Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[C:16]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:17]4[CH2:23][CH2:22][NH:21][CH2:20][C:18]=4[N:19]=3)=[C:10]([F:31])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.CCN(CC)CC.[CH3:39][N:40]([CH3:44])[C:41](Cl)=[O:42]>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[C:16]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:17]4[CH2:23][CH2:22][N:21]([C:41]([N:40]([CH3:44])[CH3:39])=[O:42])[CH2:20][C:18]=4[N:19]=3)=[C:10]([F:31])[CH:9]=2)[CH2:2][CH2:3]1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CCNC2
Reactant: CN(C)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CCN(C(=O)N(C)C)C2
Temperature: 20 °C
Reaction time: 8 h
Yield: 36.7 %

Procedure:
To a stirring solution of (S)-1-cyclopropyl-3-(3-fluoro-4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (example 163) (99 mg, 0.23 mmol) and NEt3 (35 μL, 0.25 mmol) in DMF (2 ml) was added dimethylcarbamoyl chloride (29 μL, 0.25 mmol). Reaction mixture was stirred at room temperature (20° C.) overnight before being concentrated in vacuo and purified by prep. HPLC at high pH to afford a white solid (42 mg, 37%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[N:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)[NH:11][CH:12]=2)[CH2:3][CH2:2]1.C(=O)=O.B(Br)(Br)Br.CO>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[N:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[NH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(-c2nc(CN3CCOCC3)c[nH]2)cc1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: ClCCl
Solvent: CO
Product: Oc1ccc(-c2nc(CN3CCOCC3)c[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
Under N2, a solution of 52 (2.25 g, .0082 mol) in CH2Cl2 (25 ml) was added dropwise to a dry-ice cooled solution of BBr3 (2.5 ml, d=2.65, 0.0265 mol) in CH2C12 (75 ml). After the addition, the solution was stirred at room temperature overnight and then treated dropwise with CH3OH (50 ml). After stirring overnight at room temperature, the solution was concentrated to dryness, the residue treated with 10% NaOH, the aqueous layer extracted with Et2O, the pH of the solution adjusted to 8.7 and concentrated to dryness. The residue was triturated with hot CH3OH, filtered, the filtrate concentrated to dryness and the residue chromatographed on silica gel. The product was eluted with 10% CH3OH-CHCl3 to yield 1.75 g (82%) of 53.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[N:14]([CH3:23])[CH:13]=1.[NH2:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([OH:31])[CH2:27][CH2:26]1>CN1C(=O)CCC1>[OH:31][C@H:28]1[CH2:29][CH2:30][C@H:25]([NH:24][C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=2[C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]([CH3:23])[CH:13]=2)[CH2:26][CH2:27]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: Cn1cc(-c2cc(S(C)(=O)=O)ccc2F)c2ccccc2c1=O
Solvent: CN1CCCC1=O
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2N[C@H]2CC[C@H](O)CC2)c2ccccc2c1=O
Temperature: 250 °C

Procedure:
A mixture of 4-(2-fluoro-5-methylsulfonylphenyl)-2-methylisoquinolin-1-one (150 mg, 0.45 mmol) and trans-4-aminocyclohexan-1-ol (417 mg, 3.62 mmol) in NMP (0.2 mL) was heated for 20 min at 200-300° C. The cooled brownish residue was purified by prep-HPLC to give the title compound (55.64 mg, 28.8%) as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 8.54 (d, J=8.0 Hz, 1H), 7.86 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 7.66 (d, J=2.4 Hz, 1H), 7.60-7.55 (m, 2H), 7.15-7.13 (m, 2H), 6.79 (d, J=8.8 Hz, 1H), 3.91-3.85 (m, 1H), 3.67 (s, 3H), 3.63-3.55 (m, 1H), 3.37-3.34 (m, 1H), 3.06 (s, 3H), 2.04-1.92 (m, 5H), 1.44-1.35 (m, 2H), 1.11-1.02 (m, 2H). LCMS (M+H)+=427.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4]P(=O)(OCC)OCC.[Br:17][C:18]1[C:26]2[O:25][C:24]([CH:27]=O)=[CH:23][C:22]=2[CH:21]=[C:20]([O:29][CH3:30])[CH:19]=1.[H-].[Na+].O>O1CCCC1>[Br:17][C:18]1[C:26]2[O:25][C:24](/[CH:27]=[CH:4]/[C:3]3[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=3[Cl:1])=[CH:23][C:22]=2[CH:21]=[C:20]([O:29][CH3:30])[CH:19]=1
Reactant: CCOP(=O)(Cc1ccccc1Cl)OCC
Reactant: COc1cc(Br)c2oc(C=O)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Br)c2oc(/C=C/c3ccccc3Cl)cc2c1
Temperature: 60 °C
Yield: 84 %

Procedure:
To a solution of diethyl 2-chlorobenzylphosphonate (4.91 g, 0.018 mol) and 7-bromo-5-methoxybenzofuran-2-carbaldehyde (11.27 g, 0.016 mol) in tetrahydrofuran (80 mL) was added sodium hydride (60% dispersion in mineral oil, 0.74 g, 0.0185 mol). After 5 min. the reaction mixture was warmed to 60° C. for 1 h. The reaction mixture was cooled to room temperature, water (10 mL) was carefully added and the tetrahydrofuran was removed. Water (50 mL) was added and the mixture was extracted with ethyl acetate (3×100 mL). The combined ethyl acetate extracts were washed with brine (50 mL), dried over magnesium sulphate, filtered and concentrated to dryness. Trituration with diethyl ether (20 mL) gave solid material which was further washed with diethyl ether (20 ml). The liquors were concentrated and triturated with diethyl ether (10 mL), the solid being collected. The combined solids gave (859) (4.89 g, 84%). 1H NMR δ (CDCl3) 7.70 (d, J=16 Hz, 1H), 7.65 (dd, J=7.7, 1.5 Hz, 1H), 7.4 (dd, J=6.0, 1 Hz, 1H), 7.23 (m, 2H), 7.05 (d, J=2.3 Hz, 1H), 6.94 (d, J=16 Hz, 1H), 6.92 (d, J=2.3 Hz, 1H), 6.72 (s, 1H), 3.82 (s, 3H); MH+:364.9, 362.9 MH−:362.9, 360.9.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH2:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[NH:28][CH:29]=[C:30]([C:32]#[N:33])[N:31]=3)=[O:26])=[C:20]([C:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]=3)[CH:19]=2)[CH2:14][CH2:13]1)=[O:11].[BH-](OC(C)=O)(OC(C)=O)[O:41][C:42]([CH3:44])=O.[Na+].C(C=O)=O>C(Cl)Cl>[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:34]1([C:20]2[CH:19]=[C:18]([CH:15]3[CH2:16][CH2:17][N:12]([C:10](=[O:11])[CH2:9][NH:8][CH2:44][CH2:42][OH:41])[CH2:13][CH2:14]3)[CH:23]=[CH:22][C:21]=2[NH:24][C:25]([C:27]2[NH:28][CH:29]=[C:30]([C:32]#[N:33])[N:31]=2)=[O:26])[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCN(C(=O)CN)CC3)cc2C2=CCCCC2)n1
Agent: O=CC=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCN(C(=O)CNCCO)CC3)cc2C2=CCCCC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
A suspension of 4-cyano-1H-imidazole-2-carboxylic acid {4-[1-(2-amino-acetyl)-piperidin-4-yl]-2-cyclohex-1-enyl-phenyl]-amide trifluoroacetic acid salt (as prepared in the previous step, 0.42 g, 0.77 mmol) in CH2Cl2 (20 mL) was treated with Na(OAc)3BH (0.33 g, 1.54 mmol) and solid glyoxal (44.6 mg, 0.77 mmol). The mixture stirred at room temperature for 1 h, and the solvent was evaporated in vacuo. The residue was taken up in MeOH and the solids filtered off, and the filtrate was concentrated in vacuo. Reverse phase HPLC (C-18 column) (20% to 60% acetonitrile in water with 0.1% TFA over 30 min) afforded the title compound (83 mg, 19% over two steps) as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.16-8.09 (m, 1H), 8.05-8.01 (m, 1H), 7.22-7.15 (m, 1H), 7.11-7.06 (m, 1H), 5.84-5.79 (m, 1H), 4.72-4.62 (m, 1H), 4.24-3.91 (m, 2H), 3.89-3.80 (m, 2H), 3.28-3.18 (m, 2H), 2.92-2.79 (m, 2H), 2.28 (br s, 4H), 1.98-1.89 (m, 2H), 1.89-1.76 (m, 4H), 1.76-1.57 (m, 2H). LC-MS (ESI, m/z): Calcd. for C26H32N6O3 477.2 (M+H), found 477.2.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][C:10]([NH2:12])=[O:11])[CH2:3][CH2:2]1.[CH3:13][NH:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][C:22]([O:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([N:33](C(OC4C=CC=CC=4)=O)[C:34](=O)[O:35]C4C=CC=CC=4)[CH:28]=3)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1)=[O:16]>CN(C)C=O>[CH3:13][NH:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][C:22]([O:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([NH:33][C:34]([N:1]4[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][C:10](=[O:11])[NH2:12])[CH2:3][CH2:2]4)=[O:35])[CH:28]=3)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1)=[O:16]
Reactant: NC(=O)CCCC1CCNCC1
Reactant: CNC(=O)n1ccc2cc(Oc3ccnc(N(C(=O)Oc4ccccc4)C(=O)Oc4ccccc4)c3)ccc21
Solvent: CN(C)C=O
Product: CNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCC(CCCC(N)=O)CC4)c3)ccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-(Piperidin-4-yl)butanamide (547 mg, 1.41 mmol) was dissolved in N,N-dimethylformamide (3 ml); phenyl N-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate (210 mg, 0.402 mmol, the product of Production example 5-2) was added thereto; and the reaction mixture was stirred at room temperature for 1.5 hour. The reaction mixture was partitioned between ethyl acetate and water; the organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure; and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate-methanol system). The obtained amorphous solid was crystallized by adding diethyl ether. After addition of a small amount of ethanol to make a suspension, this was diluted with hexane. After separation by filtration to obtain crystals, these were rinsed with diethyl ether and dried under aeration. Thus, the title compound was obtained as colorless crystals (157 mg, 0.328 mmol, 81.7%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)[C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:11]=3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:27]([N:32]1[C:36](=[O:37])[C:35]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]2[C:33]1=[O:42])#[C:28][CH2:29][CH2:30][CH3:31].C(NCC)C>[Cu]I.CN(C)C=O>[F:18][C:16]1[CH:15]=[CH:14][C:12]2[NH:13][C:9]([CH:8]([O:19][CH:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[C:4]3[CH:3]=[C:2]([C:31]#[C:30][CH2:29][CH2:28][CH2:27][N:32]4[C:33](=[O:42])[C:34]5[C:35](=[CH:38][CH:39]=[CH:40][CH:41]=5)[C:36]4=[O:37])[CH:7]=[CH:6][CH:5]=3)=[N:10][C:11]=2[CH:17]=1
Reactant: CN1CCC(OC(c2cccc(Br)c2)c2nc3cc(F)ccc3[nH]2)CC1
Reactant: CCCC#CN1C(=O)c2ccccc2C1=O
Agent: [Cu]I
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CN1CCC(OC(c2cccc(C#CCCCN3C(=O)c4ccccc4C3=O)c2)c2nc3cc(F)ccc3[nH]2)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A screw-capped tube is charged with 2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5-fluoro-1H-benzimidazole (example 437D, 418 mg), PEPPSi-sono catalyst (19 mg), copper (I) iodide (38 mg), N-pentynylphthalimide (428 mg), diethylamine (880 μL) and N,N-dimethylformamide (1.5 mL). The tube is evacuated, filled with argon and sealed. The reaction mixture is stirred at 80° C. overnight. As the reaction is not completed, PEPPSi-sono catalyst (10 mg) and N-pentynylphthalimide (214 mg) are added, and the reaction mixture is heated at 80° C. for 24 h. The mixture is diluted with water and the aqueous phase is extracted with ethyl acetate. The pooled organic extracts are washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane/methanol from 98/2/to 90/10) to give 2-(5-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynyl)isoindole-1,3-dione. 1H NMR: 9.65 (sl, 1H), 7.84-7.65 (m, 4H), 7.54 (s, 1H), 7.48-6.95 (m, 4H), 5.84 (s, 1H), 3.90 (t, 2H, J=6.9 Hz), 3.65-3.50 (m, 1H), 2.85-2.70 (m, 2H), 2.52 (t, 2H, J=7.0 Hz), 2.32 (s, 3H), 2.28-1.50 (m, 8H).
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:8]([C:9]([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:10])=[C:7]([CH:18]=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:20](=[O:24])([O:22][CH3:23])[NH2:21].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(#N)C>[C:1]([C:5]1[CH:17]=[CH:16][C:8]([C:9](=[O:10])[N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[C:7]([CH:6]=1)[CH2:18][NH:21][C:20](=[O:24])[O:22][CH3:23])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(CC)C(=O)c1ccc(C(C)(C)C)cc1C=O
Reactant: COC(N)=O
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)C(=O)c1ccc(C(C)(C)C)cc1CNC(=O)OC
Temperature: 130 °C
Yield: 69.9 %

Procedure:
A 25-mL microwave vial equipped with a magnetic stirrer was charged with 103a (1.00 g, 3.83 mmol), methyl carbamate (575 mg, 7.66 mmol), trifluoroacetic acid (871 mg, 7.66 mmol), triethylsilane (888 mg, 7.66 mmol) and acetonitrile (10 mL). The vial was loaded in a Biotage microwave and heated at 130° C. for 1.5 h. After this time, the solution was concentrated in vacuo. The resulting residue was partitioned between methylene chloride (100 mL) and a saturated aqueous sodium bicarbonate (30 mL). The aqueous layer was extracted with methylene chloride (3×20 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 0% to 60% ethyl acetate/hexanes) to afford a 71% yield (858 mg) of 103b as a colorless oil; 1H NMR (300 MHz, CDCl3) δ 7.42 (s, 1H), 7.29 (m, 1H), 7.12 (d, 1H, J=7.7 Hz), 5.60 (br s, 1H), 4.27 (br s, 2H), 3.65 (s, 3H), 3.57 (q, 2H, J=6.8 Hz), 3.20 (q, 2H, J=6.7 Hz), 1.31 (s, 9H), 1.26 (t, 3H, J=6.7 Hz), 1.09 (t, 3H, J=6.8 Hz); MS (ESI+) m/z 321.2 (M+H).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([F:18])[CH:11]=1.CN([CH:22]=[O:23])C.O>C1COCC1>[Br:9][C:10]1[C:11]([CH:22]=[O:23])=[C:12]([F:18])[C:13]([O:16][CH3:17])=[CH:14][CH:15]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(Br)cc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Br)c(C=O)c1F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirred solution of LDA (62 mmol) in THF (100 mL) was added 4-bromo-2-fluoro-1-methoxybenzene (12 g, 59 mmol) in THF (20 mL) slowly at −78° C. The reaction mixture was left to stir at −78° C. for 2 h, treated with DMF (15 g, 210 mmol) in THF (20 mL) slowly, left to stir at −78° C. for 1 h, and allowed to warm to room temperature as the bath did. The reaction mixture was treated with water and extracted with EtOAc (×3). The combined organics were washed with brine, dried (Na2SO4), concentrated, and purified by flash chromatography to afford the title compound. 1H NMR (600 MHz, CDCl3) δ 10.34 (s, 1H); 7.39 (dd, 1H); 7.04 (t, 1H); 3.92 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][C:13]=34)=[CH:21][C:20]([CH:25]=C)=[CH:19][CH:18]=5)[C:8]=2[C:27]([F:30])([F:29])[F:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N+]1([O-])CC[O:35]CC1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][C:13]=34)=[CH:21][C:20]([CH:25]=[O:35])=[CH:19][CH:18]=5)[C:8]=2[C:27]([F:28])([F:30])[F:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a clear solution of 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 6A, 1.6 g, 3.92 mmol) in THF (15 mL) were sequentially added NMO (50% in water, 1.219 mL, 5.88 mmol) and osmium tetroxide (4% in water, 0.958 mL, 0.157 mmol) at room temperature. The solution was vigorously stirred at room temperature overnight. A cloudy solution of sodium periodate (1.425 g, 6.66 mmol) in water (14 mL) was added. The mixture was stirred at room temperature under nitrogen for 0.5 hr. Water (20 mL) was then added and the mixture was stirred at room temperature for 30 min. The solid was filtered, washed with water (2×2 mL) and methanol (2 mL) and dried to give 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (1.6 g, 3.90 mmol, 100% yield) as a white solid. The compound had an HPLC retention time=4.02 min. (condition C); LC/MS M+1=410.9.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].[CH3:14][Si:15]([CH:18](O)[CH3:19])([CH3:17])[CH3:16].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:19][CH2:18][Si:15]([CH3:17])([CH3:16])[CH3:14])=[O:12]
Reactant: CC(O)[Si](C)(C)C
Reactant: O=C(O)CCCCc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOC(=O)CCCCc1ccccn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 46.9 %

Procedure:
5-(2-Pyridyl)valeric acid (1.5 g, 8.4 mmol) was dissolved in N,N-dimethylformamide (25 ml), and trimethylsilylethanol (2.0 g, 16.7 mmol), WSC (3.2 g, 16.7 mmol) and HOBt (2.3 g, 16.7 mmol) were added thereto successively. The mixture was stirred at room temperature for 6 hrs. The solvent was evaporated, and the residue was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel (60 g) column chromatography. The fractions eluted with hexane-ethyl acetate (2:1, v/v) were collected and concentrated to give the titled compound (1.1 g, 49%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N:12]=[C:13]=[O:14].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:26]3=[N:27][CH:28]=[CH:29][CH:30]=[C:25]3[NH:24][C:23]=2[C:31]([NH2:33])=[O:32])=[CH:18][CH:17]=1>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13](=[O:14])[NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[C:26]3=[N:27][CH:28]=[CH:29][CH:30]=[C:25]3[NH:24][C:23]=2[C:31]([NH2:33])=[O:32])=[CH:20][CH:21]=1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: NC(=O)c1[nH]c2cccnc2c1-c1ccc(N)cc1
Solvent: C1CCOC1
Product: NC(=O)c1[nH]c2cccnc2c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Reaction time: 1 h
Yield: 75.8 %

Procedure:
73 mg of 2-fluoro-5-trifluoromethylphenyl isocyanate are added to a solution of 80 mg of 3-(4-aminophenyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide in 18 ml of tetrahydrofuran. After stirring for 1 hour, the mixture is concentrated under reduced pressure and the residue is purified by chromatography on a silica column, elution being carried out with a mixture of cyclohexane and ethyl acetate (20/80 by volume) to give 110 mg of 3-{4-[3-(2-fluoro-5-trifluoromethylphenyl)-ureido]phenyl}-1H-pyrrolo[3,2-b]pyridine-2-carboxamide, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:21])[CH:7](OC(=O)C)[NH:8][C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])=[O:10])[CH2:2][CH2:3][CH3:4].[CH3:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:24]=1[OH:30].B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:1]([O:5][C:6](=[O:21])[CH:7]([C:27]1[CH:26]=[C:25]([CH3:29])[C:24]([OH:30])=[C:23]([CH3:22])[CH:28]=1)[NH:8][C:9]([O:11][CH2:12][C:13]([Cl:14])([Cl:15])[Cl:16])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)C(NC(=O)OCC(Cl)(Cl)Cl)OC(C)=O
Reactant: Cc1cccc(C)c1O
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCOC(=O)C(NC(=O)OCC(Cl)(Cl)Cl)c1cc(C)c(O)c(C)c1

Procedure:
A solution of 1.8 g. (6 mmol.) of N-(β,β,β-trichloroethoxycarbonyl)-2-acetoxyglycine n-butyl ester and 1.2 g. (10 mmol.) of 2,6-dimethylphenol in 20 ml. of methylene chloride containing three drops of boron trifluoride etherate was stirred at 25° for 3 hours. The reaction mixture was concentrated in vacuo, 5 ml. of 2:1 hexanemethylene chloride was added and the resulting solution was chromatographed on silica gel. Elution with 2:1 hexanemethylene chloride then with methylene chloride containing increasing amounts of ethyl acetate gave the title compound.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([N:7]=[C:8]=[O:9])=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[CH:18]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[OH:27])([CH3:20])[CH3:19]>O>[CH:18]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[O:27][C:8](=[O:9])[NH:7][C:4]1[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=1)([CH3:20])[CH3:19]
Reactant: Cc1ccc(N=C=O)cc1
Reactant: CC(C)C1CCCCC1O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(NC(=O)OC2CCCCC2C(C)C)cc1
Yield: 56.8 %

Procedure:
75.6 g (0.56 mol) of para-tolylisocyanate were placed with 500 ml toluene in a one litre vessel and subsequently 73.4 g (0.51 mol) of 2-isopropylcyclohexanol were added. The reaction mixture was heated to reflux for 6 hours. After cooling to room temperature 50 g of water were added and the mixture was refluxed for one more hour. After phase separation the solvent was stripped off and the crude product recrystallized from 235 g of n-heptane. The product (79.8 g) was obtained in form of off-white crystals in 99.2% purity. This corresponds to a theoretical yield of 56%.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]1[O:11][C:10]2[C:12]([Cl:19])=[C:13]([Cl:18])[CH:14]=[C:15]([CH:16]=[O:17])[C:9]=2[O:8][CH2:7]1)(=[O:3])[CH3:2].[Cr](O)(O)(=O)=[O:21]>CC(C)=O>[C:1]([O:4][CH2:5][CH:6]1[O:11][C:10]2[C:12]([Cl:19])=[C:13]([Cl:18])[CH:14]=[C:15]([C:16]([OH:21])=[O:17])[C:9]=2[O:8][CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1COc2c(C=O)cc(Cl)c(Cl)c2O1
Reactant: O=[Cr](=O)(O)O
Solvent: CC(C)=O
Product: CC(=O)OCC1COc2c(C(=O)O)cc(Cl)c(Cl)c2O1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 93 %

Procedure:
To a solution of 1.03 g of 2-acetoxymethyl-7,8-dichloro-1,4-benzodioxane-5-carbaldehyde (Ia-a-39) in 70 ml of acetone is added 2 ml of 8N-chromic acid/sulfric acid. The mixture is stirred at room temperature for about 2.5 hours and then filtered after the confirmation by TLC that no starting material is remained. The filtrate is concentrated under reduced pressure to give a residue, which is extracted with dichloromethane. The organic layer is washed with water and evaporated to give 1.004 g (93%) of 2-acetoxymethyl-7,8-dichloro-1,4-benzodioxane-5-carboxylic acid (Ia-a-43: R3 '=Ac), which is recrystallized from dichloromethane/ether to yield crystals, m.p. 144°-145° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[Br:25]Br.O>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]([Br:25])=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccs2)CC1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)s2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a mixture containing 4-thiazol-2-yl-piperazine-1-carboxylic acid tert-butyl ester (0.5 g, 1.9 mmol) and cesium carbonate (0.62 mmol) in chloroform (5 mL) at 0° C., bromine (110 mL) was added through a syringe. After the addition, the reaction mixture was stirred at room temperature for 1 hour. Water was added and the organic layer was collected and dried over sodium sulfate. After removal of solvent, 0.6 g of product was obtained (95% yield).