Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:4]=[C:5]([CH:12]=[C:13]([S:15]([F:20])([F:19])([F:18])([F:17])[F:16])[CH:14]=1)[C:6](N(OC)C)=[O:7].[CH2:22]1COCC1.C[Mg]Br.Cl>C(OCC)(=O)C.O>[CH3:1][N:2]([CH3:21])[C:3]1[CH:4]=[C:5]([C:6](=[O:7])[CH3:22])[CH:12]=[C:13]([S:15]([F:19])([F:18])([F:20])([F:17])[F:16])[CH:14]=1
Reactant: C1CCOC1
Reactant: CON(C)C(=O)c1cc(N(C)C)cc(S(F)(F)(F)(F)F)c1
Agent: C[Mg]Br
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)c1cc(N(C)C)cc(S(F)(F)(F)(F)F)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3-Dimethylamino-N-methoxy-N-methyl-5-pentafluorosulfanylbenzamide (980 mg) was dissolved in abs. THF (50 ml), and methylmagnesium bromide solution (2.1 ml; 3M solution in diethyl ether) was added dropwise while stirring at 0° C. After the addition had ended, the ice bath was removed and the mixture was stirred at RT for 1 h. To complete the reaction, more methylmagnesium bromide solution (0.3 ml) was added and the mixture was stirred for a further 2 h. After storing overnight in a refrigerator, the reaction mixture was admixed with 1 N hydrochloric acid while cooling. Addition of water and ethyl acetate was followed by extraction twice more with ethyl acetate, and the combined organic phases were dried with magnesium sulfate, filtered and concentrated. The residue was purified by means of chromatography on silica gel (100/0 to 50/50 n-heptane/ethyl acetate within 30 min). The product-containing fractions were combined, the solvent was removed and the residue was dried under high vacuum. 650 mg of the title compound were obtained.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]([CH3:28])=[C:11]([CH3:27])[C:12]=1[C:13]([C:15]1[CH:20]=[C:19]([CH2:21][CH3:22])[C:18]([O:23]C)=[C:17]([CH2:25][CH3:26])[CH:16]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.[K+].[Br-]>>[CH3:28][C:10]1[O:9][C:8]2[CH:1]=[C:2]3[C:7](=[C:13]([C:15]4[CH:16]=[C:17]([CH2:25][CH3:26])[C:18]([OH:23])=[C:19]([CH2:21][CH3:22])[CH:20]=4)[C:12]=2[C:11]=1[CH3:27])[CH:6]=[CH:5][CH:4]=[CH:3]3
Reactant: CCc1cc(C(=O)c2c(Cc3ccccc3)oc(C)c2C)cc(CC)c1OC
Agent: BrB(Br)Br
Agent: [Br-]
Agent: [K+]
Product: CCc1cc(-c2c3ccccc3cc3oc(C)c(C)c23)cc(CC)c1O

Procedure:
The title compound was prepared according to the procedure in Example 1, step 5, using (2-benzyl-4,5-dimethyl-furan-3-yl)-(3,5-diethyl-4-methoxy-phenyl)-methanone (22.0 g, 58.4 mmol) and boron tribromide (36.8 mL, 0.389 mol). Purification on Biotage KP-Sil, eluting with a 0, 2 & 5% EtOAc/hexane step gradient followed by trituration with hexane gave 1.34 g (8%), of the title compound as an off white solid. 1H NMR (DMSO-d6) δ 1.15 (t, 6 H), 1.59 (s, 3 H), 2.37 (s, 3 H), 2.59-2.72 (m, 4 H), 6.89 (s, 2 H), 7.29 (d of t, 1 H), 7.39 (d of t, 1 H), 7.56 (d, 1 H), 7.90 (s, 1 H), 7.96 (d, 1 H), 8.29 (s, 1 H). IR (KBr) 3540, 2960, 1475, 1180 and 1140 cm-1. mass spectrum (EI) m/z 344 (M+). Anal. Calcd. for C24H24O2.0.3H2O: C, 82.39; H, 7.09; N, 0.00. Found: C, 82.53; H, 7.11; N, 0.05.
Reaction SMILES: Br[CH:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:3]([NH:5][C:6]1[S:7][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:9][N:10]=1)=[O:4].[CH3:25][NH2:26]>CN(C)C=O>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][C:8]1[S:7][C:6]([NH:5][C:3](=[O:4])[CH:2]([NH:26][CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:10][CH:9]=1
Reactant: O=C(Nc1ncc(Cc2ccccc2Cl)s1)C(Br)c1ccccc1
Reactant: CN
Solvent: CN(C)C=O
Product: CNC(C(=O)Nc1ncc(Cc2ccccc2Cl)s1)c1ccccc1

Procedure:
2-Bromo-N-[5-(2-chloro-benzyl)-thiazol-2-yl]-2-phenyl-acetamide (42 mg, 0.10 mmol) was dissolved in 0.5 mL of N,N-dimethylformamide containing 1.0 mL of methylamine (2.0 M in tetrahydrofuran, 2.0 mmol). The reaction vessel was sealed and then subjected to microwave irradiation for 5 minutes at 80° C. The crude mixture was evaporated to dryness, dissolved in 1 mL of dimethylsulfoxide and purified by reverse-phase preparative liquid chromatography (29 mg, 0.078, 78%) ESI-MS m/z calc. 371.1, found 372.2 (M+1)+ Retention time 2.33 minutes. 1H NMR (400 MHz, MeOD) δ 2.66 (s, 3H), 4.23 (s, 2H), 5.09 (s, 1H), 7.13-7.56 (m, 10H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1B(O)O.Br[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[CH2:21][OH:22].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[CH2:21][OH:22]
Reactant: Cn1c(B(O)O)cc2ccccc21
Reactant: OCc1ccncc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(-c2cnccc2CO)cc2ccccc21
Temperature: 120 °C

Procedure:
A microwave reactor is charged with 1-methyl-indole-2-boronic acid (1.18 g, 6.78 mmol), (3-bromo-pyridin-4-yl)-methanol (0.850 g, 4.52 mmol), potassium phosphate (1.91 g, 9.04 mmol) and DMF (10 mL). The reactor is evacuated and filled with nitrogen thrice and Pd(PPh3)4 (0.261 g, 0.226 mmol) is added. The reactor is evacuated and filled with nitrogen thrice again. The mixture is heated to 120° C. for 1 h under microwave irradiation, then diluted with ethyl acetate and washed with water thrice. The organic layer is dried over sodium sulfate and concentrated in vacuo to give a residue which is purified by silica gel flash chromatography (dichloromethane-methanol, 19:1) to afford [3-(1-methyl-1H-indol-2-yl)-pyridin-4-yl]-methanol as a white solid. 1H NMR (400 MHz, MeOD) δ ppm 3.58 (s, 3H), 4.57 (s, 2H), 6.54 (s, 1H), 7.14 (t, J=7.5 Hz, 1H), 7.27 (ddd, J=7.6, 1.1 Hz, 1H), 7.46 (d, J=8.3 Hz, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.81 (d, J=5.1 Hz, 1H), 8.49 (s, 1H), 8.67 (d, J=5.1 Hz, 1H). HRMS (ESI) m/z 239.1177 [(M+H)+ Calcd for C15H15N2O: 239.1184].
Reaction SMILES: [Si]([O:8][C@@H:9]1[C:13]2([CH2:15][CH2:14]2)[C:12](=[O:16])[N:11]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([Cl:25])[CH:18]=2)[C@@H:10]1[CH3:26])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.O>C1COCC1>[Cl:25][C:19]1[CH:18]=[C:17]([N:11]2[C@H:10]([CH3:26])[C@H:9]([OH:8])[C:13]3([CH2:15][CH2:14]3)[C:12]2=[O:16])[CH:24]=[CH:23][C:20]=1[C:21]#[N:22]
Reactant: C[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)C2(CC2)C(=O)N1c1ccc(C#N)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1[C@H](O)C2(CC2)C(=O)N1c1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.6 %

Procedure:
To a solution of rac-4-((6R,7R)-7-(tert-butyldimethylsilyloxy)-6-methyl-4-oxo-5-azaspiro[2.4]hept-5-yl)-2-chlorobenzonitrile (140 mg) in THF (5 mL) was added tetrabutylammonium fluoride-THF solution (2.00 mL, 1 mol/L), and the mixture was stirred at room temperature for 18 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=1/0→3/1) to give the title compound as a colorless solid (yield: 32.3 mg, 32.5%).
Reaction SMILES: Cl[C:2]1[N:3]([CH3:13])[C:4](=[O:12])[CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9].[F:14][C:15]1[CH:20]=[C:19]([S:21][CH3:22])[CH:18]=[CH:17][C:16]=1[NH2:23]>>[F:14][C:15]1[CH:20]=[C:19]([S:21][CH3:22])[CH:18]=[CH:17][C:16]=1[NH:23][C:2]1[N:3]([CH3:13])[C:4](=[O:12])[CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CSc1ccc(N)c(F)c1
Reactant: COC(=O)c1ccc(=O)n(C)c1Cl
Product: COC(=O)c1ccc(=O)n(C)c1Nc1ccc(SC)cc1F

Procedure:
Methyl 2-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate was prepared from methyl 2-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate and 2-fluoro-4-(methylthio)benzenamine as described in Step C of Example 153.
Reaction SMILES: C(OC(=O)[N:7]([C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[CH:30][CH:29]=1)[C:8]1[C:9]2[N:10]([N:25]=[CH:26][N:27]=2)[C:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[C:20](=[O:24])[NH:19][CH2:18][CH2:17]3)=[CH:12][N:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:34]1([C:31]2[CH:30]=[CH:29][C:28]([NH:7][C:8]3[C:9]4[N:10]([N:25]=[CH:26][N:27]=4)[C:11]([C:14]4[CH:15]=[C:16]5[C:21](=[CH:22][CH:23]=4)[C:20](=[O:24])[NH:19][CH2:18][CH2:17]5)=[CH:12][N:13]=3)=[CH:33][CH:32]=2)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1
Reactant: CC(C)(C)OC(=O)N(c1ccc(N2CCOCC2)cc1)c1ncc(-c2ccc3c(c2)CCNC3=O)n2ncnc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NCCc2cc(-c3cnc(Nc4ccc(N5CCOCC5)cc4)c4ncnn34)ccc21

Procedure:
A solution of (4-morpholin-4-yl-phenyl)-[5-(1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]-carbamic acid tert-butyl ester (30 mg, 0.055 mmol) in a 1:1 mixture of TFA:DCM (1 drop of H2O), is stirred at room temperature for 2 hours. The solvent is removed in vacuo and the residue partitioned between ethyl acetate and sat. NaHCO3 (aq). The water layer is extracted with ethyl acetate (2×). The organic layers are combined and evaporated to afford a residue purified by silica gel column chromatography eluting with ethyl acetate. The title compound is isolated (18 mg, 75%) and converted into the mesylate salt (16.6 mg, 97%) using 0.1M methanesulfonic acid (0.317 mL) in MeOH. 1H-NMR (400 MHz, d6-DMSO) δ(ppm) 2.36 (3H, s MsOH), 3.04 (2H, t), 3.21 (4H, m), 3.47 (2H, t), 3.83 (4H, m), 7.11 (2H, d), 7.95-8.02 (6H, m), 8.05 (1H, s), 8.74 (1H, s), 10.09 (1H, br s). LCMS: Rt 2.81 min (97.9%), m/z (APCI) 442 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:5]=2[C:4]([Sn](CCCC)(CCCC)CCCC)=[N:3]1.[C:25]([NH:29][C:30]([C:32]1[C:40]2[C:35](=[N:36][CH:37]=[C:38](Br)[N:39]=2)[N:34]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[CH:33]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:25]([NH:29][C:30]([C:32]1[C:40]2[C:35](=[N:36][CH:37]=[C:38]([C:4]3[C:5]4[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]=4[N:2]([CH3:1])[N:3]=3)[N:39]=2)[N:34]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[CH:33]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2c1CCCCC2
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2c1CCCCC2
Temperature: 80 °C
Yield: 60.4 %

Procedure:
To a solution of 1-methyl-3-tributylstannyl-1,4,5,6,7,8-hexahydrocycloheptapyrazole (74 mg, 0.17 mmol) and 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (60 mg, 0.14 mmol) in DMF (2 mL) were added Pd(PPh3)4 (8 mg, 0.007 mmol) and copper(I) iodide (5 mg, 0.028 mmol). The reaction mixture was heated at 80° C. for 1.5 h then cooled to room temperature, quenched with water and extracted with EtOAc (2×). The combined organics were washed with water (3×) and brine then dried over MgSO4 and concentrated. The residue was absorbed on SiO2 and chromatographed with 20% to 50% EtOAc/hexanes to isolate 42 mg (60%) of 2-(1-methyl-1,4,5,6,7,8-hexahydrocycloheptapyrazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide as a pale orange-yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:8])=[N:4][NH:5][C:6]=1[CH3:7].C([O-])([O-])=O.[K+].[K+].Cl[CH2:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)=[O:18].CN(C=O)C>C(OCC)(=O)C>[NH2:8][C:3]1[C:2]([Br:1])=[C:6]([CH3:7])[N:5]([CH2:16][C:17]([N:19]2[CH2:20][CH2:21][N:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH2:23][CH2:24]2)=[O:18])[N:4]=1
Reactant: Cc1[nH]nc(N)c1Br
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(Br)c(N)nn1CC(=O)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 4-Bromo-5-methyl-1H-pyrazol-3-ylamine, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography ethyl acetate afforded the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3): 6.94–7.02 (m, 2H), 6.82–6.88 (t, 2H), 4.84 (s, 2H), 4.1 (s, 2H), 3.72–3.78 (m, 4H), 3.04–3.08 (m, 4H), 2.16 (s, 3H). MS (ES) M+H expected 317.37, found 318.1. MS (ES) M+H expected 396.27, found 396.
Reaction SMILES: [CH2:1]([C:5]1[O:9][N:8]=[C:7]([C:10]([OH:12])=[O:11])[CH:6]=1)[CH:2]([CH3:4])[CH3:3].[CH3:13][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[CH2:1]([C:5]1[O:9][N:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)Cc1cc(C(=O)O)no1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(CC(C)C)on1
Yield: 85.4 %

Procedure:
To a solution of 5-isobutylisoxazole-3-carboxylic acid (1.0 g, 5.91 mmol) in a mixture of dichloromethane (18 mL) and methanol (6 mL) was added trimethylsilyldiazomethane (2.0 M in ether) (5.91 mL, 11.8 mmol) dropwise until the yellow color persisted and the bubbling ceased (˜3.9 mL was required). The solvent was removed under reduced pressure, and the residue was diluted with dichloromethane, washed with a saturated aqueous solution of sodium bicarbonate, and dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by purification by flash silica gel chromatography using a 5% mixture of ethyl acetate in hexane afforded methyl 5-isobutylisoxazole-3-carboxylate (0.925 g, 5.05 mmol, 85% yield) as a flakey, white solid. The product had an HPLC ret. time=1.83 min.−Column: (condition A); LC/MS M+1=184.1. 1H NMR (500 MHz, CDCl3) δ ppm [mixture of isobutyl rotomers] 0.96-1.00 (m, 6H), [1.94-2.03 (m, 0.1H) and 2.03-2.14 (m, 0.9H)], [2.62 (d, J=7.21 Hz, 0.2H) and 2.70 (d, J=7.21 Hz, 1.8H)], 3.96-3.99 (m, 3H), and [6.41-6.44 (m, 0.9H) and 6.80 (s, 0.1H)].
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1([CH3:18])[CH:14]=[CH:13][C:12]([C:15](O)=[O:16])=[CH:11][CH:10]=1.O.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>ClC1C=CC=CC=1>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:15]([C:12]2[CH:13]=[CH:14][C:9]([CH3:18])=[CH:10][CH:11]=2)=[O:16])=[CH:3][CH:2]=1
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: COc1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: Clc1ccccc1
Solvent: O
Product: COc1ccc(C(=O)c2ccc(C)cc2)cc1
Yield: 7 %

Procedure:
In like manner to Example 8, anisole and para-toluic acid were reacted together (4 hour reflux) in chlorobenzene in the presence of ytterbium (III) trifluoromethanesulfonate hydrate, to give crude 4-methoxy-4′-methylbenzophenone (0.15 g, 7% yield).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:12]=O)[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[NH:20]1[CH2:23][CH:22]([N:24]2[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]2)[CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:20]3[CH2:23][CH:22]([N:24]4[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]4)[CH2:21]3)[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1
Reactant: Cn1c(C=O)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: O=S1(=O)CCN(C2CNC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cn1c(CN2CC(N3CCS(=O)(=O)CC3)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Reaction time: 40 h
Yield: 90.7 %

Procedure:
A mixture of 2-chloro-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (400 mg, 1.42 mmol), 4-azetidin-3-ylthiomorpholine-1,1-dioxide (324 mg, 1.70 mmol) and 4 Å powdered molecular sieves (900 mg) in DCE (20 mL) was stirred at room temperature for 4 h before the addition of sodium triacetoxyborohydride (602 mg, 2.84 mmol). The reaction mixture was stirred for 40 h then filtered through celite, washing with DCM. The organic phase was washed with brine (×1) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-15%) affording 2-Chloro-8-[3-(1,1-Dioxo-1-thiomorpholin-4-yl)azetidin-1-ylmethyl]-9-methyl-6-morpholin-4-yl-9H-purine as a cream solid (587 mg, 91%). LCMS (Method H): RT 2.25 min [M+H]+ 456.3
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([CH2:14][CH2:15][OH:16])[CH2:12][N:11]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[CH3:24])[C:10](=[O:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26]I.[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([CH2:14][CH2:15][O:16][CH3:26])[CH2:12][N:11]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[CH3:24])[C:10](=[O:25])[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1cccc(N2C[C@H](CCO)N(C(=O)OC(C)(C)C)CC2=O)c1C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC[C@H]1CN(c2cccc(C)c2C)C(=O)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The product from Step E (0.241 g, 0.699 mmol) was dissolved in DMF (10 mL) containing methyl iodide (0.21 mL, 3.44 mmol) and the stirred solution cooled to 0° C. under nitrogen. Sodium hydride (0.070 g, 60% dispersion in oil, 1.72 mmol) was added and the reaction stirred for 1 h. The reaction was quenched with water, and the DMF removed under vacuum. The residue was partitioned between ethyl acetate and water, and the organic phase washed with saturated brine and dried over magnesium sulfate. The crude product was chromatographed on silica gel with 40% ethyl acetate in hexane to give the title compound.
Reaction SMILES: CS[C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1.[NH2:15][C:16]1[CH:17]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:20][CH:21]=1>C(O)C>[O:14]=[C:5]1[NH:4][C:3]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=2)=[N:8][CH:7]=[C:6]1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1cnc(SC)[nH]c1=O
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: CCO
Product: CCOC(=O)c1cnc(Nc2cccc(C(F)(F)F)c2)[nH]c1=O
Reaction time: 17 h
Yield: 45 %

Procedure:
Ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate (50 g) and 3-aminobenzotrifluoride (45.2 g) are added to ethanol (300 ml), and the mixture is refluxed with stirring for 17 hours. After cooling, the precipitate is collected by filtration and recrystallized from a mixture of DMF and water to give ethyl 1,6-dihydro-6-oxo-2-(3-trifluoromethylanilino)-5-pyrimidinecarboxylate (34.4 g). M.p. 229°-230° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](Cl)[N:5]=[C:4]([C:11]([NH:13][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[S:26][C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[F:33])=[N:24][CH:23]=3)[CH2:17][CH2:16]2)=[O:12])[CH:3]=1.[CH:34]1([CH2:37][OH:38])[CH2:36][CH2:35]1>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:38][CH2:37][CH:34]2[CH2:36][CH2:35]2)[N:5]=[C:4]([C:11]([NH:13][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[S:26][C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[F:33])=[N:24][CH:23]=3)[CH2:17][CH2:16]2)=[O:12])[CH:3]=1
Reactant: N#Cc1c(N)cc(C(=O)NCC2CCN(Cc3cnc(-c4ccccc4F)s3)CC2)nc1Cl
Reactant: OCC1CC1
Product: N#Cc1c(N)cc(C(=O)NCC2CCN(Cc3cnc(-c4ccccc4F)s3)CC2)nc1OCC1CC1

Procedure:
According to the same procedure described in Example 204, using the compound prepared in Example 393 instead of the compound prepared in Example 215 and cyclopropylmethanol instead of 1-cyclopropylethanol, the title compound having the following physical data was obtained.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)([CH3:5])[CH2:3][CH3:4].[NH2:22][CH2:23][CH:24]([OH:40])[CH2:25][O:26][C:27]1[C:39]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][C:31]=2[CH:30]=[CH:29][CH:28]=1>>[CH:30]1[C:31]2[NH:32][C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:39]=2[C:27]([O:26][CH2:25][C@@H:24]([OH:40])[CH2:23][NH:22][CH:18]2[CH2:19][CH2:20][N:15]([S:12]([C:9]3[CH:8]=[CH:7][C:6]([C:2]([CH3:1])([CH3:5])[CH2:3][CH3:4])=[CH:11][CH:10]=3)(=[O:14])=[O:13])[CH2:16][CH2:17]2)=[CH:28][CH:29]=1
Reactant: NCC(O)COc1cccc2[nH]c3ccccc3c12
Reactant: CCC(C)(C)c1ccc(S(=O)(=O)N2CCC(=O)CC2)cc1
Product: CCC(C)(C)c1ccc(S(=O)(=O)N2CCC(NC[C@H](O)COc3cccc4[nH]c5ccccc5c34)CC2)cc1

Procedure:
The title compound was prepared from 4-(1,1-dimethyl-propyl)-benzenesulfonyl-piperidin-4-one and 1-amino-3-(9H-carbazol-4-yloxy)-propan-2-ol according to the reductive amination procedure of Intermediate 21 as an off-white solid; 1H′NMR (DMSO) δ 0.55-0.63 )m, 3H), 1.27 (d, J=6.9 Hz, 6H), 1.40-1.46 (m, 2H), 1.58-1.65 (m, 2H), 1.81(m, 2H), 2.38-2.45 (m, 2H), 2.63-2.82 (m, 2H), 3.07-3.13 (m, 2H), 3.51-3.54 (m, 1H), 3.90 (m, 1H), 4.08-4.13 (m, 2H), 4.66 (d, J=3.78 Hz, 1H), 5.07 (bs, 1H), 6.64 (d, J=7.95 Hz, 1H), 7.04-7.11 (m, 2H), 7.20-7.35 (m, 2H), 7.43 (d, J=8.07 Hz, 1H), 7.54-7.67 (m, 4H), 8.15 (d, J=7.71 Hz, 1H), 11.25 (s, 1H); MS (ES) m/z: 550.1 (MH+); HRMS for C31H39N3O4S: 550.2751
Reaction SMILES: C(N(CC)CC)C.N12CCN(CC1)CC2.[CH2:16]([N:18]=[C:19]=[O:20])[CH3:17].[Cl:21][C:22]1[CH:31]=[C:30]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=2)[CH:29]=[CH:28][C:23]=1[O:24][CH2:25][CH2:26][OH:27]>O1CCCC1>[Cl:21][C:22]1[CH:31]=[C:30]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=2)[CH:29]=[CH:28][C:23]=1[O:24][CH2:25][CH2:26][O:27][C:19]([NH:18][CH2:16][CH3:17])=[O:20]
Reactant: OCCOc1ccc(Oc2cccc(Cl)c2)cc1Cl
Reactant: CCN=C=O
Agent: C1CN2CCN1CC2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNC(=O)OCCOc1ccc(Oc2cccc(Cl)c2)cc1Cl

Procedure:
0.1 ml of triethylamine, 15 mg of 1,4-diazabicyclo[2.2.2]octane and 1.3 g of ethyl isocyanate are added to a solution of 4.49 g of 2-[2-chloro-4-(3-chlorophenoxy)phenoxy] ethanol in 40 ml of tetrahydrofuran. The reaction mixture is heated at 55° for 18 hours, with stirring, and then evaporated to dryness in vacuo. The residue is purified by chromatography [silica gel; diethyl ether/hexane (2:3)]. This gives the title compound which melts at 73°-74° C.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:3]=1[CH2:4][CH:5]1[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][NH:6]1.CCN(C(C)C)C(C)C.[C:29](Cl)(=[O:32])[O:30][CH3:31]>C(Cl)Cl>[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:3]=1[CH2:4][CH:5]1[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][N:6]1[C:29]([O:30][CH3:31])=[O:32]
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(Cc2c(F)cccc2F)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2c(F)cccc2F)C1
Yield: 98.2 %

Procedure:
Methyl 2-(2,6-difluorobenzyl)piperidine-4-carboxylate (5.008 g, 18.60 mmol) was dissolved in DCM (121 mL) and DIPEA (3.89 mL, 22.32 mmol) followed by methyl carbonochloridate (2.050 mL, 26.04 mmol) were added. After 3.5 h at room temperature the solution was washed with 0.1 M HCl and satd NaHCO3. The organic phase was dried and concentrated to yield dimethyl 2-(2,6-difluorobenzyl)piperidine-1,4-dicarboxylate (5.98 g, 98%). MS m/z 328 (M+H)+