Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@@H:4]1[CH:8]([CH2:9][CH3:10])[CH2:7][CH2:6][N:5]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[OH-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:18])[C@@H:4]1[C@H:8]([CH2:9][CH3:10])[CH2:7][CH2:6][N:5]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CCC1CCN(C(=O)OC(C)(C)C)[C@@H]1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC[C@@H]1CCN(C(=O)OC(C)(C)C)[C@@H]1C(=O)OC
Temperature: 0 °C
Reaction time: 20 h
Yield: 44 %

Procedure:
N-[(tert-Butyloxy)carbonyl]-3-ethylproline methyl ester (29.1 g, 0.113 mol) was dissolved in CH3OH (114 mL) with cooling to 0° C., then treated with 1N NaOH (114 mL). After stirring for 20 h at 23° C., the solution was concentrated to remove the CH3OH and then extracted with EtOAc (3×). The organic layers were combined, dried (MgSO4), filtered, and concentrated to give 12.8 g of N-[(tert-Butyloxy)carbonyl]-cis-3-ethylproline methyl ester as an oil. The aqueous layer was acidified with solid citric add and extracted with EtOAc (2×), the organic layers combined, dried (MgSO4), filtered, and concentrated to give 15.5 g of N-[(tert-Butyloxy)carbonyl]-trans-3-ethylproline as an oil. 1H NMR (CD3OD) δ 3.86 and 3.78 (2 d, 1H, J=6 Hz), 3.33-3.58 (m, 2H), 2.01-2.22 (m, 2H), 1.5-1.74 (m, 2H), 1.33-1.5 (m, 1H), 1.45 and 1.42 (2 s, 9H), 0.98 (t, 3H, J=8 Hz).
Reaction SMILES: Cl[CH:2]([C:8]([C:10]([F:13])([F:12])[F:11])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:14]([NH2:17])(=[S:16])[CH3:15].C(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH3:15][C:14]1[S:16][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([C:10]([F:13])([F:12])[F:11])[N:17]=1
Reactant: CC(N)=S
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1sc(C)nc1C(F)(F)F
Yield: 56.4 %

Procedure:
6.00 g of ethyl 2-chloro-4,4,4-trifluoroacetoacetate and 2.06 g of thioacetamide were dissolved in 30 ml of acetic acid and the mixture was refluxed for 6 hours with stirring. The resulting solution was neutralized with aqueous sodium bicarbonate solution, then extracted with ethyl acetate and the organic layer was concentrated. The residue was chromatographed on silica gel (eluent; n-hexane:chloroform:tetrahydrofuran=6:2:1 V/V) to obtain 3.7 g of ethyl 2-methyl-4-trifluoromethylthiazole-5-carboxylate (yield 56%).
Reaction SMILES: [O:1]=[C:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=[CH:4][C:5]1[O:9][C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:7][CH:6]=1.[CH2:25](O)[CH3:26]>>[CH2:25]([O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:8]1[O:9][C:5]([CH:4]=[CH:3][C:2](=[O:1])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:6][CH:7]=1)[CH3:26]
Reactant: CCO
Reactant: CCCCCC(=O)C=Cc1ccc(CCCCCCCC(=O)O)o1
Product: CCCCCC(=O)C=Cc1ccc(CCCCCCCC(=O)OCC)o1
Temperature: 0 °C
Yield: 79 %

Procedure:
A mixture of II (9.94 g, 0.0298 mole), ethanol (190 ml), and ethyl ether-borontrifluoride complex (0.97 g) was stirred and heated under reflux for 1.5 hours. After cooling, the reaction mixture was poured into ice-water (600 ml) and extracted with three 300-ml portions of ether. The combined ethereal extracts were washed with cold 10% sodium carbonate (100 ml) and then with two 200-ml portions of cold water. The ethereal solution was dried over magnesium sulfate and evaporated to dryness from a water bath (60°C), at last under 15 mm Hg. The residual yellow oil (9.84 g) was purified by distillation under nitrogen from a potassium acetatecoated flask giving 8.57 g (79%) of IV, b0.2 198°-201°C, nD25 1.5217.
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH2:4][CH2:3][CH2:2]1.[C:7]1([Mg]Br)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1COCC1.C(OCC)(=O)C>[C:7]1([C:1]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)([OH:6])[CH2:2][CH2:3][CH2:4][OH:5])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1CCCO1
Reactant: Br[Mg]c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCCCC(O)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 61.6 %

Procedure:
A solution of butyrolactone (10.5 g, 122 mmol) in anhydrous THF (500 mL) was chilled to −78° C. under nitrogen atmosphere. Phenylmagnesium bromide (3M in ether, 100 mL, 300 mmol) was added via syringe at a rate that keeps the reaction temperature below −40° C. After the addition was complete, the reaction was stirred at −78° C. for two hours then the cold bath was removed and the reaction mixture was allowed to warm to room temperature overnight. The solution was then re-cooled to 10° C. on an ice bath before adding 2N aqueous ammonium chloride (200 mL) to quench the reaction. The resulting mixture was diluted with ethyl acetate (1 L) and the organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and filtered. Evaporation of solvent from the filtrate afforded crude 1,1-diphenylbutan-1,4-diol as an oil, which was purified by chromatography on silica gel, eluting with a gradient of 50% to 60% ethyl acetate in hexane. Evaporation of solvents gave a colorless solid that was triturated with hexane and collected by filtration to afford 18.2 g of pure 1,1-diphenylbutan-1,4-diol. MS (EI+): 243 (M+1); 225 (M-H2O+1).
Reaction SMILES: C([NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:9][CH:8]=1)(=O)C.[CH3:27]O>>[NH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:27])=[O:19])=[CH:9][CH:8]=1
Reactant: CO
Reactant: CC(=O)NCCc1ccc(C(=CCCCC(=O)O)c2cccnc2)cc1
Product: COC(=O)CCCC=C(c1ccc(CCN)cc1)c1cccnc1

Procedure:
Prepared by hydrolysis of 6-(4-(2-acetylaminoethyl)-phenyl)-6-(3-pyridyl)hex-5-enoic acid and subsequent esterification with methanol analogously to Example 8b.
Reaction SMILES: [CH3:1][CH:2]([S:25]([NH2:28])(=[O:27])=[O:26])[CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][C:14](Br)=[CH:13][C:12]=3[N:11]=[C:10]([NH2:20])[C:9]=2[N:8]=[C:7]1[CH2:21][O:22][CH2:23][CH3:24].B1([C:35]2[CH:40]=[CH:39][CH:38]=[N:37][CH:36]=2)OCCCO1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][CH:2]([S:25]([NH2:28])(=[O:27])=[O:26])[CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][C:14]([C:35]4[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=4)=[CH:13][C:12]=3[N:11]=[C:10]([NH2:20])[C:9]=2[N:8]=[C:7]1[CH2:21][O:22][CH2:23][CH3:24]
Reactant: c1cncc(B2OCCCO2)c1
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCC(C)S(N)(=O)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCCC(C)S(N)(=O)=O
Yield: 97.9 %

Procedure:
Methyl 4-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-sulfonamide (0.78 g, 1.7 mmol) and pyridine-3-boronic acid 1,3-propanediol cyclic ester (0.33 g, 2.0 mmol) were coupled according to the method described in Part J of Example 1. The reaction was heated at reflux for 15 hours, at which time additional pyridine-3-boronic acid 1,3-propanediol cyclic ester, palladium acetate, and triphenylphosphine were added, and the reaction was heated for an additional three hours. The work-up procedure used in Part F of Examples 125–135 was followed. The crude product was purified twice by column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 95:5 to 70:30) and then triturated with methanol, isolated by filtration, and dried for eight hours under high vacuum at 100° C. to provide 0.78 g of methyl 4-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]butane-1-sulfonamide as off-white needles, mp 216–218° C.
Reaction SMILES: [BH4-].[Na+].Cl[C:4]1[N:8]2[N:9]=[C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1.[SH:19][C:20]1[CH:36]=[CH:35][C:23]2[N:24]=[C:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[S:26][C:22]=2[CH:21]=1>C(O)C>[N:13]1([C:10]2[CH:11]=[CH:12][C:7]3[N:8]([C:4]([S:19][C:20]4[CH:36]=[CH:35][C:23]5[N:24]=[C:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:33])[CH3:31])[S:26][C:22]=5[CH:21]=4)=[N:5][N:6]=3)[N:9]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: Clc1nnc2ccc(N3CCOCC3)nn12
Reactant: CC(C)(C)OC(=O)Nc1nc2ccc(S)cc2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1nc2ccc(Sc3nnc4ccc(N5CCOCC5)nn34)cc2s1
Reaction time: 8 h
Yield: 42.5 %

Procedure:
68 mg of sodium borohydride are added to a mixture of 430 mg of 3-chloro-6-(morpholin-4-yl)[1,2,4]triazolo[4,3-b]pyridazine and 510 mg of 1,1-dimethylethyl (6-sulphanyl-1,3-benzothiazol-2-yl)carbamate in 9 cm3 of degassed ethanol and then the reaction is refluxed for 23 h. The suspension is left at 20° C. overnight and is then concentrated to dryness under vacuum. The product is chromatographed by solid deposit on a Merck cartridge of 70 g of silica 15-40 μm, elution being carried out with a gradient of 100% dichloromethane to 95/5 dichloromethane/methanol. 370 mg of 1,1-dimethylethyl (6-{[6-(morpholin-4-yl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1,3-benzothiazol-2-yl)carbamate are thus obtained in the form of a white solid, the characteristics of which are as follows:
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[CH:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].Br[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: Brc1ccccn1
Reactant: C#Cc1ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccn2)cc1[N+](=O)[O-]
Yield: 86.3 %

Procedure:
Prepared from (4-ethynyl-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example F2) (262 mg, 1.0 mmol) and 2-bromopyridine (0.15 mL, 1.6 mmol) according to the general procedure F. Obtained as a yellow solid (293 mg).
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[C:15](Br)[CH:14]=[CH:13][C:12]=3[O:18][CH3:19])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Mg].II.CN([CH:26]=[O:27])C.Cl>C1COCC1.ClCCl>[C:1]12([C:11]3[CH:16]=[C:15]([CH:14]=[CH:13][C:12]=3[O:18][CH3:19])[CH:26]=[O:27])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COc1ccc(Br)cc1C12CC3CC(CC(C3)C1)C2
Reactant: CN(C)C=O
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(C=O)cc1C12CC3CC(CC(C3)C1)C2
Reaction time: 0.5 h

Procedure:
11.09 g 37 mmoles) of 2-(1-adamantyl)-4-bromo anisole dissolved in 85 ml of THF are slowly added to 1 g of magnesium and an iodine crystal. At the beginning of the addition, the reaction mixture is heated until the reaction begins, then the remainder of the solution is added in a manner to maintain a regular reflux. This reaction mixture is heated at reflux for 30 minutes after the end of the addition at which point 2.70 g (37 mmoles) of dry DMF are added. The reaction mixture is then stirred for 30 minutes without heating and then poured into 300 ml of mixture of 2N aqueous HCl and dichloromethane.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:34]([CH2:38][CH2:39][CH3:40])[CH2:35][CH2:36][CH3:37])=[N:4][N:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17](=[O:33])[NH:18][S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[C:25]([Cl:32])[CH:26]=[CH:27][CH:28]=4)[CH:23]=3)(=[O:21])=[O:20])=[CH:13][C:9]=2[C:10](O)=[O:11])[C:6]=1[CH3:7].[N:41]([CH2:44][C@@H:45]1[CH2:54][C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH2:47][NH:46]1)=[N+:42]=[N-:43]>>[N:41]([CH2:44][C@@H:45]1[CH2:54][C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH2:47][N:46]1[C:10]([C:9]1[CH:13]=[C:14]([CH:15]=[CH:16][C:8]=1[N:5]1[C:6]([CH3:7])=[C:2]([Cl:1])[C:3]([N:34]([CH2:38][CH2:39][CH3:40])[CH2:35][CH2:36][CH3:37])=[N:4]1)[C:17]([NH:18][S:19]([C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[C:25]([Cl:32])[CH:26]=[CH:27][CH:28]=2)[CH:23]=1)(=[O:21])=[O:20])=[O:33])=[O:11])=[N+:42]=[N-:43]
Reactant: CCCN(CCC)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4cccc(Cl)c4c3)cc2C(=O)O)c(C)c1Cl
Reactant: [N-]=[N+]=NC[C@@H]1Cc2ccccc2CN1
Product: CCCN(CCC)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4cccc(Cl)c4c3)cc2C(=O)N2Cc3ccccc3C[C@H]2CN=[N+]=[N-])c(C)c1Cl

Procedure:
Following a procedure analogous to that for the synthesis of Example 91, 2-(4-chloro-3-(dipropylamino)-5-methyl-1H-pyrazol-1-yl)-5-(8-chloronaphthalen-2-ylsulfonylcarbamoyl)benzoic acid (Intermediate 193B, 50 mg, 0.083 mmol) and (S)-3-(azidomethyl)-1,2,3,4-tetrahydroisoquinoline (Intermediate 92A, 17 mg, 0.091 mmol) were converted to the title compound. 1H NMR (CDCl3, 2:1 mixture of amide rotamers) δ 9.15 (s, 1H), 8.27-8.13 (m, 1.5H), 8.07-7.80 (m, 2H), 7.72 (d, J=7.5 Hz, 1.5H), 7.61-7.51 (m, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.28-7.11 (m, 3.5H), 7.08-6.98 (m, 1H), 6.94-6.82 (m, 0.5H), 5.34 (d, J=18.5 Hz, 1H), 4.38-3.93 (m, 3H), 3.48-3.36 (m, 2H), 3.32-2.72 (m, 5H), 2.24 (s, 1H), 2.16 (s, 2H), 1.60-1.12 (m, 4H), 0.94-0.62 (m, 6H); MS(ESI+) m/z 773.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH:12]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:11][O:10]1.[NH:20]1[CH:24]=[N:23][CH:22]=[N:21]1.[Na].C(OCC)(=O)C>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([CH:12]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:11][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1
Reactant: c1nc[nH]n1
Reactant: CC(c1cccnc1)C1(c2ccc(F)cc2F)CO1
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(c1cccnc1)C(O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
Treatment of the product of part (iii) (4.30 g) with 1H-1,2,4-triazole, sodium salt (3.0 g) in N,N-dimethylformamide (50 ml) according to the method of Example 1(ii), followed by chromatography of the crude product on silica gel using ethyl acetate as eluant, first gave, after combination and evaporation of appropriate fractions, the title compound, diastereoisomeric pair A, (1.13 g), m.p. 113°-114° (from ether).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:7]([NH:9][C@@H:10]([CH3:15])[C:11]([F:14])([F:13])[F:12])=O)[S:5][CH:6]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[N:3]=[C:4]([C:7](=[S:25])[NH:9][C@@H:10]([CH3:15])[C:11]([F:14])([F:13])[F:12])[S:5][CH:6]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: C[C@H](NC(=O)c1nc(Br)cs1)C(F)(F)F
Solvent: Cc1ccccc1
Product: C[C@H](NC(=S)c1nc(Br)cs1)C(F)(F)F
Yield: 87.4 %

Procedure:
To a solution of (S)-4-bromo-N-(1,1,1-trifluoropropan-2-yl)thiazole-2-carboxamide (50 g, 1.0 eq.) in toluene (1000 ml) was added Lawesson's Reagent (100 g, 1.5 eq.). It was refluxed overnight. TLC and LCMS showed the reaction was complete. It was concentrated and the residue was purified by column to obtain 46 g (88% y) of (S)-4-bromo-N-(1,1,1-trifluoropropan-2-yl)thiazole-2-carbothioamide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[F:15][C:14]([F:17])([F:16])[C:12]1[CH:11]=[C:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([C:32]3[CH:33]=[CH:34][C:29]([NH2:28])=[N:30][CH:31]=3)[CH:7]=[CH:6][CH:5]=2)[N:13]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)cc1
Product: Nc1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)cn1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.3) (0.22 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as an off-white solid (0.124 g, 54%). MS (ISP) 461.1 [(M+H)+]; mp 205° C.
Reaction SMILES: [CH3:1][NH2:2].F[C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>CS(C)=O>[CH3:1][NH:2][C:4]1[CH:5]=[C:6]([CH2:7][N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(CN2CCOCC2)cc1F
Reactant: CN
Solvent: CS(C)=O
Product: CNc1cc(CN2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 47 °C

Procedure:
An aqueous solution of methylamine (40 wt %, 910 ml) at 30° C. is added to a 61° C. solution of 4-(3-fluoro-4-nitrobenzyl)morpholine (504 g) in DMSO (810 ml) followed by a DMSO rinse (150 ml) over ½ h. The mixture is allowed to reflux at 47 ° C. over 5 min then maintained at <51° C. by occasional ice bath cooling for remainder of the addition. The mixture is stirred at 50° C. for ¾ h and then water (2000 ml) is added. The mixture is cooled to 0° C. and the precipitate is collected by filtration, washed with water (1500 ml) and is dried in a nitrogen stream to give a bright orange solid (529 g). Physical characteristics: 1H NMR (400 MHz, DMSO-d6) δ2.35, 2.93, 3.44, 3.56, 6.63, 6.64, 7.78, 8.15; 13C NMR (100 MHz, DMSO-d6) δ29.95, 53.57, 62.27,66.54, 113.69, 115.76, 126.49, 130.16, 146.27, 148.07.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][S:6][C:7]=1/[CH:8]=[CH:9]\[S:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:30]([OH:34])[CH2:31][CH2:32][OH:33]>>[OH:33][CH2:32][CH2:31][CH2:30][O:34][CH2:2][C:3]1[N:4]=[CH:5][S:6][C:7]=1/[CH:8]=[CH:9]\[S:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCCCO
Reactant: ClCc1ncsc1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: OCCCOCc1ncsc1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
In the same manner as in step b) in Example 2, 674 mg of the title compound was prepared from 665 mg of 4-chloromethyl-5-((Z)-2-tritylthioethen-1-yl)thiazole prepared in step a) in Example 2 and 3 ml of 1,3-propanediol.
Reaction SMILES: Cl[C:2]1[N:3]=[N+:4]([O-:13])[C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1.C[O:15][C:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)=[O:17].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:2]2[N:3]=[N+:4]([O-:13])[C:5]3[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=3[N:7]=2)=[CH:20][CH:19]=1)([OH:17])=[O:15]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: [O-][n+]1nc(Cl)nc2ccc(O)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(-c2nc3ccc(O)cc3[n+]([O-])n2)cc1

Procedure:
3-chloro-7-hydroxybenzo[e][1,2,4]-triazine 1-oxide (2 mmol) was mixed with 1.0 equivalent of 4-(methoxycarbonyl)phenylboronic acid and 2 equivalents of K2CO3 in 20 ml of 50% dioxane/water. A catalytic amount of Pd(PPh3)4 was added and the mixture was heated to reflux for 2 hours. The reaction was concentrated and re-dissolved in 20 ml water and 5 ml 1N NaOH was added to hydrolyze the ester. The mixture was extracted with DCM (3×10 ml). The aqueous layer was filtered and the filtrate was neutralized with 1N HCl to pH=5. The precipitate was filtered and washed with water and dried. 500 mg of product was obtained. 1H NMR (DMSO-d6 400 MHz): δ 11.38 (s, 1H), 8.44 (d, 2H), 8.15 (m, 3H), 7.67 (d, 1H), 7.60 (s, 1H). MS (ESI): m/z 284.5 [M+H]+.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][N:41](CC3C=CC=CC=3)[CH2:42][CH2:43][C:44](=[O:46])[NH2:45])=[CH:33][C:32]=2[CH3:54])=[C:28]([CH:55]([CH3:57])[CH3:56])[NH:27][N:26]=1)(=[O:3])[CH3:2]>CO.[C].[Pd]>[C:44]([CH2:43][CH2:42][NH:41][CH2:40][CH2:39][CH2:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][C:29]2[C:25]([O:24][C@@H:6]3[O:7][C@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:5]3[O:4][C:1](=[O:3])[CH3:2])=[N:26][NH:27][C:28]=2[CH:55]([CH3:56])[CH3:57])=[C:32]([CH3:54])[CH:33]=1)(=[O:46])[NH2:45]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCN(CCC(N)=O)Cc3ccccc3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Pd]
Solvent: CO
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCNCCC(N)=O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99.3 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{3-[N-benzyl-N-(2-carbamoylethyl)amino]propoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole (75 mg) in methanol (3 mL) was added 10% palladium-carbon powder (20 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 2.5 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give 4-[(4-{3-[2-(carbamoyl)ethylamino]propoxy}-2-methylphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-5-isopropyl-1H-pyrazole (66 mg). This material was dissolved in methanol (3 mL). To the solution was added sodium methoxide (28% methanol solution, 0.03 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added acetic acid (0.04 mL), and the resulting mixture was concentrated under reduced pressure. The residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (43 mg).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:18])=[C:10]2[CH:17]=[CH:16][S:15][C:11]2=[C:12](Br)[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[C:19]([Cu])#[N:20].CN(C)C=O>O>[CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:18])=[C:10]2[CH:17]=[CH:16][S:15][C:11]2=[C:12]([C:19]#[N:20])[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2sccc2c1O
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOC(=O)c1nc(C#N)c2sccc2c1O
Temperature: 160 °C
Reaction time: 0.25 h
Yield: 52.1 %

Procedure:
A mixture of 7-bromo-4-hydroxy-thieno[2,3-c]pyridine-5-carboxylic acid butyl ester (example 43a, 165 mg, 0.5 mmol), CuCN (91 mg, 1 mmol), and dimethylformamide (2 ml) was heated in a microwave oven at 160° C. with stirring for 15 min. After cooling to ambient temperature water (20 ml) was added and the mixture was extracted with ethyl acetate (1×60 ml). The resulting mixture was filtered through a pad of celite. The organic phase was washed with water (2×25 ml), dried over MgSO4, and concentrated in vacuo to give the title compound as tan solid (72 mg); MS-(−)-ion: MS-(−)-ion: M−1=275.1.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][C:23]([CH3:24])=[C:18]3[N:17]([CH:25]([CH3:27])[CH3:26])[C:16]2=[O:28])=[CH:11][CH:10]=1)C1C=CC=CC=1>CCO.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][C:23]([CH3:24])=[C:18]3[N:17]([CH:25]([CH3:26])[CH3:27])[C:16]2=[O:28])=[CH:13][CH:14]=1
Reactant: Cc1ccnc2c1n(C(C)C)c(=O)n2-c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccnc2c1n(C(C)C)c(=O)n2-c1ccc(O)cc1
Reaction time: 1 h

Procedure:
A mixture of 3-[4-(benzyloxy)phenyl]-7-methyl-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (215 mg) and 10% Pd—C (30.6 mg) in EtOH (10 mL) was hydrogenated under balloon pressure at room temperature for 1 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give 3-(4-hydroxyphenyl)-7-methyl-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one as a colorless solid. To a solution of this solid in DMF (10 mL) were added sodium hydride (27.8 mg) and 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (164 mg) at 100° C. The mixture was heated at 180° C. for 30 min under microwave irradiation. The precipitate was collected by filtration and washed with AcOEt and MeOH to give the title compound (175 mg) as colorless crystals.