Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C([S:41][CH:42]([CH:64]([O:67][CH3:68])[O:65][CH3:66])[CH2:43][NH:44][C:45]([C:47]1[NH:48][C:49]2[C:54]([CH:55]=1)=[CH:53][C:52]([O:56][CH2:57][CH2:58][O:59][CH3:60])=[CH:51][C:50]=2[N+:61]([O-:63])=[O:62])=O)C1C=CC=CC=1.C1(SC)C=CC=CC=1>ClCCl.CCCCCC.C(OCC)(=O)C.O>[CH3:66][O:65][CH:64]([O:67][CH3:68])[CH:42]1[S:41][C:45]([C:47]2[NH:48][C:49]3[C:54]([CH:55]=2)=[CH:53][C:52]([O:56][CH2:57][CH2:58][O:59][CH3:60])=[CH:51][C:50]=3[N+:61]([O-:63])=[O:62])=[N:44][CH2:43]1
Reactant: COCCOc1cc([N+](=O)[O-])c2[nH]c(C(=O)NCC(SCc3ccccc3)C(OC)OC)cc2c1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CSc1ccccc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COCCOc1cc([N+](=O)[O-])c2[nH]c(C3=NCC(C(OC)OC)S3)cc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 173.2 %

Procedure:
Triphenylphosphine oxide (3 g) was dissolved in dichloromethane (30 mL), trifluoroacetic anhydride (3.1 g) was added under ice-cooling, and the mixture was stirred for 10 min. A solution of N-[2-(benzylthio)-3,3-dimethoxypropyl]-5-(2-methoxyethoxy)-7-nitro-1H-indole-2-carboxamide (5.0 g) and thioanisole (2.5 g) in dichloromethane (20 mL) was added dropwise to this suspension under ice-cooling. The reaction solution was allowed to warm to room temperature, and stirred for 10 min. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtrated, and the filtrate was concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate:hexane=10:90-40:60), and the obtained solid was washed with ethyl acetate-hexane to give the title compound (6.8 g, yield 97%) as yellow crystals. melting point 100-101° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21]([C:23]3[C:24](F)=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[NH:32]1[C:36]2=[N:37][CH:38]=[CH:39][C:40]([CH2:41][NH2:42])=[C:35]2[CH:34]=[CH:33]1.CCN(C(C)C)C(C)C>C(O)(C)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21]([C:23]3[C:24]([NH:42][CH2:41][C:40]4[CH:39]=[CH:38][N:37]=[C:36]5[NH:32][CH:33]=[CH:34][C:35]=45)=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ccnc2[nH]ccc12
Reactant: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3cccnc3F)ccc2C(C)(C)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3cccnc3NCc3ccnc4[nH]ccc34)ccc2C(C)(C)C1
Reaction time: 0.33 h

Procedure:
A mixture of 7-[(2-fluoro-pyridine-3-carbonyl)-amino]-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.99 g, 4.98 mmol) and C-(1H-pyrrolo[2,3-b]pyridin-4-yl)-methylamine, dihydrochloride (1.79 g, 8.14 mmol), DIEA (6 mL), and t-butanol (9 mL) in 3 microwave vials was subjected to 170° C., 1200 s of microwave. The combined mixture was concentrated and purified by column chromatography (Biotage, 0 to 7% MeOH with 10% NH4OH in CH2Cl2) to afford the title compound.
Reaction SMILES: [CH:1]([C:3]1[C:8]([CH3:9])=[CH:7][C:6]([NH:10][C:11]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([O:21][C:22](=[O:36])[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:17][CH2:16]2)=[O:12])=[C:5]([CH3:37])[CH:4]=1)=O.C(O)(=O)C.[NH2:42][CH2:43][C@@H:44]([C:53]1[CH:54]=[CH:55][C:56]([OH:62])=[C:57]([NH:59][CH:60]=[O:61])[CH:58]=1)[O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47].CO>C1(C)C=CC=CC=1>[Si:46]([O:45][C@H:44]([C:53]1[CH:54]=[CH:55][C:56]([OH:62])=[C:57]([NH:59][CH:60]=[O:61])[CH:58]=1)[CH2:43][N:42]=[CH:1][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([NH:10][C:11]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([O:21][C:22](=[O:36])[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:17][CH2:16]2)=[O:12])=[C:5]([CH3:37])[CH:4]=1)([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c(NC=O)c1
Reactant: Cc1cc(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c(C)cc1C=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c(C)cc1C=NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(NC=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.7 %

Procedure:
To a 250 mL round-bottom flask was added biphenyl-2-ylcarbamic acid 1-[2-(4-formyl-2,5-dimethylphenylcarbamoyl)ethyl]piperidin-4-yl ester (7.1 g, 14.2 mmol) and N-{5-[(R)-2-amino-1-(tert-butyldimethylsilanyloxy)ethyl]-2-hydroxyphenyl}formamide acetic acid salt (5.8 g, 15.6 mmol). Methanol (100 mL) was added to form a slurry and this mixture was stirred at 45° C. to 50° C. under nitrogen for 1 hour. The mixture was then cooled to room temperature and toluene (50 mL) was added and the solvent was removed on a rotary evaporator at temperature ranging from 35° C. to 45° C. Toluene (50 mL) was added to the residue and the solvent was removed to provide biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-(tert-butyldimethylsilanyloxy)-2-(3-formylamino-4-hydroxyphenyl)ethylimino]methyl}-2,5-dimethylphenylcarbamoyl)ethyl]piperidin-4-yl ester (12 g) as a yellow-orange solid.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](Cl)[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)[C:5]1=[O:26])(=O)C.[CH3:27][N:28]([CH2:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1)[CH3:29].[OH-].[Na+]>CN(C=O)C.CO>[CH3:29][N:28]([CH2:30][C:31]1[CH:32]=[CH:33][C:34]([NH:35]/[C:16](=[C:6]2\[C:5](=[O:26])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)=[CH:36][CH:37]=1)[CH3:27]
Reactant: CN(C)Cc1ccc(N)cc1
Reactant: COc1cccc(C(Cl)=C2C(=O)N(C(C)=O)c3ccc([N+](=O)[O-])cc32)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cccc(/C(Nc2ccc(CN(C)C)cc2)=C2/C(=O)Nc3ccc([N+](=O)[O-])cc32)c1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-[1-chloro-1-(3-methoxyphenyl)-methylidene)-5-nitro-2-indolinone and 4-dimethylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:4][C@H:3]1[C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=2)[NH:7][N:6]=1.[H][H]>CO.[Pd]>[CH3:1][C@H:2]1[CH2:4][C@H:3]1[C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([NH2:14])[CH:12]=2)[NH:7][N:6]=1
Reactant: [H][H]
Reactant: C[C@H]1C[C@H]1c1n[nH]c2ncc([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: CO
Product: C[C@H]1C[C@H]1c1n[nH]c2ncc(N)cc12
Reaction time: 0.33 h

Procedure:
3-(cis-2-Methylcyclopropyl)-5-nitro-1H-pyrazolo[3,4-b]pyridine (0.0462 g, 0.212 mmol) and Pd/C were taken up in MeOH. Hydrogen gas was passed through for 10 minutes, and the reaction mixture was stirred under a hydrogen atmosphere for 20 minutes. The solution was filtered through celite and concentrated to provide 3-(cis-2-methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridin-5-amine as an oil, which was used without further purification.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]2[C:24]([O:25]C)=[N:23][C:22]3[C:17]2=[N:18][C:19]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[N:20][C:21]=3[NH2:27])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(Br)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(N(C(C)C)C(C)C)C>C1COCC1>[NH2:27][C:21]1[N:20]=[C:19]([O:28][CH2:29][CH2:30][O:31][CH3:32])[N:18]=[C:17]2[C:22]=1[NH:23][C:24](=[O:25])[N:16]2[CH2:15][CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:6][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:9][CH2:10]1
Reactant: COCCOc1nc(N)c2nc(OC)n(CCC3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Reactant: BrCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COCCOc1nc(N)c2[nH]c(=O)n(CCC3CCN(Cc4ccccc4)CC3)c2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 22.4 %

Procedure:
To the compound (0.26 g, 0.58 mmol) obtained in Step (i) was added trifluoroacetic acid (4 ml), and the mixture was stirred at room temperature for 20 minutes. Trifluoroacetic acid was evaporated with an evaporator, and to the resultant were added THF (10 ml), benzyl bromide (0.21 ml, 1.74 mmol) and ethyl diisopropylamine (0.75 ml, 4.35 mmol), and the mixture was stirred at room temperature for 15 hours, then stirred at 50° C. for one hour. The resultant was concentrated by an evaporator, and water was added to the residue. The mixture was extracted three times with chloroform, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column (chloroform/methanol=100/1 to 20/1). Then, methanol (1 ml) and a 4N hydrochloric acid in dioxane (1 ml) were added thereto, and the mixture was stirred at room temperature for one hour. The mixture was cooled to 0° C., and neutralized with 4% aqueous ammonia. The precipitated solid was collected by filtration, and washed with water to give the title compound (55 mg, 0.13 mmol) as a white solid. Yield: 22%.
Reaction SMILES: C1(NC2CCCCC2)CCCCC1.Br[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.[CH3:22][C:23]([OH:27])([C:25]#[CH:26])[CH3:24].[Cl-].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC([B-](C2C=CC(C)=CC=2)(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.C1(C)C=CC=CC=1.O1CCCC1>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:22][C:23]([CH3:24])([OH:27])[C:25]#[CH:26])=[CH:16][CH:17]=1
Reactant: C#CC(C)(C)O
Reactant: Fc1ccc(Br)cc1
Agent: [Pd+2]
Agent: C1CCC(NC2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C#CC(C)(O)Cc1ccc(F)cc1
Yield: 96.7 %

Procedure:
A 50-ml four-necked flask was equipped with a stirrer, a thermometer and a reflux condenser. 0.034 g (0.15 mmol) of palladium (II) acetate, 1.088 g (6 mmol) of dicyclohexylamine and 5 ml of tetrahydrofuran were weighed in the flask, followed by stirring. Further, 0.174 g (0.3 mmol) of tri-tert-butylphosphonium tetra-para-tolylborate obtained in Example B-3 was weighed in air and added into the flask. The flask was purged with argon, followed by stirring at 30° C. for 30 minutes. 0.875 g (5 mmol) of 1-bromo-4-fluorobenzene and 0.505 g (6 mmol) of 2-methyl-3-butyne-2-ol were added, followed by stirring at 30° C. for 17 hours. After the completion of the reaction, 10 ml of tetrahydrofuran, 5 ml of toluene and 15 ml of saturated sodium chloride solution were added, followed by separation. The organic phase was purified by column chromatography to afford 0.862 g of (4-fluorophenyl)-2-methyl-3-butyne-2-ol (yield: 97 mol % based on 1-bromo-4-fluorobenzene). The identification of the product was made by 1H-NMR and 13C-NMR.
Reaction SMILES: O[CH2:2][C:3]1([CH3:19])[CH2:18][CH2:17][CH2:16][C:5]2([O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:6]2)[CH2:4]1.[Br:20]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>CC#N>[Br:20][CH2:2][C:3]1([CH3:19])[CH2:18][CH2:17][CH2:16][C:5]2([O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:6]2)[CH2:4]1
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)CN1CC2(CCCC(C)(CO)C2)OC1=O
Solvent: CC#N
Product: CC(C)(C)CN1CC2(CCCC(C)(CBr)C2)OC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.5 %

Procedure:
To a colorless solution of 7-(hydroxymethyl)-7-methyl-3-neopentyl-1-oxa-3-azaspiro[4.5]decan-2-one (14.7 g, 54.6 mmol) in MeCN (273 ml) was added dibromotriphenylphosphorane (34.6 g, 82.0 mmol). The reaction was stirred at rt for 3 h and then heated to 80° C. for 42 h. The reaction was cooled to rt and concentrated onto florisil for purification on a 220 g silica gel column (5-15% EtOAc/hexanes, 30 min gradient; 15% EtOAc/hexanes, 10 min; 15-50% EtOAc/hexanes, 15 min gradient; 50% EtOAc/hexanes, 15 min; 50-100% EtOAc/hexanes, 5 min gradient; 100% EtOAc, 5 min; 100 mL/min elution; 254 nm detection) to yield the title compound (9.7 g, 54% yield). 1H NMR (400 MHz, CDCl3) δ 3.35 (dd, J=8.78, 12.05 Hz, 2H), 3.26 (s, 2H), 3.08 (d, J=14.05 Hz, 1H), 2.93 (d, J=14.05 Hz, 1H), 1.96-2.03 (m, 1H), 1.78 (dt, J=1.95, 14.18 Hz, 1H), 1.52-1.65 (m, 3H), 1.28-1.48 (m, 3H), 1.24 (s, 3H), 0.97 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[C:4]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:11][CH2:10]2)[CH:5]=[C:4]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH:3]=1
Reactant: Clc1cc(-c2c[nH]c3ncccc23)cc(NC2CCNCC2)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCC(Nc2cc(-c3c[nH]c4ncccc34)cc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of Example 33 (0.04 g, 0.095 mmol) in 2 mL anhydrous THF was added diisopropylethylamine (0.07 mL, 0.38 mmol) followed by methanesulfonyl chloride (0.009 mL, 0.114 mmol). The resulting solution was stirred at room temperature for 2.5 hours. The reaction mixture was diluted with ethyl acetate and washed with water, brine, dried over magnesium sulfate, filtered, and concentrated to give the title compound as an off-white solid. 1H NMR (300 MHz, DMSO-d6) ppm 1.16-1.35 (m, 1H) 1.38-1.61 (m, 3H) 1.93-2.10 (m, 3H) 2.90-3.04 (m, 2H) 3.52 (d, J=12.21 Hz, 2H) 3.84 (s, 1H) 6.82-7.00 (m, 3H) 7.21 (dd, J=7.80, 5.09 Hz, 1H) 8.14 (d, J=3.05 Hz, 1H) 8.24-8.37 (m, 2H) 12.16 (s, 1H). MS (ESI+) m/z 406.0 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:6]([OH:7])[C:5]=1[OH:14])([O-:3])=[O:2].S(=O)(=O)(O)O>C(OC(=O)CC)(=O)CC>[C:6]([O:7][C:6]1[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=1[O:14][C:5](=[O:14])[CH2:4][CH3:10])(=[O:7])[CH2:8][CH3:9]
Reactant: O=[N+]([O-])c1cc(O)c(O)c([N+](=O)[O-])c1
Agent: CCC(=O)OC(=O)CC
Agent: O=S(=O)(O)O
Product: CCC(=O)Oc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1OC(=O)CC

Procedure:
A solution of 2.0 g of 3,5-dinitropyrocatechol in 25 ml of propionic anhydride is heated at 110° for 18 hours in the presence of a catalytic amount of conc. sulfuric acid, the excess anhydride is distilled off at 70° in a high vacuum (1.33 Pa), the residue is dissolved in methylene chloride, washed with water, dried over sodium sulfate, filtered and evaporated. There is obtained 1,2-dipropionyloxy-3,5-dinitrobenzene of m.p. 74°-76° (from methylene chloride/petroleum ether).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[Cl:12][C:13]1[CH:14]=[C:15]2[N:33]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:32](S(C)(=O)=O)=[N:31][C:16]2=[N:17][C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.[NH2:46][C@H:47]1[CH2:51][O:50][C@@H:49]2[C@H:52]([NH:55][C:56](=[O:62])[O:57][C:58]([CH3:61])([CH3:60])[CH3:59])[CH2:53][O:54][C@H:48]12>CN(C=O)C.C(OCC)(=O)C>[Cl:12][C:13]1[CH:14]=[C:15]2[N:33]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:32]([NH:46][C@H:47]3[CH2:51][O:50][C@@H:49]4[C@H:52]([NH:55][C:56](=[O:62])[O:57][C:58]([CH3:60])([CH3:59])[CH3:61])[CH2:53][O:54][C@H:48]34)=[N:31][C:16]2=[N:17][C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1
Reactant: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Reactant: CC(C)(C)OC(=O)N[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2Nc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2n1COCC[Si](C)(C)C
Reaction time: 18 h

Procedure:
DBU (18.3 uL, 0.122 mmol) was added to a mixture of 2-[[6-chloro-2-methylsulfonyl-5-(4-phenylphenyl)imidazo[4,5-b]pyridin-1-yl]methoxy]ethyl-trimethyl-silane (50 mg, 0.097 mmol) and tert-butyl N-[(3S,3aR,6R,6aR)-3-amino-2,3,3a,5,6,6a-hexahydrofuro-[3,2-b]furan-6-yl]carbamate (72.6 mg, 0.297 mmol) in DMF (0.39 mL). After 18 hours, the mixture was diluted with ethyl acetate (20 mL) and washed with water (5×20 mL). The organic layer was separate, washed with brine (1×10 mL), dried with MgSO4, filtered and the solvent was removed under vacuum. The crude reaction mixture was then purified on preparative silica gel plates (1×1000 u—developed with 30% EtOAc/hexanes and eluted with EtOAc) to give the title compound. LC-MS: calculated for C35H44ClN5O5Si 677.28 observed m/e minor isomer 678.31 (M+H)+ (Rt 1.34/2 min) and major isomer 608.23 (M+H)+ (Rt 1.04/2 min)
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([N:9]2[C:13](=[O:14])[C:12]([N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)=[CH:11][NH:10]2)[CH:4]=1.Cl.[F:21][C:22]1([F:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(N(C(C)C)C(C)C)C>O1CCCC1>[F:21][C:22]1([F:28])[CH2:27][CH2:26][N:25]([C:3]2[N:8]=[CH:7][N:6]=[C:5]([N:9]3[C:13](=[O:14])[C:12]([N:15]4[CH:19]=[CH:18][N:17]=[CH:16]4)=[CH:11][NH:10]3)[CH:4]=2)[CH2:24][CH2:23]1
Reactant: O=c1c(-n2ccnc2)c[nH]n1-c1cc(Cl)ncn1
Reactant: FC1(F)CCNCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=c1c(-n2ccnc2)c[nH]n1-c1cc(N2CCC(F)(F)CC2)ncn1

Procedure:
100 mg (0.3 mmol) of the compound from Example 13A, 63 mg (0.4 mmol) of 4,4-difluoropiperidine hydrochloride and 116 μl (86 mg, 0.7 mmol) of N-ethyl-N-(propan-2-yl)propane-2-amine are initially charged in 2 ml of tetrahydrofuran and reacted in a single mode microwave (Emrys Optimizer) at 120° C. for 2.5 h. After concentration under reduced pressure, the residue is taken up in acetonitrile/water and purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). Yield: 82 mg (71% of theory)
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]3[S:28][C:27](Br)=[N:26][CH:25]=3)[CH2:19][CH2:18]2)=[O:14])[CH:3]=1.[NH:30]1[CH:34]=[CH:33][C:32](B(O)O)=[N:31]1.C(=O)([O-])[O-].[Na+].[Na+]>COC.O.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>[NH:30]1[CH:34]=[CH:33][C:32]([C:27]2[S:28][C:24]([CH2:23][N:20]3[CH2:21][CH2:22][CH:17]([CH2:16][NH:15][C:13](=[O:14])[C:4]4[CH:3]=[C:2]([NH2:1])[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=4)[CH2:18][CH2:19]3)=[CH:25][N:26]=2)=[N:31]1
Reactant: CCOc1nc(C(=O)NCC2CCN(Cc3cnc(Br)s3)CC2)cc(N)c1C#N
Reactant: OB(O)c1cc[nH]n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COC
Agent: O=C([O-])[O-]
Solvent: O
Product: CCOc1nc(C(=O)NCC2CCN(Cc3cnc(-c4cc[nH]n4)s3)CC2)cc(N)c1C#N
Temperature: 95 °C
Yield: 7.3 %

Procedure:
To a mixture of the compound prepared in Example 336 (0.028 g), 1H-pyrazol-3-ylboronic acid (0.013 g) and tetrakis(triphenylphosphine)palladium (0.003 g) in dimethyl ether (0.3 mL) was added a solution of sodium carbonate (0.016 g) in water (0.1 mL). Argon was bubbled through the mixture for 10 minutes. The mixture was then heated at 95° C. for 8 hours. An additional tetrakis(triphenylphosphine)palladium (4.5 mg) and 1H-pyrazol-3-ylboronic acid (13 mg) were added, and the reaction mixture was again purged with argon for 10 minutes and then heated at 110° C. for 6 hours. An additional tetrakis(triphenylphosphine)palladium (10 mg) was added, and the reaction mixture was again purged with argon and then heated at 110° C. for another 38 hours. The reaction mixture was diluted with water and then filtered. The solid was purified by column chromatography on silica gel (dichloromethane:methanol=94:6) to obtain the title compound (2 mg) having the following physical data.
Reaction SMILES: C(O)(C)C.[CH3:5][C:6]1([CH3:14])[CH:12]2[CH2:13][CH:7]1[CH2:8][CH2:9][C:10]2=[CH2:11].[S:15](=[O:18])([OH:17])[O-:16].[NH4+:19]>O>[C:10]1([CH2:11][S:15]([O-:18])(=[O:17])=[O:16])[CH2:12][CH2:13][C@H:7]([CH:6]([CH3:14])[CH3:5])[CH2:8][CH:9]=1.[NH4+:19]
Reactant: O=S([O-])O
Reactant: C=C1CCC2CC1C2(C)C
Agent: [NH4+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)[C@@H]1CC=C(CS(=O)(=O)[O-])CC1
Reaction time: 22 h

Procedure:
Into a 1 liter flask equipped with magnetic stirrer were placed 450 ml isopropanol, 240 ml water and 54.4 grams (0.4 mole) β-pinene. Ammonium bisulfite, 105 grams (45%) was then added thereto. The mixture was stirred at 40°-45° C. for 22 hours. Thereafter, the solution was evaporated to dryness. Residue was extracted with methanol. The methanolic solution was filtered, and the resultant filtrate evaporated to dryness. Obtained were 84 grams product (85.8% purity; 77% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5](Cl)[C:6]1[CH:7]=[C:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1.[C:16]([NH2:19])(=[S:18])[CH3:17]>>[CH3:1][O:2][C:3]([C:4]1[N:19]=[C:16]([CH3:17])[S:18][C:5]=1[C:6]1[CH:7]=[C:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1)=[O:15]
Reactant: COC(=O)C(=O)C(Cl)c1cccc(C)c1
Reactant: CC(N)=S
Product: COC(=O)c1nc(C)sc1-c1cccc(C)c1

Procedure:
prepared by reaction of 3-chloro-2-oxo-3-m-tolyl-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.94 min; [M+H]+=248.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=O.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[NH2:16]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:16][C:15]2[CH:14]=[C:13]([Cl:12])[CH:19]=[C:18]([Cl:20])[CH:17]=2)=[O:8])=[C:4]([OH:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1O
Reactant: Nc1cc(Cl)cc(Cl)c1
Product: O=C(Nc1cc(Cl)cc(Cl)c1)c1ccc(Cl)cc1O
Yield: 57.2 %

Procedure:
Using 4-chlorosalicylic acid and 3,5-dichloroaniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9]1[N:18]=[C:17]([N:19]2[CH2:23][CH2:22][C@@H:21]([NH:24]C(=O)OCC3C=CC=CC=3)[CH2:20]2)[C:16]2[C:11](=[CH:12][C:13]([CH3:35])=[CH:14][CH:15]=2)[N:10]=1>CO.[Pd]>[NH2:24][C@@H:21]1[CH2:22][CH2:23][N:19]([C:17]2[C:16]3[C:11](=[CH:12][C:13]([CH3:35])=[CH:14][CH:15]=3)[N:10]=[C:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[OH:8])[N:18]=2)[CH2:20]1
Reactant: Cc1ccc2c(N3CC[C@@H](NC(=O)OCc4ccccc4)C3)nc(-c3c(O)cccc3F)nc2c1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc2c(N3CC[C@@H](N)C3)nc(-c3c(O)cccc3F)nc2c1
Reaction time: 16 h
Yield: 93.2 %

Procedure:
Under an N2 atmosphere, Pd/C (10% weight, 210 mg) was added to a solution of (R)-benzyl 1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (2.1 g, 4.44 mmol) in MeOH (60 mL). After purging 2 times with N2 and evacuating the atmosphere in the flask containing the reaction mixture, the reaction was stirred under an H2 atmosphere for 16 h. Since the reaction was not complete, an additional 200 mg Pd/C was added, and the reaction was stirred for an additional 4 h. The mixture was filtered through a pad of Celite (150 mL) using 1.8 mL MeOH, and the filtrate was concentrated under reduced pressure to obtain (R)-2-(4-(3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol as a yellow solid (1.4 g, 93%). LC/MS: m/z 339.1 (M+H)+ at 1.05 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).