Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[O:23]1[CH2:28][CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH2:25][CH2:24]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[O:23]1[CH2:24][CH:25]=[C:26]([C:2]2[C:3]([O:8][C:9]3[CH:14]=[CH:13][C:12]([NH:15][C:16]4[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=4)=[CH:11][CH:10]=3)=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:27][CH2:28]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: Cc1cccnc1Nc1ccc(Oc2ncccc2Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cccnc1Nc1ccc(Oc2ncccc2C2=CCOCC2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a round-bottomed flask was added N-(4-(3-bromopyridin-2-yloxy)phenyl)-3-methylpyridin-2-amine (0.2898 g, 0.814 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.214 g, 1.017 mmol), trans-dichlorobis(triphenylphosphine) palladium (II) (0.046 g, 0.065 mmol), and sodium carbonate (0.431 g, 4.07 mmol) in DME (1.302 mL) and water (0.325 mL) to stir at 80° C. overnight. The crude product was adsorbed onto a plug of silica gel and chromatographed to provide N-(4-(3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)-3-methylpyridin-2-amine. MS (ESI, pos. ion) m/z: 360.0. IC50 (uM) 0.00701.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:21]([CH3:33])[CH:20]=2)[NH:11][N:10]=1)(=O)=O.[CH2:34]1[CH2:40][O:39][CH2:38][CH2:37][NH:36][CH2:35]1>>[CH2:26]([O:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[NH:11][N:10]=[C:9]([O:8][CH2:7][CH2:6][N:36]4[CH2:35][CH2:34][CH2:40][O:39][CH2:38][CH2:37]4)[C:17]=23)=[CH:20][C:21]=1[CH3:33])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1cc(Nc2ncnc3[nH]nc(OCCOS(C)(=O)=O)c23)ccc1OCc1ccccc1
Reactant: C1CNCCOC1
Product: Cc1cc(Nc2ncnc3[nH]nc(OCCN4CCCOCC4)c23)ccc1OCc1ccccc1
Yield: 22 %

Procedure:
The procedure described in Example 55 was repeated using 2-[(4-{[4-(benzyloxy)-3-methylphenyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy]ethyl methanesulfonate (prepared as described in Example 110) and homomorpholine to give the title compound in 22% yield; NMR Spectrum: 1.75-1.79 (m, 2H), 2.22 (s, 3H), 2.76-2.78 (m, 4H), 2.97 (t, 2H), 3.57-3.59 (m, 2H), 3.62-3.64 (m, 2H), 4.40 (t, 2H), 5.13 (s, 2H), 7.02 (d, 1H), 7.32-7.48 (m, 7H), 8.21 (s, 1H), 8.24 (s, 1H); Mass Spectrum: 475 (MH+).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][C@@H:6]1[C:18]2[N:17]([C@H:19]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH3:20])[C:16]3[C:11](=[CH:12][C:13]([F:32])=[CH:14][C:15]=3[S:28]([CH3:31])(=[O:30])=[O:29])[C:10]=2[CH2:9][CH2:8][CH2:7]1)C.C(OC(=O)C[C@H]1C2N([C@H](C3C=CC(Cl)=CC=3)C)C3C(=CC(F)=CC=3S(C)(=O)=O)C=2CCC1)C.[Li+].[OH-].CC(O)=O>C1COCC1.CO>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([C@@H:19]([N:17]2[C:18]3[C@@H:6]([CH2:5][C:4]([OH:33])=[O:3])[CH2:7][CH2:8][CH2:9][C:10]=3[C:11]3[C:16]2=[C:15]([S:28]([CH3:31])(=[O:29])=[O:30])[CH:14]=[C:13]([F:32])[CH:12]=3)[CH3:20])=[CH:26][CH:25]=1
Reactant: CCOC(=O)C[C@H]1CCCc2c1n([C@@H](C)c1ccc(Cl)cc1)c1c(S(C)(=O)=O)cc(F)cc21
Agent: CCOC(=O)C[C@@H]1CCCc2c1n([C@@H](C)c1ccc(Cl)cc1)c1c(S(C)(=O)=O)cc(F)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H](c1ccc(Cl)cc1)n1c2c(c3cc(F)cc(S(C)(=O)=O)c31)CCC[C@@H]2CC(=O)O
Temperature: 0 °C

Procedure:
The diastereomeric mixture of ethyl[(1R)-9-[(1S)-1-(4-chlorophenyl)ethyl]-6-fluoro-8-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-1-yl]acetate and ethyl[(1S)-9-[(1S)-1-(4-chlorophenyl)-ethyl]-6-fluoro-8-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-1-yl]acetate (1 eq) was dissolved in a 3.5/1 mixture of THF/MeOH (0.25M) and cooled at 0° C. Aqueous LiOH 1N (1 eq) was slowly added and the mixture was stirred at 0° C. for 12 h or until almost complete hydrolysis of ethyl[(1R)-9-[(1S)-1-(4-chlorophenyl)ethyl]-6-fluoro-8-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-1-yl]acetate, the other diastereomer was only slightly hydrolyzed under these conditions. AcOH was added and the solvent was removed by evaporation. The residue was taken up in EtOAc/H2O and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. Ethyl[(1S)-9-[(1S)-1-(4-chlorophenyl)ethyl]-6-fluoro-8-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-1-yl]acetate and [(1R)-9-[(1S)-1-(4-chloro-phenyl)ethyl]-6-fluoro-8-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-1-yl]acetic acid were separated by flash chromatography eluting with 40% EtOAc in hexanes containing 1% AcOH to give the desired [(1R)-9-[(1S)-1-(4-chlorophenyl)ethyl]-6-fluoro-8-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-1-yl]acetic acid with de>90% which was swished in 30% EtOAc in hexane to give the desired compound as a white solid with de>95%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH:12]=[O:13])[O:8][CH2:7][CH:6]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:5]2.[BH4-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH2:12][OH:13])[O:8][CH2:7][CH:6]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:5]2
Reactant: CCCCCC1COc2cc(C=O)c(F)cc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCCC1COc2cc(CO)c(F)cc2C1
Reaction time: 3 h

Procedure:
11.1 g (44.3 mmol) of 6-fluoro-3-pentylchroman-7-carbaldehyde are dissolved in 100 ml of ethanol, and 2.0 g (52.8 mmol) of sodium borohydride are added in portions. After 3 h, the batch is diluted with water and extracted three times with MTB ether. The combined org. phases are washed with sat. sodium chloride soln. and dried over sodium sulfate, the solvent is removed in vacuo, and the residue is filtered through silica gel with dichloromethane (Rf=0.3), giving (6-fluoro-3-pentylchroman-7-yl)methanol as a colourless solid.
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28]([N:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)=[O:29])[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:18][CH:19]1[CH2:20][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28]([N:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)=[O:29])[N:27]=2)[CH2:22]1
Reactant: CN1CCN(C(=O)c2csc(N3CC(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)C3)n2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CN1CCN(C(=O)c2csc(N3CC(O)C3)n2)CC1
Reaction time: 1 h
Yield: 82.6 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-[4-(4-methylpiperazine-1-carbonyl)-1,3-thiazol-2-yl]azetidine (941 mg, 1.81 mmol) (obtained as described in Reference Example 30(1)) in anhydrous tetrahydrofuran (47 ml) was added a solution of 1.0M tetra-n-butylammonium fluoride in tetrahydrofuran (2.17 ml, 2.17 mmol) in an ice bath, and the mixture was stirred for 1 hour. After checking the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (3:1) as the eluant to afford 3-hydroxy-1-[4-(4-methylpiperazine-1-carbonyl)-1,3-thiazol-2-yl]azetidine (422 mg, yield 83%) as a white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[O:16][CH2:17][CH:18]2[O:23][CH2:22][C:21](=O)[N:20]([CH2:25][CH2:26][CH3:27])[CH2:19]2)[CH:9]=[CH:8]1>O1CCCC1>[CH2:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[O:16][CH2:17][CH:18]2[O:23][CH2:22][CH2:21][N:20]([CH2:25][CH2:26][CH3:27])[CH2:19]2)[CH:9]=[CH:8]1
Reactant: CCCN1CC(COc2cccc3c2CC=C3)OCC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCN1CCOC(COc2cccc3c2CC=C3)C1
Yield: 89.5 %

Procedure:
In 50 ml. of anhydrous tetrahydrofuran was suspended 0.5 g. of lithium aluminum hydride and after adding slowly to the suspension a solution prepared by dissolving 2.0 g. of 2-(7-indenyloxymethyl)-4-propylmorpholin-5-one in 10 ml. of anhydrous tetrahydrofuran, the mixture was treated in a similar manner as in Example 1 to provide 1.7 g. (yield 89.5%) of oily 2-(7-indenyloxymethyl)-4-propylmorpholine.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[N:21]=[C:22]([C:33]2[CH:37]=[CH:36][O:35][N:34]=2)[N:23]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:24]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[O:35]1[CH:36]=[CH:37][C:33]([C:22]2[N:23]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:24]=[C:20]([CH2:19][OH:18])[N:21]=2)=[N:34]1
Reactant: CC(C)(C)[Si](OCc1cn(COCC[Si](C)(C)C)c(-c2ccon2)n1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(CO)nc1-c1ccon1
Reaction time: 4 h
Yield: 46.8 %

Procedure:
The compound obtained in step (2) (6.22 g) was dissolved in THF (200 ml), TBAF (a 1.0 M THF solution, 11.6 ml) was added under stirring, and stirring was conducted for 4 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by flash chromatography (ethyl acetate/hexane=50%→100%) using an amino column (trade name: Hi-Flash Column 3L Amino, manufactured by Yamazen Corporation) to give the title compound (1.61 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.Br[CH2:40][CH2:41][CH2:42][CH2:43][O:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[Cl:51]>>[Cl:51][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=1[O:44][CH2:43][CH2:42][CH2:41][CH2:40][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1
Reactant: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(O)cc3)cc21
Reactant: Clc1ccccc1OCCCCBr
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCCOc4ccccc4Cl)cc3)cc21

Procedure:
Analogously to Method I, 0.100 g of tert-butyl 4-(4-hydroxyphenyl)-3-[1-(3-methoxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethoxy]piperidine-1-carboxylate (Example 44d) and 0.060 g of 1-(4-bromobutoxy)-2-chlorobenzene are used to prepare the title compound. Rf=0.28 (2:1 EtOAc-heptane); Rt=6.17.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([C:17]#N)[CH:11]=3)=[N:7][C:6]=2[CH:19]=1.[OH-:20].[Na+].[H-].[H-].[H-].[H-].[Li+].[Al+3]>S(=O)(=O)(O)O.O.C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([CH2:17][OH:20])[CH:11]=3)=[N:7][C:6]=2[CH:19]=1
Reactant: [OH-]
Reactant: N#Cc1cc(-c2nc3cc(F)ccc3s2)ccc1N
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(-c2nc3cc(F)ccc3s2)cc1CO
Temperature: 100 °C
Reaction time: 2 h

Procedure:
5-Fluoro-2-(4′-amino-3′-cyanophenyl)benzothiazole (1 g, 3.75 mmol) was dissolved in 80% sulfuric acid (50 ml) and heated at 100° C. for 2 hrs. After cooling, the reaction mixture was diluted with water (100 ml) and the pH adjusted to 7.5 using 50% sodium hydroxide. The product was extracted with ethyl acetate(3×50 ml), the extracts dried (Na2SO4) and evaporated to leave a yellow solid which was taken up in THF (20 ml) and added dropwise to a solution of LiAlH4 (0.7 g, 0.019 mol) in THF (15 ml). After stirring at 25° C. for 2 hrs, water (20 ml) was added and the product extracted with ethyl acetate (3×50 ml). The organic extracts were washed with brine (10 ml), dried (Na2SO4) and evaporated. The residue was purified by column chromatography (10% ethyl acetate/dichloromethane) to leave a yellow powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[CH3:17][O-:18].[Na+]>CO>[NH2:1][C:2]1[N:7]=[C:6]([O:18][CH3:17])[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: C[O-]
Reactant: N#Cc1c(Cl)nc(N)nc1-c1ccccc1
Agent: [Na+]
Solvent: CO
Product: COc1nc(N)nc(-c2ccccc2)c1C#N
Yield: 66 %

Procedure:
To a stirred solution of 200 mg (0.87 mmol) 2-amino-4-chloro-6-phenyl-pyrimidine-5-carbonitrile in 5 ml methanol was added 0.4 ml (2.16 mmol) sodium methylate solution (5.4 M in methanol) and the mixture heated at reflux for 16 h. The reaction mixture was then concentrated in vacuo and the residue partitioned between ethyl acetate and water. The organic phase was dried over sodium sulfate and concentrated in vacuo to afford 130 mg (66%) 2-amino-4-methoxy-6-phenyl-pyrimidine-5-carbonitrile as a light yellow crystalline solid. ES-MS m/e (%): 227 (M+H+, 100).
Reaction SMILES: C([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:17][C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][N:19]=3)[CH:14]=2)[CH2:9]1)C1C=CC=CC=1>[Pd].CCO>[CH2:9]1[C:10]2[C:15](=[CH:14][C:13]([O:17][C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][N:19]=3)=[CH:12][CH:11]=2)[CH2:16][NH:8]1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CN(Cc2ccccc2)C3)nc1
Agent: [Pd]
Solvent: CCO
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CNC3)nc1
Yield: 11.9 %

Procedure:
Combine 6-(2-benzyl-2,3-dihydro-1H-isoindol-5-yloxy)-nicotinamide (230.0 mg, 0.67 mmol), EtOH (5 mL), and 10% Pd—C (45.0 mg) and place under a hydrogen balloon. Stir the reaction at room temperature for 168 hours at atmospheric pressure. Filter the reaction mixture through a pad of Celite® using MeOH eluent and then concentrate the filtrate under reduced pressure. Add the mixture to a 2 g SCX column, wash with MeOH, and elute using 1.0 N NH3—MeOH. After concentrating under reduced pressure, purify the mixture by flash chromatography using 10% 1.0 N NH3-MeOH/DCM eluent to afford 19.2 mg, 0.08 mmol (11% yield) of the title compound as a white solid: 1H NMR (500 MHz, CD3OD); 4.1-4.3 (4H, br m), 6.9-7.1 (3H, m), 7.3-7.4 (1H, m), 8.2-8.3 (1H, m), 8.6 (1H, s); MS m/z 254 (M−1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([C@@:8]2([CH3:21])[NH:17][C:16](=O)[C:11]3([CH2:15][CH:14]=[CH:13][CH2:12]3)[S:10](=[O:20])(=[O:19])[CH2:9]2)[CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([C@@:8]2([CH3:21])[NH:17][C:16](=[S:32])[C:11]3([CH2:15][CH:14]=[CH:13][CH2:12]3)[S:10](=[O:20])(=[O:19])[CH2:9]2)[CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: C[C@@]1(c2cc(Br)ccc2F)CS(=O)(=O)C2(CC=CC2)C(=O)N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@@]1(c2cc(Br)ccc2F)CS(=O)(=O)C2(CC=CC2)C(=S)N1
Temperature: 80 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
A mixture of (R)-8-(5-bromo-2-fluoro-phenyl)-8-methyl-6,6-dioxo-6λ6-thia-9-aza-spiro[4.5]dec-2-en-10-one (410 mg, 1.06 mmol, Eq: 1.00) and Lawesson's reagent (427 mg, 1.06 mmol, Eq: 1.00) in dioxane (10 ml) was stirred at 80° C. for 2 hours. More Lawesson's reagent (427 mg, 1.06 mmol, Eq: 1.00) was added and stirring continued at 85° C. for 16 hours. More Lawesson's reagent (427 mg, 1.06 mmol, Eq: 1.00) was added and stirring continued at 95° C. for 6 hours. The reaction mixture was poured into sat. NaHCO3-solution and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to give light yellow oil. The residue was chromatographed on 20 g silica gel with dichloromethane/heptane to give (R)-8-(5-bromo-2-fluoro-phenyl)-8-methyl-6,6-dioxo-6λ6-thia-9-aza-spiro[4.5]dec-2-en-10-thione (305 mg, 754 μmol, 71.4% yield) as a light yellow foam. MS (ISP): m/z=404.1 [M+H]+ and 406.2 [M+2+H]+.
Reaction SMILES: P(Br)(Br)Br.Br[CH2:6][C:7]1[N:11]([CH3:12])[N:10]=[CH:9][CH:8]=1.[CH3:13][C:14]1[N:19]=[C:18]([SH:20])[N:17]=[C:16]([OH:21])[CH:15]=1>>[CH3:13][C:14]1[N:19]=[C:18]([S:20][CH2:6][C:7]2[N:11]([CH3:12])[N:10]=[CH:9][CH:8]=2)[N:17]=[C:16]([OH:21])[CH:15]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Cn1nccc1CBr
Agent: BrP(Br)Br
Product: Cc1cc(O)nc(SCc2ccnn2C)n1
Yield: 55 %

Procedure:
The title compound was prepared by following the procedure described for Example 55 from 1-methyl-1H-pyrazole-5-carbaldehyde to provide (1-methyl-1H-pyrazol-5-yl)methanol, which gave 5-(bromomethyl)-1-methyl-1H-pyrazole upon reaction with phosphorous tribromide. The reaction of 5-(bromomethyl)-1-methyl-1H-pyrazole and 6-methyl-2-sulfanylpyrimidin-4-ol provided 6-methyl-2-{[(1-methyl-1H-pyrazol-5-yl)methyl]sulfanyl}pyrimidin-4-ol as a white solid (0.742 g, 55% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.21 (s, 3H), 3.82 (s, 3H), 4.47 (s, 2H), 6.04 (bs, 1H), 6.23 (d, J=1.7 Hz, 1H), 7.29 (d, J=1.7 Hz, 1H), 8.19 (s, 1H); M+ 236.3.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([CH3:50])[C:11](=[O:49])[CH2:12][N:13]([C:36]2[CH:41]=[C:40]([C:42]3[N:46]=[C:45]([CH3:47])[O:44][N:43]=3)[CH:39]=[CH:38][C:37]=2[CH3:48])[CH2:14][C:15]([NH:17][CH2:18][CH2:19][N:20]([CH:33]([CH3:35])[CH3:34])S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)=[O:16])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C1(S)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.ClCCl>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([N:10]([CH3:50])[C:11](=[O:49])[CH2:12][N:13]([C:36]2[CH:41]=[C:40]([C:42]3[N:46]=[C:45]([CH3:47])[O:44][N:43]=3)[CH:39]=[CH:38][C:37]=2[CH3:48])[CH2:14][C:15]([NH:17][CH2:18][CH2:19][NH:20][CH:33]([CH3:35])[CH3:34])=[O:16])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(N(C)C(=O)CN(CC(=O)NCCN(C(C)C)S(=O)(=O)c2ccccc2[N+](=O)[O-])c2cc(-c3noc(C)n3)ccc2C)CC1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [Cs+]
Solvent: CC#N
Solvent: ClCCl
Product: CC(=O)N1CCC(N(C)C(=O)CN(CC(=O)NCCNC(C)C)c2cc(-c3noc(C)n3)ccc2C)CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 83.6 %

Procedure:
The compound (260 mg, 0.365 mmol) obtained in step D was dissolved in acetonitrile (3 ml). Then, benzenethiol (0.057 ml, 0.547 mmol) and cesium carbonate (594 mg, 1.82 mmol) were added, and the mixture was stirred at room temperature for 10 hr. The reaction mixture was diluted with dichloromethane, and the organic layer was washed with diluted aqueous sodium hydroxide solution, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (NH silica gel use, methanol-dichloromethane) to give the title compound (161 mg, yield 84%) as a pale-yellow amorphous solid. This was directly used for the next step.
Reaction SMILES: [CH3:1][N:2]([C:4]([C:6]1[NH:7][CH:8]=[CH:9][CH:10]=1)=[O:5])[NH2:3].C1C=CC2N(O)N=NC=2C=1.[I:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH3:1][N:2]([C:4]([C:6]1[NH:7][CH:8]=[CH:9][CH:10]=1)=[O:5])[NH:3][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:22]([I:21])=[CH:23][CH:24]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: CN(N)C(=O)c1ccc[nH]1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(NC(=O)c1ccc(I)cc1)C(=O)c1ccc[nH]1
Temperature: 40 °C

Procedure:
1H-Pyrrole-2-carboxylic acid, 1-methyl-hydrazide (139 mg), EDC (230 mg), HOBt (162 mg), 4-iodobenzoic acid (248 mg) and DIPEA (0.21 ml) were mixed in DMF (3 ml). The reaction was heated at 40° C. for 6 hours, the DMF was evaporated under vacuum and the residue applied to a bond-elut (silica) and eluted with an ethyl acetate/cyclohexane gradient to give, after evaporation of the solvent, 1H-pyrrole-2-carboxylic acid, 1-methyl-2-(4-iodobenzoyl)hydrazide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])[C:17]([C:27](=[O:30])[NH:28][CH3:29])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[K+].[F:41][C:42]([F:56])([F:55])[C:43]1[CH:44]=[C:45]([CH:48]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:50]=1)[CH2:46]Br.[OH-].[Na+]>O1CCCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])[C:17]([C:27](=[O:30])[N:28]([CH2:46][C:45]3[CH:48]=[C:49]([C:51]([F:53])([F:54])[F:52])[CH:50]=[C:43]([C:42]([F:41])([F:55])[F:56])[CH:44]=3)[CH3:29])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: CNC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccccc1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1-c1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.7 %

Procedure:
To a solution of 6.28 g (15.3 mmol) 4-(5-methylcarbamoyl-4-o-tolyl-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester in 250 ml tetrahydrofuran 20 ml of a 1 M solution (20 mmol) of potassium hexamethyldisilazide in tetrahydrofuran were added at 0° C. After 30 min, 2.81 ml (15.3 mmol) 3,5-bis(trifluoromethyl)benzyl bromide were added dropwise. The reaction mixture was allowed to warm to room temperature over night. Addition of water and 1 M aqueous sodium hydroxide solution was followed by extraction with three portions of ethyl acetate. The combined organic extracts were dried with sodium sulfate and concentrated. Flash column chromatography gave 6.89 g (70.8%) of the parent compound as a white solid.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH3:10][C:11]1([CH3:30])[CH2:16][CH:15]([NH:17][CH:18]2[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]2)[CH2:14][C:13]([CH3:29])([CH3:28])[NH:12]1>O>[Cl:3][C:2]1[N:1]=[C:8]([N:17]([CH:18]2[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]2)[CH:15]2[CH2:16][C:11]([CH3:30])([CH3:10])[NH:12][C:13]([CH3:29])([CH3:28])[CH2:14]2)[N:7]=[C:5]([N:17]([CH:15]2[CH2:14][C:13]([CH3:29])([CH3:28])[NH:12][C:11]([CH3:30])([CH3:10])[CH2:16]2)[CH:18]2[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:26])([CH3:27])[CH2:19]2)[N:4]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CC1(C)CC(NC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Solvent: O
Product: CC1(C)CC(N(c2nc(Cl)nc(N(C3CC(C)(C)NC(C)(C)C3)C3CC(C)(C)NC(C)(C)C3)n2)C2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1

Procedure:
Following the procedure described in Preparation 11(b), cyanuric chloride was reacted with bis(2,2,6,6-tetramethyl-4-piperidyl)amine [prepared as described in Preparation 12(a)]. After completion of the reaction, the reaction mixture was poured into water and extracted with chloroform. The extract was dried over anhydrous potassium carbonate and then the chloroform was distilled off. The residue was recrystallized from chloroform, to afford the desired product, in the form of crystals melting at 295° C. (with decomposition).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[CH3:19]I>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[CH2:7][N:8]([CH3:19])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)NCc1cccc(Br)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(Cc1cccc(Br)c1)C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 113.6 %

Procedure:
19 g (475 mmol) of sodium hydride (60% in oil) are added portionwise to a solution of 128 g (447 mmol) of tert-butyl (3-bromobenzyl)carbamate in 800 ml of DMF, and the reaction medium is stirred until the evolution of gas has ceased. 29.3 ml (470 mmol) of methyl iodide are added dropwise and stirring is continued for 18 hours. The reaction medium is poured into ice-cold water and extracted with ethyl acetate. The organic phase is separated out after settling has taken place, dried over magnesium sulfate and evaporated. 152.5 g of tert-butyl (3-bromobenzyl)-N-methylcarbamate are obtained in a yield of 92%.