Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7](Br)=[CH:8][N:9]=1)(=[O:3])[CH3:2].[OH:11][C:12]1[C:13]([SH:18])=[N:14][CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([S:18][C:13]2[C:12]([OH:11])=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ncc(Br)s1
Reactant: Oc1cccnc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncc(Sc2ncccc2O)s1
Temperature: 90 °C
Yield: 110.3 %

Procedure:
A mixture of 2-acetylamino-5-bromothiazole (1.8 g), 3-hydroxy-2-mercaptopyridine (1.3 g) and potassium carbonate (2.0 g) in N,N-dimethylformamide (40 ml) was heated at 90° C. for 3.5 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was triturated with water. The mixture was extracted with a mixture of tetrahydrofuran and ethyl acetate (1:1), washed with aqueous saturated sodium chloride and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 150 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 2-acetylamino-5-(3-hydroxypyridin-2-ylthio) thiazole (2.4 g, yield: 89.9%).
Reaction SMILES: [F:1][C:2](=[CH:5][C:6]([F:9])([F:8])[F:7])[CH2:3][OH:4].C([O-])(=O)C.[Na+].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CCOCC>C(Cl)Cl>[F:1]/[C:2](=[CH:5]\[C:6]([F:9])([F:8])[F:7])/[CH:3]=[O:4]
Reactant: OCC(F)=CC(F)(F)F
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: O=C/C(F)=C/C(F)(F)F
Reaction time: 12 h

Procedure:
To the solution of 2,4,4,4-tetrafluoro-2-butenol (1.40 g) and anhydrous sodium acetate (60 mg) in methylene chloride (5 ml) was added in portionwise pyridinium chlorochromate (3.23 g) at 20° C. The resulting mixture was stirred for 12 hours. The mixture was passed through a short silica gel column with dry ether (20 ml) to obtain the ether solution of (Z)-2,4,4,4-tetrafluoro-2-butenal. Without evaporation, a tetrahydrofuran solution of ethynylmagnesium bromide (21 ml) was added portionwise to the solution of (Z)-2,4,4,4-tetrafluoro-2-butenal at 0° C. The resulting mixture was stirred for 12 hours at 20° C. This was poured into the cooled 5% hydrochloric acid, and the resulting mixture was extracted with ether. The ether extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[CH2:21][CH:22]([CH3:24])[CH3:23]>CN(C=O)C>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([O:7][CH2:2][CH2:3][CH:4]([CH3:8])[CH3:5])=[O:6])[CH2:21][CH:22]([CH3:24])[CH3:23]
Reactant: O=C(O)c1cc(O)cc([N+](=O)[O-])c1
Reactant: CC(C)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)CCOC(=O)c1cc(OCCC(C)C)cc([N+](=O)[O-])c1
Temperature: 90 °C
Yield: 113.8 %

Procedure:
5.15 g (28 mmol) 8 were dissolved in 15 mL DMF (anhydrous, Aldrich) and added to a suspension of 15.5 g (112 mmol, 4 eq.) K2CO3 in 25 mL DMF under nitrogen atmosphere. 13.4 mL (112 mmol, 4 eq.) iso-pentyl bromide were added. The thick, canary-yellow reaction mixture was heated to 90° C. and became stirrable again. It was left at this temperature for at least 8 h. Product formation could be followed by TLC (hexanes/ethyl acetate 9:1, Rf (product)=0.85). After cooling to r.t., DMF was removed with a vacuum rotovap, then ethyl acetate and water were added. After phase separation, the water layer was extracted with ethyl acetate two more times, the organics were pooled, washed with brine, dried with MgSO4, concentrated and put under vacuum overnight. The crude product was purified by column chromatography (hexanes/ethyl acetate 9:1), yielding 5.15 g (80%) of a yellow liquid. 1H NMR (CDCl3) δ 8.42 (dd, J1=1.5 Hz, J2=2.4 Hz, 1H), 7.90 (t, J1=2.4 Hz, J2=2.4 Hz, 1H),7.87 (dd, J1=1.5 Hz, J2=2.4 Hz, 1H), 4.40 (t, J=6.7 Hz, 2H, PhOCH2CH2CH(CH3)2), 4.11 (t, J=6.6 Hz, 2H, PhOCH2CH2CH(CH3)2), 1.93-1.65 (m, 6H), 0.99 (d, J=6.6 Hz, 12H, 2×CH(CH3)2); 13C NMR (CDCl3) 164.38, 159.51, 148.94, 132.69, 121.46, 116.10, 112.87, 67.40, 64.42, 37.38, 37.08, 24.97, 24.77, 22.29; ESI-MS m/z 360 [M+K−2]+, 408 [M+2Na+K], 669 [M2+Na]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]([NH2:18])=[S:17])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:20][C:21](=O)[CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25].C(N(CC)CC)C>CO>[CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]2[S:17][CH:20]=[C:21]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[N:18]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=S)Nc1ncccc1OCc1ccccc1
Reactant: COC(=O)CCC(=O)CBr
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)CCc1csc(Nc2ncccc2OCc2ccccc2)n1
Yield: 81.4 %

Procedure:
1-(3-(Benzyloxy)pyridin-2-yl)thiourea (3.30 g, 12.7 mmol), methyl 5-bromo-4-oxopentanoate (3.19 g, 15.3 mmol) (prepared according to Synthetic Communications (1994) 2557-2562), and triethylamine (3.10 mL, 22.3 mmol) were heated in methanol (100 mL) at reflux for 3 hours according to the method of Example 2, Step C, to provide methyl 3-(2-(3-(benzyloxy)pyridin-2-ylamino)thiazol-4-yl)propanoate (3.82 g, 81.3% yield) as a light yellow powder: 1H NMR (DMSO-d6) δ 9.93 (bs, 1H), 7.86 (d, 1H), 7.57 (d, 2H), 7.34-7.42 (m, 4H), 6.89 (m, 1H), 6.63 (s, 1H), 5.26 (s, 2H), 3.60 (s, 3H), 2.85 (t, 2H), 2.69 (t, 2H). Mass spectrum (esi) m/z=370 (100).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:20]([NH:22][C@H:23]([C:28]([NH:30][C@H:31]([C:36]([NH:38][CH:39]([C:44]([NH2:46])=[O:45])[CH2:40][CH2:41][CH2:42][CH3:43])=[O:37])[CH2:32][C:33](=[O:35])[OH:34])=[O:29])[CH2:24][CH2:25][S:26][CH3:27])=[O:21])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=O)(C)(C)C.[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50]>O1CCOCC1>[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].[NH2:8][C@H:9]([C:20]([NH:22][C@H:23]([C:28]([NH:30][C@H:31]([C:36]([NH:38][CH:39]([C:44]([NH2:46])=[O:45])[CH2:40][CH2:41][CH2:42][CH3:43])=[O:37])[CH2:32][C:33](=[O:34])[OH:35])=[O:29])[CH2:24][CH2:25][S:26][CH3:27])=[O:21])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1
Reactant: CCCCC(NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(N)=O
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CCCCC(NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(N)=O

Procedure:
the reaction of N-t-butoxycarbonyl-L-tryptophanyl-L-methionyl-L-aspartyl-DL-norleucine amide according to the procedure of Example 7 using trifluoroacetic acid instead of hydrochloric acid in dioxane affords L-tryptophanyl-L-methionyl-L-aspartyl-DL-norleucine amide trifluoroacetate. This compound is represented by the following formula.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=3)=[CH:17][C:16]=2[NH:31][C:32]2[C:33]3[CH:41]=[CH:40][C:39]([CH:42]([CH3:44])[CH3:43])=[N:38][C:34]=3[N:35]=[CH:36][N:37]=2)=[CH:10][CH:9]=1)(C)(C)C.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49]>C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=3)=[O:30])=[CH:17][C:16]=2[NH:31][C:32]2[C:33]3[CH:41]=[CH:40][C:39]([CH:42]([CH3:44])[CH3:43])=[N:38][C:34]=3[N:35]=[CH:36][N:37]=2)=[CH:10][CH:9]=1.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49]
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4cccc(Br)c4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4cccc(Br)c4)ccc3Sc3ccc(N)cc3)ncnc2n1

Procedure:
The product of Example 64B was treated with trifluoroacetic acid (3 mL) in methylene chloride (3 mL) at room temperature for 30 minutes. The solvents were removed under vacuum to provide the title compound as a trifluoroacetic acid salt. 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.37 (d, J=6.99 Hz, 6 H) 3.30 (m, 1 H) 6.65 (d, J=8.46 Hz, 2 H) 6.97 (d, J=8.46 Hz, 1 H) 7.16 (d, J=8.46 Hz, 2 H) 7.30 (m, 2 H) 7.72 (m, 1 H) 7.88 (dd, J=8.46, 1.84 Hz, 1 H) 7.96 (m, 2 H) 8.05 (s, 1 H) 8.92 (s, 1 H) 9.07 (d, J=8.46 Hz, 1 H) 10.37 (s, 1 H) 11.82 (s, 1 H); MS (ESI+) m/z 585, 587 (M+H)+.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH:6]1[C:18]2CC3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1.BrCC.Cl>C1COCC1.O>[CH2:3]([CH:2]1[C:1]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:9]1=[CH:8][CH:7]=[CH:6][CH:18]=2)[CH3:4]
Reactant: [Li]CCCC
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCBr
Product: CCC1c2ccccc2-c2ccccc21
Temperature: -75 °C
Reaction time: 1 h

Procedure:
A solution of n-butyllithium (79.52 cm3, 0.2168 mol, 2.5M in hexane) was added slowly to a solution of fluorene (30.00 g, 0.1807 mol) in THF (300 cm3) at −70° C. The solution was stirred for 1 hour at −75° C. and 1-bromoethane (17.59 cm3, 0.2349 mol) was added slowly. The solution was allowed to warm to room temperature and then stirred overnight. Dilute hydrochloric acid (200 ml, 20%) was added to the reaction mixture and stirred for a further 10 minutes. Water (250 cm3) was added and the product extracted into diethyl ether (3×300 cm3). The combined organic extracts were dried (MgSO4) and the solvent removed on a rotary evaporator. The resulting oil was purified by distillation to yield a pale yellow oil (25.00 g, 71%, b.pt. −150° C. @ 1 mbar Hg).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[CH:33][N:32]=[N:31][CH:30]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:14][C:12]1[C:11]([C:15]([F:16])([F:17])[F:18])=[CH:10][C:9]2[NH:19][C:20](=[O:36])[CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:34]=[CH:33][N:32]=[N:31][CH:30]=4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnnc3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnnc3)c1)=N2

Procedure:
The title compound was prepared from {5-methyl-2-[3-oxo-3-(3-pyridazin-4-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M45) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (110 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][OH:13])[CH2:8][CH2:7]1.[H-].[Na+].[F:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24](F)[C:21]=1[C:22]#[N:23]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][CH:6]1[CH2:7][CH2:8][CH:9]([CH2:12][O:13][C:24]2[CH:25]=[CH:26][CH:27]=[C:20]([F:19])[C:21]=2[C:22]#[N:23])[CH2:10][CH2:11]1
Reactant: OCC1CCC(Cc2cccc(Cl)c2)CC1
Reactant: N#Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(F)cccc1OCC1CCC(Cc2cccc(Cl)c2)CC1
Reaction time: 2 h
Yield: 76.7 %

Procedure:
[4-(3-Chlorobenzyl)cyclohexyl]-methanol (150 mg; 0.63 mmol) was added to a suspension of sodium hydride (33 mg; 0.82 mmol) in 3 mL of dimethylformamide at 0° C. After 2 hours, mixture was added to a mixture of 2,6-difluorobenzonitrile (88 mg; 0.63 mmol) in 2 mL of dimethylformamide at 0° C. After 16 hours mixture was quenched with 5 g of ice. Aqueous mixture was extracted with 5×15 mL of ethyl acetate. Combined ethyl acetates were washed with 6×15 mL water, brine and dried over MgSO4. Residue was purified via flash chromatography using 5-15% ethyl acetate in hexanes gradient to give 173 mgs of title compound. (77% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH:5]([C:7]([O:9][CH3:10])=[O:8])[CH2:4][CH:3]([C:11]([O:13][CH3:14])=[O:12])[CH2:2]1.C([O-])([O-])=O.[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C>[CH2:21]([N:1]1[CH2:2][CH:3]([C:11]([O:13][CH3:14])=[O:12])[CH2:4][CH:5]([C:7]([O:9][CH3:10])=[O:8])[CH2:6]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)C1CNCC(C(=O)OC)C1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C1CC(C(=O)OC)CN(Cc2ccccc2)C1
Temperature: 23 °C
Reaction time: 4 h

Procedure:
To dimethyl piperidine-3,5-dicarboxylate (7.5 g, 37.3 mmol) in acetonitrile (100 mL) was added K2CO3 (20.6 g, 149.1) and benzylbromide (4.43 mL, 37.3 mmol). The reaction mixture was stirred at 23° C. for 4 hours. The K2CO3 was removed by filtration and the solvent evaporated in vacuo. A solution of NaHCO3 (1M, 150 mL) was added and the organic material extracted with ethyl acetate (3×50 mL), then dried (MgSO4) and concentrated in vacuo. The crude material was purified on a Silica gel column (Biotage flash chromatography system), eluting with a gradient of ethyl acetate/hexane (10:90) to (35:65) to afford the title compound as the cis diastereomer 1.6 g which eluted after the corresponding trans diastereomer. (based on the NMR reported in Synthetic Communications 1997, 27 (1), 69-71.). 1H NMR (400 MHz, CDCl3) δ ppm 7.26-7.36 (5 H, m), 3.68 (6 H, s), 3.59 (2 H, s), 3.15 (2 H, m), 2.66 (2 H, t, J=12.0 Hz), 2.36 (1 H, d, J=13.1 Hz), 2.05 (2 H, t, J=11.4 Hz), 1.56 (1 H, q, J=12.9 Hz). LCMS (+ESI, M+H+) m/z: 292.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]2=[N:12][N:13]=[CH:14][N:4]2[N:3]=1.[NH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>COCCO>[N:18]1([CH2:17][CH2:16][NH:15][C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[C:5]3=[N:12][N:13]=[CH:14][N:4]3[N:3]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NCCN1CCCC1
Reactant: Clc1nn2cnnc2c2c1CCCC2
Solvent: COCCO
Product: c1nnc2c3c(c(NCCN4CCCC4)nn12)CCCC3

Procedure:
A solution of 5.0 g of 6-chloro-7,8,9,10-tetrahydro-1,2,4-triazolo[3,4-a]phthalazine and 10.0 g of 1-(2-aminoethyl)pyrrolidine in 50 ml of 2-methoxyethanol was heated at reflux for 15 hours. The solution was then concentrated and the resulting residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate and concentrated. The concentrate was triturated with ether and the solid which formed was separated by filtration to give 6-[2-(1-pyrrolidinyl)ethylamino]-7,8,9,10-tetrahydro-1,2,4-triazolo[3,4-a]phthalazine melting at about 160°-162° C. after recrystallization from a mixture of toluene and hexane. This compound has the following structural formula ##STR3##
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[NH2:10][C:11]1[C:12]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])=[N:13][C:14](Br)=[CH:15][N:16]=1>CN(C=O)C>[NH2:10][C:11]1[C:12]([C:18]([NH:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:19])=[N:13][C:14]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:15][N:16]=1
Reactant: Sc1ccccc1
Reactant: Nc1ncc(Br)nc1C(=O)Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncc(Sc2ccccc2)nc1C(=O)Nc1ccccc1
Temperature: 100 °C
Yield: 36.4 %

Procedure:
Benzenethiol (73.29 mg, 68.30 μL, 0.6652 mmol) was added slowly to a suspension of sodium hydride (60% dispersion in mineral oil) (19.16 mg, 21.29 μL, 0.7983 mmol) in anhydrous DMF (1.300 mL) at 0° C. The reaction mixture was stirred until the evolution of H2 ceased. 3-Amino-6-bromo-N-phenyl-pyrazine-2-carboxamide (130 mg, 0.4435 mmol) was added followed by Cu2O (15.87 mg, 0.1109 mmol) and reaction mixture heated to 100° C. for 4 hours. The reaction mixture was cooled to ambient temperature and quenched with crushed ice. The aqueous layer was extracted with EtOAc (×3) and the combined organic extracts washed with ammonium hydroxide (×1), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a yellow solid (52 mg, 31% Yield). 1H NMR (400.0 MHz, DMSO) δ 7.19-7.23 (m, 1H), 7.43-7.54 (m, 7H), 7.77-7.80 (m, 4H), 8.37 (s, 1H) and 10.15 (s, 1H) ppm; MS (ES+) 322.99.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][NH:12][CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:14]1([C:19]2[S:28][C:27]3[NH:26][C:25]4[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=4[NH:23][C:22](=S)[C:21]=3[N:20]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1>N1C=CC=CC=1>[CH:14]1([C:19]2[S:28][C:27]3[NH:26][C:25]4[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=4[N:23]=[C:22]([N:12]4[CH2:11][CH2:10][NH:9][C@@H:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH2:13]4)[C:21]=3[N:20]=2)[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: c1ccc(C[C@H]2CNCCN2)cc1
Reactant: S=C1Nc2ccccc2Nc2sc(C3CCCC3)nc21
Solvent: c1ccncc1
Product: c1ccc(C[C@H]2CN(C3=Nc4ccccc4Nc4sc(C5CCCC5)nc43)CCN2)cc1

Procedure:
Using a method similar to the method of Example 491, using (S)-2-benzyl-piperazine (1.23 g, 7.0 mmol), 2-cyclopentyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo{f}azulene-10-thione (0.602 g, 2.0 mmol) in 8 ml of pyridine Obtain 240 mg light brown foam of title compound. Mass spectrum (electrospray) (m/e): C26H29N5S, Cacl. Mass: 443.36; Found: 444.1 (M+1); 1H NMR (400 MHz, CDCl3) δ ppm: 7.32–7.21 (m, 5H), 7.03–6.97 (m, 2H), 6.86 (dt, 1H, J=7.8 Hz, J=1.9 Hz), 6.61 (d, 1H, J=7.8 Hz), 5.00 (br, 1H), 3.21–2.90 (m, 4H), 2.78–2.72 (m, 1H), 2.62–2.56 (m, 1H), 2.03–1.95 (m, 2H), 1.77–1.62 (m, 10H).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)=[N:5][C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)=[N:7][CH:8]=1)#[N:2].[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>>[C:1]([C:3]1[C:4]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)=[N:5][C:6]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][O:19][S:31]([C:28]3[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=3)(=[O:33])=[O:32])=[CH:14][CH:15]=2)=[N:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cnc(Nc2ccc(OCCO)cc2)nc1-c1cccs1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc(Nc3ncc(C#N)c(-c4cccs4)n3)cc2)cc1

Procedure:
5cyano-N-[4-(2-p-toluenesulphonyloxyethoxy)phenyl]-4-thien-2-ylpyrimidin-2-amine was prepared from 5-cyano-N-[4-(2-hydroxyethoxy)-phenyl]-4-thien-2-ylpyrimidine-2-amine (8.02 g, 23.7 mmol) and 4-toluene-sulphonylchloride (9.0 g, 47.4 mmol) to give a yellow solid (4.97 g), m.p. 160°. δH (d6 DMSO) 10.32 (1H, s), 8.84 (1H, s), 8.26 (1H, d, J 3.9 Hz), 7.99 (1H, d, J 5.0 Hz), 7.80 (2H, d, J 8.3 Hz), 7.64 (2H, m), 7.47 (2H, d, J 8.3hz), 7.33 (1H, t, J 4.5 Hz), 6.85 (2H, d, J 9.0 Hz), 4.33 (2H, t, J 4.0 Hz), 4.15 (2H, m) and 2.41 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:14]([O-])=O)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.C([O-])=O.[NH4+]>C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[NH2:14]
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)c(F)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: Nc1ccc(N2CCOCC2)c(F)c1
Reaction time: 8 h
Yield: 95 %

Procedure:
10% Pd—C 4.0 g was added to 3-fluoro-4-morpholinyl nitrobenzene (40 g, 177 mmol), ammonium formate (50 g, 793 mmol) in 200 mL of ethyl acetate and stirred at 45˜50° C. for 8 h until the completion of the reaction. The mixture was then filtrated and separated by water. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated to provide 33 g of solid in 95% yield.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:17][C:18]([CH:20]1[CH2:22][CH2:21]1)=[O:19]>C(Cl)Cl>[CH2:1]([S:8][CH2:17][C:18]([CH:20]1[CH2:22][CH2:21]1)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CBr)C1CC1
Reactant: SCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CSCc1ccccc1)C1CC1
Reaction time: 48 h

Procedure:
Benzyl mercaptan (15.6 ml, 0.133 mol) was stirred in DCM (100 ml), triethylamine (20.5 ml, 0.146 mol) added, the mixture cooled in an ice/acetone bath and 2-bromo-1-cyclopropyl-ethanone, prepared as in WO 03/074495, (21.77 g, 0.133 mol) dissolved in DCM (100 ml) was added dropwise. The mixture was stirred for 48 h, washed with water, then brine, dried over sodium sulphate and evaporated.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([NH2:16])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].C[Al](C)C.[OH:21][C:22]1([CH3:29])[CH2:27][CH2:26][O:25][C:24](=[O:28])[CH2:23]1.Cl>C1(C)C=CC=CC=1>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([NH:16][C:24](=[O:28])[CH2:23][C:22]([OH:21])([CH3:29])[CH2:27][CH2:26][OH:25])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: CC1(O)CCOC(=O)C1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: CCn1c2ccccc2c2cc(NC(=O)CC(C)(O)CCO)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
To a solution of 9-ethyl-9H-carbazol-3-amine (300 mg, 1.43 mmol) in toluene (4 mL) was added trimethylaluminium (1.8M in toluene solution, 1.189 mL, 2.14 mmol), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added a solution of 4-hydroxy-4-methyltetrahydro-2H-pyran-2-one (186 mg, 1.43 mmol) in toluene (4 mL) at room temperature, and the mixture was stirred at 80° C. for 4 hr. The reaction mixture was cooled to 0° C., neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10 to 100% ethyl acetate/hexane) to give N-(9-ethyl-9H-carbazol-3-yl)-3,5-dihydroxy-3-methylpentanamide (359 mg, 1.056 mmol, 74.0%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[CH3:11][Mg+].[Br-]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:6]([C:7](=[O:8])[CH3:11])[CH:5]=[N:4][CH:3]=1
Reactant: C[Mg+]
Reactant: O=C(Cl)c1cncc(Br)c1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)c1cncc(Br)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
5-Bromo-nicotinoyl chloride (0.5 g, 2.268 mmol) is suspended in THF (24 ml) at room temperature under an atmosphere of Argon. Fe(acac)3 (0.04 g, 0.113 mmol) is added and the reaction mixture is stirred for 10 minutes until a solution forms. The reaction mixture is cooled to −78° C. and a solution of MeMgBr (3M in diethyl ether, 0.907 ml, 2.722 mmol) is added dropwise with stirring for 2 hours at −78° C. On warming to room temperature silica is added to the reaction mixture and the solvents are reduced in vacuo. Purification by flash chromatography eluting with 50:50 EtOAc/iso-hexanes affords the title compound as a yellow solid [MH+199.90 and 201.90].