Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][C:14](=[O:18])[NH:15]3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:19][C:20]1[N:21]=[CH:22][N:23]([C:25]2[CH:26]=[C:27]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=2)[C:28](O)=[O:29])[CH:24]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH3:19][C:20]1[N:21]=[CH:22][N:23]([C:25]2[CH:26]=[C:27]([CH:31]=[C:32]([C:34]([F:37])([F:35])[F:36])[CH:33]=2)[C:28]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]3[CH:17]=[C:16]4[C:12]([CH2:13][C:14](=[O:18])[NH:15]4)=[CH:11][CH:10]=3)[CH:3]=2)=[O:29])[CH:24]=1
Reactant: Cc1cn(-c2cc(C(=O)O)cc(C(F)(F)F)c2)cn1
Reactant: Nc1cccc(Nc2ccc3c(c2)NC(=O)C3)c1
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: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cn(-c2cc(C(=O)Nc3cccc(Nc4ccc5c(c4)NC(=O)C5)c3)cc(C(F)(F)F)c2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-(3-Amino-phenylamino)-1,3-dihydro-indol-2-one (36 mg, 0.15 mmol) and 3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzoic acid (53 mg, 0.195 mmol) in DMF (1.5 mL) is added N,N-diisopropylethylamine (78 μL, 0.45 mmol) followed by addition of HATU (63 mg, 0.165 mmol). The mixture is stirred at ambient temperature overnight. The mixture is diluted with EtOAc and washed with 10% Na2S2O3 aqueous solution and brine. The organic layer is separated, dried over MgSO4, and concentrated. The crude product is used in the next step without further purification: LC-MS: 492.1 (MH+).
Reaction SMILES: C([Li])(CC)C.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][Si](C(C)(C)C)(C)C)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[N:27]12[CH2:34][CH2:33][CH:30]([CH2:31][CH2:32]1)[C:29](=[O:35])[CH2:28]2.[ClH:36]>C1CCCCC1.O1CCCC1>[ClH:36].[OH:19][C:16]1[CH:15]=[CH:14][C:13]([C:10]2[CH:9]=[CH:8][C:7]([C:29]3([OH:35])[CH:30]4[CH2:33][CH2:34][N:27]([CH2:32][CH2:31]4)[CH2:28]3)=[CH:12][CH:11]=2)=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2ccc(Br)cc2)cc1
Reactant: O=C1CN2CCC1CC2
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: Oc1ccc(-c2ccc(C3(O)CN4CCC3CC4)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of sec-butyllithium in cyclohexane (7.4 ml, 1.3M) was added dropwise, with stirring, to a solution of 4-bromo-4'-(tert-butyldimethylsilyloxy)biphenyl (2.9 g) in dry tetrahydrofuran (30 ml) under an atmosphere of argon at -78° C. The mixture was stirred for 5 minutes and a solution of quinuclidin-3-one (0.9 g) in dry tetrahydrofuran (12 ml) was then added over a period of 2 minutes. The mixture was stirred at -78° C. for a further 30 minutes and the mixture then allowed to warm to room temperature over 2 hours. Aqueous 2M hydrochloric acid (18 ml) was added to the reaction mixture, whilst keeping the temperature of the reaction mixture below 10° C. The aqueous layer was separated and washed with diethyl ether (2×20 ml) before the addition of excess sodium hydroxide solution (density 1.35 g/cm3) to pH 14. The mixture was extracted with warm ethyl acetate (50° C.) and the ethyl acetate phase separated, dried (Na2SO4) and evaporated. The residue was dissolved in dry tetrahydrofuran (20 ml) and added to a solution of tetrabutyl ammonium fluoride in tetrahydrofuran (1.6 ml, 1.0M). The mixture was stirred at room temperature for 2 hours. The tetrahydrofuran was evaporated, an excess of saturated ethereal hydrogen chloride solution was added to precipitate a solid which was crystallised from methanol/ethyl acetate to give as a colourless solid, 3-(4'-hydroxybiphenyl-4-yl)-3-hydroxy-quinuclidine hydrochloride (0.93 g), m.p. 270°-271° C., microanalysis, found: C, 66.5; H, 6.5; N, 4.1%; C19H21NO2.HCl.0.66H2O requires: C, 66.5: H, 6.8: N, 4.1%; NMR ([CD3 ]2SO): 1.4-1.6(1H, m), 1.7-1.9(2H, m), 2.3-2.4(2H, m), 3.1-3.4(5H, m), 3.8-3.9(1H, d), 5.9(1H, s), 6.9-7.5(4H, d of d), 7.6(4H, s), 9.6(1H, s); m/Z 296 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([C:11]1[NH:12][C:13]([CH:17]=[O:18])=[C:14]([I:16])[N:15]=1)[CH2:8][CH2:9][CH3:10].Br[CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([C:31]([O:33][CH3:34])=[O:32])=[CH:23][CH:22]=1.O>CN(C)C=O>[CH3:34][O:33][C:31]([C:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21]([CH2:20][N:12]2[C:13]([CH:17]=[O:18])=[C:14]([I:16])[N:15]=[C:11]2[CH2:7][CH2:8][CH2:9][CH3:10])=[CH:22][CH:23]=1)=[O:32]
Reactant: COC(=O)c1ccc(CBr)c2ccccc12
Reactant: CCCCc1nc(I)c(C=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nc(I)c(C=O)n1Cc1ccc(C(=O)OC)c2ccccc12
Temperature: 70 °C
Reaction time: 15 h
Yield: 85.2 %

Procedure:
A suspension of 29.53 g (0.214 mol) of powdered potassium carbonate, 60.00 g (0.214 mol) of 2-butyl-4-iodoimidazole-5-carboxaldehyde and 65.68 g (0.235 mol) of methyl 4-bromomethylnaphthalene-1-carboxylate (E. A. Dixon, A. Fischer, and F. P. Robinson, Can. J. Chem. 59, 2629 (1981)) in 600 mL of dimethylformamide was stirred for 5 hours under argon at 70° C. An additional 6.56 g (0.0235 mol) of the bromomethyl ester was added and the suspension was stirred an additional 15 hours at 70° C. The reaction mixture was poured into water and the resulting solid was collected by filtration, washed with water, and triturated several times with 250 mL of boiling methanol to give 86.8 g (85%) of a solid; mp 177.5°-179° C.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:9]=[N:10][NH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl.Cl.[NH2:35][CH2:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:45](=[O:56])[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[C:52]([F:55])([F:54])[F:53])[CH2:41][CH2:40]1)=[O:38]>C(Cl)Cl.O>[O:38]=[C:37]([N:39]1[CH2:40][CH2:41][N:42]([C:45](=[O:56])[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[C:52]([F:55])([F:53])[F:54])[CH2:43][CH2:44]1)[CH2:36][NH:35][C:23]([N:10]1[CH:9]=[C:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:12]=[N:11]1)=[O:25]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: c1ccc(-c2cn[nH]c2)cc1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: O=C(CNC(=O)n1cc(-c2ccccc2)cn1)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.97 %

Procedure:
A mixture of 4-Phenyl-1H-pyrazole hydrochloride salt (prepared by the method described above)(44 mg, 0.3 mmol), DIPEA (88 mg, 0.119 ml, 0.685 mmol) and DCM (2 ml) was added to a stirred solution of triphosgene (36 mg, 0.12 mmol) in DCM (1 mL) at room temperature. After 30 minutes, to the above solution, a mixture of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (prepared by the method described above)(108 mg, 0.3 mmol), DIPEA (88 mg, 0.119 ml, 0.685 mmol) and DCM (2 ml) was added and the resulting mixture was stirred at room temperature for 30 minutes. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 30-70% EtOAc in Hexane as eluent) to afford 48.8 mg (32.97% yield) 4-Phenyl-pyrazole-1-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 97.25%. 1H NMR (CDCl3): δ 8.48-8.4 (d, 1H), 8.04-7.98 (bs, 1H), 7.96-7.92 (s, 1H), 7.8-7.74 (d, 1H), 7.7-7.58 (m, 2H), 7.56-7.5 (d, 2H), 7.44-7.1 (m, 4H), 4.38-4.3 (d, 2H), 4.28-4.2 (t, 1H), 4.1-4.0 (bs, 1H), 3.82-3.66 (m, 2H), 3.64-3.5 (m, 2H), 3.46-3.38 (t, 1H),), 3.32-3.2 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([NH:11][C:12]2[CH:20]=[C:19]([C:21]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:22]=3[CH:23]=[CH:24][NH:25]4)[CH:18]=[C:17]3[C:13]=2[CH:14]=[N:15][NH:16]3)=[O:10])=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.CCN(C(C)C)C(C)C>CS(C)=O.CS(C)=O.CO>[Cl:1][C:2]1[C:3]([C:9]([NH:11][C:12]2[CH:20]=[C:19]([C:21]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:22]=3[CH:23]=[CH:24][NH:25]4)[CH:18]=[C:17]3[C:13]=2[CH:14]=[N:15][NH:16]3)=[O:10])=[N:4][C:5]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:6][CH:7]=1
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1nc(Cl)ccc1Cl
Reactant: C1CCNCC1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1nc(N2CCCCC2)ccc1Cl
Temperature: 160 °C
Yield: 18.7 %

Procedure:
To a microwave vial was added 2 ml of a solution of 3,6-dichloro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (306 mg, 0.71 mmol) in DMSO (6 ml). Piperidine (0.024 ml, 0.25 mmol) and DIPEA (0.129 ml) were added and the mixture was heated at 160° C. for 2 h under microwave irradiation. The crude reaction mixture was dissolved in DMSO/MeOH (1:1) and purified by Mass Directed Automated Preparative HPLC (Method E). The sample was further purified by Mass Directed Automated Preparative HPLC (Method E) and product-containing fractions were dried under a stream of nitrogen to afford the title compound (22 mg).
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccccc2F)cc1
Yield: 18.4 %

Procedure:
The title compound (50 mg, 18%, white foam) was prepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine (260 mg, 0.773 mmol, prepared in example 1), 2-fluorobenzeneboronic acid (130 mg, 0.929 mmol), dichlorobis(triphenylphosphine)palladium(II) (22 mg, 0.031 mmol), 2 M sodium carbonate (280 mg in 1.3 mL water), and 1,2-dimethoxyethane (5.2 mL) in a manner analogous to the procedure described in Example 8. The crude material was purified utilizing a Chromatotron® with a 2000 μm rotor in a 1:1 hexane:ethyl acetate solvent system, yielding 230 mg of a co-eluting mixture of unreacted starting material and title compound. This mixture was further purified by reverse phase chromatography on a Vydac C-18 column on a gradient of 5 to 70% of 0.1% trifluoroacetic acid/acetonitrile in water over 45 minutes at 200 mL/min elution rate.
Reaction SMILES: C([O-])(=O)C.[NH4+].[CH2:6]([N:13]1[CH2:18][CH2:17][C:16](=O)[C:15]([CH2:21][CH3:22])([CH3:20])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([BH3-])#[N:24].[Na+]>CO>[NH2:24][CH:16]1[CH2:17][CH2:18][N:13]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:14][C:15]1([CH2:21][CH3:22])[CH3:20]
Reactant: [BH3-]C#N
Reactant: CCC1(C)CN(Cc2ccccc2)CCC1=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCC1(C)CN(Cc2ccccc2)CCC1N
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Ammonium acetate (2.5 g, 32.46 mmol) was added to the stirred solution of 1-benzyl-3-ethyl-3-methyl-4-piperidinone (0.9 g, 3.9 mmol) in methanol (20 ml) and stirring was continued for 3 hr at ambient temperature. The resulting mixture was cooled at 0° C. and sodium cyanoborohydride (0.2 g, 3.1 mmol) was added to it. Cooling was removed after 10 min. and resulting mixture was stirred for 6 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water, acidified with conc. HCl (pH 3˜4) and extracted with ethyl acetate to remove impurities. The aqueous layer was basified with 1 M sodium hydroxide solution (pH˜10) and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to furnish 4-amino-1-benzyl-3-ethyl-3-methylpiperidine. Yield 0.6 g (66%), C15H24N2, m/z 233 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[CH:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.Br[C:23]1[CH:24]=[C:25]([S:29]([NH2:32])(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[C:21][C:23]4[CH:24]=[C:25]([S:29]([NH2:32])(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1cccc(Br)c1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Product: NS(=O)(=O)c1cccc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.5) (73 mg, 0.25 mmol) and 3-bromo-benzenesulfonamide (59 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (44 mg, 39%). MS (ISP) 449.3 [(M+H)+]; mp 236-237° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][CH:3]=1.[N:10]1([CH2:16][C:17](O)=O)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:17]([CH2:16][N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[NH:9][C:5]2=[CH:4][CH:3]=1
Reactant: O=C(O)CN1CCOCC1
Reactant: Nc1ccc(Cl)nc1N
Product: Clc1ccc2[nH]c(CN3CCOCC3)nc2n1

Procedure:
The title compound was prepared as described in Example 23, Step 2 using 6-chloropyridine-2,3-diamine (650 mg, 4.53 mmol) (Example 23, Step 1) and morpholin-4-ylacetic acid (660 mg, 4.53 mmol) as starting materials.
Reaction SMILES: [CH:1]1([CH:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8]([NH:10][C@@H:11]2[C@H:18]3[C@H:14]([CH2:15][NH:16][CH2:17]3)[CH2:13][CH2:12]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH:30]=O.C(O)(=O)C.C([BH3-])#N>ClCCl>[CH:19]1([CH:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8]([NH:10][C@@H:11]2[C@H:18]3[C@H:14]([CH2:15][N:16]([CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[C:27]([C:26]([F:25])([F:35])[F:36])[CH:28]=4)[CH2:17]3)[CH2:13][CH2:12]2)=[O:9])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(N[C@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)C(C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2,2-Dicyclohexyl-N-[(3aS,4S,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide (154 mg, 0.463 mmol) from Example 53 and 3-(trifluoromethyl)benzaldehyde (0.062 mL, 0.463 mmol) were combined in dichloromethane (5 mL), and then 2 mL of acetic acid was added. The reaction was stirred at room temperature for 20 minutes, and then PS-cyanoborohydride (396 mg, 0.926 mmol) was added. The reaction was stirred at room temperature overnight, then filtered and the resin was washed with dichloromethane. The solvent was removed in vacuo, and the crude material was purified using a silica gel cartridge (Analogix®, Burlington, Wis., RS-25) eluting with 1-10% methanol (2 N ammonia)/dichloromethane to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.73 (s, 1H), 7.66 (d, J=7.7, 1H), 7.56 (s, 1H), 7.50 (t, J=7.7, 1H), 4.51-4.43 (m, 1H), 3.55 (d, J=12.9, 1H), 3.46 (d, J=12.9, 1H), 2.75 (d, J=8.6, 2H), 2.52-2.41 (m, J=8.5, 19.1, 2H), 2.34-2.29 (m, 1H), 2.20 (dd, J=7.7, 9.8, 1H), 2.14 (s, 3H, OAc), 1.96-1.54 (m, 15H), 1.49-1.05 (m, 12H), 1.03-0.93 (m, J=11.7, 21.1, 1H); MS (ESI+) m/z 491 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])[CH:7]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[P:25](Cl)(Cl)(=[O:29])[O:26][CH2:27][CH3:28].ClCCl>C(#N)C>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]2[O:12][P:25]([O:26][CH2:27][CH3:28])(=[O:29])[O:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:8]=2[CH:7]=1)(=[O:4])=[O:3]
Reactant: CCOP(=O)(Cl)Cl
Reactant: CC(C)(CO)c1cc(OS(C)(=O)=O)ccc1O
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOP1(=O)OCC(C)(C)c2cc(OS(C)(=O)=O)ccc2O1
Reaction time: 6 h
Yield: 44.6 %

Procedure:
4-Hydroxy-3-(2-hydroxy-1,1-dimethylethyl)phenyl methanesulphonate (10 g) from Example 1 was suspended in acetonitrile (100 ml) and triethylamine (8 g) was added. The mixture was cooled in ice, and ethyl phosphorodichloridate (6.9 g) was added dropwise with vigorous stirring. Stirring was continued for 6 hours prior to the addition of dichloromethane (200 ml), after which the solution was washed with water, dilute sodium hydroxide solution and water again, dried over magnesium sulphate and run down. The crude product was recrystallised from toluene, yielding 6.0 g of the desired product, melting point 113°-115° C.
Reaction SMILES: [CH2:1]([O:5][CH:6]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:7][NH:8][CH2:9][CH:10]1[O:15][CH:14]([CH3:16])[CH:13]([CH3:17])[CH2:12][O:11]1)[CH2:2][CH2:3][CH3:4].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:35][CH2:36][C:37](Cl)=[O:38]>O>[CH2:19]([O:18][CH:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH2:7][N:8]([CH2:9][CH:10]1[O:15][CH:14]([CH3:16])[CH:13]([CH3:17])[CH2:12][O:11]1)[C:37](=[O:38])[CH2:36][Cl:35])[CH2:20][CH2:21][CH3:22]
Reactant: O=C(Cl)CCl
Reactant: CCCCOC(CNCC1OCC(C)C(C)O1)OCCCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCCCOC(CN(CC1OCC(C)C(C)O1)C(=O)CCl)OCCCC

Procedure:
N-(2,2-Dibutoxyethyl)-N-(4,5-dimethyl-1,3-dioxan-2-ylmethyl)amine (0.05 mole), benzene (100 ml), water (100 ml) and sodium carbonate (2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is cooled to a temperature of from 5° to 10° C and chloroacetyl chloride (0.05 mole) is added dropwise with stirring. After the addition is completed stirring is continued until the reaction mixture has reached room temperature. After this time the organic phase is separated from the aqueous phase and is washed with water. The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2,2-dibutoxyethyl)-N-(4,5-dimethyl-1,3-dioxan-2-ylmethyl)-α-chloroacetamide as the residue.
Reaction SMILES: [C:1]([CH2:3][C:4](N)=O)#N.[OH:7][C:8]1[C:12]([C:13]#[N:14])=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:10][N:9]=1>>[OH:7][C:8]1[C:12]([C:13]#[N:14])=[C:11]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH:3]([CH3:4])[CH3:1])=[CH:20][CH:21]=2)[S:10][N:9]=1
Reactant: N#Cc1c(O)nsc1Nc1ccccc1
Reactant: N#CCC(N)=O
Product: CC(C)c1ccc(Nc2snc(O)c2C#N)cc1

Procedure:
The title compound was prepared from 1-isothiacyanato-4-isopropyl-benzene and 2-cyanoacetamide by the procedure analogous to Method 2 for 3-Hydroxy-5-phenylamino-isothiazol-4-carbonitrile. 1H NMR (CD3OD) δ: 7.2–7.4 (m, 4H); 2.9 (q, 1H); 1.24 (d, 6H); MS (ES, m/z): 259.8, [M-H]+, 258.3 [M-H]−.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]2([C:16]([NH:18][C:19]3[CH:20]=[N:21][C:22](Cl)=[CH:23][C:24]=3[C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[CH3:32])=[O:17])[CH2:15][CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:36]1[NH:41][CH2:40][CH2:39][N:38]2[C:42](=[O:45])[CH2:43][CH2:44][C@@H:37]12.[C:46](=O)([O-])[O-].[K+].[K+].[NH4+].[Cl-]>CS(C)=O>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]2([C:16]([N:18]([C:19]3[CH:20]=[N:21][C:22]([N:41]4[CH2:40][CH2:39][N:38]5[C:42](=[O:45])[CH2:43][CH2:44][C@H:37]5[CH2:36]4)=[CH:23][C:24]=3[C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[CH3:32])[CH3:46])=[O:17])[CH2:15][CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C1CC[C@H]2CNCCN12
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1NC(=O)C1(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CS(C)=O
Product: Cc1cc(F)ccc1-c1cc(N2CCN3C(=O)CC[C@H]3C2)ncc1N(C)C(=O)C1(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Temperature: 150 °C
Yield: 43.6 %

Procedure:
The title compound was prepared starting from 50 mg (0.094 mmoles) of 1-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]cyclopropanecarboxamide (D2), 39 mg (0.278 mmol) of (8aS)-hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (WO 2003/066635), 26.2 mg (0.189 mmol) of potassium carbonate; the reagents were dissolved in 0.4 ml of DMSO. The reaction mixture was heated at 150° C. overnight and then added to a saturated NH4Cl solution and back extracted with DCM; the crude material was purified on SPE cartridge (Silica) eluting with a gradient from cyclohexane/ethyl acetate 1:1, to ethyl acetate 100% and affording 26 mg of the title compound as pale yellow solid.
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:4](O)=O)C.[NH:24]([C:41]([O:43]CC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:25]([C:38]([OH:40])=O)[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33]C(C)(C)C)=[CH:29][CH:28]=1.C[N:59](C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CN1C(=O)CCC1>[NH2:1][C@H:2]([C:41]([NH:24][C@H:25]([C:38]([NH2:59])=[O:40])[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=1)=[O:43])[CH3:4]
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Reactant: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](N)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
The H-Ala-Tyr-NH2 and H-Ala-Ala-Tyr-NH2 peptides were prepared by solid phase synthesis using a Liberty microwave peptide synthesizer (CEM Corp., Matthews, N.C.). The Fmoc deprotection and the coupling steps were performed at 75° C. using microwave heating provided by power pulsing sequences of 20 W. The reaction temperatures were monitored with a fiberoptic probe inserted into the reaction vessel. The synthesis was started from 1.0 mmol of Fmoc-protected Sieber amide resin (0.72 mmol/g) placed into a 50 mL polypropylene vessel. The amino acids were coupled using the 1.0 mmol scale method provided by the manufacturer. At the beginning of each coupling step, the Fmoc group was removed by two 5 minute treatment with 5% piperazine in DMF containing 0.1 M HOBt. After 5 20 mL DMF washes, Fmoc-Ala-OH and Fmoc-Tyr(tBu)-OH were successively coupled by activation with 0.5 M HCTU (4 eq.) in DMF and 2 M DIEA (8 eq.) in NMP for 5 minutes. At the end of each coupling, the resin was washed with 5 20 mL DMF washes. Upon completion of the sequence assembly, the resin was washed with DCM and dried in vacuo. The peptides were then released from their respective resins by treatment with (95:5) TFA/water (10 mL) for 90 minutes at room temperature. The spent resin was filtered off and rinsed with additional cleavage solution (2×3 mL). The combined filtrates were evaporated to −4 mL and the product was precipitated by addition of ether (45 mL). The precipitated product was cooled to 0° C. for 30 minutes, collected by centrifugation, washed with additional ether and dried to yield an off-white solid in 85-90% yield.