Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:19]2[CH2:18][C@@:17]([OH:24])([C:20](=[O:23])[CH2:21][OH:22])[CH2:16][C@H:15]([O:25][C@@H:26]3[O:40][C@@H:39]([CH3:41])[C@H:29]4[O:30][C@H:31]5[N:36]([C@H:28]4[CH2:27]3)[CH2:35][CH2:34][O:33][C@@H:32]5[O:37][CH3:38])[C:14]=2[C:13]([OH:42])=[C:12]2[C:3]=1[C:4](=[O:46])[C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([O:44][CH3:45])[C:10]=1[C:11]2=[O:43].[O:47]1[CH:52]=[CH:51][CH2:50][CH2:49][CH:48]1[CH2:53][O:54][CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>ClCCl.CO>[O:23]=[C:20]([C@@:17]1([OH:24])[CH2:16][C@H:15]([O:25][C@@H:26]2[O:40][C@@H:39]([CH3:41])[C@H:29]3[O:30][C@H:31]4[N:36]([C@H:28]3[CH2:27]2)[CH2:35][CH2:34][O:33][C@@H:32]4[O:37][CH3:38])[C:14]2[C:19](=[C:2]([OH:1])[C:3]3[C:4](=[O:46])[C:5]4[C:10]([C:11](=[O:43])[C:12]=3[C:13]=2[OH:42])=[C:9]([O:44][CH3:45])[CH:8]=[CH:7][CH:6]=4)[CH2:18]1)[CH2:21][O:22][CH:52]1[O:47][CH:48]([CH2:53][O:54][CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57])[CH2:49][CH2:50][CH2:51]1
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)CO)C[C@@H]3O[C@H]1C[C@H]2[C@H](O[C@@H]3[C@@H](OC)OCCN32)[C@H](C)O1
Reactant: CCOC(=O)COCC1CCC=CO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)COCC1CCCC(OCC(=O)[C@]2(O)Cc3c(O)c4c(c(O)c3[C@@H](O[C@H]3C[C@H]5[C@H](O[C@@H]6[C@@H](OC)OCCN65)[C@H](C)O3)C2)C(=O)c2c(OC)cccc2C4=O)O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62 %

Procedure:
To a solution of (8S,10S)-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-10-{[(1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4′,3′:4,5] [1,3] oxazolo[2,3-c][1,4]oxazin-3-yl]oxy}-7,8,9,10-tetrahydrotetracene-5,12-dione (50 mg, 0.078 mmol) [PNU-159682, formula IIA, prepared as reported in WO 9802446] in 4 ml of dry dichloromethane under argon atmosphere, ethyl (3,4-dihydro-2H-pyran-2-ylmethoxy)acetate from step 1 (118.5 mg, 0.592 mmol) and anhydrous p-toluenesulfonic acid (22.3 mg, 0.12 mmol) were added. The reaction mixture was stirred at room temperature for 4 hours, until no starting material was detectable (TLC analysis, MeOH:CH2Cl2=0.3:9.7). Sodium bicarbonate 10% aqueous solution was then added to the reaction mixture and the aqueous phase was extracted with dichloromethane (4×20 ml).The combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated under vacuum. The residue was purified by flash column chromatography (MeOH:CH2Cl2=0.3:9.7) on silica gel (230-400 mesh), affording 41 mg (red wax, yield 62%) of 48, as a mixture of four diastereoisomers. MS (ESI): 842 [M+H]+. Retention time=7.47, 7.83 min (method 2).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][O:14][C:15]3=[O:18])=[CH:11][CH:10]=2)O1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]([C:30]2([C:33]3[CH:43]=[CH:42][C:36]4[O:37][C:38]([F:41])([F:40])[O:39][C:35]=4[CH:34]=3)[CH2:32][CH2:31]2)=[O:29])[CH:24]=[CH:23][C:22]=1[CH3:44].C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[F:41][C:38]1([F:40])[O:37][C:36]2[CH:42]=[CH:43][C:33]([C:30]3([C:28]([NH:27][C:25]4[CH:24]=[CH:23][C:22]([CH3:44])=[C:21]([C:9]5[CH:17]=[C:16]6[C:12](=[CH:11][CH:10]=5)[CH2:13][O:14][C:15]6=[O:18])[N:26]=4)=[O:29])[CH2:32][CH2:31]3)=[CH:34][C:35]=2[O:39]1
Reactant: CC1(C)OB(c2ccc3c(c2)C(=O)OC3)OC1(C)C
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc2c(c1)C(=O)OC2
Temperature: 120 °C

Procedure:
6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)isobenzofuran-1(3H)-one (39 mg, 0.15 mmol), N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (37 mg, 0.10 mmol) and Pd(PPh3)4 (6 mg, 0.005 mmol) were placed in a microwave vial. DME (1 mL) and saturated aq. Na2CO3 (100 μL) were added and the reaction vial was flushed with N2 and sealed. The reaction was heated in the microwave at 120° C. for 20 minutes before it was partitioned between ethyl acetate and H2O. The organic layer was filtered and concentrated. The residue was dissolved in DMSO and purified by reverse-phase HPLC to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(3-oxo-1,3-dihydroisobenzofuran-5-yl)pyridin-2-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 464.1, found 465.3 (M+1)+. Retention time 1.96 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H), 7.94-7.86 (m, 3H), 7.76-7.73 (m, 2H), 7.56 (d, J=1.5 Hz, 1H), 7.41-7.33 (m, 2H), 5.47 (s, 2H), 2.26 (s, 3H), 1.53-1.50 (m, 2H), 1.19-1.16 (m, 2H).
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.Cl.[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:23][CH2:24][C:25]([CH3:29])([CH3:28])[CH2:26][OH:27])=[C:19]([CH:22]=1)[C:20]#[N:21]>C(N(CC)CC)C>[C:20]([C:19]1[CH:22]=[C:15]([NH:14][C:6]([C:5]2[S:1][C:2]3[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=3[CH:4]=2)=[O:8])[CH:16]=[CH:17][C:18]=1[O:23][CH2:24][C:25]([CH3:28])([CH3:29])[CH2:26][OH:27])#[N:21]
Reactant: O=C(O)c1cc2ccccc2s1
Reactant: CC(C)(CO)COc1ccc(N)cc1C#N
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(C)(CO)COc1ccc(NC(=O)c2cc3ccccc3s2)cc1C#N
Yield: 30.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 6 using benzo[b]thiophene-2-carboxylic acid (0.77 g), 5-amino-2-(2,2-dimethyl-3-hydroxypropoxy)benzonitrile monohydrochloride (1.0 g) and triethylamine (0.6 ml), the title compound (0.45 g) was obtained. melting point: 188-189° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](F)(=[O:10])=[O:9].CN([S+](N(C)C)N(C)C)C.C[Si-](F)(F)(C)C.C[Si]([C:32]([F:35])([F:34])[F:33])(C)C>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C:32]([F:35])([F:34])[F:33])(=[O:10])=[O:9]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=S(=O)(F)c1ccccc1F
Agent: CN(C)[S+](N(C)C)N(C)C
Agent: C[Si-](C)(C)(F)F
Solvent: O
Product: O=S(=O)(c1ccccc1F)C(F)(F)F

Procedure:
The solution of EXAMPLE 12 (44.3 g) in a solution of 450 ml was added to a round bottomed flask fitted with overhead stirrer, nitrogen inlet, cold-water bath and temperature probe. It was cooled down to 12° C. (((CH3)2N)3S)+(F2Si(CH3)3)−, also known as TASF (6.1 g), was added in one portion. Ruppert's reagent (370 g, CH3SiCF3) was charged slowly to the reaction mixture while maintaining the internal temperature less than 23° C. The reaction was completed after addition. Water (220 g) was added to quench the reaction, the layers were separated, and the organic layer was washed twice with 220 g of water. The organic solution was distilled under vacuum with the bath temperature at 50° C. Heptanes (500 g) were added to the residue, and the mixture was distilled down until the solvent was removed. 1H NMR (400 MHz, CDCl3) δ 8.01-8.05 (m, 1H), 7.84-7.87 (m, 1H), 7.44-7.48 (m, 1H), 7.36-7.39 (m 1H).
Reaction SMILES: C([SiH](CC)CC)C.[CH3:8][O:9][C:10](=[O:41])[CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([S:21]([N:24]3[CH2:29][CH2:28][N:27]([C:30]4[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)(=[O:23])=[O:22])[CH:19]=2)[CH:14]=[CH:13]1.FC(F)(F)C(O)=O>[OH-].[Na+]>[CH3:8][O:9][C:10](=[O:41])[CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([S:21]([N:24]3[CH2:29][CH2:28][N:27]([C:30]4[CH:35]=[CH:34][C:33]([O:36][C:37]([F:39])([F:40])[F:38])=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)(=[O:23])=[O:22])[CH:19]=2)[CH2:14][CH2:13]1
Reactant: COC(=O)Cn1ccc2ccc(S(=O)(=O)N3CCN(c4ccc(OC(F)(F)F)cc4)CC3)cc21
Agent: CC[SiH](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CN1CCc2ccc(S(=O)(=O)N3CCN(c4ccc(OC(F)(F)F)cc4)CC3)cc21
Reaction time: 1 h

Procedure:
Triethylsilane (0.13 mL, 0.77 mmol) was added to a solution of {6-[4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indol-1-yl}-acetic acid methyl ester (82 mg, 0.16 mmol) and trifluoroacetic acid (4 mL) at rt. After 1 h, more triethylsilane (0.2 mL, 1.2 mmol) was added. After an additional 4 h, the reaction was poured into 1.2 M NaOH (50 mL) and extracted with CH2Cl2 (3×30 mL). The combined organic extracts were dried, filtered, concentrated and purified by silica gel chromatography (4:1→3:2; hexanes:ethyl acetate) to give {6-[4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-2,3-dihydroindol-1-yl}-acetic acid methyl ester: MS (ESI): 500.1 (M+H). {6-[4-(4-Trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-2,3-dihydro-indol-1-yl}-acetic acid methyl ester was hydrolyzed following the procedure outlined in Example 1 Step 2 to give {6-[4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-2,3-dihydro-indol-1-yl}-acetic acid: 1H NMR (400 MHz, DMSO-d6): δ 7.24 (d, 1H), 7.19 (d, 2H), 6.98 (d, 2H), 6.93 (d, 1H), 6.68 (s, 1H), 4.05 (s, 2H), 3.57 (t, 2H), 3.24-3.17 (m, 4H), 3.03 (t, 2H), 3.00-2.94 (m, 4H); MS (ESI): 486.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]([OH:12])=O)=[CH:4][N:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:14]>C(OCC)C>[ClH:14].[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]([Cl:14])=[O:12])=[CH:4][N:3]=1
Reactant: COc1nc(N)ncc1C(=O)O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOCC
Product: COc1nc(N)ncc1C(=O)Cl
Product: Cl
Reaction time: 3 h

Procedure:
To 16.9 g of 2-amino 4-methoxy 5-pyrimidinyl carboxylic acid prepared in stage 2, in suspension in 300 ml of anhydrous ethyl ether, were added at 0° C., 20.8 g of phosphorous pentachloride while stirring. After returning to room temperature for 3 hours, the precipitate was separated by filtration, rinsed several times with 50 ml of absolute ethyl ether. The hydrochloride of the 2-amino 4-methoxy 5-chlorocarbonyl pyrimidine thus obtained was used in the raw state in the following stage.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:9]([CH3:20])[CH:10]([C:12]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14][CH2:13]1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)S(O[Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])(=O)=O.CC1C=CC=C(C)N=1.O>C1COCC1>[Si:34]([O:11][CH:10]([C:12]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14]1)[CH:9]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH3:20])([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]
Reactant: CCOC(=O)C1(C(O)C(C)N(Cc2ccccc2)Cc2ccccc2)CC1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Solvent: O
Product: CCOC(=O)C1(C(O[Si](C)(C)C(C)(C)C)C(C)N(Cc2ccccc2)Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 76 %

Procedure:
A solution of ethyl 1-[(1RS,2RS)-2-(dibenzylamino)-1-hydroxypropyl]cyclopropanecarboxylate (1.30 g) in THF (15 mL) was cooled to 0° C., tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.98 mL) and 2,6-dimethylpyridine (0.621 mL) were added, and the mixture was stirred at room temperature for 17 hr. Water was added to the reaction mixture, 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→4/1) to give the title compound as a colorless oil (yield: 1.30 g, 76%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1.[F:20][C:21]([F:34])([F:33])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O>>[CH3:19][S:16]([CH2:15][C:11]1[CH:10]=[C:9]([NH:8][C:4]2[N:3]=[C:2]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[O:23][CH2:22][C:21]([F:20])([F:34])[F:33])[N:7]=[CH:6][N:5]=2)[CH:14]=[CH:13][CH:12]=1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: OB(O)c1ccccc1OCC(F)(F)F
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccccc3OCC(F)(F)F)n2)c1

Procedure:
Example 16 was prepared under similar conditions as described in the preparation of Example 1 using crude 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine and [2-(2,2,2-trifluoroethoxy)phenyl]boronic acid (Combi-Blocks Inc.). The batch was purified by preparative HPLC:
Reaction SMILES: [OH:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[N:13][N:14]([CH:16]4[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]4)[CH:15]=3)[CH:9]=2)[CH:4]=[CH:3]1.Br[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]([F:40])([F:39])[F:38].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH:19]1[CH2:20][CH2:21][CH:16]([N:14]2[CH:15]=[C:11]([C:8]3[CH:9]=[C:10]4[N:2]([O:1][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=5[C:37]([F:40])([F:39])[F:38])[CH:3]=[CH:4][C:5]4=[N:6][CH:7]=3)[CH:12]=[N:13]2)[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc4ccn(O)c4c3)cn2)CC1
Reactant: FC(F)(F)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccccc1COn1ccc2ncc(-c3cnn(C4CCNCC4)c3)cc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
tert-butyl 4-[4-(1-hydroxy-1H-pyrrolo[3,2-b]pyridin-6-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (30 mg, 0.078 mmol, 1.0 eq), 1-(bromomethyl)-2-(trifluoromethyl)benzene (0.066 mmol), and K2CO3 (30 mg) in 1.5 ml of DMF were shaken at r.t. for 30 min and then filtered and evaporated. The resulting crude product was dissolved in 1.5 ml of methanol and 0.5 ml of 4.0 M HCl/dioxane was dropped in. The reaction was shaken at room temperature for 0.5-1 h. The solvent was evaporated and the residue was dissolved in 2 ml of DCM. To this solution were added 20 mg of NaHCO3, 10 mg of Na2CO3, and drops of water. After stirred for 10 min, the organic solution was separated and purified with preparation HPLC to give the final product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][CH2:20]Cl>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[C:3]=1[O:11][CH2:18][O:19][CH3:20]
Reactant: COCCl
Reactant: COc1c(O)ccc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCOc1c(Br)ccc(O)c1OC
Temperature: 25 °C
Reaction time: 7 h
Yield: 46.3 %

Procedure:
To a stirring solution of 4-bromo-2-methoxybenzene-1,3-diol (4.5 g, 20.54 mmol) in acetone (40 mL) at 0° C. was added potassium carbonate (2.83 g, 20.54 mmol) and methoxymethyl chloride (1.32 mg, 16.43 mmol) and the resultant reaction mixture was stirred at RT for 7 h. The reaction mixture was quenched with ice-cold water, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0-10% ethyl acetate in pet ether) afforded 4-Bromo-2-methoxy-3-(methoxymethoxy)phenol as a liquid (2 g, 37%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH2:7][CH2:6]1)=[O:4].[Cl:20][S:21](O)(=[O:23])=[O:22]>ClCCl>[CH3:17][C:12]1[CH:13]=[CH:14][C:15]([S:21]([Cl:20])(=[O:23])=[O:22])=[CH:16][C:11]=1[N:8]1[CH2:7][CH2:6][N:5]([C:3](=[O:4])[C:2]([F:1])([F:18])[F:19])[CH2:10][CH2:9]1
Reactant: O=S(=O)(O)Cl
Reactant: Cc1ccccc1N1CCN(C(=O)C(F)(F)F)CC1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Cl)cc1N1CCN(C(=O)C(F)(F)F)CC1
Temperature: -5 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
To a solution of 2 g of 2,2,2-trifluoro-1-(4-o-tolyl-piperazin-1-yl)-ethanone (7.35 mmol) in 5 mL of dichloromethane at −5° C. were slowly added 19.7 g of chlorosulfonic acid (169 mmol). After stirring for 2 h at −5° C., the reaction mixture continued stirring for 16 h, thereby slowly allowed to warm to room temperature. After cooling to 0° C., the reaction mixture was slowly added to a water/ice mixture. The aqueous phase was extracted five times with dichloromethane, the combined organic phases washed with aqueous sodium bicarbonate solution and saturated sodium chloride solution. The organic layer was dried over magnesium sulphate, filtered, and the solvent evaporated to yield 2.2 g of product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][N:17]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C=O)C.O>[CH2:36]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([C:11]2[N:12]=[C:13]3[C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][N:17]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[C:14]3=[N:15][CH:16]=2)=[N:7]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(Cc4ccccc4)c4cc(Cl)ccc34)nc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
2-(6-Chloro-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (120 mg, 247 μmol) was dissolved in DMF (1 mL) and cooled to 0° C. Sodium hydride (12.9 mg, 322 μmol) was added and the mixture was stirred for 30 min. Benzyl bromide (63.5 mg, 44.1 μL, 371 μmol) was added and the mixture was warmed to 20° C. After 15 h the mixture was diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (silica, 40 g Analogix column, 20-50% ethyl acetate in hexanes, 15 min gradient) to give 2-(1-benzyl-6-chloro-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (87 mg, 151 μmol, 61.1%) as a pale yellow powder. 1H NMR (CDCl3) δ: 9.29 (s, 1H), 8.48 (d, J=8.7 Hz, 1H), 8.38 (s, 1H), 8.20 (d, J=7.9 Hz, 1H), 7.43 (d, J=1.5 Hz, 1H), 7.20-7.39 (m, 6H), 5.73 (s, 2H), 5.68 (s, 2H), 4.38-4.55 (m, 1H), 3.52-3.64 (m, 2H), 1.42 (d, J=6.4 Hz, 6H), 0.86-1.00 (m, 2H), −0.03 (s, 9H).
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([S:15][C:16]4[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=4[C:18]([OH:20])=O)=[N:11][N:10]3[CH:25]=2)=[O:5])[CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([S:15][C:16]4[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=4[C:18]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:20])=[N:11][N:10]3[CH:25]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccccc1Sc1ccc2nc(NC(=O)C3CC3)cn2n1
Reactant: Nc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccccc1)c1ccccc1Sc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 91.8 %

Procedure:
In the same manner as in Example 278 and using 2-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}thio)benzoic acid (250 mg, 0.71 mmol), aniline (184 mg, 2.0 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (380 mg, 1.0 mmol), N,N-diisopropylethylamine (270 mg, 2.0 mmol) and N,N-dimethylformamide (7 mL) as starting materials, the title compound (280 mg, 93%) was obtained as a white solid.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]1[CH2:25][CH2:24][CH:23]=[CH:22][N:21]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([Zn]CC)C.ICI.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Si:1]([O:18][CH2:19][C@@H:20]1[CH2:25][CH2:24][C@@H:23]2[C@@H:22]([CH2:33]2)[N:21]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C=CCC[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CC[Zn]CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ICI
Product: CC(C)(C)OC(=O)N1[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC[C@H]2C[C@H]21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice cold solution of (S)-tert-butyl 2-((tert-butyldiphenylsilyloxy)methyl)-3,4-dihydropyridine-1(2H)-carboxylate (3.6 g, 8.0 mmol) in DCM (40 mL) was added a 1 M solution of diethylzinc (9.0 mL) followed by diiodomethane (3.2 g, 12.0 mmol) over 15 min. The reaction mixture was stirred for 30 min at 0° C., warmed to RT and stirred for 3 h. The pH of the reaction mixture was adjusted to pH 8 with saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, concentrated under reduced pressure, purified by silica gel chromatography (eluting with 0-15% EtOAc in petroleum ether) and combined with the product of a similar run to provide the title intermediate (4.5 g) as a colorless gummy liquid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:20]([O:34]C(=O)C)[CH2:21][NH:22][CH:23]([CH3:33])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N(CC)CC)C>CO.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:20]([OH:34])[CH2:21][NH:22][CH:23]([CH3:33])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CC(C)NCC(OC(C)=O)c2ccc(OCc3ccccc3)c3[nH]c(=O)ccc23)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: COc1ccc(CC(C)NCC(O)c2ccc(OCc3ccccc3)c3[nH]c(=O)ccc23)cc1
Yield: 79.7 %

Procedure:
0.5 g of 8-benzyloxy-5-{1-acetoxy-2-[N-(2-(p-methoxyphenyl)-1-methylethyl)amino]ethyl}carbostyril (α-isomer) hydrochloride.methanol is dissolved in a mixture of 10 ml of methanol and 2 ml of water, and 180 mg of triethylamine are added thereto. The mixture is refluxed for 5 hours under stirring. The mixture is concentrated under reduced pressure to remove solvent. The residue is extracted with chloroform, and the extract is washed with 5% hydrochloric acid. The chloroform solution is dried and concentrated under reduced pressure to remove solvent. The residue is recrystallized from a mixture of isopropanol and ether. 365 mg of 8-benzyloxy-5-{1-hydroxy-2-[N-(2-(p-methoxyphenyl)-1-methylethyl)amino]ethyl}carbostyril (α-isomer) hydrochloride are obtained. Yield: 86.1%
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][C:6]([C:8]1[C@H:9]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:10]([C:16]([OH:18])=[O:17])=[C:11]([CH3:15])[NH:12][C:13]=1[CH3:14])=[O:7])#[N:2].C(=O)([O-])[O-].[K+].[K+].[CH3:34][O:35][CH2:36]Cl>CN(C)C=O.C(OCC)(=O)C>[C:1]([CH2:3][CH2:4][O:5][C:6]([C:8]1[C@H:9]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:10]([C:16]([O:18][CH2:34][O:35][CH3:36])=[O:17])=[C:11]([CH3:15])[NH:12][C:13]=1[CH3:14])=[O:7])#[N:2]
Reactant: COCCl
Reactant: CC1=C(C(=O)O)[C@@H](c2cccc([N+](=O)[O-])c2)C(C(=O)OCCC#N)=C(C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCOC(=O)C1=C(C)NC(C)=C(C(=O)OCCC#N)[C@@H]1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 10 mg of (4R)-5-(2-cyanoethoxycarbonyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid in 0.5 ml of N,N-dimethylformamide were added 4.3 mg of potassium carbonate, and then 8 μl of chloromethyl methyl ether. The mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with 5 ml of ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and with water, and dried over anhydrous Glauber's salt (sodium sulfate), followed by distilling off the solvent under reduced pressure the residue was purified using preparative TLC to obtain 3.6 mg of the objective compound.