Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[OH-].[C:3]1([B+2])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F-].[K+].Cl[C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[CH2:15][C:16]#[N:17]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.C1COCC1>[C:16]([CH2:15][C:14]1[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)#[N:17]
Reactant: N#CCc1ccccc1Cl
Reactant: [B+2]c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: C1CCOC1
Product: N#CCc1ccccc1-c1ccccc1
Yield: 92.1 %

Procedure:
An oven dried resealable Schlenk tube was evacuated and backfilled with argon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol %), 2-(di-tert-butylphosphino)biphenyl (6.0 mg, 0.020 mmol, 2.0 mol %), phenylboron dihydroxide (183 mg, 1.5 mmol), and potassium fluoride (174 mg, 3.0 mmol). The tube was evacuated and backfilled with argon, and THF (1 mL) and 2-chlorobenzyl cyanide (152 mg, 1.0 mmol) were added through a rubber septum. The tube was sealed with a teflon screwcap, and the reaction mixture was stirred at room temperature until the starting aryl chloride had been completely consumed as judged by GC analysis. The reaction mixture was then diluted with ether (30 mL) and poured into a separatory funnel. The mixture was washed with 1.0 M NaOH (20 mL), and the aqueous layer was extracted with ether (20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography on silica gel to afford 178 mg (92%) of the title compound.
Reaction SMILES: [OH-].[NH4+:2].[F:3][C:4]([F:13])([F:12])[C:5]1[CH:6]=[CH:7][C:8](=O)[O:9][CH:10]=1.[OH-].[Na+].Cl>O>[F:3][C:4]([F:13])([F:12])[C:5]1[CH:6]=[CH:7][C:8](=[O:9])[NH:2][CH:10]=1
Reactant: O=c1ccc(C(F)(F)F)co1
Reactant: [NH4+]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1ccc(C(F)(F)F)c[nH]1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To 2 cc of concentrated ammonium hydroxide was added 0.1 g of this new 5-trifluoromethyl-2-pyrone compound isolated in Example 4 and the mixture was stirred for 0.5 hours. The mixture was cooled to 20° C., 1 cc of 50% sodium hydroxide solution was added and the mixture then boiled for 5 minutes. The solution was cooled to 20° C., diluted with 5 cc of water and the pH adjusted to 4 with concentrated hydrochloric acid. The solution was extracted with diethyl ether (3×25 cc), and the extract was evaporated under reduced pressure to give 5-trifluoromethyl-2-pyridone, mp 142°-145°, as in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=2)=[CH:19][CH:18]=1)=[O:15]>>[F:31][C:30]([F:33])([F:32])[C:27]1[CH:28]=[CH:29][C:24]([O:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][C:14](=[O:15])[N:11]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:10][C:6]=3[C:7](=[O:8])[NH2:9])[CH3:12])=[CH:18][CH:19]=2)=[N:25][CH:26]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CNc1ccc(Cl)cc1C(N)=O
Product: CN(C(=O)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)c1ccc(Cl)cc1C(N)=O

Procedure:
The title product was prepared from 5-chloro-2-(methylamino)-benzamide and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, preparative HPLC (method C) (31%, light yellow oil). HPLC-MS m/z=466.1 (M+1), Rt: 3.99 min.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:12][CH:11]=2)[C:5]([C:21]#[N:22])=[C:4]([SH:23])[N:3]=1.C(=O)(O)[O-].[Na+].Cl[CH2:30][C:31]1[N:32]=[C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)[S:34][CH:35]=1.O>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:14][CH:15]=2)[C:5]([C:21]#[N:22])=[C:4]([S:23][CH2:30][C:31]2[N:32]=[C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[S:34][CH:35]=2)[N:3]=1
Reactant: ClCc1csc(-c2ccccn2)n1
Reactant: COCCOc1ccc(-c2c(C#N)c(N)nc(S)c2C#N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1ccc(-c2c(C#N)c(N)nc(SCc3csc(-c4ccccn4)n3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg (0.15 mmol) of 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-sulphanyl-pyridine-3,5-dicarbonitrile are dissolved in 1 ml of DMF. 51.5 mg (0.61 mmol) of sodium bicarbonate and 58.6 mg (0.23 mmol) of 4-chloromethyl-2-(2-pyridyl)-1,3-thiazole are then added. The suspension is shaken RT overnight, and water is added. The precipitate is filtered off with suction, washed with ethanol and diethyl ether and dried at 40° C. under reduced pressure. This gives 67.4 mg (87.9% of theory) of product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9](O)[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([SH:25])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)C>S(Cl)(Cl)=O.CN(C)C=O.C(OCC)(=O)C.CCCCCC>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25][CH:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]=2)=[CH:21][CH:20]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: Cc1ccnc(C(O)c2cc(F)ccc2F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Cc1ccnc(C(Sc2ccc(Cl)cc2)c2cc(F)ccc2F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 151.2 %

Procedure:
After the 2-[(2,5-difluorophenyl)-hydroxymethyl]-4-methylpyridine (235 mg, 0.53 mmol) obtained in Referential Example 6 was dissolved in thionyl chloride (2.0 ml), a catalytic amount of dimethylformamide was added to the resulting solution. The resulting mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added dioxane, followed by further concentration. The residue thus obtained was dissolved in dimethylformamide (10 ml). To the resulting solution were added 4-chlorobenzenethiol (217 mg, 1.5 mmol) and potassium carbonate (828 mg, 6.0 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at 50° C. for 1 hour. After the reaction mixture was cooled to room temperature, diethyl ether (50 ml) was added thereto. The resulting mixture was washed with water and brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue thus obtained was subjected to silica gel chromatography (hexane:ethyl acetate=10:1) to give the title compound (290 mg, 80%) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[C:20](=[O:21])[N:19]([CH3:22])[C:12]3[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=3[CH:10]=2)=[CH:4][C:3]=1[NH:23][C:24]([NH:26][C:27]1[O:31][N:30]=[C:29]([C:32]([F:35])([F:34])[F:33])[CH:28]=1)=[O:25].[CH3:36][NH2:37].C1COCC1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[C:20](=[O:21])[N:19]([CH3:22])[C:12]3[N:13]=[C:14]([NH:37][CH3:36])[N:15]=[CH:16][C:11]=3[CH:10]=2)=[CH:4][C:3]=1[NH:23][C:24]([NH:26][C:27]1[O:31][N:30]=[C:29]([C:32]([F:35])([F:34])[F:33])[CH:28]=1)=[O:25]
Reactant: CSc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(F)(F)F)no4)c(F)cc3F)c(=O)n(C)c2n1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(F)(F)F)no4)c(F)cc3F)c(=O)n(C)c2n1
Yield: 13 %

Procedure:
Using a procedure analogous to Example A1, 1-(2,4-difluoro-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea (65 mg, 0.130 mmol) and 2.0N methylamine in THF (0.63 mL, 1.3 mmol) were combined to afford 1-(2,4-difluoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea (8 mg, 13% yield). MS (ESI) m/z: 496.0 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]>CCO.N.O.[Ni]>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][NH2:21])=[CH:18][CH:19]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(C#N)cc2)n1
Agent: [Ni]
Agent: N
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(CN)cc2)n1
Reaction time: 6 h

Procedure:
A suspension of [6-(4-cyano-phenyl)-pyridin-2-yl]carbamic acid tert-butyl ester (7.0 g, 24 mmol), Raney Ni (1.0 g) in EtOH (500 mL) and NH3.H2O (10 mL) was hydrogenated under H2 (50 psi.) at 50° C. for 6 h. The catalyst was filtered off and the filtrate was concentrated to dryness to give [6-(4-aminomethyl-phenyl)-pyridin-2-yl]-carbamic acid tert-butyl ester, which was used directly in next step. 1H NMR (300 MHz, CDCl3) δ 7.83-7.92 (m, 3 H), 7.70 (t, J=7.8 Hz, 1 H), 7.33-7.40 (m, 4 H), 3.92 (br s, 2 H), 1.53 (s, 9 H).
Reaction SMILES: [Na].Br[C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)=[C:7]([C:16](=[O:18])[CH3:17])[CH:6]=[C:5]([Cl:19])[C:4]=1[CH3:20].[CH2:21]([O:23][CH:24]([N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1)[CH3:25])[CH3:22]>O.C1(C)C=CC=CC=1.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>[Cl:19][C:5]1[C:4]([CH3:20])=[C:3]([C:29]2[CH:28]=[N:27][N:26]([CH:24]([O:23][CH2:21][CH3:22])[CH3:25])[CH:30]=2)[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)=[C:7]([C:16](=[O:18])[CH3:17])[CH:6]=1
Reactant: CCOC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(=O)c1cc(Cl)c(C)c(Br)c1-c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(C)n1cc(-c2c(C)c(Cl)cc(C(C)=O)c2-c2cccc(F)c2)cn1
Temperature: 80 °C
Yield: 31.8 %

Procedure:
To a solution of sodium hydrogenecarbonate (0.049 g, 0.58 mmol) in water (1 mL) was added a solution of 1-(6-bromo-4-chloro-3′-fluoro-5-methylbiphenyl-2-yl)ethanone (0.10 g, 0.29 mmol) in toluene (1 mL) followed by 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.093 g, 0.35 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.017 g, 0.015 mmol). The resulting mixture was bubbled with N2 for 5 min and then heated at 80° C. over a weekend. The organic layer was concentrated and purified on silica gel (eluting with 0-30% of ethyl acetate in hexanes) to give the desired product (37 mg, 32%). LCMS calculated for C22H23ClFN2O2 (M+H)+: m/z=401.1. found: 401.1.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=2)[C:8]([NH2:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:24][N:25]=[C:26]=[O:27]>C1(C)C=CC=CC=1>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=2)[C:8]([NH:10][C:26]([NH:25][CH3:24])=[O:27])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(N)=O)cc1[N+](=O)[O-]
Reactant: CN=C=O
Solvent: Cc1ccccc1
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c([N+](=O)[O-])c1
Temperature: 120 °C
Yield: 34 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionamide (126 mg, 0.37 mmol) and methyl isocyanate (211 mg, 3.70 mmol) in toluene (2 mL) was heated under reflux (120° C.) for 15 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo. The resulting yellow oil was treated with a small amount of a 1/1 mixture of hexanes/ethyl acetate, and a precipitate started to form. The material was further cooled in the freezer for 2 h to facilitate additional precipitation. The solid was collected by filtration and then dried in vacuo to afford 1-[3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionyl]-3-methyl-urea (50 mg, 35%) as a pale yellow solid: mp 241-242° C.; FAB-HRMS m/e calcd for C17H23N3O6S (M+H)+398.1386, found 398.1399.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][S:39]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)(=[O:41])=[O:40]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:45]3[CH2:46][CH2:47][N:42]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:43][CH2:44]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(S(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 1-methanesulfonyl-piperazine (Astatech) to give the title compound. HR-MS (ES, m/z) calculated for C34H42Cl2N5O4S [(M+H)+] 686.2329, observed 686.2329.
Reaction SMILES: C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[K+].[K+].[C:12]([C:15]1[N:16]=[CH:17][S:18][C:19]=1[C:20]([O:22]C)=[O:21])(=[O:14])[CH3:13].O.[OH-].[Li+]>CS(C)=O>[C:12]([C:15]1[N:16]=[CH:17][S:18][C:19]=1[C:20]([OH:22])=[O:21])(=[O:14])[CH3:13]
Reactant: COC(=O)c1scnc1C(C)=O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)c1ncsc1C(=O)O

Procedure:
Following the procedure of Example 28, methyl 4-ethyl-5-thiazolecarboxylate is reacted with NBS and AIBN to give methyl 4-(1-bromoethyl)-5-thiazolecarboxylate, which is then reacted with sodium bicarbonate, or alternatively with potassium carbonate, and DMSO and the resulting methyl 4-acetyl-5-thiazolecarboxylate is treated with lithium hydroxide monohydrate to yield 4-acetyl-5-thiazolecarboxylic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:7][CH2:6][CH:5]([C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]3[CH2:16][O:15]3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[N:20]#[C:21][NH2:22].[Na]>>[CH3:19][C:2]1([CH3:1])[CH2:3][CH2:4][CH:5]([C:8]2[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH:14]3[O:15][C:21]([NH2:22])=[N:20][CH2:16]3)=[CH:17][CH:18]=2)[CH2:6][CH2:7]1
Reactant: N#CN
Reactant: CC1(C)CCC(c2ccc(OCC3CO3)cc2)CC1
Agent: [Na]
Product: CC1(C)CCC(c2ccc(OCC3CN=C(N)O3)cc2)CC1

Procedure:
The title compound was prepared from 2-[4-(4,4-dimethyl-cyclohexyl)-phenoxymethyl]-oxirane and sodium hydrogen cyanamide according to the procedures employed for the preparation of the compound in Step 2 of Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(Cl)(Cl)[Cl:13]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([Cl:13])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: ClC(Cl)Cl
Product: O=C(Cl)Cc1ccc(Br)cc1

Procedure:
4-Bromophenylacetyl chloride is prepared according to the method described in Example 8 using 4-bromophenylacetic acid (2.75 g, 12.8 mmol) to give an oil which is dissolved in chloroform (10 mL). This solution is refluxed for 19 hours with a solution of (±)-trans-[2-(4-morpholinyl)]cyclohexanol (2.25 g, 12.2 mmol) in chloroform (10 mL) under nitrogen. The solvent is removed in vacuo, and the residue is treated as in Example 13 to give the crude free ester, which is then dissolved in 1M hydrochloric acid (70 mL). Sodium chloride (14 g) is added to the solution which is then extracted with chloroform (60 mL then 2×40 mL). The combined extracts are dried over sodium sulfate and the solvent removed in vacuo. The residue is recrystallised from hot ethyl acetate/methanol to give the title compound.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[CH:13]1([CH2:16][N:17]2[C:25]([N:26]3[CH2:31][C@H:30]([CH3:32])[NH:29][C@H:28]([CH3:33])[CH2:27]3)=[N:24][C:23]3[C:18]2=[N:19][C:20]([C:40]2[CH:41]=[N:42][C:43]([NH2:46])=[N:44][CH:45]=2)=[N:21][C:22]=3[N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH2:15][CH2:14]1>ClCCl.ClCCl.CO>[CH:13]1([CH2:16][N:17]2[C:25]([N:26]3[CH2:31][C@H:30]([CH3:32])[N:29]([S:9]([CH3:8])(=[O:11])=[O:10])[C@H:28]([CH3:33])[CH2:27]3)=[N:24][C:23]3[C:18]2=[N:19][C:20]([C:40]2[CH:41]=[N:42][C:43]([NH2:46])=[N:44][CH:45]=2)=[N:21][C:22]=3[N:34]2[CH2:35][CH2:36][O:37][CH2:38][CH2:39]2)[CH2:15][CH2:14]1
Reactant: C[C@@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC2CC2)C[C@H](C)N1
Reactant: CS(=O)(=O)Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC2CC2)C[C@H](C)N1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 13.1 %

Procedure:
Triethylamine (127.1 μl, 0.91 mmol) and methanesulfonyl chloride (35.3 ml, 0.46 mmol) were added to a dichloromethane suspension (2.0 ml) of 5-[9-(cyclopropylmethyl)-8-(cis-3,5-dimethylpiperazin-1-yl)-6-morpholin-4-yl-9H-purin-2-yl]pyrimidin-2-amine (105.9 mg, 0.23 mmol) with ice cooling and the resulting mixture was stirred at the same temperature for 2.5 hours and at room temperature for 4 hours. Triethylamine (127.1 μl, 0.91 mmol) and methanesulfonyl chloride (35.3 ml, 0.46 mmol) were added at room temperature and the resulting mixture was stirred for 16 hours followed by the addition of dichloromethane-methanol (10:1) and washed with water. The organic layer was dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was dissolved in 1,2-dichloroethane (2.0 ml). Triethylamine (127.1 μl, 0.91 mmol) and methanesulfonyl chloride (35.3 ml, 0.46 mmol) were added at room temperature and the resulting mixture was stirred for 19 hours followed by the addition of dichloromethane and washed with 10% aqueous citric acid solution. The organic layer was dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (dichloromethane:methanol=10:1) to give the title compound (16.3 mg, 13%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[S:11].[CH2:12]([N:19]1[C:23]2([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[NH:22][CH:21]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:20]1=[O:36])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([N:26]1[CH2:27][CH2:28][C:23]2([N:19]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:20](=[O:36])[CH:21]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[NH:22]2)[CH2:24][CH2:25]1)=[S:11]
Reactant: Fc1ccc(N=C=S)c(F)c1
Reactant: O=C1C(Cc2ccccc2)NC2(CCNCC2)N1Cc1ccccc1
Solvent: Cc1ccccc1
Product: O=C1C(Cc2ccccc2)NC2(CCN(C(=S)Nc3ccc(F)cc3F)CC2)N1Cc1ccccc1
Temperature: 25 °C

Procedure:
2,4-Difluorophenyl isothiocyanate (256 mg, 1.50 mmol was added to a solution of 1,3-dibenzyl-1,4,8-triazaspiro[4,5]decan-2-one (503 mg, 1.50 mmol) in toluene (14.3 ml) with stirring under a blanket of nitrogen at RT and the reaction mixture was stirred at 50° C. for 8 h. After removal of the solvent, the desired product 1,3-dibenzyl-2-oxo-1,4,8-triazaspiro[4,5]decane-8-thiocarboxylic acid (2,4-difluorophenyl)amide was obtained by means of preparative HPLC.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:13].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]1[C:23](O)=[O:24]>>[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]1[C:23]([NH:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:13])=[O:24]
Reactant: NC1Cc2ccccc2NC1=O
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: Cl
Product: O=C(NC1Cc2ccccc2NC1=O)c1cc2ccccc2[nH]1

Procedure:
The title compound was prepared by the methods of Example 5 using 3-amino-3,4-dihydrocarbostyril hydrochloride in place of (R)-3-amino-3,4-dihydrocarbostyril hydrochloride and indole-2-carboxylic acid in place of 5-chloroindole-2-carboxylic acid. HPLC/MS [M+H]+, 306; [M+Na]+, 328.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:4]([NH2:5])[C:3]=1[CH3:9].[C:10](O)(=[O:12])[CH3:11].C(OC(=O)C)(=O)C>O>[CH3:9][C:3]1[C:2]([Cl:1])=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C:10]([CH3:11])=[O:12]
Reactant: CC(=O)O
Reactant: Cc1c(N)cccc1Cl
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cccc(Cl)c1C

Procedure:
3-Chloro-o-toluidine (90 g) in a mixture of glacial acetic acid (90 ml) and acetic anhydride (90 ml) was heated on a steam bath for 10 minutes. The solution obtained was then poured into water. A colourless powder precipitated, which was filtered off and dried to give 3-chloro-2-methylacetanilide (104 g), m.p. 156°-159° C., which was then dissolved with stirring in concentrated sulphuric acid (230 ml), while maintaining the temperature at not more than 30° C. The stirred solution was maintained at 5°-10° C. whilst concentrated nitric acid (38 ml; S.G. 1.42) was added during 30 minutes. The solution obtained was then stirred at 0° C. for one hour and then poured on to ice. The solid precipitate which was obtained was separated by filtration, washed with water and dried, to give a mixture of nitro-acetanilides (145 g), m.p. 135°-147° C., in the form of a yellow powder. This mixture of nitroacetanilides (94 g) was then heated at reflux for 6 hours in a mixture of glacial acetic acid (560 ml) and concentrated hydrochloric acid (370 ml). The mixture was then cooled, poured into water (1200 ml) and basified by the addition of aqueous 50% sodium hydroxide solution. The yellow precipitate which was obtained was separated by filtration, washed with water and dried, to give a mixture of nitroanilines (72 g), m.p. 150°-164° C. This mixture was then steam-distilled in the presence of concentrated hydrochloric acid (200 ml). The solid which separated from the distillate was filtered off to give 3-chloro-2-methyl-4-nitroaniline (19.1 g), m.p. 152°-154° C., in the form of a yellow solid. Further steam distillation gave a distillate containing a mixture of products (8.6 g), m.p. 134°-138° C. The insoluble material, which had not been distilled, was separated from the acid solution to give 3-chloro-2-methyl-6-nitroaniline (18 g), m.p. 164°-165° C., in the form of a brown powder.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:10](OC(=O)C)(=[O:12])[CH3:11]>CCO>[F:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:5][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(N)cccc1F
Solvent: CCO
Product: CC(=O)Nc1cccc(F)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a solution of 3-fluoro-2-methylaniline (2.65 g, 21.2 mmol) in EtOH (25 mL) at 0° C. was added acetic anhydride (2.60 g, 25.5 mmol). The mixture was stirred at rt overnight then concentrated under reduced pressure to give the title compound (3.54 g). LCMS: m/z 168[M+H]+