-methyl-propane-2-sulfinic acid [2-cyclopropyl-1-methyl-eth-(E)-ylidene]-amide which was taken directly to the next step without purification.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:8]=1[CH3:9].[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C=O)C>[N:16]([CH2:3][C:4]1[N:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:8]=1[CH3:9])=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1[nH]c(-c2ccccc2)nc1CCl
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1[nH]c(-c2ccccc2)nc1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.8 %

Procedure:
To a solution of 4-chloromethyl-5-methyl-2-phenyl-1H-imidazole hydrochloride (4.86 g) [CAS 58731-95-6] in DMF (50 ml) was added sodium azide (7.79 g). The reaction mixture was stirred at room temperature for 18 h under argon and concentrated without heating under high vacuum. To the residue was added ice/1 molar K2CO3 solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulphate and concentrated. The residue was purified by chromatography on silica gel using methylene chloride/methanol 2% as eluent to obtain 4-azidomethyl-5-methyl-2-phenyl-1H-imidazole (3.70 g) as a light yellow amorphous powder.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.[C:11]1([NH:17][NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:19][C:20]([CH3:27])([CH3:26])[C:21](=O)[CH2:22][C:23]#[N:24]>C(O)C>[C:20]([C:21]1[CH:22]=[C:23]([NH2:24])[N:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:18]=1)([CH3:27])([CH3:26])[CH3:19]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(N)n(-c2ccccc2)n1
Yield: 70 %

Procedure:
N,N-Diisopropylethylamine (1.7 mL, 7.99 mmol) was added to a mixture of phenyl hydrazine hydrochloride (1.5 g, 10.39 mmol) and 4,4-dimethyl-3-oxopentane nitrile (1.0 g, 7.99 mmol) in ethanol (15 mL) and the mixture was heated under reflux for 18 hours. The cooled mixture was then concentrated to low volume and partitioned between ethyl acetate and saturated sodium hydrogen carbonate solution. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with heptanes:ethyl acetate, 75:25, to afford the title compound as a pale orange oil that crystallised on standing (1.21 g, 70% yield).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34]C)=[O:33])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[OH2:33].[C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CCCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O
Product: O=C(O)CCCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Yield: 172.3 %

Procedure:
A mixture of methyl 3,4,5-triphenyl-1H-pyrazol-1-nonanoate (3.45 g, 7.4 mmol), 5N sodium hydroxide solution (4.44 mL, 22 mmol) and methanol (60 mL) was heated at reflux for 1 hour. The solvent was evaporated, the residue diluted with water and 2N hydrochloric acid solution added until pH=1. A yellow solid was filtered off and recrystallized from dichloromethane/hexane to afford 3,4,5-triphenyl-1H-pyrazol-1-nonanoic acid hydrate (3 g, 89%); m.p.=110°-112° C. MS(CI): m/e=453 (MH+).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].O=[CH:14][C:15]([Cl:18])([Cl:17])[Cl:16].CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[CH2:11]([OH:12])[C@@H:9]([OH:10])[C@H:7]1[O:8][C@@H:2]2[O:1][C@H:14]([C:15]([Cl:18])([Cl:17])[Cl:16])[O:4][C@@H:3]2[C@H:5]1[OH:6]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: OC[C@@H](O)[C@H]1O[C@@H]2O[C@H](C(Cl)(Cl)Cl)O[C@@H]2[C@H]1O
Reaction time: 0.33 h

Procedure:
A mixture of 4.5 g of glucose, 19 g of chloral, 20 ml of chloroform and 0.05 g of 4-methyl-benzene-sulphonic acid is kept at reflux temperature for 7 hours and the formed water is separated by means of a Dean-Stark apparatus. The solvent is distilled off and the residue is kept at 60° C. for 20 minutes. The sedimented material is filtrated and the pH value of the mother lye adjusted to 6.5 with sodium hydroxide. The separated precipitate is filtered.