Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.[SH:29][C:30]1[CH:31]=[C:32]([OH:36])[CH:33]=[CH:34][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.[Cu]I>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[S:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=1
Reactant: Oc1cccc(S)c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3I)n(-c3ccccc3)c(=O)c12
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Sc3cccc(O)c3)n(-c3ccccc3)c(=O)c12
Yield: 29.4 %

Procedure:
(S)-2-(1-((6-Amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.21 mmol) was treated with 3-mercaptophenol (39 mg, 0.31 mmol), potassium carbonate (128 mg, 0.93 mmol) and copper(I) iodide (59 mg, 0.31 mmol) in a microwave vessel with dichloromethane as a solvent according to the method described in Preparation 44. The residue was purified using SP1® Purification System (0% to 100%, hexane-ethyl acetate) to give 30 mg (30% yield) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](S(C)(=O)=O)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][N:34]([C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39])[CH2:33]1>O1CCOCC1>[NH2:1][C:2]1[N:3]=[C:4]([NH:31][CH:32]2[CH2:37][CH2:36][CH2:35][N:34]([C:38]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[O:39])[CH2:33]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)c1nc(N)nc2sc(CCc3ccc(F)cc3)nc12
Reactant: NC1CCCN(C(=O)OCc2ccccc2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Nc1nc(NC2CCCN(C(=O)OCc3ccccc3)C2)c2nc(CCc3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.2 %

Procedure:
To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-methanesulfonyl-thiazolo[5,4-d]pyrimidine (50 mg, 0.14 mmol) in 1,4-dioxane (5 ml) was added potassium carbonate (0.42 mmol) and benzyl 3-aminopiperidine-1-carboxylate hydrogen chloride (0.15 mmol). The reaction mixture was stirred at room temperature for 24 hours whereupon the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH2Cl2 to 1% CH3OH in CH2Cl2), yielding the pure title compound (59 mg) which was characterized by its mass spectrum: MS m/z (%): 507 ([M+H]+, 100).
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:4])[CH:2]=[CH2:3].[CH3:14][Si:15]([CH3:18])([CH3:17])Cl.O>C(C(C)=O)C(C)C>[C:1]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][Si:15]([CH3:18])([CH3:17])[CH3:14])=[CH:11][CH:12]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C[Si](C)(C)Cl
Reactant: C=CC(=O)OCc1ccc(O)cc1
Solvent: CC(=O)CC(C)C
Solvent: O
Product: C=CC(=O)OCc1ccc(O[Si](C)(C)C)cc1
Temperature: -5 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
1500 g of methyl isobutyl ketone and 100 g of 4-hydroxybenzyl acrylate werecharged into a separable flask of the same type as used in Reference Example 1, and cooled to -5° C. while replacing the flask inside gas with a nitrogen gas, and then 67 g of trimethylchlorosilane was dropwise added thereto over one hour, and then stirring was continued for 2 hours. After completion of the reaction, the reaction mixture was washedwith water and methyl isobutyl ketone was distilled off, whereby 83 g of p-trimethylsilyloxybenzyl acrylate of the following chemical formula was obtained (yield: 59%): ##STR10##
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[CH3:12][N:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14](Cl)=[O:15].N12CCN(CC1)CC2>ClCCl>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([O:1][C:14](=[O:15])[N:13]([CH3:12])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc2ncccc2c1
Reactant: CN(C(=O)Cl)c1ccccc1
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Product: CN(C(=O)Oc1ccc2ncccc2c1)c1ccccc1
Yield: 69.4 %

Procedure:
A solution of 6-hydroxyquinoline (1.00 g, 6.89 mmol), N-methyl-N-phenylcarbamoyl chloride (1.17 g, 6.89 mmol) and 1,4-diazabicyclo[2,2,2]octane (0.77 g, 6.89 mmol) in dichloromethane (20 mL) was stirred at room temperature for 1.25 hours. More dichloromethane was added and the solution was extracted with water. The organic layer was dried over sodium sulphate, filtered and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane 50:50). Evaporation of the solvent and recrystalllised from ethylacetate/heptane yielded the title compound (1.33 g, 69% yield) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([O:15]C1C(F)=C(F)C(F)=C(F)C=1F)(=[O:14])=O)=[CH:7]2.[N:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[N:29][CH:28]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C(O)(=O)C>>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([NH:33][C:30]1[CH:31]=[CH:32][N:27]=[CH:28][N:29]=1)(=[O:14])=[O:15])=[CH:7]2
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Br)cccc2c1
Reactant: Nc1ccncn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC(=O)O
Product: O=S(=O)(Nc1ccncn1)c1ccc2c(Br)cccc2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
A round bottom flask was charged with perfluorophenyl 5-bromonaphthalene-2-sulfonate (Intermediate M) (0.677 g, 1.494 mmol) and pyrimidin-4-amine (0.185 g, 1.942 mmol). A septum was attached and the flask flushed with N2. THF (7.47 mL) was added and the solution was cooled to −78° C., lithium bis(trimethylsilyl)amide (1.195 mL, 1.195 mmol) was added and after addition was complete, the cold bath was removed and the solution was allowed to warm to rt. After 30 min at rt, acetic acid (0.257 mL, 4.48 mmol) was added to the solution to produce a precipitate. The mixture was concentrated and the resulting tan solid was suspended in DCM (20 mL) and collected by vacuum filtration to provide 5-bromo-N-(pyrimidin-4-yl)naphthalene-2-sulfonamide (0.54 g) as a tan solid, which was of sufficient purity for further use.
Reaction SMILES: [Cl-].[NH4+].O.[Br:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C@@H:12]([CH3:15])[CH2:13][OH:14])=[C:7]([N+:16]([O-])=O)[CH:6]=1>C(O)C.[Fe]>[NH2:16][C:7]1[CH:6]=[C:5]([Br:4])[CH:10]=[CH:9][C:8]=1[NH:11][C@@H:12]([CH3:15])[CH2:13][OH:14]
Reactant: C[C@@H](CO)Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: C[C@@H](CO)Nc1ccc(Br)cc1N
Temperature: 80 °C
Reaction time: 4 h
Yield: 92.8 %

Procedure:
A 2-L, three-necked, round bottomed flask fitted with a nitrogen inlet, overhead stirrer, thermocouple, and condenser was charged with iron power (117 g, 2090 mmol), ammonium chloride (1.118 g, 20.90 mmol), ethanol (375 mL), and water (201 mL). The mixture was heated to 80° C., and a solution of (S)-2-(4-bromo-2-nitrophenylamino)propane-1-ol (57.5 g, 209 mmol) in ethanol (200 mL) was slowly added. The mixture stirred at 80° C. for 4 h. The reaction mixture was filtered through a pad of Celite and washed with ethanol (100 mL). The filtrate was concentrated under reduced pressure to remove the ethanol, and the resulting aqueous slurry stirred at rt for 3 h. The slurry was then filtered, and the solids were washed with water (100 mL) and dried under a nitrogen atmosphere overnight to afford (S)-2-(2-amino-4-bromophenylamino)propane-1-ol (47.55 g, 89%) as an off-white solid. MS (ESI, pos. ion) m/z 245 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.C=O.[CH3:15][C:16]1(C)O[C:21](=O)[CH2:20][C:18](=[O:19])[O:17]1.C([O-])(=O)C.[NH4+]>C(O)C>[CH2:16]([O:17][C:18](=[O:19])[CH2:20][CH2:21][C:3]1[C:4](=[O:12])[O:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:15]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=c1cc(O)c2ccccc2o1
Agent: C=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)CCc1c(O)c2ccccc2oc1=O
Temperature: 25 °C
Yield: 37.3 %

Procedure:
A solution of 4-hydroxy-chromen-2-one (2.0 g), aqueous formaldehyde (37%, 0.37 g), Meldrum's acid (1.77 g) and ammonium acetate (0.95 g) in ethanol (75 mL) was heated to reflux for 6 hours, then cooled to room temperature. The reaction mixture was conc. in vacuo to give the crude as yellow oil, which was purified by column chromatography to provide 3-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid ethyl ester as colorless oil (1.2 g).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([Cl:11])[C:3]=1[CH2:4]Cl.[Na].[SH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=1[O-:20]>>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([Cl:11])[C:3]=1[CH2:4][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=1[O-:20]
Reactant: ClCc1c(Cl)ccc(Cl)c1Cl
Reactant: [O-][n+]1ccccc1S
Agent: [Na]
Product: [O-][n+]1ccccc1SCc1c(Cl)ccc(Cl)c1Cl

Procedure:
The compound 2-(2,3,6-trichlorophenylmethylthio)-pyridine N-oxide is prepared from 2,3,6-trichlorobenzylchloride and 2-mercaptopyridine N-oxide sodium salt by the procedure employed in Example 1. Melting point 232° - 234°C. Yield quantative. Structure confirmed by IR and NMR.
Reaction SMILES: [C:1]([CH:5]([NH:13][NH:14][C:15]([C:17]1[CH:26]=[CH:25][C:20]2[O:21][CH2:22][CH2:23][O:24][C:19]=2[C:18]=1[CH2:27][CH3:28])=[O:16])[CH:6]=[C:7]([CH3:12])[C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([O:41][CH3:42])[C:39]=1[CH3:40])[C:34](Cl)=[O:35].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[C:1]([CH:5]([N:13]([C:34](=[O:35])[C:33]1[CH:37]=[C:38]([O:41][CH3:42])[C:39]([CH3:40])=[C:31]([O:30][CH3:29])[CH:32]=1)[NH:14][C:15]([C:17]1[CH:26]=[CH:25][C:20]2[O:21][CH2:22][CH2:23][O:24][C:19]=2[C:18]=1[CH2:27][CH3:28])=[O:16])[CH:6]=[C:7]([CH3:12])[C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1c(C(=O)NNC(C=C(C)C(C)(C)C)C(C)(C)C)ccc2c1OCCO2
Reactant: COc1cc(C(=O)Cl)cc(OC)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCc1c(C(=O)NN(C(=O)c2cc(OC)c(C)c(OC)c2)C(C=C(C)C(C)(C)C)C(C)(C)C)ccc2c1OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
5-Ethyl-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid N′-(1-tert-butyl-3,4,4-trimethyl-pent-2-enyl)-hydrazide (150 mg, 0.39 mmol) and 3,5-dimethoxy-4-methylbenzoyl chloride (83 mg, 0.39 mmol) were dissolved in 5 mL CH2Cl2. 5 mL of 25% K2CO3 were added, and the reaction mixture was stirred at room temperature overnight. The reaction was monitored by TLC. The phases were separated, adding additional CH2Cl2 and/or water as needed to aid manipulation. The CH2Cl2 layer was dried and solvent was removed in vacuo to provide 210 mg of crude product. This material was purified by silica gel column chromatography, eluting with a step gradient of 10-25% ethyl acetate in hexane to yield 3,5-dimethoxy-4-methyl-benzoic acid N-(1-tert-butyl-3,4,4-trimethyl-pent-2-enyl)-N′-(5-ethyl-2,3-dihydro-benzo[1,4]dioxine-6-carbonyl)-hydrazide RG115898 (83 mg, Rf=0.19 in 25% ethyl acetate in n-hexane, yield 38%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.19 (s, 1H), 6.75 (d, J=8.0 Hz, 1), 6.69 (s, 2H), 6.61 (d, J=8.0 Hz, 1H), 5.43 (d, J=10.0 Hz, 1H), 5.41 (d, 14.4 Hz, 1H), 4.30-4.20 (m, 4H), 3.80 (s, 6H), 2.21-2.15 (m, 1H), 2.01 (s, 3H), 1.81 (m, 1H), 1.76-1.64 (m, 1H), 1.06 (s, 9H), 1.00 (s, 9H), 0.70 (t, J=7.6 Hz, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6](=[S:8])[NH2:7].Br[CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[CH2:15]([O:14][C:12]([C:11]1[N:7]=[C:6]([C:2]2[NH:1][CH:5]=[CH:4][N:3]=2)[S:8][CH:10]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)c1ncc[nH]1
Product: CCOC(=O)c1csc(-c2ncc[nH]2)n1
Temperature: 75 °C
Yield: 57.1 %

Procedure:
A mixture of 1H-Imidazole-2-carbothioic acid amide (200 mg, 1.57 mmol) and Ethyl bromopyruvate (340 mg, 1.57 mmol) is heated at 75° C. for about 5 hours. After the volatiles are evaporated in vacuo, the residue is partitioned between Ethyl acetate (40 mL) and aqueous NaHCO3 (10 mL). The organic layer is separated, washed with water, dried and concentrated. The residue is purified on a silica gel column with 3% MeOH in CH2Cl2 as eluent to give 200 mg of the titled compound. 1H NMR (CDCl3): δ 8.15 (s, 1H), 7.20 (br, 1H), 7.10 (br, 1H), 4.33 (q, 2H), 1.23 (t, 3H). LRMS calcd 223. found 224 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].Cl.[CH3:13]O>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:13])=[O:8]
Reactant: CO
Reactant: Nc1ccc(F)c(C(=O)O)c1
Agent: Cl
Product: COC(=O)c1cc(N)ccc1F

Procedure:
5-Amino-2-fluorobenzoic acid (100 g) was suspended in 1.3 liters of methanol, 100 g of concentrated hydrochloric acid was gradually added thereto and the mixture was heated to reflux for 24 hours. Methanol was evaporated and the residue was poured into ice water, the mixture was neutralized with sodium bicarbonate and extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The crystals separated out therefrom were filtered to give 88 g of methyl 5-amino-2-fluorobenzoate.
Reaction SMILES: [OH-].[Na+].C([O:6][CH2:7][C:8]1[C:13]([CH3:14])=[C:12]([O:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])[CH:11]=[CH:10][N:9]=1)(=O)C>C(O)C>[OH:6][CH2:7][C:8]1[C:13]([CH3:14])=[C:12]([O:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])[CH:11]=[CH:10][N:9]=1
Reactant: COCCCOc1ccnc(COC(C)=O)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCCCOc1ccnc(CO)c1C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
500 mg of sodium hydroxide and 15 cc of ethanol were added to the 2-acetoxymethyl-4-(3-methoxypropoxy)-3-methylpyridine prepared above. The obtained mixture was stirred at 50° C. for one hour. After the completion of the reaction, the reaction mixture was distilled to remove the ethanol, followed by the addition of water. The obtained mixture was extracted with chloroform. The obtained chloroform layer was concentrated to obtain 450 mg of 2-hydroxymethyl-4-(3-methoxypropoxy)-3-methylpyridine as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2=[N:9][C:10]([C:12]3[CH:13]=[CH:14][C:15]([CH3:19])=[C:16]([CH:18]=3)[NH2:17])=[CH:11][N:5]2[N:4]=1.C([O-])([O-])=O.[K+].[K+].[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1>C(#N)C>[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH:17][C:16]2[CH:18]=[C:12]([C:10]3[N:9]=[C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[N:4][N:5]4[CH:11]=3)[CH:13]=[CH:14][C:15]=2[CH3:19])=[CH:29][CH:28]=1
Reactant: COc1ccc2nc(-c3ccc(C)c(N)c3)cn2n1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc2nc(-c3ccc(C)c(NCc4ccc(F)cc4)c3)cn2n1
Reaction time: 0.5 h
Yield: 34.5 %

Procedure:
An 8 mL vial is charged with 5-(6-methoxyimidazo[2,1-f]pyridazin-2-yl)-2-methyl-aniline (20.3 mg, 0.08 mmol) in acetonitrile (0.5 mL), K2CO3 (13 mg) and 4-fluorobenzyl bromide (19 mg, 0.1 mmol). The mixture is stirred for 30 min then filtered, and the filtrate is added into water (10 mL). Solids precipitated and are collected by filtration to give the title compound (10 mg, 34% yield) (compound same as Example 102). LCMS m/z=363.3 [M+H]+, tR=2.57 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C:7]([CH3:28])([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][N:17]2C(=O)C3=CC=CC=C3C2=O)[N:14]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].O.NN>C(O)C>[C:1]([O:5][C:6](=[O:29])[C:7]([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][NH2:17])[N:14]=1)([CH3:28])[CH3:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCN2C(=O)c3ccccc3C2=O)cs1
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCN)cs1
Yield: 81.6 %

Procedure:
2-Methyl-2-{[4-(2-phthalimidoethyl)-1,3-thiazol-2-yl]thio}propionic acid tert-butyl ester (136 g) synthesized in Example 6 was dissolved in ethanol (800 mL), hydrazine monohydrate (47.2 g) was added, and the mixture was refluxed for 4 hr. White precipitate was filtered off from the reaction mixture, and the filtrate was concentrated under reduced pressure. Water was added thereto, and the mixture was extracted with dichloroethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (77.6 g) as a brown oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH2:20])=[C:8]([CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])=[O:10])(=[O:3])[CH3:2].[CH3:21][S:22](Cl)(=[O:24])=[O:23].N1C=CC=CC=1>C1C=CC=CC=1>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:20][S:22]([CH3:21])(=[O:24])=[O:23])=[C:8]([C:9](=[O:10])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[CH:19]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(N)c(C(=O)c2ccc(F)cc2F)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(=O)c1ccc(NS(C)(=O)=O)c(C(=O)c2ccc(F)cc2F)c1
Temperature: 0 °C

Procedure:
A mixture of 5-acetyl-2-amino-2',4'-difluorobenzophenone (3.3 g), methanesulfonyl chloride (5.5 ml) and pyridine (1 ml) in benzene (30 ml) was refluxed for 4 hours. The reaction mixture was poured into ice-water (100 ml ) and extracted with ethyl acetate (100 ml). The extract was washed with an aqueous solution of sodium bicarbonate, dried and concentrated. The residue (5 g) was purified by column chromatography on silica gel (120 g) eluting with a mixture of toluene and ethyl acetate (20:1), and recrystallized from ethanol to afford yellow crystals of 4'-acetyl-2'-(2,4-difluorobenzoyl)methanesulfonanilide (1.5 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[C:17]([C:19]1[CH:20]=[C:21]([S:25](Cl)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1)#[N:18]>>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:25]([C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:17]#[N:18])[CH:20]=1)(=[O:27])=[O:26])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Product: N#Cc1cccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccccc2)c1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-amino-5-chloro-phenyl)-phenyl-methanone and 3-Cyano-benzenesulfonyl chloride. 1H NMR (CDCl3): δ 7.39-7.45 (m, 6H), 7.53-7.62 (m, 3H), 7.43 (d, J=8.4 Hz, 1H), 7.91 (bs, 2H), 9.77 (s, 1H). MS: m/z 396.9 (M++1).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[N:6]2)[CH2:2]1.[CH3:28][N:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:28][N:29]1[CH2:34][CH2:33][CH:32]([N:1]2[CH2:2][CH:3]([N:5]3[C:9]4=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]4[C:7]([C:15]4[CH:16]=[CH:17][C:18]([O:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[CH:19][CH:20]=4)=[N:6]3)[CH2:4]2)[CH2:31][CH2:30]1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CNC1
Reactant: CN1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CN1CCC(N2CC(n3nc(-c4ccc(Oc5ccccc5)cc4)c4c(N)ncnc43)C2)CC1
Temperature: 25 °C
Yield: 37.6 %

Procedure:
A mixture of 1-(3-azetanyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.06 g, 0.00017 mol), 1-methyl-4-piperidinone (0.057 g, 0.0005 mol), and acetic acid (0.03 g, 0.0005 mol) in dichloroethane (2.5 mL) was stirred at room temperature under an atmosphere of nitrogen for one and a half hours. Sodium triacetoxyborohydride (0.072 g, 0.00034 mol) was added to the mixture and stirred at ambient temperature under an atmosphere of nitrogen for two hours. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel using ammonium hydroxide/methanol/dichloromethane (2:15:83) as mobile phase to yield 1-[1-(1-methyl-4-piperidyl)-3-azetanyl]-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.029 g, 0.000064 mol).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11](C)[C:10]2C=C[C:15](=[O:20])[C:16]([O:18][CH3:19])=[CH:17][C:9]=2[C:8](=[O:21])[CH:7]=1)=[O:5])C>Cl>[O:21]=[C:8]1[CH:7]=[C:6]([C:4]([OH:3])=[O:5])[NH:11][C:10]2[C:15](=[O:20])[C:16]([O:18][CH3:19])=[CH:17][C:9]1=2
Reactant: CCOC(=O)c1cc(=O)c2cc(OC)c(=O)ccc2n1C
Agent: Cl
Product: COC1=Cc2c([nH]c(C(=O)O)cc2=O)C1=O

Procedure:
A solution of 4,7-dihydro-4,7-dioxo-6-methoxy-1-methyl-1H-cyclohepta[b]pyridine-2-carboxylic acid ethyl ester (2.0 g, described in Example 7) and 19% hydrochloric acid (60 ml) is refluxed for 30 min. The precipitate is collected and washed with water and acetone to give the title compound. The precipitate is dissolved in aqueous aminoethanol (1M, 4 ml) and acetone (50 ml) is added. The precipitate is collected, washed with acetone and crystallized from water-acetone to give crystals of the aminoethanol salt of the title compound, mp 236°-237° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[I-:12].[Na+]>CC(C)=O>[I:12][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: [I-]
Reactant: CCOC(=O)CCCCCBr
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCCCI
Yield: 100.1 %

Procedure:
To 112 ml of a solution of 13.38 g of ethyl 6-bromohexanoate in acetone, 26.97 g of sodium iodide was added and heated to reflux for 18 hours. The reaction solution was cooled, filtered to remove insolubles and washed with acetone. The filtrate was concentrated and, after addition of water, extracted with ethyl acetate. The organic layer was washed with water and brine sequentially, dried over anhydrous magnesium sulfate and concentrated to provide 16.21 g of the objective compound as red-yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:10]([CH3:12])[CH3:11])[C:7]([OH:9])=[O:8])=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CC(N(C)C)=O.[Cl:43][C:44]1[CH:45]=[CH:46][C:47]([F:74])=[C:48]([C:50]2[CH:55]=[CH:54][C:53]([CH2:56][N:57]([CH2:68][C@@H:69](O)[C:70]([OH:72])=[O:71])[NH:58][C:59]([C:61]3[O:65][N:64]=[C:63]([O:66][CH3:67])[CH:62]=3)=[O:60])=[CH:52][CH:51]=2)[CH:49]=1.CCN(C(C)C)C(C)C>>[C:70]([C@H:69]([O:8][C:7](=[O:9])[C@@H:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[CH:10]([CH3:12])[CH3:11])[CH2:68][N:57]([CH2:56][C:53]1[CH:54]=[CH:55][C:50]([C:48]2[CH:49]=[C:44]([Cl:43])[CH:45]=[CH:46][C:47]=2[F:74])=[CH:51][CH:52]=1)[NH:58][C:59]([C:61]1[O:65][N:64]=[C:63]([O:66][CH3:67])[CH:62]=1)=[O:60])([OH:72])=[O:71]
Reactant: COc1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)on1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COC(=O)N[C@H](C(=O)O[C@H](CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(OC)no1)C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.1 %

Procedure:
(S)-2-Methoxycarbonylamino-3-methylbutyric acid (5.7 mg, 32.3 μmol) and HATU (12.3 mg, 32.3 μmol) were stirred in DMA (1.0 mL, 11 mmol) for 15 minutes. (R)-3-[N-(5′-Chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-(3-methoxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid (10.0 mg, 21.6 μmol) and DIPEA (11.3 μL, 64.7 μmol) were added, and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was dissolved in AcOH (1.5 mL), filtered, and purification by reverse phase preparative HPLC to yield the title compound (2.7 mg). MS m/z [M+H]+ calc'd for C28H30ClFN4O9, 621.17. found 621.3.