Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1(/[CH:7]=[C:8](\[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=2)/[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:31]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:31][C:14]1[S:13][C:12]([NH:11][C:9](=[O:10])/[C:8](/[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[C:19]([C:27]([F:28])([F:29])[F:30])[CH:18]=2)=[CH:7]/[CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:16][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CS(=O)(=O)c1ccc(/C(=C\C2CCCCC2)C(=O)Nc2nccs2)cc1C(F)(F)F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCCCC2)C(=O)Nc2ncc(Br)s2)cc1C(F)(F)F
Temperature: 90 °C
Reaction time: 8 h
Yield: 28.6 %

Procedure:
A suspension of (E)-3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-thiazol-2-yl-acrylamide (prepared in Example 12, 150 mg, 3.27 mmol) and N-bromosuccinimide (69 mg, 0.384 mmol) in carbon tetrachloride (2 mL) at 25° C. was treated with benzoyl peroxide (4.65 mg, 0.02 mmol). The resulting reaction mixture was heated to 90° C. where it was stirred overnight at this temperature. The reaction mixture was then allowed to cool to 25° C. and then concentrated in vacuo. The residue was dissolved in ethyl acetate (25 mL). The organic phase was then washed with water (1×30 mL) and a saturated aqueous sodium chloride solution (1×30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 4/1 hexanes/ethyl acetate) afforded (E)-N-(5-bromo-thiazol-2-yl)-3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-acrylamide (59 mg, 33%) as an amorphous white solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][N:24]([C:27]3[C:28]([CH3:41])=[C:29]([CH3:40])[C:30]4[O:34][C:33]([CH3:36])([CH3:35])[CH:32]([OH:37])[C:31]=4[C:38]=3[CH3:39])[CH2:23][CH2:22]2)=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:22][CH2:23][N:24]([C:27]3[C:28]([CH3:41])=[C:29]([CH3:40])[C:30]4[O:34][C:33]([CH3:36])([CH3:35])[CH:32]([O:37][CH2:2][C:3]5[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=5)[C:31]=4[C:38]=3[CH3:39])[CH2:25][CH2:26]2)=[CH:19][CH:20]=1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)C(C)(C)O4)CC2)cc1
Reactant: COC(=O)c1ccc(CBr)cc1
Product: COC(=O)c1ccc(COC2c3c(C)c(N4CCN(c5ccc(OC)cc5)CC4)c(C)c(C)c3OC2(C)C)cc1
Yield: 76 %

Procedure:
Using methyl 4-(bromomethyl)benzoate and 5-(4-(4-methoxyphenyl)piperazin-1-yl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-ol obtained in Reference Example 18, the title compound was synthesized in the same manner as in Example 94. Oily material. Yield 76%. 1H-NMR (CDCl3) δ: 1.36 (3H, s), 1.59 (3H, s), 2.09 (3H, s), 2.26 (6H, s), 3.10–3.30 (8H, m), 3.79 (3H, s), 3.91 (3H, s), 4.57 (2H, s), 4.69 (1H, s), 6.86 (2H, d, J=9.2 Hz), 6.97 (2H, d, J=9.2 Hz), 7.39 (2H, d, J=8.0 Hz), 7.99 (2H, d, J=8.0 Hz).
Reaction SMILES: [F-].[K+].C1OCCOCCOCCOCCOCCOC1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C@H:29]([N:31]2[C:35](=[O:36])[CH2:34][C@@H:33]([CH:37]=[O:38])[CH2:32]2)[CH3:30])=[CH:25][CH:24]=1.[F:39][CH:40]([Si](C)(C)C)[F:41].Cl>O.CCOC(C)=O>[F:39][CH:40]([F:41])[CH:37]([CH:33]1[CH2:32][N:31]([C@@H:29]([C:26]2[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[CH3:30])[C:35](=[O:36])[CH2:34]1)[OH:38]
Reactant: COc1ccc([C@@H](C)N2C[C@H](C=O)CC2=O)cc1
Reactant: C[Si](C)(C)C(F)F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc([C@@H](C)N2CC(C(O)C(F)F)CC2=O)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Under a nitrogen atmosphere, KF (0.28 g, 1.87 mmol) and 18-crown-6 (0.49 g, 1.87 mmol) were added to a solution of (3R)-1-[(1R)-1-(4-methoxyphenyl)ethyl]-5-oxopyrrolidine-3-carbaldehyde 1.07 (420 mg, 1.7 mmol) and (difluoromethyl)trimethylsilane (530 mg, 0.52 mmol, 68 uL), and the mixture was stirred at room temperature for 5 hours. 1M HCl was added, and the reaction was stirred for 15 minutes. EtOAc and water were added and the aqueous layer was extracted with EtOAc. The combined organics were dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (0→15% MeOH in EtOAc) to afford 4-(2,2-difluoro-1-hydroxyethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 1.24 as a mixture of diastereomers, which were not separated at this stage.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12](=[O:24])[CH2:13][C:14]([O:16]CC2C=CC=CC=2)=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12](=[O:24])[CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(NC(=O)CC(=O)OCc2ccccc2)cc1OC
Agent: [Pd]
Solvent: CO
Product: COc1ccc(NC(=O)CC(=O)O)cc1OC
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
Benzyl 3-(3,4-dimethoxyphenylamino)-3-oxopropanoate (200 mg, 0.607 mmol) was dissolved in MeOH, and then Pd/C 5% (129 mg, 0.061 mmol) was added. The solution was shaken under hydrogen atmosphere at 30 psi on a Parr apparatus for 30 minutes. The catalyst was filtered off, and the solvent removed under vacuum to give 3-(3,4-dimethoxyphenylamino)-3-oxopropanoic acid (120 mg, 83% yield).
Reaction SMILES: Cl.C[O:3][C:4](=O)[CH2:5][NH2:6].[NH2:8][C@H:9]([C:15]([OH:17])=[O:16])[CH2:10][CH2:11][C:12](=[O:14])[NH2:13]>O>[NH2:6][CH2:5][C:4]([NH:8][C@H:9]([C:15]([OH:17])=[O:16])[CH2:10][CH2:11][C:12](=[O:14])[NH2:13])=[O:3]
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: COC(=O)CN
Agent: Cl
Solvent: O
Product: NCC(=O)N[C@@H](CCC(N)=O)C(=O)O

Procedure:
The same procedures used in Example 9 were repeated except that glycine methyl ester hydrochloride (hereunder referred to as Gly-OMe.HCl) was dissolved in L-Gln-TBP prepared by converting L-glutamine (L-Gln) into its ionic liquid form according to the same method used in Example 9 such that the concentration of the former was adjusted to 900 mmol/kg-L-Gln-TBP (the amount of water relative to the total mass of the reaction system: 14% by mass) and that the reaction time was changed from 20 hours to 23 hours to form the intended dipeptide, i.e., glycyl glutamine (Gly-Gln) and in this respect, the formation of such a desired dipeptide was confirmed according to the HPLC technique.
Reaction SMILES: O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-].[CH3:12][C:13]1([CH3:20])[C:17](=[O:18])[CH:16]=[CH:15][C:14]1=[O:19].[BH4-].[Na+].[Cl-].[NH4+]>CO.CCCCCC.C(OCC)C>[OH:19][CH:14]1[C:13]([CH3:20])([CH3:12])[C:17](=[O:18])[CH:16]=[CH:15]1
Reactant: CC1(C)C(=O)C=CC1=O
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: O
Solvent: CCCCCC
Product: CC1(C)C(=O)C=CC1O
Temperature: -78 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
Cerium (III) chloride heptahydrate (16.5 g, 44.3 mmol) was added to a stirred solution of the enedione 3 (5.00 g, 40.3 mmol) in methanol (150 ml) at room temperature, under an atmosphere of nitrogen. The resulting mixture was then cooled to −78° C. and sodium borohydride (1.68 g, 44.4 mmol) was added in portions over 30 minutes. The mixture was stirred at −78° C. for a further 2 hours, then at −30° C. for 45 minutes. Ammonium chloride (sat'd. aq., 150 ml) was then added and the mixture was extracted with ethyl acetate (3×150 ml). The combined organic extracts were then dried over MgSO4, and evaporated in vacuao. Flash chromatography (SiO2, 80% diethyl ether in hexane) gave the hydroxy-ketone 4 (3.58 g, 28.4 mmol, 71%) as a white solid; δH (300 MHz, CDCl3) 7.46 (1H, dd J 5.9 & 2.2 Hz, CH═CHC═O), 6.20 (1H, dd J 5.9 & 1.4 Hz, CH═CHC═O), 4.59-4.57 (1H, m, CHOH), 1.16 (3H, s, CH3), 1.07 (3H, s, CH3); δC (75.5 MHz, CDCl3) 211.7 (s), 160.6 (d), 132.7 (d), 79.8 (d), 48.2 (s), 22.7 (q), 20.0 (q).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=O)=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].Cl.[NH2:23][OH:24]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[N:23][OH:24])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C(Cc1ccc(F)cc1)c1ccncc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: ON=C(Cc1ccc(F)cc1)c1ccncc1

Procedure:
21.5 g (0.1 mol) of 2-(4-fluorophenyl)-1-(4-pyridyl)-ethanone was suspended in 330 ml of 50% aqueous methanol. After addition of 36.1 g (0.44 mol) of sodium acetate and 22.0 g (0.32 mol) of hydroxylamine hydrochloride, the reaction mixture was refluxed for 1 h with stirring. On cooling in an ice bath, the title compound deposited as a beige-colored precipitate. The precipitate was filtered off, washed with dist. water and dried over P2O5 in vacuo. Yield: 14.3 g (62%).
Reaction SMILES: Br[C:2]1[C:10]2[CH:11]=[C:12]3[C:20]([C:21]([CH3:23])([CH3:22])[C:9]=2[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:7]=2)=[C:19]1[C:14]([CH:15]=[CH:16][CH:17]=[CH:18]1)=[N:13]3.[C:30]1([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[CH:35]=[CH:34][C:33]([N:36]([C:52]2[CH:57]=[CH:56][C:55](C3C=CC=CC=3)=[CH:54][CH:53]=2)C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[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.C1(C)C=CC=CC=1.C(O)C>[C:6]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:7]=[CH:8][C:3]([N:36]([C:33]2[CH:32]=[CH:31][C:30]([C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[CH:35][CH:34]=2)[C:52]2[CH:57]=[CH:56][C:55]([C:2]3[C:10]4[CH:11]=[C:12]5[C:20]([C:21]([CH3:23])([CH3:22])[C:9]=4[C:8]4[C:3]=3[CH:4]=[CH:5][CH:6]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:7]=4)=[C:19]3[C:14]([CH:15]=[CH:16][CH:17]=[CH:18]3)=[N:13]5)=[CH:54][CH:53]=2)=[CH:4][CH:5]=1
Reactant: CC1(C)C2=C(C=C3N=c4ccccc4=C31)C(Br)=C1C=CC(c3ccccc3)C=C12
Reactant: CC1(C)OB(c2ccc(N(c3ccc(-c4ccccc4)cc3)c3ccc(-c4ccccc4)cc3)cc2)OC1(C)C
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1(C)C2=C(C=C3N=c4ccccc4=C31)C(c1ccc(N(c3ccc(-c4ccccc4)cc3)c3ccc(-c4ccccc4)cc3)cc1)=C1C=CC(c3ccccc3)C=C12
Temperature: 73 °C
Reaction time: 8 h
Yield: 143.2 %

Procedure:
7-Bromo-12,12-dimethyl-10-phenyl-10,12-dihydro-indeno[2,1-b]carbazole synthesized in Example 1 (3.0 g), bis(biphenyl-4-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]amine (4.3 g), a toluene/ethanol (4/1, v/v) mixed solvent (50 ml), and a 2M potassium carbonate aqueous solution (10 ml) were added to a nitrogen-substituted reaction vessel and aerated with nitrogen gas for 30 min under ultrasonic irradiation. The mixture was heated after adding tetrakis(triphenylphosphine)palladium (0.4 g), and stirred at 73° C. for 8 hours. After the mixture was cooled to a room temperature, a precipitated crude product was collected by filtration. 1,2-dichlorobenzene (140 ml) was added to the crude product, and the crude product was dissolved while being heated, and after removing insoluble matter by filtration, a filtrate was concentrated under reduced pressure. Purification by recrystallization using 1,2-dichlorobenzene (100 ml) was performed to obtain a white powder of 7-[4-{bis(biphenyl-4-yl)amino}-phenyl]-12,12-dimethyl-10-phenyl-10,12-dihydroindeno[2,1-b]carbazole (3.7 g; yield 71.6%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1OS(C(F)(F)F)(=O)=O.C(N(C(C)C)CC)(C)C.[CH3:29][N:30]1[CH:34]=[C:33]([C:35]2[CH:36]=[CH:37][C:38]3[N:39]([C:41]([SH:44])=[N:42][N:43]=3)[N:40]=2)[CH:32]=[N:31]1.[OH-].[Na+]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[S:44][C:41]1[N:39]2[N:40]=[C:35]([C:33]3[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=3)[CH:36]=[CH:37][C:38]2=[N:43][N:42]=1
Reactant: Cc1cc2ncccc2cc1OS(=O)(=O)C(F)(F)F
Reactant: Cn1cc(-c2ccc3nnc(S)n3n2)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc2ncccc2cc1Sc1nnc2ccc(-c3cnn(C)c3)nn12
Temperature: 100 °C
Reaction time: 1 h
Yield: 61.4 %

Procedure:
A solution of trifluoromethanesulfonic acid 7-methyl-quinolin-6-yl ester (1.38 g, 4.74 mmol), diisopropylethylamine (1.5 mL, 8.61 mmol) in DMF (8 mL) under nitrogen was degassed by bubbling in nitrogen for 20 min. Tris(dibenzylideneacetone)dipalladium (99 mg, 0.11 mmol, Strem catalyst) and Xantphos (125 mg, 0.215 mmol) were added together in one portion, followed by 6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-3-thiol (1 g, 4.36 mmol) under a stream of nitrogen. The reaction mixture was stirred at 100° C. for 1 h. The reaction mixture was cooled to room temperature and poured onto 2 M aqueous NaOH (100 mL). The resulting precipitate was filtered, washed with water, and air-dried for 30 min. The resulting cake was dissolved in MeOH (80 mL) and CHCl3 (80 mL), and 2 g of activated decolorizing charcoal were added. The suspension was stirred at 60° C. for 2.5 h. Celite (10 g) was then added and the warm mixture was filtered over a short silica gel plug. The filtrate was evaporated in vacuo to give a beige solid. Recrystallization from EtOH and chloroform afforded 1.0 g of 7-methyl-6-[6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl]-quinoline as white crystals (62% yield).
Reaction SMILES: C(#N)C.C(=O)([O-])[O-].[Na+].[Na+].[NH2:10][C:11]1[CH:16]=[C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[C:14](Br)=[CH:13][N:12]=1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>CO.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:10][C:11]1[CH:16]=[C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[C:14]([C:37]2[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=2)=[CH:13][N:12]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(N)ncc2Br)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: COc1ccc(-c2cnc(N)cc2NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 150 °C
Yield: 39.7 %

Procedure:
Acetonitrile (1212 μL) and 0.5M sodium carbonate solution (0.36 mL, 1.5 eq) were added to tert-butyl 4-(2-amino-5-bromopyridin-4-ylamino)piperidine-1-carboxylate (45 mg, 0.121 mmol), 4-methoxyphenylboronic acid (27.6 mg, 0.182 mmol), and tetrakis(triphenylphosphine) palladium(0) (7.00 mg, 6.06 μmol) in a microwave vial (0.5 mL). The capped vial was heated to 150° C. by microwave irradiation for 20 min. After cooling the solution was diluted with MeOH and purified by ion exchange on SCX-II acidic resin (2 g) column, eluting with MeOH then 2M ammonia in MeOH. The basic fractions were combined and concentrated. The crude product was dissolved in dichloromethane and loaded onto a Biotage SNAP silica column (10 g) which was eluted with a gradient of MeOH/NH3 (99/1) in dichloromethane to give tert-butyl 4-(2-amino-5-(4-methoxyphenyl)pyridin-4-ylamino)piperidine-1-carboxylate (19 mg, 0.048 mmol, 39%) as a colourless foam.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]([CH3:37])[CH:8]1[CH2:11][N:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([NH:20][C:21]3[N:26]=[C:25]([C:27]4[CH:28]=[N:29][N:30]5[CH2:35][CH2:34][CH2:33][CH2:32][C:31]=45)[CH:24]=[CH:23][N:22]=3)=[CH:14][C:13]=2[NH2:36])[CH2:9]1>C(Cl)Cl>[CH3:37][N:7]([CH3:6])[CH:8]1[CH2:9][N:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([NH:20][C:21]3[N:26]=[C:25]([C:27]4[CH:28]=[N:29][N:30]5[CH2:35][CH2:34][CH2:33][CH2:32][C:31]=45)[CH:24]=[CH:23][N:22]=3)=[CH:14][C:13]=2[NH:36][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:11]1
Reactant: COc1cc(N2CC(N(C)C)C2)c(N)cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cnn4c3CCCC4)n2)c(OC)cc1N1CC(N(C)C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45.8 %

Procedure:
A solution of acryloyl chloride (22.5 mg, 0.25 mmol) in CH2Cl2 (1 mL) was added dropwise to a stirred solution of 4-(3-dimethylaminoazetidin-1-yl)-6-methoxy-N-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 139, 108 mg, 0.25 mmol) in CH2Cl2 (12 mL), which was cooled in an ice/water bath. The solution was stirred for 10 minutes while being cooled by the bath, was then allowed to warm to r.t. and was then stirred for 1 h. The mixture was then diluted with CH2Cl2 and washed with sat. NaHCO3, brine and was then dried (MgSO4). Purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave the title compound (56 mg, 46%) as a brown solid after trituration with diethyl ether; 1H NMR: 1.75-1.82 (2H, m), 1.90-1.97 (2H, m), 2.08 (6H, s), 2.98-3.09 (3H, m), 3.54 (2H, t), 3.85 (3H, s), 3.93 (2H, t), 4.09 (2H, t), 5.69 (1H, dd), 6.18-6.25 (2H, m), 6.49 (1H, dd), 6.95 (1H, d), 7.70 (1H, s), 7.89 (1H, s), 8.03 (1H, s), 8.26 (1H, d), 9.24 (1H, s); m/z: ES+ MH+ 489.63.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][S:6][C:5]2[CH:8]=[CH:9][C:10]([C:12](O)=[O:13])=[N:11][C:4]=2[NH:3]1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[BH4-].[Na+].Cl>C1COCC1.O>[OH:13][CH2:12][C:10]1[CH:9]=[CH:8][C:5]2[S:6][CH2:7][C:2](=[O:1])[NH:3][C:4]=2[N:11]=1
Reactant: O=C1CSc2ccc(C(=O)O)nc2N1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CSc2ccc(CO)nc2N1
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
A solution of 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid (500 mg, 2.38 mmole) and triethylamine (0.396 mL, 2.84 mmole) in THF (24 mL) was cooled to −10° C. and isobutyl chloroformate (0.339 mL, 2.61 mmole) was added. After 20 min the suspension was filtered through kieselguhr into an ice-cooled solution of sodium borohydride (272 mg, 7.19 mmole) in water (8 mL). The mixture was stirred for 30 min, then the pH was adjusted to 7 with dilute HCl. The solvent was evaporated and the residue was triturated with water. The solid was collected and dried under vacuum to give the title compound (346 mg, 74%) as a white solid: MS (APCI−) m/e 197 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([NH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>C1(C)C=CC=CC=1.CN(C)C=O>[CH2:26]([N:17]1[CH2:18][CH2:19][CH:14]([NH:13][C:11]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]=2[CH3:1])=[O:12])[CH2:15][CH2:16]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1[nH]c2ccccc2c1C(=O)NC1CCNCC1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1[nH]c2ccccc2c1C(=O)NC1CCN(Cc2ccccc2)CC1

Procedure:
To a suspension of 1.2 g of 2-methyl-N-(4-piperidyl)indole-3-carboxamide and 1 g of potassium carbonate in 50 ml of toluene and 10 ml of dimethylformamide was added dropwise 0.6 g of benzyl chloride. The mixture was refluxed under heating for 3 hours. After cooling, 50 ml of water was poured into the mixture. The insoluble materials precipitated were filtered by suction and recrystallized from methanol to give N-(1-benzyl-4-piperidyl)-2-methylindole-3-carboxamide, melting at 150°-153° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C:17]([CH3:18])=[C:16]2[C:11]([CH2:12][CH2:13][C@H:14]([C:19]([CH3:27])([CH3:26])[O:20][SiH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[O:15]2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH:29]([Li])([CH2:31]C)[CH3:30].C(Br)C=C>O1CCCC1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C:17]([CH2:18][CH2:31][CH:29]=[CH2:30])=[C:16]2[C:11]([CH2:12][CH2:13][C@H:14]([C:19]([CH3:27])([CH3:26])[O:20][SiH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[O:15]2)=[CH:10][CH:9]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: [Li]C(C)CC
Reactant: Cc1c(NC(=O)OC(C)(C)C)ccc2c1O[C@@H](C(C)(C)O[SiH2]C(C)(C)C)CC2
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCCc1c(NC(=O)OC(C)(C)C)ccc2c1O[C@@H](C(C)(C)O[SiH2]C(C)(C)C)CC2
Reaction time: 1.5 h
Yield: 75 %

Procedure:
To a solution of (2R)-[2-(tert-butyl-dimethyl-silanyloxymethyl)-8-methyl-chroman-7-yl]-carbamic acid tert-butyl ester (0.41 g, 1 mmole) in anhydrous tetrahydrofuran (20 mL) containing 10 mg of 1,10-phenanthroline at −40° C. was slowly added 2.4 equivalents of 1.3 M s-butyl lithium. After 1 equivalent of s-butyl lithium had been added, the deep red color of the indicator became apparent. The reaction was allowed to stand for 1.5 hours, after which allyl bromide (0.24 g, 2.0 mmole) was added. The reaction was allowed to stand for an additional 4 hours and then was quenched with water (4 mL). The reaction mixture was next diluted with ether (250 mL) and washed with saturated aqueous sodium bicarbonate (50 mL). The organic layer was separated and the solvent removed under vacuum. Column chromatography on silica gel (5% methylene chloride/hexane) afforded 0.37 g (75%) of the title compound as an oil, [α]25D=−32.42° (3.7, THF).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C@H:11]([NH:18][C:19]1[O:20][C:21]([CH3:42])([CH3:41])[CH:22]([C:27]2[CH:32]=[CH:31][C:30](OS(C(F)(F)F)(=O)=O)=[CH:29][CH:28]=2)[S:23](=[O:26])(=[O:25])[N:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.[CH3:43][Al](C)C.CO>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].CC(P(C(C)(C)C)C1[CH-]C=CC=1)(C)C.C1C=CC([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)=CC=1.[Fe+2]>[CH3:41][C:21]1([CH3:42])[O:20][C:19]([NH:18][C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][CH2:9][OH:8])=[N:24][S:23](=[O:26])(=[O:25])[CH:22]1[C:27]1[CH:32]=[CH:31][C:30]([CH3:43])=[CH:29][CH:28]=1
Reactant: CC1(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c2ccccc2)=NS(=O)(=O)C1c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Reactant: C[Al](C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P(c1ccc[cH-]1)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1ccc(C2C(C)(C)OC(N[C@@H](CCO)c3ccccc3)=NS2(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Under inert gas, 60 mg of trifluoromethanesulfonic acid 4-{2-[(S)-3-(tert-butyldimethylsilanyloxy)-1-phenylpropylamino]-6,6-dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-1,4,3-oxathiazin-5-yl}phenyl ester, 5.3 mg of bis(dibenzylideneacetone)palladium and 13.1 mg of 1,2,3,4,5-pentaphenyl-1-(di-tert-butylphosphino)ferrocene were initially charged, dissolved in 1.2 ml of toluene and stirred at room temperature for 5 minutes. After the addition of 0.09 ml of a 2 N solution of trimethylaluminum, the reaction mixture was stirred at 80° C. for 2 hours. After cooling to room temperature, 1 ml of methanol was added and the solvent was removed under reduced pressure. The residue was dissolved in 2 ml of methanol, 0.2 ml of concentrated hydrochloric acid was added and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with 20 ml of ethyl acetate and 10 ml of water, and neutralized with sodium hydroxide solution. The organic phase was washed once again with saturated aqueous sodium chloride solution, dried over MgSO4 and concentrated by rotary evaporation. The residue was purified in a purification laboratory by means of preparative HPLC. The product-containing fractions were combined, the acetonitrile was removed under reduced pressure, and the aqueous residue was basified with saturated aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The organic phase was dried over MgSO4 and concentrated by rotary evaporation, and the residue was taken up again in a mixture of acetonitrile and water and lyophilized. This gave the product (22.8 mg) with a molecular weight of 402.5 g/mol (C21H26N2O4S); MS (ESI): m/e=403 (M+H+).