Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[C:15]3[CH2:23][N:22]([C:24]4[CH:25]=[N:26][C:27]([O:34][CH3:35])=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=4)[CH2:21][CH2:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:9]1)=[O:7])(C)(C)C.[C:36](O)([C:38](F)(F)F)=O.C([O-])(O)=O.[Na+].C(Cl)(=O)CC>C(Cl)Cl.CCOC(C)=O>[CH3:35][O:34][C:27]1[N:26]=[CH:25][C:24]([N:22]2[CH2:21][CH2:20][C:16]3[N:17]=[CH:18][N:19]=[C:14]([NH:13][C@H:10]4[CH2:11][CH2:12][N:8]([C:6](=[O:7])[CH2:36][CH3:38])[CH2:9]4)[C:15]=3[CH2:23]2)=[CH:29][C:28]=1[C:30]([F:33])([F:31])[F:32]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ncc(N2CCc3ncnc(N[C@H]4CCN(C(=O)OC(C)(C)C)C4)c3C2)cc1C(F)(F)F
Agent: CCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCC(=O)N1CC[C@H](Nc2ncnc3c2CN(c2cnc(OC)c(C(F)(F)F)c2)CC3)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of (S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 24) (13.4 g, 27.1 mmol) in CH2Cl2 (100 mL), was added TFA (41.8 mL) and the mixture stirred at rt for 1 h. Concentrated in vacuo and partitioned between 2M NaOH(aq) (300 mL) and CH2Cl2 (200 mL). The organic phase was separated and the aqueous phase extracted with CH2Cl2 (2×200 mL). The organic phases were combined, dried (MgSO4) and evaporated in vacuo to give a brown foam. The foam was dissolved in CH2Cl2 (50 mL) and was added simultaneously portionwise with sat.NaHCO3(aq) (50 mL) to a vigourously stirring solution of propionyl chloride (2.63 g, 28.5 mmol) in CH2Cl2 (50 mL) at rt. The resulting biphasic mixture was stirred at rt for 1 h. Further propionyl chloride (0.566 g, 6.12 mmol) was added and continued stirring vigorously for 20 min. The organic layer was separated and the aqueous layer extracted with CH2Cl2 (100 mL). The organic layers were combined, dried (MgSO4) and concentrated in vacuo to give a brown gum. The gum was stirred in EtOAc (100 mL) and the resulting solid filtered (9.4 g). The mother liquors were concentrated in vacuo and purified by column chromatography through a Biotage® amino silica gel eluting with EtOAc/MeOH, 100/0 to 90/10 to give a yellow foam which was then stirred in EtOAc (20 mL) and the resulting solid filtered (870 mg). Both batches of solids were combined and stirred in refluxing EtOAc (50 mL) for 1 h. Filtered to give 1-{(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1-yl}-propan-1-one as a colourless solid (9.42 g, 76% yield). 1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 0.95-1.05 (m, 3H) 1.87-2.32 (m, 4H) 2.77-2.86 (m, 2H) 3.25-3.88 (m, 6H) 3.93 (s, 3H) 3.98 (s, 2H) 4.55-4.80 (m, 1H) 6.70-6.80 (m, 1H, N—H) 7.86-7.92 (m, 1H) 8.27-8.33 (m, 1H) 8.33-8.37 (m, 1H) LCMS: [M+H]+=451.0, Rt(6)=1.49 min.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:4]=[C:3]1[CH:18]=O.N.[CH2:21]=[N:22][CH:23](S(C1C=CC(C)=CC=1)(=O)=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[NH:40]1CCNCC1>C1COCC1.O.C([O-])(O)=O.[Na+]>[C:24]1([C:23]2[N:22]=[CH:21][NH:40][C:18]=2[C:3]2[C:2](=[O:1])[CH:7]=[CH:6][N:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=3)[N:4]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C1CNCCN1
Reactant: C=NC(c1ccccc1)S(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Agent: N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1[nH]cnc1-c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.7 %

Procedure:
A mixture of 4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carbaldehyde (129 mg, 0.479 mmol) and NH3 (30% aqueous solution, 0.168 mL, 129 mmol) in THF (1.5 mL) was stirred at room temperature for 4 h. To the mixture were added N-methylidene-1-[(4-methylphenyl)sulfonyl]-1-phenylmethanamine (131 mg, 0.479 mmol) and piperazine (41.3 mg, 0.479 mmol) at room temperature. The mixture was stirred at room temperature for 2 days. The mixture was diluted with water and saturated NaHCO3 aqueous solution, extracted with AcOEt, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on basic silica gel (hexane/AcOEt=40/60 to 0/100 and AcOEt/MeOH=100/0 to 70/30) and recrystallized with AcOEt/hexane to yield the title compound (85.6 mg, 47% yield) as a pale yellow solid: NMR (DMSO-d6, 300 MHz): δ ppm 6.70 (1H, d, J=7.7 Hz), 7.22-7.44 (3H, m), 7.57-7.85 (7H, m), 8.97 (1H, d, J=8.0 Hz), 12.75 (1H, s). Anal. Calcd for C20H13F3N4O.0.7H2O: C, 60.82; H, 3.67; N, 14.19. Found: C, 60.79; H, 3.76; N, 13.84.
Reaction SMILES: [CH3:1][C:2]1[C:6]2=[C:7]3[C:11](=[CH:12][CH:13]=[C:5]2[S:4][CH:3]=1)[NH:10][C:9]1[CH2:14][CH2:15][N:16]([CH3:18])[CH2:17][C:8]3=1.[H-].[Na+].[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][Cl:26]>CN(C)C=O>[ClH:26].[ClH:26].[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][N:10]1[C:11]2[C:7](=[C:6]3[C:2]([CH3:1])=[CH:3][S:4][C:5]3=[CH:13][CH:12]=2)[C:8]2[CH2:17][N:16]([CH3:18])[CH2:15][CH2:14][C:9]1=2
Reactant: Cc1csc2ccc3[nH]c4c(c3c12)CN(C)CC4
Reactant: CN(C)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1csc2ccc3c(c4c(n3CCCN(C)C)CCN(C)C4)c12
Product: Cl
Reaction time: 1 h

Procedure:
4.0 g of 1,9-dimethyl-7,8,9,10-tetrahydrothieno[3,2-e]pyrido[4,3-b]indole are dissolved in 60 ml of dimethylformamide, 0.78 g of a 50% strength dispersion of NaH is added, whilst stirring, and, after 1 hour, 2.4 g of 3-dimethylaminopropyl chloride are added. After leaving the mixture is stand for 15 hours, the solvent is evaporated off, the residue is taken up in ethyl acetate, the ethyl acetate mixture is washed and dried and the product is purified on SiO2 with chloroform/methanol (1:1). The dihydrochloride is then prepared with isopropyl alcohol/HCl. Melting point: 263° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C@H:5]1[CH2:9][CH2:8][N:7]([CH2:10][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)O)[CH2:6]1.COCO[C@H]1CCN([C@@H](C2C=CC=CC=2)CO)C1.[CH3:37][NH:38][C:39]1[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][CH:40]=1>>[CH3:1][O:2][CH2:3][O:4][C@H:5]1[CH2:9][CH2:8][N:7]([CH2:10][C@H:11]([N:38]([C:39]2[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][CH:40]=2)[CH3:37])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6]1
Reactant: COCO[C@H]1CCN(C[C@H](O)c2ccccc2)C1
Reactant: CNc1ccc(C(=O)OC)cc1
Agent: COCO[C@H]1CCN([C@H](CO)c2ccccc2)C1
Product: COCO[C@H]1CCN(C[C@@H](c2ccccc2)N(C)c2ccc(C(=O)OC)cc2)C1
Yield: 49 %

Procedure:
This was prepared from 2-(3-(S)-methoxymethoxypyrrolidin1-yl)-1-(R)-phenylethanol and 2-(3-(S)methoxymethoxypyrrolidin-1-yl)-2-(S)-phenylethanol and methyl 4-methylaminobenzoate in 49% yield according to a procedure simliar to hat described in Example 1 (i).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH:3]1[CH2:25][N:7]2[C:8]3[CH:20]=[C:19](C(F)(F)F)[CH:18]=[CH:17]C=3S[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH:6]2[CH2:5][CH2:4]1.[CH3:27][OH:28].[CH3:29]C(C)=O>>[CH3:26][N:2]([CH3:1])[CH:3]1[CH2:25][N:7]2[C:8]3[CH:20]=[CH:19][CH:18]=[CH:17][C:27]=3[O:28][C:13]3[C:14]([CH3:29])=[CH:15][CH:16]=[CH:11][C:12]=3[CH:6]2[CH2:5][CH2:4]1
Reactant: CO
Reactant: CN(C)C1CCC2c3ccccc3Sc3ccc(C(F)(F)F)cc3N2C1
Reactant: CC(C)=O
Product: Cc1cccc2c1Oc1ccccc1N1CC(N(C)C)CCC21

Procedure:
Rf in methanol:acetone (8:2) = 0.20 (equatorial). 3-dimethylamino-7-trifluoromethyl-1,3,4,14b-tetrahydro-2H-pyridino[ 1,2-d]-dibenzo[b,f](1,4)-thiazepine:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH:13]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[CH3:20][C:21]1[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=1>>[ClH:1].[CH:13]1([NH:19][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([N:22]3[C:21]([CH3:20])=[CH:25][C:24]([CH3:26])=[N:23]3)[N:11]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Cc1cc(C)[nH]n1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: NC1CCCCC1
Product: Cc1cc(C)n(-c2nc(NC3CCCCC3)c3ccccc3n2)n1
Product: Cl

Procedure:
Was prepared according to Method A from 2,4-dichloroquinazoline, cyclohexylamine and 3,5-dimethylpyrazole Mp. 137.6-142.7° C.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:20](/[C:23](=[CH:29]\[CH:30]=[CH:31]\[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH3:39])=[CH:34][CH:33]=1)/[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N+]=[N-]>C(OCC)C>[CH2:27]([O:26][C:24]([C:23](=[CH:29][CH:30]=[CH:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:38][CH3:39])=[CH:36][CH:37]=1)[N:20]=[P:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:25])[CH3:28]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)/C(=C/C=C/c1ccc(CC)cc1)N=[N+]=[N-]
Solvent: CCOCC
Product: CCOC(=O)C(=CC=Cc1ccc(CC)cc1)N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
General Procedure J. A solution of triphenylphosphine (1.2 g, 4.54 mmol) in diethyl ether (10 ml) was added dropwise to a solution of ethyl (2Z,4E)-2-azido-5-(4-ethylphenyl)penta-2,4-dienoate (Compound 44, 1.2 g, 4.54 mmol) in diethyl ether (20 ml) at 0° C. The solution was stirred for 12 hours at room temperature. Evaporation of solvent afforded a crude yellow solid, which was purified by column chromatography (silica gel, 20% ethyl acetate in hexane) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH3:13]O>>[NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: CO
Reactant: Nc1cc(Cl)ccc1C(=O)O
Agent: Cl
Product: COC(=O)c1ccc(Cl)cc1N
Temperature: 25 °C
Reaction time: 12 h
Yield: 62 %

Procedure:
To a mixture of 2-amino-4-chlorobenzoic acid (150 g, 0.88 mol) in MeOH (2.6 L) was added conc. HCl (0.5 L, 16.5 mol) and the reaction mixture was allowed to stir at reflux. After 12 h, the reaction mixture was allowed to cool to rt and was concentrated. Water (0.5 L) was added to the residue and the solution basified with 10% aqueous NaOH. The resulting precipitate was filtered to give methyl 2-amino-4-chlorobenzoate (101 g, 62%).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]([OH:16])=O)=[CH:4]1)[CH3:2].C(Cl)Cl.C(Cl)(=O)C(Cl)=O.[NH4+:26].[OH-]>CN(C=O)C>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]([NH2:26])=[O:16])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c2ccc(OC)cc21
Reactant: [NH4+]
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCn1cc(C(N)=O)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
1-Ethyl-6-methoxy-1H-indole-3-carboxylic acid (250 mg, 1.14 mmol) was suspended in a solution of CH2Cl2 (12.5 mL) and DMF (10 μL). Oxalyl chloride (230 μL, 2.64 mmol) was added, and the reaction mixture was stirred for 1 hour at room temperature. This mixture was then slowly poured into a rapidly stirring solution of concentrated NH4OH (5 mL). This was then partitioned in H2O and EtOAc. The residue from the ethyl acetate layer was triturated with acetone to yield 1-ethyl-6-methoxy-1H-indole-3-carboxamide (134 mg, 54%) as a white solid.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[C:12]([F:13])=[CH:11][C:10]([F:14])=[C:9]([F:15])[C:8]=1[CH3:16].[C:17](=[O:19])=[O:18].Cl>COCOC.O>[CH3:16][C:8]1[C:7]([F:6])=[C:12]([F:13])[C:11]([C:17]([OH:19])=[O:18])=[C:10]([F:14])[C:9]=1[F:15]
Reactant: Cc1c(F)c(F)cc(F)c1F
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: COCOC
Product: Cc1c(F)c(F)c(C(=O)O)c(F)c1F
Temperature: -70 °C
Reaction time: 1 h

Procedure:
A solution of n-butyllithium (2.7M in n-hexane, 21 cm3) was added dropwise to a stirred solution of 2,3,5,6-tetrafluorotoluene (9.0 g) in dry dimethoxymethane cooled to -70° C. under a nitrogen atmosphere and the mixture stirred for one hour. Carbon dioxide was then passed into the mixture for 3 hours during which time a white solid precipitate formed. After allowing the mixture to attain the ambient temperature (ca. 22° C.) it was poured into water. The resultant mixture was acidified with dilute hydrochloric acid and extracted with diethyl ether. The ethereal extract was washed with water and dried over anhydrous magnesium sulphate. Removal of the solvent yielded a semi solid residue which on trituration with petroleum ether (boiling range 40°-60° C.) gave 4-methyl-2,3,5,6-tetrafluorobenzoic acid (2.5 g) white crystals, mp 168° C. (Infra red C=O, 1700 cm-1.)
Reaction SMILES: Cl[C:2](Cl)(Cl)[CH:3]=[O:4].S([O-])([O-])(=O)=O.[Na+].[Na+].Cl[C:15]1[CH:16]=[C:17]([CH:19]=[C:20](Cl)[CH:21]=1)[NH2:18].Cl.[NH2:24][OH:25]>O.Cl>[CH:21]1[CH:20]=[CH:19][C:17]([NH:18][C:3](/[CH:2]=[N:24]/[OH:25])=[O:4])=[CH:16][CH:15]=1
Reactant: O=CC(Cl)(Cl)Cl
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: NO
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(/C=N/O)Nc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of trichloroacetaldehyde monohydate (13.25 g, 1.3 eq) in H2O (150 mL) was successively added sodium sulfate (17.55 g, 4.0 eq), a hot solution (ca. 80° C.) of 3,5-dichloroaniline (10.0 g, 61.5 mmol) in H2O (50 mL) and 37% HCl (6.1 mL), and a solution of hydroxylamine hydrochloride (16.3 g, 3.8 eq) in H2O (75 mL) with rapid stirring. Once the addition was completed the reaction mixture was heated at reflux for 2 minutes and then allowed to cool to room temperature. The resulting light brown precipitate was filtered, washed with H2O (200 mL) and then dried to yield the crude isonitrosoacetanilide (20.13 g).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[NH:4][C:5](=[S:15])[N:6]([CH2:9][CH:10]([O:12][CH2:13][CH3:14])[CH3:11])[C:7]=1[NH2:8].[CH:17](O)=O>>[CH2:13]([O:12][CH:10]([CH3:11])[CH2:9][N:6]1[C:7]2[N:8]=[CH:17][NH:1][C:2]=2[C:3](=[O:16])[NH:4][C:5]1=[S:15])[CH3:14]
Reactant: O=CO
Reactant: CCOC(C)Cn1c(N)c(N)c(=O)[nH]c1=S
Product: CCOC(C)Cn1c(=S)[nH]c(=O)c2[nH]cnc21
Temperature: 70 °C
Yield: 29 %

Procedure:
5,6-Diamino-1-(2-ethoxy-propyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (0.60 g, 2.45 mmol) obtained from Example 5(d) was suspended in formic acid (6 mL) and the obtained solution was heated at 70° C. for 2 h. Excess formic acid was evaporated off under reduced pressure. 10% sodium hydroxide (6 mL) was added to the solid and the obtained solution was heated at 70° C. for 2 h. The pH of the solution was adjusted to neutral pH with 2M sulphuric acid. The obtained precipitate was collected by filtration and washed with water. Purified by preparative HPLC, the title compound (0.18 g, 29% yield) was obtained as a solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].[C:15]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C:19]1=O)(=[O:17])[CH3:16].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH:21]1[CH2:22][CH2:23][N:18]([C:15](=[O:17])[CH3:16])[CH2:19][CH2:20]1
Reactant: CC(=O)N1CCCCC1=O
Reactant: Nc1ccccc1Sc1ncccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(=O)N1CCC(Nc2ccccc2Sc2ncccn2)CC1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 22.3 %

Procedure:
A solution of 2-(pyrimidin-2-ylsulfanyl)-phenylamine (AMR01106, 100 mg, 0.492 mmol), 1-acetylpiperidone (69.5 mg, 0.492 mmol) and acetic acid (0.15 mL, 2.46 mmol) in DCE (2 mL) was treated with NaBH(OAc)3 (261 mg, 1.23 mmol) and stirred under microwave irradiation for 15 min at 100° C. The reaction mixture was diluted with DCM (10 mL) and quenched with saturated NaHCO3 solution. The aqueous layer was washed with DCM (2×20 mL), and the combined organic layers were dried (MgSO4), filtered and evaporated to dryness. Column chromatography on silica gel of the crude product using AcOEt/MeOH 98:2 as eluent gave 1-{4-[2-(pyrimidin-2-ylsulfanyl)-phenylamino]-piperidin-1-yl}-ethanone 36 mg, 22%) as a colorless oil. 1H NMR (270 MHz, CDCl3) δ 1.20-1.40 (2H, m, CH2), 1.90-2.10 (2H, m, CH2), 2.05 (3H, s, CH3), 2.89 (1H, m, ½CH2), 3.18 (1H, m, ½CH2), 3.54-3.74 (2H, m, CH2), 4.26 (1H, m, CH), 4.75 (1H, br s, NH), 6.69-6.75 (2H, m, ArH), 6.97 (1H, t, J=4.7 Hz, Pyrimidine-H), 7.33 (1H, m, ArH), 7.49 (1H, dd, J=7.4, 1.7 Hz, ArH) and 8.47 (2H, d, J=4.7 Hz, Pyrimidine-H), 13C NMR (270 MHz, CDCl3) δ 21.57 (CH3), 31.74, 32.56, 40.14, 45.00 (CH2), 49.63 (CH), 111.45, 111.57, 117.35, 132.12, 138.13, 148.49, 157.88 (ArC and Pyridine-C), and 171.77 (C═O).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH:3]=[C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)[C:5](=[O:12])[CH2:6][C:7](=[O:11])[CH2:8][O:9][CH3:10].COC(OC)N(C)C.CN>>[CH3:10][O:9][CH2:8][C:7]([C:6]1[C:5](=[O:12])[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:21])([F:20])[F:22])[CH:14]=2)=[CH:3][N:2]([CH3:1])[CH:23]=1)=[O:11]
Reactant: COCC(=O)CC(=O)C(=CN(C)C)c1cccc(C(F)(F)F)c1
Agent: CN
Agent: COC(OC)N(C)C
Product: COCC(=O)c1cn(C)cc(-c2cccc(C(F)(F)F)c2)c1=O

Procedure:
A 1 g. portion of impure 1-dimethylamino-6-methoxy-2-(3-trifluoromethylphenyl)-1-hexene-3,5-dione was reacted with 10 ml. of N,N-dimethylformamide dimethyl acetal, and then with 5 ml. of 40% aqueous methylamine, as described in Preparation 1. The product was purified as described in that example, except that 1:1 ethyl acetate:dichloromethane was used as the eluent, to obtain 0.13 g. of the desired product, m.p. 104°, dec. Nmr analysis in DMSOd6 showed peaks at δ7.6-8.5 (m, 6H, aromatic); 4.8 (s, 2H, COCH2); 3.9 (s, 3H, N--CH3); 3.4 (s, 3H, OCH3).
Reaction SMILES: [CH2:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]1=[NH:13])[CH:2]=[CH2:3].C(N(CC)CC)C.[C:21](Cl)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23].O>O1CCCC1>[CH2:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]1=[N:13][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH:2]=[CH2:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: C=CCn1c(=N)sc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: C=CCn1c(=NC(=O)C(C)(C)C)sc2ccccc21
Reaction time: 5 h
Yield: 90.1 %

Procedure:
To a solution of 2.0 g of 3-allyl-2-iminobenzothiazole and 1.5 g of triethylamine in 30 ml of tetrahydrofuran was added 1.3 g of pivaloyl chloride dropwise at room temperature under stirring. After reacting for five hours, the reaction mixture was poured into approximately 200 ml of water. The crystals precipitated were collected by filtering to thereby obtain 2.6 g of the objective compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][NH:23][C:22](=[O:26])[CH:21]=2)=[O:19])[S:9][C:10]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.[H-].[Na+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl>CN(C=O)C.O>[CH2:29]([N:23]1[CH:24]=[CH:25][C:20]([C:18]([NH:17][C:8]2[S:9][C:10]([C:11]3[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=3)=[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[N:7]=2)=[O:19])=[CH:21][C:22]1=[O:26])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Nc1nc(-c2ccco2)c(-c2ccncc2)s1)c1cc[nH]c(=O)c1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1nc(-c2ccco2)c(-c2ccncc2)s1)c1ccn(Cc2ccccc2)c(=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.8 %

Procedure:
Compound 112 (146 mg, 0.400 mmol) was dissolved in DMF (2 mL), 60% sodium hydride (35.2 mg, 0.880 mmol) was added thereto, followed by stirring at room temperature for 30 minutes. Benzyl bromide (0.0523 mL, 0.440 mmol) was added dropwise to the reaction mixture, followed by stirring overnight at room temperature. The reaction mixture was poured into water, and 1 mol/L hydrochloric acid was added thereto to adjust the pH to 7, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=99:1) to afford the entitled Compound 113 (25.0 mg, 14%).
Reaction SMILES: Br[C:2]1[C:3]([CH3:9])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[CH2:10]([Li])[CH2:11][CH2:12]C.C(#N)CC.[OH2:19]>C(OCC)C.CCCCCC>[CH3:9][C:3]1[C:2]([C:10](=[O:19])[CH2:11][CH3:12])=[CH:7][CH:6]=[C:5]([CH3:8])[N:4]=1
Reactant: O
Reactant: Cc1ccc(Br)c(C)n1
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: CCC#N
Solvent: CCOCC
Product: CCC(=O)c1ccc(C)nc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-bromo-2,6-dimethyl-pyridine, (3.72 g, 20 mmol) were dissolved in 40 mL diethylether at −78° C. and treated with 10 mL of n-butyllithium (20 mmol) as a 2 M commercial solution in hexane. After stirring for 0.5 h, propionitrile (1.21 g, 22 mmol) was added and the mixture allowed to slowly warm to room temperature while stirring overnight. The mixture was then poured into water (0.5 volume equivalents relative to ether) and the mixture partitioned. The aqueous solution was extracted with ethyl acetate and the combined organic layers washed with water, dried with sodium sulfate, and concentrated in vacuo. Chromatography on silica using an ethyl acetate/hexane gradient gave the final product. Yield: 0.3 g (9%) 1H NMR (300 MHz, CDCl3), •1.18 (t, CH3, 3H), 2.56 (s, CH3, 3H), 2.68 (s, —CH3, 3H), 2.86 (q, CH2, 2H), 7.04 (d, Ar, 1H,), 7.8 (d, Ar, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]([CH2:16][C:17]2[N:18]=[C:19]([CH2:22][CH2:23][CH2:24][CH:25]=O)[S:20][CH:21]=2)[CH2:10][C:11]([O:13]CC)=[O:12])=[CH:5][CH:4]=1.[N:27]1([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([NH2:39])[CH:34]=2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(Cl)[Cl:55]>>[ClH:55].[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]([CH2:16][C:17]2[N:18]=[C:19]([CH2:22][CH2:23][CH2:24][CH2:25][NH:39][C:35]3[CH:34]=[C:33]([N:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)[CH:38]=[CH:37][N:36]=3)[S:20][CH:21]=2)[CH2:10][C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1
Reactant: ClCCl
Reactant: CCOC(=O)CC(Cc1csc(CCCC=O)n1)c1ccc(OC)nc1
Reactant: Nc1cc(N2CCOCC2)ccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: COc1ccc(C(CC(=O)O)Cc2csc(CCCCNc3cc(N4CCOCC4)ccn3)n2)cn1
Product: Cl

Procedure:
Dissolve ethyl 3-(6-methoxypyridin-3-yl)-4-[2-(4-oxobutyl)-1,3-thiazol-4-yl]butanoate (374mg, 1.0 mmol) and 4-morpholin-4-ylpyridin-2-amine (150 mg, 0.836 mmol) prepared according to Scheme 6, Example 1, in CH2Cl2. Add NaBH(OAc)3 (251 mg, 1.12 mmol) and stir at room temperature for 18 hours. The reaction was concentrated in vacuo and purified via reverse phase HPLC using a gradient of 10–60% CH3CN/H2O/0.5% HCl over 30 minutes to obtain the crude desired product.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]3[CH:18]=[CH:17][S:16][CH:15]=3)=[CH:8][C:9](=[O:13])[O:10]2)=[CH:5][CH:4]=1.CN(C)P(N(C)C)N(C)C.C(Cl)(Cl)(Cl)[Cl:30]>C1COCC1.CCOCC>[Cl:30][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]3[CH:18]=[CH:17][S:16][CH:15]=3)=[CH:8][C:9](=[O:13])[O:10]2)=[CH:5][CH:4]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: O=c1cc(-c2ccsc2)c2ccc(CO)cc2o1
Agent: CN(C)P(N(C)C)N(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=c1cc(-c2ccsc2)c2ccc(CCl)cc2o1
Reaction time: 0.5 h

Procedure:
To a solution of the alcohol from Step 1 (1.65 g) and hexamethylphosphorous triamide in 35 mL THF at 0° C. was added CCl4 (1.3 mL) and the mixture stirred for 30 min. The mixture was diluted with Et2O, filtered, concentrated and the residue chromatographed (30% EtOAc/hexane) to provide the title compound as a solid, m.p. 125°-127° C.