Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C:4]([F:32])([F:31])[CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([O:27][C:28](=[O:30])[CH3:29])[CH2:18][CH2:19]2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1)[CH3:7].[N+](=C)=[N-].O1C=C[CH2:40][CH2:39][CH2:38]1.CC1C=CC(S(O)(=O)=O)=CC=1>CCOCC.O1CCOCC1>[CH3:1][O:2][C:3](=[O:33])[C:4]([F:31])([F:32])[CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([O:27][CH:28]4[CH2:29][CH2:40][CH2:39][CH2:38][O:30]4)[CH2:18][CH2:19]2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1)[CH3:7]
Reactant: C1=COCCC1
Reactant: COC(=O)C(F)(F)C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(C)=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: C=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC(=O)C(F)(F)C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 95 %

Procedure:
The difluoroester (5) (880 mg, 1.9 mmol) was treated with 2% KOH--MeOH (30 ml) at room temperature for 2 hr. The usual work-up (ether for extraction) gave a crude acid. This in ether (10 ml) was treated with etheral solution of diazomethane until the gas evolution was ceased. This solution was concentrated under reduced pressure to leave the residue. This is dioxane (10 ml) was treated with 2,3-dihydropyran (516 μl) and TsOH (10 mg) at room temperature for 3 hr. The usual work-up (ether for extraction) gave a crude product, which was applied to a column of silica gel (200 g). Elution with n-hexane-ether (15:1) provided the THP-ester (6) (907 mg, 95%), amorphous. 1H-NMR δ: 0.70 (3H, s, 18-H3), 1.03 (3H, s, 19-H3), 1.10 (3H, d, J=6 Hz, 21-H3), 3.53 (2H, m, THP), 3.86 (3H, s, --CO2CH3), 3.93 (1H, m, 3-H), 4.73 (1H, m, THP), 5.36 (1H, m, 6-H). 19F-NMR δ: +40.0. MS m/z: 424 (M+ -DHP), 406, 391.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[CH:8]3[CH2:17][CH2:16][CH2:15][CH:9]3[C:10](=[O:14])[NH:11][C:12]=2[CH:13]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.[Cl:40][C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][CH:48]=1)[CH2:44][NH2:45].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl.C(OCC)(=O)C>[Cl:40][C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][CH:48]=1)[CH2:44][NH:45][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[CH:8]3[CH2:17][CH2:16][CH2:15][CH:9]3[C:10](=[O:14])[NH:11][C:12]=2[CH:13]=1
Reactant: NCc1cccc(Cl)c1
Reactant: O=C1Nc2cc(CCO)ccc2C2CCCC12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C1Nc2cc(CCNCc3cccc(Cl)c3)ccc2C2CCCC12
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 23.7 %

Procedure:
A solution of 0.19 g (0.82 mmol) of 7-hydroxyethyl-1,2,3,3a,5,9b-hexahydro-cyclopenta[c]quinolin-4-one in 20 ml of dichloromethane is mixed at 0° C. with 0.38 g (0.90 mmol) of 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (D. B. Dess, J. C. Martin, J. Am. Chem. Soc. 1991, 113, 7277). The batch is stirred for 10 minutes at 0° C. and for 40 minutes at room temperature, diluted with dichloromethane (100 ml), washed with saturated NaHCO3 (30 ml), dried (Na2SO4) and concentrated by evaporation in a vacuum. The residue is dissolved in 1,2-dichloroethane (20 ml) and mixed with 0.11 ml (0.90 mmol) of 3-chlorobenzylamine, 0.30 g (1.40 mmol) of sodium (triacetoxy)borohydride and 0.05 ml (0.85 mmol) of acetic acid. After 20 hours at room temperature, the batch is diluted with ethyl acetate (150 ml), washed with water (2×50 ml), dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography on silica gel with dichloromethane-ethanol yields 69 mg of product.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[C:16]3[NH:23][CH:22]=[C:21]([C:24](O)=[O:25])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[C:27]([O:31][C:32](=[O:41])[NH:33][C@H:34]1[CH2:39][CH2:38][C@@H:37]([NH2:40])[CH2:36][CH2:35]1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32](=[O:41])[NH:33][C@H:34]1[CH2:35][CH2:36][C@@H:37]([NH:40][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[C:8]5[O:12][CH2:11][O:10][C:9]=5[CH:13]=[CH:14][C:6]=4[O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:16]=3[NH:23][CH:22]=2)=[O:25])[CH2:38][CH2:39]1)([CH3:30])([CH3:28])[CH3:29]
Reactant: O=C(O)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from 4-(5-cyclopropylmethoxy-1,3-benzodioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A67) and cis-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH:13]([F:15])[F:14].Cl[C:17]1[N:22]=[C:21]([NH:23][CH3:24])[C:20]([Cl:25])=[CH:19][N:18]=1.Cl.O1CCOCC1>C(O)CCC>[Cl:25][C:20]1[C:21]([NH:23][CH3:24])=[N:22][C:17]([NH:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[O:12][CH:13]([F:14])[F:15])=[N:18][CH:19]=1
Reactant: COC(=O)c1ccc(N)c(OC(F)F)c1
Reactant: CNc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: CCCCO
Solvent: C1COCCO1
Product: CNc1nc(Nc2ccc(C(=O)OC)cc2OC(F)F)ncc1Cl
Temperature: 150 °C

Procedure:
Methyl 4-amino-3-(difluoromethoxy)benzoate (70 mg), 2,5-dichloro-N-methylpyrimidin-4-amine, 0.1 mL of 4N HCl/dioxane and 1 mL of n-butanol were placed in a microwave vial. The reaction was heated for 30 minutes at 150° C. and monitored by LCMS. The mixture was concentrated and purified by silica gel chromatography to give 100 mg of pure methyl 4-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-3-(difluoromethoxy)benzoate.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[CH:10]([C:12]1[N:13]=[CH:14][NH:15][CH:16]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(O)(=O)C.C(OCC)(=O)C>[CH2:1]([N:3]([CH2:10][C:12]1[NH:13][CH:14]=[N:15][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: O=Cc1c[nH]cn1
Reactant: CCNc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCN(Cc1cnc[nH]1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.5 %

Procedure:
To a solution of N-ethylaniline (0.145 g, 1.2 mmol) in 1,2-dichloroethane (5 ml) were added molecular sieves (2 g, size 0.4 nM) and 4-formylimidazole (0.3 g, 3.12 mmol). After stirring the mixture for 5 min at room temperature sodium triacetoxyborohydride (1.02 g, 4.8 mmol) and acetic acid (5 drops) were added. The reaction mixture was stirred at room temperature overnight. For workup ethyl acetate (50 ml) and 1 M sodium bicarbonate solution (30 ml) were added and the mixture was shaken. The organic layer was separated, dried over magnesium sulfate and evaporated. The residue was purified using flash chromatography (column: Isolute® Flash-NH2 (Separtis); eluent: ethyl acetate/methanol=95:5) to yield a white solid (122 mg, 51%); MS (ISP): 202.0 ((M+H)+.).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:5](=[O:21])[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:10][C:9]([S:19][CH3:20])=[CH:8][CH:7]=2.S(=O)(=O)(O)[OH:27].OOS([O-])=O.[K+].C(=O)([O-])O.[Na+]>O.CO>[NH2:1][CH2:2][C:3]1[N:4]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:5](=[O:21])[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:10][C:9]([S:19]([CH3:20])=[O:27])=[CH:8][CH:7]=2
Reactant: O=S(=O)(O)O
Reactant: CSc1ccc2c(=O)n(CC(C)C)c(CN)c(-c3ccccc3)c2c1
Agent: O=C([O-])O
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)Cn1c(CN)c(-c2ccccc2)c2cc(S(C)=O)ccc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
To a mixture of 3-(aminomethyl)-2-isobutyl-6-(methylsulfanyl)-4-phenyl-1(2H)-isoquinolinone (0.18 g, 0.52 mmol), conc. sulfuric acid (0.0168 mL, 0.31 mmol), methanol (2 mL) and water (5 mL) was added Oxone® (0.19 g, 0.31 mmol), and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into saturated, aqueous sodium hydrogencarbonate (50 mL) and extracted 3 times with ethyl acetate (25 mL). The extracts were combined, washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate (9 g) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1 (v/v)). The resulting oil was solidified from diisopropyl ether (1 mL) to give the title compound (0.081 g, 42%) as a pale-yellow powder.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:11]([NH:13][C@@H:14]([C:19](=O)[CH3:20])[C:15]([O:17][CH3:18])=[O:16])=[O:12])[CH3:10])=O)(C)(C)C.Cl>O1CCOCC1>[OH:12][C:11]1[N:13]=[C:14]([C:15]([O:17][CH3:18])=[O:16])[C:19]([CH3:20])=[N:8][C:9]=1[CH3:10]
Reactant: COC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(C)=O
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1nc(O)c(C)nc1C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of methyl (2S)-2-{[N-(tert-butoxycarbonyl)-L-alanyl]amino}-3-oxobutanoate (3.05 g, 10.1 mmol) and 4N hydrochloric acid in 1,4-dioxane (10 mL) was stirred at room temperature. After being stirred for 1 h at same temperature, the reaction mixture was concentrated in vacuo. A solution of the residue in pyridine (50 mL) was heated at 60° C. for 4 h. After being cooled to ambient temperature, the mixture was concentrated in vacuo. The residue was poured into water, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtrated and concentrated in vacuo. The residue was triturated with hexane-ethyl acetate (1:1) to give methyl 6-hydroxy-3,5-dimethylpyrazine-2-carboxylate. MS (APCI): m/z 183 (M+H).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[CH3:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][C:18](=[O:24])[NH:19]2>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=[C:17]1[C:16]2[C:20](=[CH:21][CH:22]=[CH:23][C:15]=2[CH3:14])[NH:19][C:18]1=[O:24])([CH3:3])[CH3:2]
Reactant: COc1ccc(C=O)cc1C(C)C
Reactant: Cc1cccc2c1CC(=O)N2
Product: COc1ccc(C=C2C(=O)Nc3cccc(C)c32)cc1C(C)C

Procedure:
3-Isopropyl-4-methoxybenzaldehyde was condensed with 4-methyl-2-oxindole to give 0.25 g of 3-(3-isopropyl-4-methoxybenzylidene)-4-methyl-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[CH3:37][O:38][N:39]([CH3:49])[C:40](=[O:48])[CH2:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:45]3[CH2:44][CH2:43][N:42]([CH2:41][C:40]([N:39]([O:38][CH3:37])[CH3:49])=[O:48])[CH2:47][CH2:46]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CON(C)C(=O)CN1CCNCC1
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)OC)CC1

Procedure:
2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-N-methoxy-N-methyl-acetamide was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12j) and N-methoxy-N-methyl-2-piperazin-1-yl-acetamide (example 16b) in an analogous manner as described in example 25. LR-MS: 691.3 [(M+H)+]
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14]2[C:5]([CH:6]([CH2:16][C:17]([OH:19])=[O:18])[CH2:7][C:8]32[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)=[CH:4][CH:3]=1.Cl[C:21]([O:23][CH:24]1[CH:31]2[CH2:32][CH:27]3[CH2:28][CH:29]([CH2:33][CH:25]1[CH2:26]3)[CH2:30]2)=[O:22]>>[CH3:1][C:2]1[CH:15]=[C:14]2[C:5]([CH:6]([CH2:16][C:17]([OH:19])=[O:18])[CH2:7][C:8]32[CH2:9][CH2:10][N:11]([C:21]([O:23][CH:24]2[CH:25]4[CH2:33][CH:29]5[CH2:28][CH:27]([CH2:32][CH:31]2[CH2:30]5)[CH2:26]4)=[O:22])[CH2:12][CH2:13]3)=[CH:4][CH:3]=1
Reactant: O=C(Cl)OC1C2CC3CC(C2)CC1C3
Reactant: Cc1ccc2c(c1)C1(CCNCC1)CC2CC(=O)O
Product: Cc1ccc2c(c1)C1(CCN(C(=O)OC3C4CC5CC(C4)CC3C5)CC1)CC2CC(=O)O

Procedure:
The title compound was prepared from 2-(6-methyl-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic acid and 2-adamantyl chloroformate following a procedure analogous to that described in Example 57. LC-MS Method 1 tR=2.24 min, m/z=438; 1H NMR (CDCl3) δ=7.06 (q, 2H), 6.97 (s, 1H), 4.88 (s, 1H), 4.20 (t, 2H), 3.60 (m, 1H), 3.13-2.94 (m, 3H), 2.64 (dd, 1H), 2.48 (dd, 1H), 2.35 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.CN(C1C=CC=CN=1)C.Cl[C:28]([O:30][CH3:31])=[O:29]>C(Cl)Cl>[CH3:31][O:30][C:28]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)=[O:29]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)Nc1ccc(C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 71.7 %

Procedure:
Methyl 4-aminobenzoate (Aldrich, 5.0 g, 33 mmol) was dissolved in 120 mL of anhydrous methylene chloride containing pyridine (3.2 mL, 39.6 mmol) and dimethylaminopyridine (DMAP, 500 mg) was added. To the ice-cooled mixture was added methyl chloroformate (2.80 mL, 36.3 mmol) while stirring. The stirring was continued for 16 h at room temperature. The reaction was quenched with water (50 mL) and the organic layer separated. The aqueous layer was extracted with chloroform (50 mL). The combined organic extract was dried over sodium sulfate. The volatiles were evaporated on a rotoevaporator to give a residue, which was crystallized from chloroform-methanol. The white solid was separated, dried in air followed by drying in a pistol at acetone reflux in vacuo to give 4.95 g (71.7%) of methyl 4-(methoxycarbonyl)aminobenzoate, mp 177°-178° C.
Reaction SMILES: [SH:1][CH2:2][C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11]C(NC1C=CC=CC=1)=O)=[O:4].[CH2:21]([N:28]=[C:29]=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([NH:28][C:29](=[O:30])[NH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[CH2:2][SH:1])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(CS)NCCCCCNC(=O)Nc1ccccc1
Reactant: O=C=NCc1ccccc1
Product: O=C(CS)NCCCCCNC(=O)NCc1ccccc1

Procedure:
Compound 11 was prepared using the methodology described for the preparation of Compound 9, by substituting phenylisocyanate with benzylisocyanate. 1H NMR (300 MHz, DMSO-d6) δ (ppm) 7.98 (br s, 1H), 7.35-7.18 (m, 5H), 6.27 (br s, 1H), 5.91 (br s, 1H), 4.19 (s, 2H), 3.07 (d, J=8.1 Hz, 2H), 3.02 (m, 4H), 2.71 (t, J=8.1 Hz, 1H), 1.37 (m, 4H), 1.26 (m, 2H). 13C NMR (75 MHz, DMSO-d6) δ (ppm) 169.4, 158.1, 141.0, 128.2, 127.0, 126.5, 42.9, 39.2, 38.8, 29.7, 28.7, 27.1, 23.7.
Reaction SMILES: [F:1][CH2:2][CH:3]([OH:6])[CH2:4][F:5].[S:7](Cl)([C:10]1[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=1)(=[O:9])=[O:8]>N1C=CC=CC=1>[S:7]([O:6][CH:3]([CH2:4][F:5])[CH2:2][F:1])([C:10]1[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: OC(CF)CF
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC(CF)CF)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
1,3-difluoro-2-propanol (60.75 g, 633 mmol) was dissolved in pyridine (375 mL) at 0° C. Tosyl chloride (134 g, 700 mmol) was added in portions and stirred overnight at room temperature. Pyridine was removed under reduced pressure and the residue was diluted with ethyl acetate. The mixture was washed sequentially with dilute aqueous HCl, water, sat. aq. NaHCO3 and brine. The organic layer was dried over MgSO4, filtered and concentrated. The residue was cooled to −78° C. until crystals began to form. The material was triturated with ice-cold hexane (2×200 mL) and filtered to provide O-Tosyl-1,3-difluoro-2-propanol as a white low-melting solid (143.9 g, 91%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:24][CH3:25])[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:26]CC3C=CC=CC=3)=[CH:5][C:4]=2[N:3]=1.[H][H].Cl.[OH-].[Na+]>C(#N)C.[Pd].O.CO>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:24][CH3:25])[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:26])=[CH:5][C:4]=2[N:3]=1
Reactant: [H][H]
Reactant: CCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CCCCNS(C)(=O)=O
Agent: [Pd]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CO
Product: CCc1nc2c(N)nc3cc(O)ccc3c2n1CCCCNS(C)(=O)=O
Yield: 53.2 %

Procedure:
A warm solution of N-[4-(4-amino-7-benzyloxy-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide (2.00 g, 4.28 mmol), prepared in Example 106, in acetonitrile (250 mL) and methanol (50 mL) was added to a Parr vessel containing 10% palladium on carbon (1.00 g) and a small amount of acetonitrile. The vessel was placed under hydrogen pressure (25 psi, 1.7×105 Pa) and recharged three times with hydrogen over a period of 21 hours. Concentrated hydrochloric acid (30 mL) was then added to the reaction mixture, which was filtered through a layer of CELITE filter aid. The filter cake was washed with water (200 mL), and the filtrate was concentrated under reduced pressure. Ethanol (2×100 mL) was added to the residue and concentrated under reduced pressure to afford a white solid. The solid was mixed with water (30 mL), and the pH was adjusted to 8 with the addition of 1M aqueous sodium hydroxide. The resulting white, granular precipitate was isolated by filtration, washed with water and ethanol, stirred with hot ethanol, and isolated by filtration to provide 0.860 g of N-[4-(4-amino-2-ethyl-7-hydroxy-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide as a white powder, mp 220° C. (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:10]2[NH:11][C:12]3[C:13]([N:18]=2)=[N:14][CH:15]=[CH:16][CH:17]=3)[CH:6]=[C:7]([OH:9])[CH:8]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:10]2[NH:11][C:12]3[C:13]([N:18]=2)=[N:14][CH:15]=[CH:16][CH:17]=3)[CH:6]=[C:7]([O:9][S:20]([CH3:19])(=[O:22])=[O:21])[CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(O)cc(-c2nc3ncccc3[nH]2)c1
Product: COc1cc(OS(C)(=O)=O)cc(-c2nc3ncccc3[nH]2)c1

Procedure:
Prepared analogously to Example 1 from 2-(3'-methoxy-5'-hydroxy-phenyl)-imidazo[4,5-b]pyridine and methanesulfonic acid chloride.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]2[CH:8]=[C:9]([NH:13][C:14]3[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=3)[CH:10]=[CH:11][CH:12]=2)=[CH:5][N:6]=1.C([O-])([O-])=O.[K+].[K+].[O:30]1[CH2:34][CH2:33][NH:32][C:31]1=[O:35].CN(C)CCN>C(OCC)(=O)C.[Cu](I)I.O1CCOCC1>[F:21][C:20]([F:23])([F:22])[C:18]1[CH:17]=[CH:16][N:15]=[C:14]([NH:13][C:9]2[CH:8]=[C:7]([C:4]3[S:3][C:2]([N:32]4[CH2:33][CH2:34][O:30][C:31]4=[O:35])=[N:6][CH:5]=3)[CH:12]=[CH:11][CH:10]=2)[N:19]=1
Reactant: FC(F)(F)c1ccnc(Nc2cccc(-c3cnc(Br)s3)c2)n1
Reactant: O=C1NCCO1
Agent: I[Cu]I
Agent: CN(C)CCN
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C1OCCN1c1ncc(-c2cccc(Nc3nccc(C(F)(F)F)n3)c2)s1
Temperature: 110 °C
Reaction time: 4 h
Yield: 53.6 %

Procedure:
To N-[3-(2-bromo-1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (180 mg, 0.449 mmol) were added copper iodide (17.09 mg, 0.090 mmol), K2CO3 (124 mg, 0.897 mmol), 1,3-oxazolidin-2-one (78 mg, 0.897 mmol) and dioxane. N,N-dimethylethane-1,2-diamine (7.91 mg, 0.090 mmol) was added and the reaction was allowed to stir at 110° C. for 4 hours. The reaction mixture was diluted with ethyl acetate washed with brine, dried over Na2SO4 and concentrated in vacuo. The product was purified by column chromatography on silica gel (50-70% ethyl acetate/hexane) to afford 3-[5-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1,3-oxazolidin-2-one (98 mg, 54%) as an off-white solid. APCI [M+H]+ m/z 408.0. 1H NMR (500 MHz, CDCl3): δ 8.71 (d, J=4.9 Hz, 1H); 8.08 (s, 1H); 7.69 (s, 1H); 7.51 (d, J=8.1 Hz, 1H); 7.43-7.38 (m, 2H); 7.30 (s, 1H); 7.11 (d, J=4.9 Hz, 1H); 4.68 (t, J=8.1 Hz, 2H); 4.39 (t, J=8.1 Hz, 2H). rhSYK activity=+++.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[C@@H:9]([CH2:10]OS(C)(=O)=O)[O:8]1)(=O)=O.[Br:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:16][C:17]1[CH:18]=[C:19]([N:20]2[CH2:10][CH:9]3[O:8][CH:7]3[CH2:6]2)[CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cccc(Br)c1
Reactant: CS(=O)(=O)OC[C@@H]1O[C@@H]1COS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1cccc(N2CC3OC3C2)c1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of 5.4 g of cis-2,3-bis(methanesulfonyloxymethyl)oxirane, 2 ml of 3-bromoaniline, 4.3 g of anhydrous potassium carbonate and 30 ml of N,N-dimethylformamide was stirred under nitrogen atmosphere at 60° C. for 2 hours and at 110° C. for 2 hours. The reaction mixture was extracted with ethyl acetate-water, and the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and then evaporated. The residue was purified by silica gel column chromatography with 5–10% ethyl acetate/hexane, to give 420 mg of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22]1([CH3:31])[C:23]([C:28](Cl)=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=1>C1(C)C=CC=CC=1>[CH3:31][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)=[O:29]
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccccc1C(=O)OC1CCN(Cc2ccccc2)CC1
Yield: 79 %

Procedure:
1.0 g (0.00532 mol) of 1-benzyl-4-hydroxypiperidine and 0.72 ml (0.00532 mol) of triethylamine were dissolved in 50 ml of toluene and treated with 0.7 ml (0.00532 mol) of o-toluoyl chloride. The mixture was boiled at reflux for 2 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:1). 1.3 g (80%) of 1-benzyl-piperidin-4-yl 2-methyl-benzoate were obtained as a brownish oil. MS: me/e (% basic peak)=309 (C20H23NO2+, 6), 232 (5.5), 173 (22.6), 119 (17.2), 91 (100), 82 (96).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[CH2:12][CH:11]=[CH:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC([O-])=O.CC([O-])=O.[Pd+2].C(N(CC)CC)C>[C:17]1([C:11]2[CH2:12][C:13]3[C:9]([CH:10]=2)=[N:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:15][CH:14]=3)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Ic1ccccc1
Reactant: C1=Cc2nc(-c3ccccc3)ccc2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Product: C1=C(c2ccccc2)Cc2ccc(-c3ccccc3)nc21

Procedure:
20 ml of triethylamine, 3.86 g (20 mmol) of 5-phenyl-4-aza-indene, 4.08 g (20 mmol) of iodo-benzene and 0.134 g (0.6 mmol) of Pd(OAc)2 were stirred under reflux for 10 h. After that all triethylamine was removed under reduced pressure. The residue was treated with the mixture 50 ml of dichloromethane and 50 ml of water. Organic layer was separated, washed twice with water, filtered and dried over Na2SO4. Dichloromethane was removed and the residue was recrystallized from 20 ml of EtOH. The yield of product was 23%.