Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:23][CH:22]=[CH:21][N:5]2[C:6](=[O:20])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:10][CH:9]=1.[CH:24]1([CH2:27][O:28][C:29]2[C:36]([O:37][CH3:38])=[CH:35][CH:34]=[CH:33][C:30]=2[CH:31]=O)[CH2:26][CH2:25]1.[O-]CC.[Na+]>C(O)C>[CH:24]1([CH2:27][O:28][C:29]2[C:36]([O:37][CH3:38])=[CH:35][CH:34]=[CH:33][C:30]=2/[CH:31]=[CH:1]/[C:2]2[N:3]=[C:4]3[S:23][CH:22]=[CH:21][N:5]3[C:6](=[O:20])[C:7]=2[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])=[CH:10][CH:9]=2)[CH2:25][CH2:26]1
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(OCC(F)(F)F)cc1
Reactant: COc1cccc(C=O)c1OCC1CC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2-c2ccc(OCC(F)(F)F)cc2)c1OCC1CC1
Yield: 46.8 %

Procedure:
The title compound was synthesized by condensation of Intermediate 11 (325 mg, 0.95 mmol) with 2-cyclopropylmethoxy-3-methoxybenzaldehyde (255 mg, 1.20 mmol) in presence of sodium ethoxide (129 mg, 1.90 mmol) in ethanol (25 ml) according to the procedure of Example 24 to give 235 mg of the desired product; 1H NMR (300 MHz, DMSO-d6) δ 0.27 (br s, 2H), 0.51 (br s, 2H), 1.04-1.06 (m, 1H), 3.68-3.70 (m, 2H), 3.77 (m, 3H), 4.81-4.83 (m, 2H), 6.89-6.98 (m, 4H), 7.13-7.15 (m, 2H), 7.27-7.29 (m, 2H), 7.49 (br s, 1H), 7.98 (br s, 1H), 8.14 (d, J=16.2 Hz, 1H); ESI-MS (m/z) 529.23 (M+H)+.
Reaction SMILES: [P:1]([O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O=[CH:23][CH2:24][C@@H:25]([NH:34][C:35]1[CH:40]=[CH:39][C:38]([S:41]([NH2:44])(=[O:43])=[O:42])=[CH:37][C:36]=1[S:45]([C:48]([F:51])([F:50])[F:49])(=[O:47])=[O:46])[CH2:26][S:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.ClC(Cl)C.C(Cl)Cl>[P:1]([O:13][CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][N:19]([CH2:23][CH2:24][C@@H:25]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([S:41](=[O:42])(=[O:43])[NH2:44])=[CH:37][C:36]=2[S:45]([C:48]([F:50])([F:49])[F:51])(=[O:47])=[O:46])[CH2:26][S:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:20][CH2:21]1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:2]
Reactant: CC(C)(C)OP(=O)(OCCN1CCNCC1)OC(C)(C)C
Reactant: NS(=O)(=O)c1ccc(N[C@H](CC=O)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OP(=O)(OCCN1CCN(CC[C@H](CSc2ccccc2)Nc2ccc(S(N)(=O)=O)cc2S(=O)(=O)C(F)(F)F)CC1)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
A solution of di-tert-butyl 2-(piperazin-1-yl)ethyl phosphate (INTERMEDIATE 60, 0.31 g, 0.95 mmol) in 1,2-dichloroethane (4 ml) was added to a solution of (R)-4-(4-oxo-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 45, 0.46 g, 0.95 mmol) in dichloroethane (5.0 ml) at room temperature. The reaction mixture was allowed to stir for 15 minutes at r.t, and solid sodium triacetoxyborohydride (0.30 g, 1.43 mmol) was added. The mixture was stirred for 1 hour at ambient temperature. To the reaction mixture was added 0.5 N NaOH (10 ml) and DCM (20 ml). After stirring for 15 mins at r.t, the layers were separated and the organic layer was washed with NaHCO3 (saturated aq.) and brine, and dried (Na2SO4). The volatiles were removed under reduced pressure. Purification by column chromatography (ISCO, silica gel, eluting with 0→100% EtOAc/hexanes) gave the title compound (0.71 g, yield: 94%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@H:4]([CH2:25][CH2:26][S:27][CH3:28])[NH:5][C:6](=[O:24])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=1.O.O.Cl[Sn]Cl.COC(=O)[C@H](CCSC)NC(=O)C1C=CC(N)=CC=1C1C=CC=CC=1>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:29])[C@H:4]([CH2:25][CH2:26][S:27][CH3:28])[NH:5][C:6](=[O:24])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:16]1[CH:17]=[C:18]([CH3:23])[CH:19]=[C:20]([CH3:22])[CH:21]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc([N+](=O)[O-])cc1-c1cc(C)cc(C)c1
Agent: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1cc(C)cc(C)c1

Procedure:
4-nitro-2-(3,5-dimethylphenyl)benzoyl methionine methyl ester (0.11 g, 0.26 mmol) was taken up in ethyl acetate (3.0 ml). To this mixture was added SnCl2.2H2O (0.30 g, 1.30 mmol) and the reaction was heated under nitrogen at reflux for 6 h. The mixture was worked up as described for 4-amino-2-phenylbenzoyl methionine methyl ester in Example 2, to give 0.15 g of a yellow film that was wet with solvent. The material was otherwise pure by NMR and was used without further purification. 1H NMR (CDCl3)1.60-1.70 (1 H, m), 1.80-1.90 (1 H, m), 1.99 (3 H, s), 2.05 (2 H, t, J=7.6 Hz), 2.33 (6 H, s), 3.64 (3 H, s), 3.93 (2 H, br s), 4.61-4.64 (1 H, m), 5.82 (1 H, d, J=7.7 Hz), 6.49 (1 H, d, J=2.3 Hz), 6.62 (1 H, dd, J=8.4 Hz, 2.4 Hz), 6.98 (2 H, s), 7.00 (1 H, s), 7.65 (1 H, d, J=8.3 Hz); 13C NMR (CDCl3) 15.08, 21.17, 29.28, 31.49, 51.70, 52.18, 113.30, 115.94, 123.55, 126.36, 129.32, 131.23, 138.15, 140.72, 141.92, 148.40, 168.45, 172.01.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13]1([C:29]3[CH:28]=[CH:27][C:26]4[CH:30]=[C:31](O)[CH:32]=[CH:33][C:25]=4[C:24]=3[O:23][C:22]3[CH:21]=[C:20]([N:35]([CH3:37])[CH3:36])[CH:19]=[CH:18][C:17]1=3)[O:12][C:11]2=[O:38])([OH:7])=[O:6].C(OC(=O)C)(=O)C>O>[C:1]([O:4][C:31]1[CH:32]=[CH:33][C:25]2[C:24]3[O:23][C:22]4[CH:21]=[C:20]([N:35]([CH3:36])[CH3:37])[CH:19]=[CH:18][C:17]=4[C:13]4([C:14]5[C:10](=[CH:9][C:8]([C:5]([OH:7])=[O:6])=[CH:16][CH:15]=5)[C:11](=[O:38])[O:12]4)[C:29]=3[CH:28]=[CH:27][C:26]=2[CH:30]=1)(=[O:3])[CH3:2]
Reactant: CN(C)c1ccc2c(c1)Oc1c(ccc3cc(O)ccc13)C21OC(=O)c2cc(C(=O)O)ccc21
Reactant: CC(=O)[O-]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Oc1ccc2c3c(ccc2c1)C1(OC(=O)c2cc(C(=O)O)ccc21)c1ccc(N(C)C)cc1O3
Reaction time: 8 h

Procedure:
To prepare the acetate from 8, 300 mg 5'-carboxy-10-dimethylamino-3-hydroxy-spiro[7H-benzo[c]xanthene-7,1'(3'H)-isobenzofuran]-3'-one was added 5 ml acetic anhydride and the solution refluxed for 2 hours. The solution was poured into water and stirred overnight to hydrolyze excess actic anhydride. The resulting solid was collected and purified by silica gel chromatography with 10% methanol with chloroform to give 0.16 g dark violet solid, Rf =0.37 with methanol:chloroform (1:9). Absorbance maxima in potassium phosphate buffer at pH 7.0 at 511 and 540 nm; extinction coefficients of 24,100 and 21,700 cm-1M-1 respectively.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1I.[CH3:10][C:11]([C:13]1[CH:18]=[CH:17][C:16](Br)=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)=[O:12]>>[C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)(=[O:12])[CH3:10]
Reactant: CC(=O)c1ccc(Br)c([N+](=O)[O-])c1
Reactant: Fc1ccc(I)c(F)c1
Product: CC(=O)c1ccc(-c2ccc(F)cc2F)c([N+](=O)[O-])c1

Procedure:
2,4-Difluoroiodobenzene and 4-bromo-3-nitroacetophenone were reacted under Ullmann conditions to give 4-acetyl-2',4'-difluoro-2-nitrobiphenyl, b.p. 150°-158° C./0.2 mm., and this was reduced with stannous chloride to give 4-acetyl-2-amino-2',4'-difluorobiphenyl, m.p. 93°-95° C. By similar methods there were obtained 4-acetyl-2'-chloro-4'-fluoro-2-nitrobiphenyl, b.p. 178°-190°/0.2 mm m.p. 62°-64° C. and 4-acetyl-2-amino-2'-chloro-4'-fluorobiphenyl, m.p. 84°-86° C; 4-acetyl-4'-chloro-2'-fluoro-2-nitrobiphenyl, b.p. 174°-180°/0.2 mm., m.p. 85°-86° C. and 4-acetyl-2-amino-2'-fluoro-4'-chlorobiphenyl, m.p. 115° C; 4-acetyl-2',4'-dichloro-2-nitrobiphenyl, m.p. 72°-74° C. and 4-acetyl-2-amino-2',4'-dichlorobiphenyl, m.p. 75°-76° C; 4-acetyl-2' ,4'-dibromo-2-nitrobiphenyl, b.p. 210° C./0.3 mm. and 4-acetyl-2-amino-2',4'-dibromobiphenyl, m.p. 107°-109° C; 4-acetyl-4'-bromo-2'-fluoro-2-nitrobiphenyl, m.p. 116°-117° C. and 4-acetyl-2-amino-4'-bromo-2'-fluorobiphenyl, m.p. 120°-121° C; 4-acetyl-2'-bromo-4'-fluoro-2-nitrobiphenyl, b.p. 188°-200° C./0.3 mm., m.p. 75°-77° C. and 4-acetyl-2-amino-2'-bromo-4'-fluorobiphenyl, m.p. 98°-100° C; 4-acetyl-4'-bromo-2'-chloro-2-nitrobiphenyl, b.p. 185°-190° C./0.2 mm. and 4-acetyl-2-amino-4'-bromo-2'-chlorobiphenyl, m.p. 93°-95° C; and 4-acetyl-2'-bromo-4'-chloro-2-nitrobiphenyl, m.p. 84°-86° C; and 4-acetyl-2-amino-2'-bromo-4'-chlorobiphenyl, m.p. 98°-100° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:3][CH:2]=1.[CH2:18]([C:25]1([N:32]([CH3:34])[CH3:33])[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.FC(F)(F)S(O)(=O)=O>ClCCl>[CH2:18]([C:25]1([N:32]([CH3:34])[CH3:33])[CH2:30][CH2:29][C:28]([C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH2:8][CH2:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)([C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH2:8][CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccc2c(CCc3ccncc3)c[nH]c2c1
Reactant: CN(C)C1(Cc2ccccc2)CCC(=O)CC1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C1(Cc2ccccc2)CCC(c2[nH]c3ccccc3c2CCc2ccncc2)(c2[nH]c3ccccc3c2CCc2ccncc2)CC1
Temperature: 25 °C
Reaction time: 67 h

Procedure:
3-(2-pyridin-4-ylethyl)-1H-indole (667 mg, 3 mmol, synthesis cf. WO2008009415, indole unit Ind-14) together with 4-benzyl-4-(dimethylamino)cyclohexanone (652 mg, 3 mmol, synthesis cf. WO2008009415, ketone unit Ket-3) was dissolved in abs. dichloromethane (45 ml) and mixed with trifluoromethane sulphonic acid (0.553 ml, 6.3 mmol). The batch was stirred for 67 h at RT, and a brown oil separated out. For work up the reaction solution was mixed with 1N NaOH (10 ml) and THF (10 ml). The mixture was stirred a further 60 min. After separation of the phases the aqueous phase was extracted with dichloromethane (3×10 ml). The combined organic extracts were dried over Na2SO4 and then concentrated to low volume. The raw product obtained (1.22 g) was purified by column chromatography [silica gel 60 (100 g); ethyl acetate/methanol (10:1, 1100 ml), ethyl acetate/methanol (2:1, 500 ml) ethyl acetate/methanol (1:2, 750 ml)].
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[N:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[C:16]([OH:23])=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2.[S:24](Cl)([C:27]1[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=1)(=[O:26])=[O:25].CO>C(Cl)(Cl)Cl.O>[Br:8][C:9]1[N:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[C:16]([O:23][S:24]([C:27]2[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=2)(=[O:26])=[O:25])=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2
Reactant: COC(=O)c1nc(Br)c2cccnc2c1O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1nc(Br)c2cccnc2c1OS(=O)(=O)c1ccc(C)cc1
Temperature: 40 °C
Yield: 50 %

Procedure:
Triethyl amine (15.9 mmol) was added to a suspension of methyl 5-bromo-8-hydroxy-1,6-naphthyridine-7-carboxylate (10.6 mmol) in chloroform (22 ml) over 5 min. at 20-50° C. Tosyl chloride (12.7 mmol) was added over 5 min maintaining the temperature at 40° C. for 2 h. The mixture was cooled to 20° C. over 15 min. MeOH was added over 30 min, then a mixture of MeOH:water was added over 30 min. The resulting off-white crystalline solid was collected by filtration and dried to give the target compound in 50% yield.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:6](=[O:16])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.[CH3:29][O:30][C:31](=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:6](=[O:16])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:38][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[C:31]([O:30][CH3:29])=[O:40])=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccccc1CBr
Reactant: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)CCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)CCc1ccc(OCc2ccccc2C(=O)OC)cc1
Yield: 69.4 %

Procedure:
N-(2,4-difluorobenzyl)-N-heptyl-3-(4-hydroxyphenyl)propanamide (195 mg, 0.501 mmol), 2-bromomethylbenzoic acid methyl ester (120.4 mg, 0.526 mmol) and anhydrous potassium carbonate (103 mg, 0.751 mmol) were mixed in acetonitrile (15 ml). The mixture was heated to reflux overnight and then evaporated to dryness. Water and ethyl acetate were added and the two phases were separated. The organic phase was dried (magnesium sulphate) and evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 2 g/6 ml) using heptane/DCM (50:50), then DCM and then MeOH/DCM (0.5:99.5) as eluant gave 187 mg desired product, yield 69.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[C:13]([F:17])=[CH:12][C:3]=1[C:4](C1C=CC=CC=1)=[O:5].[OH:18]O>S(=O)(=O)(O)O.O>[Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[C:13]([F:17])=[CH:12][C:3]=1[C:4]([OH:5])=[O:18]
Reactant: OO
Reactant: O=C(c1ccccc1)c1cc(F)c(Cl)cc1Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1cc(F)c(Cl)cc1Cl
Reaction time: 5 h
Yield: 85.2 %

Procedure:
26.8 g (0.1 mol) of 2,4-dichloro-5-fluorobenzophenone are dissolved in 250 g of 96% sulfuric acid, and 17 g of 30% hydrogen peroxide solution are added at 0° C., with thorough mixing, in such a way that the temperature does not exceed 40° C. When the metered addition is complete, the temperature is allowed to drop to 20° C. and the mixture is stirred for 5 h at this temperature. If the conversion is incomplete, a further 5 g of hydrogen peroxide solution are metered in (T<40° C.) and the mixture is diluted with 1000 g of water after a further 3 h of reaction time and is subsequently stirred for 2 h. The 2,4-dichloro-5-fluorobenzoic acid which has precipitated out is filtered off and purified by recrystallization (water) to give 17.8 g (0.0852 mol, 85%) of 2,4-dichloro-5-fluorobenzoic acid melting at 144°-146° C.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]2=[N:6][N:7]([C:9]3[CH:10]=[C:11]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=3[OH:20])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[N:8]=[C:4]2[CH:3]=1.[CH3:27][O:28][N:29]1[C:34]([CH3:36])([CH3:35])[CH2:33][CH:32](O)[CH2:31][C:30]1([CH3:39])[CH3:38]>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]2=[N:6][N:7]([C:9]3[CH:10]=[C:11]([CH:17]=[C:18]([C:21]([CH3:22])([CH3:23])[CH3:24])[C:19]=3[OH:20])[CH2:12][CH2:13][C:14]([O:16][CH:32]3[CH2:33][C:34]([CH3:35])([CH3:36])[N:29]([O:28][CH3:27])[C:30]([CH3:39])([CH3:38])[CH2:31]3)=[O:15])[N:8]=[C:4]2[CH:3]=1
Reactant: CC(C)(C)c1cc(CCC(=O)O)cc(-n2nc3ccc(Cl)cc3n2)c1O
Reactant: CON1C(C)(C)CC(O)CC1(C)C
Product: CON1C(C)(C)CC(OC(=O)CCc2cc(-n3nc4ccc(Cl)cc4n3)c(O)c(C(C)(C)C)c2)CC1(C)C

Procedure:
3-(5-Chlorobenzotriazol-2-yl)-5-tert-butyl-4-hydroxyhydrocinnamic acid (12.0 g, 0.032 mol) and 1-methoxy-2,2,6,6-tetramethyl-4-hydroxypiperidine (6.66 g, 0.036 mol) are reacted together according to the procedure given in Example 3. The title compound is obtained in a yield of 8.79 g (50.5%) as a light yellow solid, melting at 132-137° C., whose structure is consistent with 1Hnmr and mass spectrometry. The compound has a molar absorptivity of 17,210 l/mole cm.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15].N1C=CC=CC=1>>[C:14]([O:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1)(=[O:16])[CH3:15]
Reactant: COC(=O)/C=C/c1ccc(O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC(=O)/C=C/c1ccc(OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 26 h
Yield: 93.1 %

Procedure:
To a solution of methyl (2E)-3-(4-hydroxyphenyl)acrylate (5.35 g, 30.0 mmol) in acetic anhydride (45.0 mL, 476 mmol) was added pyridine (4.85 mL, 60.0 mmol), and the mixture was stirred at room temperature for 26 hr. The reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The precipitated crystals were washed with ethyl acetate-hexane to give the title compound (6.15 g, yield 93%) as colorless crystals.
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][N:11]([CH2:16][C:17]3[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=4[F:30])[N:20]=[C:19]4[NH:31][N:32]=[C:33]([CH3:34])[C:18]=34)[C:10]([CH3:36])([CH3:35])[CH2:9]2)[CH2:4][O:3]1>O1CCOCC1.O>[F:30][C:24]1[CH:25]=[C:26]([OH:29])[CH:27]=[CH:28][C:23]=1[C:21]1[N:20]=[C:19]2[NH:31][N:32]=[C:33]([CH3:34])[C:18]2=[C:17]([CH2:16][N:11]2[C:10]([CH3:35])([CH3:36])[CH2:9][N:8]([CH2:7][C@H:5]([OH:6])[CH2:4][OH:3])[C:13]([CH3:15])([CH3:14])[CH2:12]2)[CH:22]=1
Reactant: Cc1n[nH]c2nc(-c3ccc(O)cc3F)cc(CN3CC(C)(C)N(C[C@H]4COC(C)(C)O4)CC3(C)C)c12
Solvent: C1COCCO1
Solvent: O
Product: Cc1n[nH]c2nc(-c3ccc(O)cc3F)cc(CN3CC(C)(C)N(C[C@H](O)CO)CC3(C)C)c12
Yield: 31.3 %

Procedure:
208 mg 4-{4-[4-((S)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethyl)-2,2,5,5-tetramethyl-piperazin-1-ylmethyl]-3-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl}-3-fluoro-phenol were dissolved in 2 ml of dioxane and 0.3 ml of water. 2 ml of hydrorchloric acid (4M in dioxane) were added. After 1.5 h at rt the volatiles were removed in vacuo and the residue was purified by HPLC. 60 mg of the title compound ewre obtained.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:49])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH2:32][CH2:33][O:34]C5CCCCO5)[N:23]=4)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([CH:3]1[CH2:4][N:5]([C:7](=[O:49])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH2:32][CH2:33][OH:34])[N:23]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:6]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCOC4CCCCO4)c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(CCO)c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 63.9 %

Procedure:
To a solution of 2-{6-chloro-1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-indazol-3-yl}-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (138 mg, 0.20 mmol) in CH2Cl2 (2 mL) was added TFA (0.75 mL). The reaction mixture was stirred at room temperature for 6 h then concentrated. The residue was redissolved in 10:90:0.5 MeOH/CH2Cl2/NH4OH (3 mL) and stirred at room temperature for 3 h. The reaction mixture was concentrated and the residue was purified by silica gel chromatography with 0% to 10% MeOH/CH2Cl2 to afford 63 mg (65%) of 2-[6-chloro-1-(2-hydroxy-ethyl)-1H-indazol-3-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a white solid. MS: (M+Na)+=515; mp=225-250° C.; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.92 (br. s., 1H), 9.14 (s, 1H), 8.69 (d, J=8.7 Hz, 1H), 8.47 (d, J=7.2 Hz, 2H), 7.95 (d, J=1.5 Hz, 1H), 7.24 (d, J=8.7 Hz, 1H), 4.92 (t, J=5.5 Hz, 1H), 4.49-4.78 (m, 5H), 4.17-4.27 (m, 1H), 4.05-4.15 (m, 1H), 3.83-3.93 (m, 3H), 1.39 (dd, J=6.6, 4.7 Hz, 3H).
Reaction SMILES: [CH:1]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[CH2:10]([N:17]=[C:18]=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.[Al]>ClCCl>[CH2:10]([NH:17][C:18](=[O:19])[O:9][CH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C=NCc1ccccc1
Reactant: OC1C=CCCCCC1
Agent: O=C(NCc1ccccc1)OC1/C=C/CCCCC1
Agent: OC1/C=C/CCCCC1
Agent: [Al]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1ccccc1)OC1C=CCCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (E)-cyclooct-2-enol 31 (minor isomer 100 mg, 0.792 mmol) in dichloromethane (6 mL) were added benzyl isocyanate (101 μL, 110 mg, 0.826 mmol, 1.04 eq) and a drop of triethylamine. The flask was covered with aluminum foil and the solution was stirred under a nitrogen atmosphere at room temperature overnight. Evaporation of the reaction mixture gave mainly starting material. Benzyl isocyanate (200 μL, 220 mg, 1.65 mmol, 2.08 eq) and a drop of triethylamine in dichloromethane (6 mL) were added and the solution was stirred overnight at room temperature, at 50° C. for 1 hr and at 25-30° C. over the weekend. The volatiles were removed by bulb-to-bulb distillation (50° C., 2 hr). The residue was purified by column chromatography to give carbamate 32 (43 mg, 0.166 mmol, 20.9%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[CH3:8].[CH3:13][OH:14].C[O-].[Na+]>O>[Br:1][C:2]1[C:3]([O:14][CH3:13])=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[CH3:8]
Reactant: Cc1c([N+](=O)[O-])cnc(Cl)c1Br
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: COc1ncc([N+](=O)[O-])c(C)c1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 53 %

Procedure:
To a solution of 3-Bromo-2-chloro-4-methyl-5-nitro-pyridine (5.00 g, 19.9 mmol) in anyhdrous Methanol was added a 25% methanolic NaOMe solution (10.7 mL, 2.5 eq). The reaction was stirred at room temperature for 24 hr. The solvent was removed under reduced pressure giving a solid. Water (100 mL) was added to the flask and the flask sonicated for 5 minutes. The precipitate was filtered and washed with water (50 mL) giving a beige powder. The aqueous mother liquor was extracted with EtOAc (1×), the organic washed with brine, and dried. The two solids were combined giving 3-Bromo-2-methoxy-4-methyl-5-nitro-pyridine (2.75 g, 10.6 mmol, 53%). 1H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 4.12 (s, 3H), 2.72 (s, 3H).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[C:5]1([CH2:15][NH2:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:5]1([CH2:15][N:16]=[C:1]=[O:2])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)Cl
Reactant: NCc1cccc2ccccc12
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C=NCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of phosgene (20% in toluene, 5 ml) was diluted with toluene (10 ml). A mixture of 1-naphthalenemethylamine (500 μl, 3.41 mmol), triethylamine (0.95 ml, 6.82 mmol) in toluene (5 ml) was added dropwise. The reaction mixture was heated at reflux overnight. The mixture was cooled to room temperature, and the solvent was removed. The residue was stirred with ether (50 ml) for 10 minutes and filtered. The filtrate was concentrated to give the crude product which was purified by flash chromatography (silica gel, methylene chloride) to give the desired product (518 mg) as a colorless oil. IR 2260 cm−1.