Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:26][CH3:27])(=[O:25])=[O:24])=[CH:19][CH:18]=1.Cl[C:29]1[C:30]2[N:37]=[CH:36][N:35]([CH:38]([CH3:40])[CH3:39])[C:31]=2[N:32]=[N:33][CH:34]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CCOC(C)=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:29]2[C:30]3[N:37]=[CH:36][N:35]([CH:38]([CH3:40])[CH3:39])[C:31]=3[N:32]=[N:33][CH:34]=2)=[CH:4][C:3]=1[C:17]1[CH:18]=[CH:19][C:20]([S:23]([NH:26][CH3:27])(=[O:24])=[O:25])=[CH:21][CH:22]=1
Reactant: CNS(=O)(=O)c1ccc(-c2cc(B3OC(C)(C)C(C)(C)O3)ccc2F)cc1
Reactant: CC(C)n1cnc2c(Cl)cnnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CNS(=O)(=O)c1ccc(-c2cc(-c3cnnc4c3ncn4C(C)C)ccc2F)cc1
Temperature: 120 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
To a solution of 2′-fluoro-N-methyl-5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-4-sulfonamide (Preparation 44, 112 mg, 0.29 mmol) and 4-chloro-7-isopropyl-7H-imidazo[4,5-c]pyridazine (Preparation 6, 54 mg, 0.27 mmol) in anhydrous dioxane (1.6 mL) was added aqueous Na2CO3 solution (2M, 0.41 mL, 0.81 mmol) and a stream of nitrogen gas was bubbled through the suspension for 5 minutes. Tetrakistriphenylphosphine palladium(0) (5.8 mg, 0.005 mmol) was added and the mixture was heated under microwave irradiation at 120° C. for 12 minutes. The reaction mixture was cooled and diluted with EtOAc (15 mL) and water (30 mL). The organic phase was extracted and the aqueous layer was back-extracted with EtOAc (2×15 mL). The organic layers were combined, washed with brine, dried over Na2SO4, filtered and the filtrate was evaporated in vacuo to leave a tan solid that was suspended in EtOAc (2.5 mL) and stirred at room temperature for 18 hours. The solid was filtered, rinsed with EtOAc (2×1 mL) and further dried to afford the title compound as an off-white solid in 82% yield, 120 mg.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][C@H:5]([N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:18][C:19]2[C:23]3[C:24]([CH3:29])=[CH:25][C:26]([CH3:28])=[CH:27][C:22]=3[S:21][N:20]=2)[C:8]1=[O:30])[CH3:6].[Li+].[OH-].Cl>C1COCC1.O>[CH3:29][C:24]1[C:23]2[C:19]([CH2:18][N:9]3[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:16](=[O:17])[N:7]([C@H:5]([CH3:6])[CH2:4][C:3]([OH:31])=[O:2])[C:8]3=[O:30])=[N:20][S:21][C:22]=2[CH:27]=[C:26]([CH3:28])[CH:25]=1
Reactant: COC(=O)C[C@@H](C)n1c(=O)c2ccccc2n(Cc2nsc3cc(C)cc(C)c23)c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)c2c(Cn3c(=O)n([C@H](C)CC(=O)O)c(=O)c4ccccc43)nsc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (R)-3-[1-(4,6-dimethyl-1,2-benzisothiazol-3-ylmethyl)-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-butyric acid methyl ester (60 mg, 0.14 mmol) in THF (1 mL) is added a solution of LiOH (8.5 mg, 0.20 mmol) in water (0.5 mL) and the resulting mixture is agitated at ambient temperature for 24 hours, heated at 50° C. for 6 hours, then agitated an additional 48 hours at ambient temperature. The reaction mixture is neutralized with 1N HCl (0.2 mL) then extracted with ethyl acetate (2×10 mL). The combined extracts are washed with water (1×10 mL) and brine (1×10 mL), dried with sodium sulfate and concentrated to provide the title compound. LCMS (ESMS): m/z 410 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[C:21]([CH3:30])[CH:20]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[C:21]([CH3:30])[CH:20]=2)=[O:13])=[CH:14][CH:15]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(CN)ccc1NS(C)(=O)=O
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(CNC(=O)COc2ccc(C(C)(C)C)cc2)ccc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 57.7 %

Procedure:
To a N,N-dimethylformamide (DMF) (15 ml) solution of (4-tert-butylphenoxy)acetic acid (312 mg, 1.50 mmol) and N-[4-(aminomethyl)-2-methylphenyl]methanesulfonamide hydrochloride (451 mg, 1.80 mmol), 1-ethyl-3-(3′-dimethylaminopr6pyl)carbodiimide hydrochloride (EDC) (518 mg, 2.70 mmol), 4-(dimethylamino)pyridine (DMAP) (55 mg, 0.45 mmol) and triethylamine (607mg, 6.0 mmol) were added and the mixture was stirred for 15 hours at ambient temperature. The reaction mixture was then quenched with saturated aqueous solution of sodium bicarbonate and then crude products were extracted with methylene dichloride. The organic layer was then washed with brine, dried over sodium sulfate. After filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give a residue, which was applied to an amino bound silica gel chromatography column and eluted with methylene dichloride/methanol=100/1 to furnish 350 mg (58% yield) of the title compound as a white solid.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:12][CH2:13][CH:14]([OH:17])[CH2:15]O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([CH:5]1[CH2:6][CH2:7][C:8]2([O:17][CH:14]([CH2:13][Cl:12])[CH2:15][O:11]2)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OCC(O)CCl
Reactant: CC(C)(C)C1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)C1CCC2(CC1)OCC(CCl)O2
Yield: 99 %

Procedure:
97.0 g (0.597 mol) of 4-t-butylcyclohexanone and 134.7 g (1.184 mol) of 3-chloro-1,2-propanediol are dissolved in 1100 ml of toluene in the presence of 11.5 g (0.060 mol) of PTSA. The mixture is brought to reflux for 6 hours while removing the water formed using a Dean-Stark trap. The reaction mixture is brought to room temperature and washed twice with 1500 ml of an aqueous solution containing 5% of NaHCO3. The organic phase is dried over MgSO4 and concentrated under vacuum. The residual oil is used directly in the following step (yield: 99%; NMR analysis).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:22][C:23]2[S:24][CH:25]=[C:26]([CH3:28])[N:27]=2)=[N:11][CH:12]=[C:13]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C([Cl:35])C=C(C(OO)=[O:37])C=1>>[ClH:35].[CH2:1]([O:8][C:9]1[C:10]([NH:22][C:23]2[S:24][CH:25]=[C:26]([CH3:28])[N:27]=2)=[N:11][CH:12]=[C:13]([S:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:37])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1csc(Nc2ncc(Sc3ccccc3)cc2OCc2ccccc2)n1
Product: Cc1csc(Nc2ncc(S(=O)c3ccccc3)cc2OCc2ccccc2)n1
Product: Cl
Yield: 50.5 %

Procedure:
3-(Benzyloxy)-N-(4-methylthiazol-2-yl)-5-(phenylthio)pyridin-2-amine (0.049 g, 0.121 mmol) (prepared according to Example 7; 0.049 g, 0.121 mmol) and MCPBA (0.0398 g, 0.166 mmol) were reacted according to Example 8 to provide 3-(benzyloxy)-N-(4-methylthiazol-2-yl)-5-(phenylsulfinyl)pyridin-2-amine hydrochloride (0.028 g, 50.6% yield). 1H NMR (DMSO-d6) δ 8.25 (d, 1H), 7.70 (m, 2H), 7.59 (s, 1H), 7.56 (m, 5H), 7.34 (m, 3H), 6.79 (s, 1H), 5.31 (s, 2H), 2.28 (s, 3H). Mass spectrum (apci) m/z=422.0 (M+H-HCl).
Reaction SMILES: O.NN.[CH3:4][N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:8]([O:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)[C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:6]1>[Pd].C(O)C>[NH2:23][C:20]1[CH:19]=[CH:18][C:17]([O:16][C:8]2[C:7]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[N:6][N:5]([CH3:4])[C:9]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:22][CH:21]=1
Reactant: Cn1nc(-c2ccccc2)c(Oc2ccc([N+](=O)[O-])cc2)c1-c1ccccc1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: Cn1nc(-c2ccccc2)c(Oc2ccc(N)cc2)c1-c1ccccc1
Yield: 101.9 %

Procedure:
Hydrazine hydrate (3 ml, 60% solution) is added to a well stirred mixture of 1-methyl-4-(p-nitrophenoxy)-3,5-diphenylpyrazole (2.56 g, 0.0069 mole), 5% Pd on carbon (0.4 g) and absolute ethanol (40 ml). Gas bubbles form immediately and an exotherm (ca. 50° C.) is observed. After the reaction subsides, the reaction mixture is refluxed for 2 hours. The reaction mixture is cooled slightly and filtered to remove the catalyst. The filtrate is stripped in vacuo to give a white solid 2.4 g (100%), m.p. 167° C. to 169° C. Recrystallization from benzene (20 ml) affords a white solid m.p. 167° C. to 168° C.
Reaction SMILES: [C:1]([C:3]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=2[Cl:15])=[CH:6][NH:5][CH:4]=1)#[N:2].N12CCCC=C1CCCCN2.[O:27]=[CH:28][C:29]([Cl:32])([Cl:31])[Cl:30].[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>O1CCCC1.C(N(CC)CC)C>[CH3:33][O:34][CH2:35][C:36]([O:27][CH:28]([N:5]1[CH:4]=[C:3]([C:1]#[N:2])[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=2[Cl:15])=[CH:6]1)[C:29]([Cl:32])([Cl:31])[Cl:30])=[O:37]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: COCC(=O)Cl
Reactant: N#Cc1c[nH]cc1-c1cccc(Cl)c1Cl
Agent: C1=C2CCCCNN2CCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCC(=O)OC(n1cc(C#N)c(-c2cccc(Cl)c2Cl)c1)C(Cl)(Cl)Cl
Temperature: -5 °C
Reaction time: 1 h

Procedure:
4.8 g of 3-cyano-4-(2,3-dichlorophenyl)pyrrole are dissolved in 50 ml of tetrahydrofuran and to the solution are added 0.2 ml of diazabicyclo[5.4.0]undec-7-ene and then 2.3 ml of chloral. The solution is cooled to -5° C., then 3.3 ml of triethylamine are added dropwise. The reaction mixture is stirred for 1 hour at -5° C. and then a solution of 2.2 ml of methoxyacetyl chloride in 10 ml of tetrahydrofuran is slowly added dropwise at -10° to -5° C. After it has been stirred for 1 hour in a thawing cooling bath, the reaction mixture is poured into ice-water and extracted twice with ethyl acetate. The organic extracts are washed twice with cold dilute hydrochloric acid and twice with a cold semi-saturated solution of sodium chloride, then dried over sodium sulfate and filtered. The filtrate is concentrated and the residue is crystallised from petroleum ether, affording colourless crystals of the title compound with a melting point of 88°-90° C.
Reaction SMILES: [OH-:1].[Na+].[Si]([O:20][CH2:21][C@@H:22]1C[C@H:23]1[CH2:25]C#N)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:28][CH2:29][OH:30]>O>[OH:30][CH2:29][C@@H:28]1[CH2:25][C@H:23]1[CH2:22][C:21]([OH:20])=[O:1]
Reactant: CC(C)(C)[Si](OC[C@@H]1C[C@H]1CC#N)(c1ccccc1)c1ccccc1
Reactant: [OH-]
Reactant: CCO
Agent: [Na+]
Solvent: O
Product: O=C(O)C[C@@H]1C[C@H]1CO
Temperature: 80 °C
Reaction time: 5 h
Yield: 134 %

Procedure:
8M Aqueous sodium hydroxide solution (1 mL) was added to a mixture of trans-2-(2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl) acetonitrile (100 mg, 0.29 mmol) in EtOH (2 mL) and water (1 mL), and the mixture was stirred at 80° C. for 5 hr. The reaction mixture was allowed to be cooled to room temperature, and washed with toluene. The aqueous layer was acidified with 6M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give trans-2-(2-(hydroxymethyl)cyclopropyl)acetic acid (50.0 mg, 0.384 mmol, 134%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[Br:21]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:21][C:6]1[N:7]=[C:2]([Cl:1])[C:3]([N:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)=[N:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)nc2Cl)CC1
Temperature: 20 °C
Reaction time: 8 h
Yield: 94.1 %

Procedure:
A 500 mL round bottom flask was charged with tert-butyl 4-(3-chloropyrazin-2-yl)piperazine-1-carboxylate (13.5 g, 45.3 mmol), N-bromosuccinimide (10.48 g, 58.9 mmol) and CHCl3 (150 mL). The resulting mixture was stirred at 20° C. overnight and it became a clear solution. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel with 0-10% EtOAc in petroleum ether, to afford 16.1 g (94%) of the product as a white solid. 1H NMR (300 MHz, CDCl3) δ: 8.18 (s, 1H), 3.57 (m, 4H), 3.39 (m, 4H), 1.48 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:11]1([Mg]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]([NH2:5])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#Cc1ccc(Cl)cc1Cl
Reactant: Br[Mg]c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(c1ccccc1)c1ccc(Cl)cc1Cl

Procedure:
The title compound was prepared from 2,4-dichloro benzonitrile and a) phenyl magnesium bromide b) NaBH4 in MeOH in analogy to known methods.9
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][CH3:10])=[C:7]([N+]([O-])=O)[CH:6]=[CH:5][N:4]=1)#[N:2].[CH3:14][O-:15].[Na+].[Na]>CO.O>[C:1]([C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:15][CH3:14])[CH:6]=[CH:5][N:4]=1)#[N:2]
Reactant: COc1c([N+](=O)[O-])ccnc1C#N
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CO
Product: COc1ccnc(C#N)c1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
3 g (0.017 moles) of 2-cyano-3-methoxy-4-nitropyridine obtained in Example a) and a sodium methoxide solution prepared from 0.77 g (0.033 moles) of sodium and 65 ml of methanol are stirred at ambient temperature for 4 hours. There is added 100 ml of water, the methanol is eliminated and the aqueous phase is extracted with dichloromethane. The organic phase is washed with water, dried, concentrated and the residue chromatographed (ethyl acetate/heptane, 1:1) to obtain 1.96 g (72% yield) of a white solid (MP=133° C.).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:16][C:17]([F:21])([F:20])[CH2:18][OH:19]>CN(C=O)C.O>[CH3:9][S:8][C:4]1[N:3]=[C:2]([O:19][CH2:18][C:17]([F:21])([F:20])[F:16])[CH:7]=[CH:6][N:5]=1
Reactant: OCC(F)(F)F
Reactant: CSc1nccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nccc(OCC(F)(F)F)n1
Reaction time: 64 h
Yield: 103 %

Procedure:
To a solution of 4-chloro-2-methylthiopyrimidine (16.0 g) and potassium carbonate (27.6 g) in DMF (90 ml) at 0° C., was added with stirring a solution of 2,2,2-trifluoroethanol (10.0 g) in DMF (10 ml). Stirring was continued for 64 hours, then the reaction mixture was diluted with water and extracted with ether (3×150 ml). The combined extracts were washed with brine, dried and concentrated to give 2-methylthio-4-(2,2,2-trifluoroethoxy)pyrimidine (23.0 g, crude yield) as a clear pale orange oil, 1H NMR δ 2.57(3H,s); 4.79(2H,q); 6.54(1H,d); 8.33(1H,d) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:39][C:40]1[CH:45]=[CH:44][C:43]([NH:46][C:47]([C@@H:49]2[CH2:53][CH2:52][CH2:51][N:50]2[C:54]([O:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[O:55])=[O:48])=[CH:42][CH:41]=1>>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:39][C:40]3[CH:45]=[CH:44][C:43]([NH:46][C:47]([C@@H:49]4[CH2:53][CH2:52][CH2:51][N:50]4[C:54]([O:56][CH2:57][C:58]4[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=4)=[O:55])=[O:48])=[CH:42][CH:41]=3)=[O:21])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:37])[CH3:38])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Nc1ccc(NC(=O)[C@@H]2CCCN2C(=O)OCc2ccccc2)cc1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(NC(=O)[C@@H]5CCCN5C(=O)OCc5ccccc5)cc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Yield: 64.9 %

Procedure:
The product from Example 1E (0.15 g, 0.28 mmol) and the Product from Example 3B (0.134 g, 0.395 mmol) were processed in the same manner as Example 1K to give a solid (0.155 g, 64%).
Reaction SMILES: Cl.[C:2]([C:4]1([NH:10][C:11]([CH:13]([NH:19][C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:12])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#[N:3].[N:28]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CN1CCOCC1>C(Cl)Cl>[C:2]([C:4]1([NH:10][C:11]([CH:13]([NH:19][C:20]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)=[O:21])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:12])[CH2:5][CH2:6][N:7]([C:34]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:35])[CH2:8][CH2:9]1)#[N:3]
Reactant: CC(C)(C)CC(NC(=O)N1CCOCC1)C(=O)NC1(C#N)CCNCC1
Reactant: O=C(Cl)N1CCOCC1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)CC(NC(=O)N1CCOCC1)C(=O)NC1(C#N)CCN(C(=O)N2CCOCC2)CC1

Procedure:
The title compound is prepared from morpholine-4-carboxylic acid [1-(4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide hydrochloride and 4-morpholine carbonyl chloride in the presence of a tertiary amine base such as N-methylmorpholine in a solvent such as methylene chloride.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1([C:10]([F:13])([F:12])[F:11])[O:7][CH:6]([CH2:8][OH:9])[CH2:5][O:4]1.[O:16]([C:18]#[N:19])[Na].FC(F)(F)C(O)=O>C(Cl)Cl>[F:13][C:10]([F:11])([F:12])[C:3]1([C:2]([F:1])([F:14])[F:15])[O:7][CH:6]([CH2:8][O:9][C:18](=[O:16])[NH2:19])[CH2:5][O:4]1
Reactant: N#CO[Na]
Reactant: OCC1COC(C(F)(F)F)(C(F)(F)F)O1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)OCC1COC(C(F)(F)F)(C(F)(F)F)O1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
A mixture of 15 grams of 2,2-bis(trifluoromethyl)-4-hydroxymethyl-1,3-dioxolane (0.0625 mols), 8.12 grams NaOCN (0.125 mols), and 75 ml methylene dichloride is stirred at 25°-35° C. while 14.3 grams trifluoroacetic acid is added dropwise. The mixture is stirred for 16 hours at 40° C. The product is filtered and the filter cake washed with methylene dichloride. The filtrate is washed with water and dried over Na2SO4 prior to vacuum-stripping. The reaction product is recrystallized from 1 part benzene to yield 2,2-bis(trifluoromethyl)-4-carbamoyloxymethyl-1,3-dioxolane (m.p. 52°-54° C.)
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@H:9]([CH2:18][OH:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.[C:20]([N:24]=[C:25]=[S:26])([CH3:23])([CH3:22])[CH3:21]>C(O)C>[C:20]([NH:24][C:25]([NH:8][C@@H:9]([CH2:18][OH:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[S:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)N=C=S
Reactant: N[C@@H](CO)Cc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)NC(=S)N[C@@H](CO)Cc1ccc(O)cc1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
0.15 cm3 of triethylamine is added to a solution of 0.2 g of 4-[(2R)-2-amino-3-hydroxypropyl]phenol in 10 cm3 of absolute ethanol, followed by addition of 0.18 cm3 of tert-butyl isothiocyanate. The mixture is stirred at a temperature in the region of 20° C. for 18 hours and is then heated at a temperature in the region of 60° C. for 4 hours. After cooling, the reaction medium is evaporated under reduced pressure (1 kPa) at a temperature in the region of 40° C. and then chromatographed under an argon pressure of 60 kPa on a column of silica gel (particle size 40-63μ; diameter 2.5 cm; height 29 cm), eluting with a mixture of dichloromethane/methanol (98/2 by volume). The fractions containing the expected product are combined and then concentrated under the above conditions. 0.2 g of N-(tert-butyl)-N′-[(1R)-1-hydroxymethyl-2-(4-hydroxyphenyl)ethyl]thiourea is obtained in the form of a colourless viscous oil [1H NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 1.42 (s: 9H); 2.63 (dd, J=13.5 and 8 Hz: 1H); 2.72 (dd, J=13.5 and 5.5 Hz: 1H); from 3.25 to 3.40 (mt: 2H); 4.29 (unresolved complex: 1H); 4.83 (t, J=4.5 Hz: 1H); 6.67 (d, J=8 Hz: 2H); 7.05 (d, J=8 Hz: 2H); 7.15 (d, J=8 Hz: 1H); 7.26 (broad s: 1H); 9.16 (s: 1H)].
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]3[O:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=3)[CH:19]([CH2:33][OH:34])[CH2:18]2)=[C:13]([CH3:35])[N:12]([CH2:36][C:37]2[C:42]([C:43]([F:46])([F:45])[F:44])=[CH:41][CH:40]=[CH:39][C:38]=2[F:47])[C:11]1=[O:48])(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[NH2:7][C@H:8]([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]3[O:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=3)[CH:19]([CH2:33][OH:34])[CH2:18]2)=[C:13]([CH3:35])[N:12]([CH2:36][C:37]2[C:42]([C:43]([F:45])([F:46])[F:44])=[CH:41][CH:40]=[CH:39][C:38]=2[F:47])[C:11]1=[O:48]
Reactant: Cc1c(N2CCN(Cc3ccc(C(F)(F)F)o3)C(CO)C2)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(N2CCN(Cc3ccc(C(F)(F)F)o3)C(CO)C2)c(=O)n(C[C@H](N)c2ccccc2)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Reaction time: 1 h
Yield: 79.8 %

Procedure:
To a solution of ((R)-2-{3-(2-fluoro-6-trifluoromethyl-benzyl)-5-[3-hydroxymethyl-4-(5-trifluoromethyl-furan-2-ylmethyl)-piperazin-1-yl]-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl}-1-phenyl-ethyl)-carbamic acid tert-butyl ester (17 mg, 0.022 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (100 μl, 1.30 mmol), followed by at room temperature for 1 hr. The solution was neutralized with an aqueous saturated sodium bicarbonate solution. After concentration of the organic layer thus formed, the residue was purified using silica gel chromatography (eluent: dichloromethane/methanol, 10/1) and dried in a vacuum to afford 12 mg of the compound as a white foam (yield 81%). 1H NMR (300 MHz, CDCl3) δ 2.29 (3H, s), 2.50 (3H, m), 2.86 (2H, m), 3.50-3.76 (3H, m), 3.95 (2H, m), 4.04 (2H, m), 4.21 (1H, t), 4.36 (1H, dd), 5.40 (2H, dd), 6.30 (1H, s), 6.73 (1H, s), 7.22 (2H, m), 7.33 (2H, t), 7.40 (3H, m), 7.54 (1H, d) MS (ESI) m/z 684.4 (MH+)
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[F:15][C:16]([F:48])([F:47])[O:17][C:18]1[CH:46]=[CH:45][C:21]([CH2:22][N:23]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[N:25]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])=[CH:35][CH:34]=3)[C:24]2=O)=[CH:20][CH:19]=1.[OH-].[Na+]>C1(C)C=CC(C)=CC=1.O>[F:15][C:16]([F:48])([F:47])[O:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][N:23]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[N:25]([CH2:32][C:33]3[CH:34]=[CH:35][C:36]([NH:39][S:40]([CH3:43])(=[O:41])=[O:42])=[CH:37][CH:38]=3)[C:24]2=[S:2])=[CH:45][CH:46]=1
Reactant: CS(=O)(=O)Nc1ccc(Cn2c(=O)n(Cc3ccc(OC(F)(F)F)cc3)c3ccccc32)cc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccc(C)cc1
Product: CS(=O)(=O)Nc1ccc(Cn2c(=S)n(Cc3ccc(OC(F)(F)F)cc3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
Phosphorus pentasulfide (444 mg, 1.0 mmol) was added to a suspension of N-{4-[3-(4-trifluoromethoxybenzyl)-2-oxo-2,3-dihydrobenzimidazol-1-ylmethyl]phenyl}methanesulfonamide (7) (300 mg, 0.61 mmol) in para-xylene (20 mL) under a blanket of argon. The reaction mixture was heated to the boil over a period of 10 h. Following cooling, there was added to the reaction mixture water (1 mL) followed by 2N NaOH solution in water (10 mL), and the mixture was stirred at RT for 30 min. The reaction mixture was extracted with ethyl acetate (4×20 mL). The combined organic phases were dried over Na2SO4 and the solvent removed in vacuo. After purifying the residue by means of column chromatography (SiO2; cyclohexane/EtOAc 2:1), the desired product N-{4-[3-(4-trifluoromethoxybenzyl)-2-thioxo-2,3-dihydrobenzimidazol-1-ylmethyl]phenyl}methanesulfonamide (8) (162 mg, 52% of theory, mp: 167-170° C.) was obtained. After recrystallizing from methanol, there were obtained crystals having a melting point of 175-179° C.