Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13]O)=[C:11]([C:15]([N:17]([CH2:39][CH:40]([CH3:42])[CH3:41])[C@H:18]2[CH2:23][C@@H:22]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])[CH2:21][N:20]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:19]2)=[O:16])[N:10]=[N:9]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:63]>ClCCl>[Br:63][CH2:13][C:12]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:9]=[N:10][C:11]=1[C:15]([N:17]([CH2:39][CH:40]([CH3:42])[CH3:41])[C@H:18]1[CH2:23][C@@H:22]([C:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:25])[CH2:21][N:20]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:19]1)=[O:16]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)CN(C(=O)c1nnn(-c2ccccc2F)c1CO)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)CN(C(=O)c1nnn(-c2ccccc2F)c1CBr)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
To a solution (4 ml) of tert-butyl (3S,5R)-3-[{[1-(2-fluorophenyl)-5-(hydroxymethyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (410 mg) and triphenylphosphine (275 mg) in dichloromethane was added under ice-cooling carbon tetrabromide (350 mg), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (10:90-100:0) was concentrated under reduced pressure to give the object product (442 mg).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](Cl)=[O:8])[N:4]=[CH:3]1.[NH2:10][C:11]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[C:24]3[C:30]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[O:37][CH3:38])=[N:29][N:28]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:25]3=[N:26][CH:27]=2)=[CH:18][C:12]=1[C:13]([N:15]([CH3:17])[CH3:16])=[O:14].N1C=CC=CC=1.ClCCl.C(O)C(N)(CO)CO>ClCCl>[CH3:17][N:15]([CH3:16])[C:13]([C:12]1[CH:18]=[C:19]([C:22]2[CH:23]=[C:24]3[C:30]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[O:37][CH3:38])=[N:29][N:28]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:44])([CH3:46])[CH3:45])[C:25]3=[N:26][CH:27]=2)[CH:20]=[CH:21][C:11]=1[NH:10][C:7]([C:5]1[N:4]=[CH:3][N:2]([CH3:1])[CH:6]=1)=[O:8])=[O:14]
Reactant: Cn1cnc(C(=O)Cl)c1
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3ccc(N)c(C(=O)N(C)C)c3)cc12
Agent: NC(CO)(CO)CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3ccc(NC(=O)c4cn(C)cn4)c(C(=O)N(C)C)c3)cc12
Reaction time: 16 h
Yield: 51.7 %

Procedure:
1-Methyl-1H-imidazole-4-carbonyl chloride (0.579 mmol) was suspended in dichloromethane (4 mL) and a solution of 2-amino-5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-benzamide (150 mg, 0.289 mmol) in 20% v/v pyridine/dichloromethane (1.0 mL) was added. After 16 h, PS-trisamine (Argonaut Technologies, Inc.) was added (3.0 eq. relative to acid chloride) and the suspension was filtered 3 hours later and the resin was rinsed with dichloromethane. After concentration of the filtrates in vacuo, the resulting residue was purified by silica gel chromatography to afford 1-methyl-1H-imidazole-4-carboxylic acid {2-dimethylcarbamoyl-4-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-amide (93.5 mg, 50.5%). MS: m/z 640 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[C:8]2[CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][C:17]=1[O:25][CH3:26])=[O:4].Cl.CN(C)CCCN=C=NCC.[CH3:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[S:46]([NH2:49])(=[O:48])=[O:47]>O1CCCC1.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[C:8]2[CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:49][S:46]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[CH3:39])(=[O:47])=[O:48])=[O:22])=[CH:18][C:17]=1[O:25][CH3:26])=[O:4]
Reactant: Cc1ccccc1S(N)(=O)=O
Reactant: COC(=O)c1ccc2c(c1)c(Cc1ccc(C(=O)O)cc1OC)cn2C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)c(Cc1ccc(C(=O)NS(=O)(=O)c3ccccc3C)cc1OC)cn2C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
To a solution of 4-(5-methoxycarbonyl-1-methylindol-3-ylmethyl)-3-methoxybenzoic acid (125.9 g) in tetrahydrofuran (3.0 l, distilled from sodium benzophenone ketyl) (prepared by heating at 50° C. until dissolution was complete, followed by cooling to room temperature with an ice-water bath) was added 4-dimethylaminopyridine (56.6 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (102.4 g), and the mixture was stirred one hour. To the mixture was added 2-methylbenzene-sulfonamide (67.1 g), and the reaction mixture was stirred about 3 days (for convenience). The reaction mixture was diluted with ethyl acetate (2.0 l) and washed with 1N hydrochloric acid (twice) and brine (3 times, until neutral), and the aqueous extracts were back washed with ethyl acetate. The combined ethyl acetate solution was dried (MgSO4), and partially evaporated to give a slurry of solid in ethyl acetate (about 0.5 l) which was refrigerated overnight. Collection of the solid afforded the crude product (158.5 g, 88%, essentially pure by TlC) as a light pink solid. Recrystallization by dissolution in hot tetrahydrofuran (1.5 l), filtration while hot, dilution with ethyl acetate (2.0 l), and boiling down to a final volume of about 2.5 l afforded a first crop of 4-(5-methoxycarbonyl-1-methylindol-3-ylmethyl)-3-methoxy-N-(2-methylphenylsulfonyl)benzamide (105.5 g, 59%) as a white solid; mp 211°-213° C.; NMR (250 MHz, DMSO-d6): 2.60 (s, 3H, ArCH3), 3.76 (s, 3H, NCH3), 3.82 (s, 3H, CO2CH3), 3.92 (s, 3H, ArOCH3), 4.04 (s, 2H, ArCH2Ar'), 7.15 (d, 1H), 7.22 (s, 1H), 7.38-7.58 (m, 6H), 7.75 (dd, 1H), 8.03 (dd, 1H), 8.17 (d, 1H). (Two additional crops (35.5 g, 20%) and crude product (39.5 g) from concentration of the mother liquors were also obtained.)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:15]=[CH:14][C:13]([C:16]3[O:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)=[CH:12][C:10]=2[NH2:11])=[CH:4][CH:3]=1.[CH:25](=O)[CH3:26].OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=[C:16]1[C:13]1[CH:14]=[CH:15][C:9]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:25]([CH3:26])=[N:11][C:10]=2[CH:12]=1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1Nc1ccc(F)cc1
Reactant: CC=O
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.9 %

Procedure:
To a solution of 2-(2-(4-fluorophenyl)aminoanilin-5-yl)benzoxazole (see Working Example 34-1) (38.0 mg, 0.119 mmol) in dimethylformamide (2 mL) was added an aqueous solution of acetaldehyde (approx. 90%, 22.6 μL, 0.360 mmol) and oxone (73.2 mg, 0.119 mmol), and this was stirred at room temperature for 3 hours. After the reaction was complete, aqueous potassium carbonate solution was added, this was filtered and washed with water. The crystals obtained were purified by silica gel column chromatography to yield the title compound (20.0 mg, 49% yield) as light brown crystals.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:9]=1[C:10]([N:12]=[S:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[O:11].[Cl:24][C:25]1[C:26]([N:31]2[C:35]([C:36](Cl)=[O:37])=[CH:34][C:33]([C:39]([F:42])([F:41])[F:40])=[N:32]2)=[N:27][CH:28]=[CH:29][CH:30]=1.O>C1(C)C=CC=CC=1>[Cl:24][C:25]1[C:26]([N:31]2[C:35]([C:36]([NH:7][C:8]3[C:9]([C:10](=[O:11])[N:12]=[S:13]([CH2:14][CH3:15])[CH2:16][CH3:17])=[CH:18][C:19]([Cl:23])=[CH:20][C:21]=3[Cl:22])=[O:37])=[CH:34][C:33]([C:39]([F:42])([F:40])[F:41])=[N:32]2)=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reactant: CCS(CC)=NC(=O)c1cc(Cl)cc(Cl)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCS(CC)=NC(=O)c1cc(Cl)cc(Cl)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reaction time: 1.5 h
Yield: 64.6 %

Procedure:
To a suspension of potassium carbonate (7.78 g, 56.3 mmol, 1.10 equiv.) and 2-amino-3,5-dichloro-N-(diethyl-λ4-sulfanylidene)benzamide (15.00 g, 51.16 mmol) in toluene (50 mL) was added a solution of 2-(3-chloro-2-pyridyl)-5-(trifluoromethyl)-pyrazole-3-carbonyl chloride (17.62 g, 51.15 mmol, 1.000 equiv.) in toluene (55 mL) at 60° C. After 1.5 h at this temperature, the mixture was cooled and water was added. The resulting precipitate was collected by filtration, washed with water and petrol ether and dried to obtain the title compound (18.73 g, 65%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)[CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[CH2:30][OH:31]>O.C(O)C>[OH:31][CH2:30][CH2:29][N:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][N:8]2[C:9]3[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=3[CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]2=3)[CH2:2]1
Reactant: c1ccc2c(c1)CCc1ccccc1N2CC1CNCCO1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: OCCN1CCOC(CN2c3ccccc3CCc3ccccc32)C1

Procedure:
A mixture of 5-(2-morpholinylmethyl)-10,11-dihydro-5H-dibenz[b,f]azepine (0.2 g), potassium carbonate (0.1 g) and ethylenebromohydrin (0.1 g) in water and ethanol was stirred under reflux for 10 hours. The reaction mixture was concentrated and extracted with chloroform. The chloroform extract was washed with water, dried over anhydrous sodium sulfate and evaporated to afford 5-(4-hydroxyethyl-2-morpholinylmethyl)-10,11-dihydro-5H-dibenz[b,f]azepine as an oily substance. M.P. 186°-188° C (oxalate).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([CH3:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.C([Li])CCC.[C:21](=[O:23])=[O:22]>C1COCC1.O>[CH3:15][C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[C:4](=[CH:3][C:2]([CH3:1])=[CH:14][CH:13]=3)[CH:5]([C:21]([OH:23])=[O:22])[C:6]=2[CH:7]=1
Reactant: O=C=O
Reactant: Cc1ccc2c(c1)Cc1cc(C)ccc1-2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2c(c1)C(C(=O)O)c1cc(C)ccc1-2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.9 %

Procedure:
A solution of 2,7-dimethylfluorene (5.0 g, 25.7 mmol) in THF (100 mL) at -78° C. was charged with butyl lithium (16.8 mL, 26.0 mmol). The reaction mixture was stirred for 15 min, then CO2 gaseous (5g, 113.6 mmol) was introduced with cannula over a period of 15 min at -78° C. The reaction mixture Was Warmed up to room temperature and stirred overnight, diluted with water (150 mL). The layers were separated, the water layer was washed with ethyl acetate (5×20 mL), then acidified with conc. HCl. The precipitate formed was collected, washed with water and dried to give 4.4 g of 2,7-dimethyl-9-fluorenecarboxylic acid (72.4%).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:5]([CH3:7])[CH:6]=1.[N+](=[CH2:21])=[N-].CN(N=O)C(N)=O.[OH-].[K+]>C(OCC)C>[CH3:21][O:1][C:2]1[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:5]([CH3:7])[CH:6]=1
Reactant: C=[N+]=[N-]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c(O)cn1C
Agent: CN(N=O)C(N)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: CCOC(=O)Cc1c(C(=O)OCC)c(OC)cn1C
Reaction time: 0.5 h

Procedure:
Ethyl 4-hydroxy-3-ethoxycarbonyl-1-methylpyrrole-2-acetate (20 mmole) is dissolved in 10 μl of diethyl ether containing diazomethane freshly prepared from N-methyl-N-nitrosourea and potassium hydroxide. After the reaction is allowed to stand at room temperature for about 0.5 hour, the ether is evaporated under reduced pressure at mild temperature and the residue, i.e., crude ethyl-4-methoxy-3-ethoxycarbonyl-1-methylpyrrole-2-acetate, is used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7](Cl)[N:6]=1.[OH:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.Cl.C(OCC)C>CN1C(=O)CCC1>[F:1][C:2]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:22][C:21]2[CH:23]=[CH:24][C:18]([OH:17])=[CH:19][CH:20]=2)[N:6]=1
Reactant: Nc1ccc(O)cc1
Reactant: Cc1ccc(F)c(Nc2ccnc(Cl)n2)c1
Agent: Cl
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: Cc1ccc(F)c(Nc2ccnc(Nc3ccc(O)cc3)n2)c1
Temperature: 100 °C

Procedure:
4-(2-Fluoro-5-methylanilino)-2-chloropyrimidine (Reference Example A-10, 1.00 g, 4.2 mmol) was dissolved in NMP (5 ml) and 4-hydroxyaniline (0.41 g, 3.7 mmol) and 1M HCl in diethyl ether (4.22 ml, 4.2 mmol) was added. The reaction mixture was heated at 100° C. for 15 hours, and then allowed to cool to ambient temperature. The mixture was evaporated under high vacuum to give the title product as a brown oil. The residue was purified by chromatography on a Mega Bond Elute column (10 g) eluting with DCM (4×25 ml), 2% NH3/MeOH in DCM (3×25 ml), 4% NH3/MeOH in DCM (3×25 ml), 6% NH3/MeOH in DCM (10×25 ml to give the title product as a white solid (0.80 g, 61%). NMR (300 MHz): 2.2 (s, 3H), 6.2 (d, 1H), 6.6 (d, 2H), 6.9 (m, 1H), 7.1 (m, 1H), 7.4 (d, 2H), 7.8 (d, 1H), 7.9 (d, 1H), 8.7 (s, 1H), 8.8 (s, 1H), 8.9 (s, 1H); m/z: (ES+) 311.0 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:35])([CH2:32][CH2:33][CH3:34])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:31])=[N:15][N:16]2[C:21]([O:22][CH2:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:20][C:19]([CH3:30])=[CH:18][C:17]=12)=[O:12])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]([CH3:35])([CH2:32][CH2:33][CH3:34])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:31])=[N:15][N:16]2[C:21]([O:22][CH2:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:20][C:19]([CH3:30])=[CH:18][C:17]=12)=[O:12]
Reactant: CCCC(C)(CNC(=O)c1c(C)nn2c(OCC3CCCCC3)cc(C)cc12)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC(C)(N)CNC(=O)c1c(C)nn2c(OCC3CCCCC3)cc(C)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 40 mg (0.047 mmol, 59% pure) of rac-[1-({[7-(cyclohexylmethoxy)-2,5-dimethylpyrazolo[1,5-a]pyridin-3-yl]carbonyl}amino)-2-methylpentan-2-yl]carbamic acid tert-butyl ester (Example 121A) in 2 ml of dichloromethane was admixed with 0.072 ml (0.94 mmol) of trifluoroacetic acid. The resulting solution was stirred at room temperature overnight. After the reaction had ended, the solvent was drawn off under reduced pressure and the residue was purified by preparative HPLC chromatography (Method 21), which gave 8 mg (43% of theory) of the target compound.
Reaction SMILES: [I:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][S:5]([NH:8][C:9]1[N:10]=[CH:11][S:12][C:13]=1[C:14]([O:16][CH3:17])=[O:15])(=[O:7])=[O:6].C(N(CC)C(C)C)(C)C.FC(F)(F)S(O[CH2:37][CH:38]([F:40])[F:39])(=O)=O>C(#N)C>[F:39][CH:38]([F:40])[CH2:37][N:8]([S:5]([CH2:4][C:3]1[CH:18]=[CH:19][CH:20]=[CH:21][C:2]=1[I:1])(=[O:7])=[O:6])[C:9]1[N:10]=[CH:11][S:12][C:13]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: COC(=O)c1scnc1NS(=O)(=O)Cc1ccccc1I
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1scnc1N(CC(F)F)S(=O)(=O)Cc1ccccc1I
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2.1 g (4.8 mmol) of methyl 4-{[(2-iodobenzyl)sulfonyl]amino}-1,3-thiazole-5-carboxylate were dissolved in 20 ml of acetonitrile, and 0.9 ml (5.3 mmol) of N,N-diisopropylethylamine was added at RT. The reaction mixture was stirred at RT for 5 min and then a solution of 1.54 g (7.2 mmol) of difluoroethyl trifluoromethane-sulfonate in 5 ml of acetonitrile was added dropwise within 10 min. The reaction mixture was stirred at RT for 12 h and then concentrated to dryness. The residue was purified by means of preparative HPLC(C18—SiO2, gradient acetonitrile/water 20:80 to 100:0). This gave 2.09 g of methyl 4-{(2,2-difluoroethyl)[(2-iodobenzyl)-sulfonyl]amino}-1,3-thiazole-5-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]=[C:13]=[O:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH2:15][C:16]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=O>>[Cl:25][C:23]1[CH:24]=[C:16]2[C:17]([C:18](=[O:20])[N:12]([S:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)(=[O:11])=[O:10])[C:13](=[O:14])[NH:15]2)=[CH:21][CH:22]=1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: COc1ccc(S(=O)(=O)N=C=O)cc1
Product: COc1ccc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)cc1
Yield: 47.8 %

Procedure:
1.14 g (5.35 mmol) of 4-methoxybenzenesulfonylisocyanate and 938 mg (5.35 mmol) of 2-amino-4-chlorobenzoic acid were treated in the same way as in Example 1 to obtain 938 mg of the above-identified compound (yield 64.3%). Properties: colorless crystal, Melting point: >200° C. (decomposition), PMR (δppm, DMSO-d6):3.88 (3H,s), 7.12 (1H,s), 7.17-7.23 (3H,m), 7.85 (1H,d), 8.10 (2H,d), 11.68 (1H,br).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[NH:29]1[CH2:34][CH2:33][S:32][CH2:31][CH2:30]1.C(=O)([O-])O.[Na+]>C1COCC1>[CH3:28][C:25]1[CH:24]=[CH:23][C:22]([C:16]2[CH:15]=[C:14]3[C:19]([CH2:20][CH2:21][C:12]([C:10]([NH:9][C:6]4[CH:5]=[CH:4][C:3]([CH2:2][N:29]5[CH2:34][CH2:33][S:32][CH2:31][CH2:30]5)=[CH:8][CH:7]=4)=[O:11])=[CH:13]3)=[CH:18][CH:17]=2)=[CH:27][CH:26]=1
Reactant: C1CSCCN1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN4CCSCC4)cc2)CC3)cc1
Temperature: 25 °C

Procedure:
In THF (10 ml) was dissolved N-[4—(chloromethyl)-phenyl]-7—(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (300 mg), and to the mixture was added thiomorpholine (233 μl). The mixture was refluxed for 20 hours. The reaction mixture was cooled to room temperature, and to the mixture was added 5% sodium hydrogen carbonate solution (50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give 7—(4-methylphenyl)-N-[4—(thiomorpholinomethyl)phenyl]-3,4-dihydro-naphthalene-2-carboxamide (Compound 50) (309 mg) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH:10]1([C:13](Cl)=O)[CH2:12][CH2:11]1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:13]([CH:10]3[CH2:12][CH2:11]3)=[N:9][N:8]=2)[CH:7]=1
Reactant: O=C(Cl)C1CC1
Reactant: NNc1ccc(Br)cn1
Solvent: ClC(Cl)Cl
Product: Brc1ccc2nnc(C3CC3)n2c1
Temperature: 90 °C
Yield: 106.5 %

Procedure:
A mixture of 5-bromo-pyridin-2-yl-hydrazine (15.0 g, 79.8 mmol) and cyclopropane carbonyl chloride (65 mL, 71.8 mmol) was heated at 90° C. for 18 hours. The brown mixture was allowed to cool to room temperature, filtered, and washed with toluene to afford a light brown solid. This solid was taken up in CHCl3, and washed with saturated aqueous NaHCO3. The organic layer was isolated, and the aqueous layer extracted with CHCl3 (2×). The combined organics were washed with brine, dried over magnesium sulfate, and concentrated in vacuo to give the title compound as a tan solid (18.2 g, 96%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][C:8]2[C:9]([CH3:19])=[N:10][CH:11]=[N:12][C:13]=2[C@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[N:31]([C:34]1[C:35]([CH3:40])=[N:36][O:37][C:38]=1[CH3:39])=[C:32]=[O:33]>ClCCl>[Cl:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][C:8]2[C:13]([C@H:14]3[CH2:18][CH2:17][CH2:16][N:15]3[C:32]([NH:31][C:34]3[C:35]([CH3:40])=[N:36][O:37][C:38]=3[CH3:39])=[O:33])=[N:12][CH:11]=[N:10][C:9]=2[CH3:19])=[CH:5][CH:4]=1
Reactant: Cc1ncnc([C@H]2CCCN2)c1Cc1ccc(Cl)cc1
Reactant: Cc1noc(C)c1N=C=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncnc([C@H]2CCCN2C(=O)Nc2c(C)noc2C)c1Cc1ccc(Cl)cc1
Yield: 28.1 %

Procedure:
(R)-5-(4-chlorobenzyl)-4-methyl-6-(pyrrolidin-2-yl)pyrimidine hydrochloride (30 mg, 0.066 mmol) and N,N-diisopropylethylamine (0.041 mL) were dissolved in dichloromethane (2 mL). 4-isocyanato-3,5-dimethylisoxazole (15 mg, 0.11 mmol) was added while stirring. The reaction mixture was stirred for 16 h then evaporated to dryness. Purification by semi-preparative HPLC afforded the desired product (7.9 mg, 27.8%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=2[C:12]([O:14]C)=[O:13])[CH2:3]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([C:31]2[O:32][C:33]([CH3:38])=[C:34]([CH2:36]I)[N:35]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([C:31]2[O:32][C:33]([CH3:38])=[C:34]([CH2:36][O:1][CH:2]3[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]4[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=4[C:12]([OH:14])=[O:13])[CH2:3]3)[N:35]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: COC(=O)c1c(C)cccc1COC1CCCC(O)C1
Reactant: COc1ccc(-c2nc(CI)c(C)o2)cc1OC
Product: COc1ccc(-c2nc(COC3CCCC(OCc4cccc(C)c4C(=O)O)C3)c(C)o2)cc1OC

Procedure:
Using methyl 2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate and 2-(3,4-dimethoxyphenyl)4-iodomethyl-5-methyloxazol as starting materials in the procedure of Example XXXI, gave the product 67 of molecular weight 495.58 (C28H33NO7), MS(ESI): 496.20 (M+H+).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:10][O:9][CH2:8][C@H:7]([O:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C@@H:6]([O:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C@H:5]([CH3:23])[O:4][C:3]1=[O:24].[OH:25][C:26]1[C:27]([C:34](O)=[O:35])=[N:28][CH:29]=[CH:30][C:31]=1[O:32][CH3:33].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:12]([O:11][C@@H:7]1[C@@H:6]([O:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C@H:5]([CH3:23])[O:4][C:3](=[O:24])[C@@H:2]([NH:1][C:34](=[O:35])[C:27]2[C:26]([OH:25])=[C:31]([O:32][CH3:33])[CH:30]=[CH:29][N:28]=2)[CH2:10][O:9][CH2:8]1)[CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: COc1ccnc(C(=O)O)c1O
Reactant: CC(C)CCO[C@H]1[C@H](C)OC(=O)[C@@H](N)COC[C@@H]1OCCC(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccnc(C(=O)N[C@H]2COC[C@H](OCCC(C)C)[C@@H](OCCC(C)C)[C@H](C)OC2=O)c1O
Temperature: 25 °C
Yield: 42.3 %

Procedure:
(3S,7S,8S,9S)-3-amino-7,8-bis(isopentyloxy)-9-methyl-1,5-dioxonan-2-one (130 mg, 0.376 mmol) and 3-hydroxy-4-methoxypicolinic acid (70.0 mg, 0.414 mmol) were diluted with DCM (3763 μl). PyBOP (215 mg, 0.414 mmol) was added, followed by N-ethyl-N-isopropylpropan-2-amine (216 μl, 1.242 mmol), and the mixture was stirred at room temperature until thin layer chromatography (TLC) indicated complete consumption of starting material. The reaction mixture was purified by column chromatography (SiO2; hexanes/EtOAc) to furnish the title compound (79.1 mg, 0.159 mmol, 42.3% yield) as a white solid: mp 61-70° C.; IR (thin film) 3530, 3371, 2955, 2873, 1750, 1649, 1529, 1262 cm−1; 1H NMR (400 MHz, CDCl3) δ 11.94 (s, 1H), 8.67 (d, J=8.1 Hz, 1H), 8.01-7.98 (m, 1H), 6.87 (d, J=5.2 Hz, 1H), 5.04 (ddd, J=8.2, 6.8, 5.0 Hz, 1H), 5.01-4.89 (m, 1H), 4.05 (dd, J=11.9, 6.8 Hz, 1H), 3.94 (s, 3H), 3.92-3.85 (m, 1H), 3.85-3.78 (m, 2H), 3.66-3.58 (m, 2H), 3.57-3.48 (m, 2H), 3.26-3.14 (m, 2H), 1.69 (dp, J=13.4, 6.7 Hz, 2H), 1.51-1.38 (m, 7H), 0.90 (dt, J=6.2, 2.7 Hz, 12H); 13C NMR (101 MHz, CDCl3) δ 170.30, 168.94, 155.32, 148.72, 140.66, 130.22, 109.56, 85.02, 83.63, 75.28, 73.94, 73.17, 72.48, 69.35, 56.09, 52.12, 39.23, 38.95, 24.96, 22.91, 22.67, 22.62, 22.50, 18.59; HRMS-ESI (m/z) [M+Na]+ calcd for C25H40N2NaO8, 519.2677, found 519.2687.