Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:19])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1.[NH2:20][C:21]1[N:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][N:30]([C:33](=[O:35])[CH3:34])[CH2:29][CH2:28]2)=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[C:33]([N:30]1[CH2:29][CH2:28][N:27]([C:24]2[CH:23]=[CH:22][C:21]([NH:20][C:16](=[O:18])[CH2:15][C:12]3[CH:11]=[CH:10][C:9]([C:7]4[CH:6]=[CH:5][N:4]=[C:3]([CH:2]([F:1])[F:19])[CH:8]=4)=[CH:14][CH:13]=3)=[N:26][CH:25]=2)[CH2:32][CH2:31]1)(=[O:35])[CH3:34]
Reactant: CC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: O=C(O)Cc1ccc(-c2ccnc(C(F)F)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(-c4ccnc(C(F)F)c4)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(4-(2-(difluoromethyl)pyridin-4-yl)phenyl)acetic acid 203-5 (30 mg, 0.11 mmol), 1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)ethanone 111-4 (28 mg, 0.13 mmol), N,N-diisopropylethylamine (99 μL, 0.57 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (65 mg, 0.17 mmol) in DMF (2 mL) was stirred at room temperature for 3 hours. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give 2 N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-(2-(difluoromethyl)pyridin-4-yl)phenyl)acetamide 201. MS m/z 418.2 (M+1); 1H NMR 400 MHz (MeOD) δ 8.61(d, 1H), 8.25(d, 1H), 7.91(d, 1H), 7.80-7.72(m, 4H), 7.49(d, 2H), 6.79(d, 1H), 6.73(t, 1H), 3.70(s, 2H), 3.66-3.58(m, 4H), 3.52-3.47(m, 2H), 3.45-3.40(m, 2H), 2.09(s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[CH3:15][CH:16]([NH2:18])[CH3:17]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:18][CH:16]([CH3:17])[CH3:15])=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: CC(C)N
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 25 °C
Yield: 95.4 %

Procedure:
A solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Preparation 5, 865 mg, 3.15 mmol) and propan-2-amine (3.725 g, 63.0 mmol) in DMF (3 mL) was heated at 120° C. for 1 h. The reaction mixture was cooled to room temperature and diluted with water. The precipitated product was filtered, washed with water and dried in vacuo to obtain the title compound as a white solid (893 mg, 95% yield). HPLC (condition B): retention time=3.28 min. LCMS MH+ m/z 297.00. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.22 (1 H, s), 7.86 (1 H, d, J=1.76 Hz), 7.02 (1 H, d, J=1.76 Hz), 4.24-4.53 (1 H, m), 1.29 (6 H, d, J=6.16 Hz).
Reaction SMILES: [Cl-:1].[Cl-].[Cl-].[CH3:4][C:5]1[C:9]([Zr+3:11])([CH3:10])[C:8]([CH3:12])=[C:7]([CH3:13])[C:6]=1[CH3:14].[CH-:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16]1.[Li+]>CCOCC>[Cl-:1].[Cl-:1].[CH3:4][C:5]1[C:9]([Zr+2:11][CH:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16]2)([CH3:10])[C:8]([CH3:12])=[C:7]([CH3:13])[C:6]=1[CH3:14]
Reactant: CC1=C(C)C(C)([Zr+3])C(C)=C1C
Reactant: c1ccc2[cH-]ccc2c1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOCC
Product: CC1=C(C)C(C)([Zr+2]C2C=Cc3ccccc32)C(C)=C1C
Reaction time: 16 h

Procedure:
To a yellow suspension of (pentamethylcyclopentadienyl)zirconium trichloride, Cp*ZrCl3, (5.00 g, 15.0 mmol, 1.00 equiv.) in ether (50 mL) was added lithium indenide (1.83 g, 15.0 mmol, 1.00 equiv.). The reaction turned slightly more manila-colored. The mixture was stirred 16 hours and then evaporated in vacuo, leaving yellow solid. The solid was extracted with dichloromethane (30 mL, then 3×5 mL) and the extracts were filtered to give light manila solid and a bright yellow solution. The solution was evaporated in vacuo, leaving yellow crystalline solid. The solid was washed with pentane (20 mL) and dried in vacuo. Yield 5.92 g (96%). 1H NMR(CD2Cl2): δ 2.03 (s, 15H, Me), 6.18 (d, 2H, Ind-H), 6.34 (t, 1H, Ind-H), 7.24 (m, 2H, Ind-H), 7.54 (m, 2H, Ind-H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([O:19]C)[CH:3]=1.[C:21]([Si:25](Cl)([CH3:27])[CH3:26])([CH3:24])([CH3:23])[CH3:22]>>[Br:1][C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:12]=[CH:13][C:14]([O:17][Si:25]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:27])[CH3:26])=[CH:15][CH:16]=3)=[N:7][C:6]=2[CH:5]=[C:4]([O:19][Si:25]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:27])[CH3:26])[CH:3]=1
Reactant: COc1ccc(-c2nc3cc(OC)cc(Br)c3o2)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2nc3cc(O[Si](C)(C)C(C)(C)C)cc(Br)c3o2)cc1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 24, Route a, Step a, from 7-bromo-5-methoxy-2-(4-methoxyphenyl)-1,3-benzoxazole, and tert-butyl(chloro)dimethylsilane. The desired product was obtained as a white solid, m.p. 90-91° C.; MS m/e 534 (M+H)+.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:27])[CH:4]([S:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]#[C:25][CH3:26])=[CH:18][CH:17]=1)=[O:15])[CH2:5][CH2:6][CH2:7][CH2:8][N:9](N)[C:10](=[O:12])[CH3:11].[N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=C(C(O)=O)[CH:29]=1>>[CH2:23]([O:22][C:19]1[CH:20]=[CH:21][C:16]([S:14]([CH:4]([C:3](=[O:27])[NH:2][OH:1])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([C:11]2[CH:29]=[N:28][C:37]3[C:32]([CH:31]=2)=[CH:33][CH:34]=[CH:35][CH:36]=3)=[O:12])=[O:15])=[CH:17][CH:18]=1)[C:24]#[C:25][CH3:26]
Reactant: O=C(O)c1cnc2ccccc2c1
Reactant: CC#CCOc1ccc(S(=O)C(CCCCN(N)C(C)=O)C(=O)NO)cc1
Product: CC#CCOc1ccc(S(=O)C(CCCCNC(=O)c2cnc3ccccc3c2)C(=O)NO)cc1

Procedure:
6-(Amino-acetylamino)-2-(4but-2-ynoxy-benzenesulfinyl)-hexanoic acid hydroxyamide resin (0.33 g, 1.1 meq/g) prepared in step B was acylated with 3-quinolinecarboxylic acid (1.2 g, 4.0 eq) according to the procedure in Example 13, Step E to give quinoline-3-carboxylic acid [5-(4-but-2-ynyloxy-benzenesulfinyl)-5-hydroxycarbamoyl-pentyl]-amide resin.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH2:15][CH2:14][NH:13][CH2:12][C:11]=2[C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24](O)(=O)[CH3:25].C(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[CH2:1]([N:8]1[C:16]2[CH2:15][CH2:14][N:13]([CH2:24][CH3:25])[CH2:12][C:11]=2[C:10]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: Clc1ccc(-c2cn(Cc3ccccc3)c3c2CNCC3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CCN1CCc2c(c(-c3ccc(Cl)cc3)cn2Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 1-benzyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine (Example 25; 0.11 g) in 1,2-dichloroethane (5 mL) was added 18 μL of acetic acid, 26 μL of acetaldehyde, and 0.10 g of NaBH(OAc)3. The mixture was stirred at RT for 15 h. The mixture was diluted with CH2Cl2 and washed with satd. aq. NaHCO3 (2×). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography on SiO2 (1% 2 M NH3 in MeOH/CH2Cl2) afforded 0.02 g of the title compound. The product was dissolved in Et2O and treated with excess 1.0 M HCl in Et2O to afford 0.02 g of the corresponding HCl salt. MS (ESI): exact mass calculated for C22H23ClN2, 350.15; found, m/z 351.2 [M+H]+, 353.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.37-7.27 (m, 7H), 7.19-7.17 (m, 3H), 5.17-5.13 (m, 2H), 4.48-4.37 (m, 2H), 3.85-3.76 (m, 2H), 3.45-3.23 (m, 2H), 3.00-2.84 (m, 2H), 1.38 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][C:7](=[O:11])[C:6]=2[CH:12]=1.Cl.[NH2:14]O.C([O-])(=O)C.[Na+].O>C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][C:7](=[O:11])[NH:14][C:6]=2[CH:12]=1
Reactant: NO
Reactant: Cc1ccc2c(c1)C(=O)CCS2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(c1)NC(=O)CCS2
Reaction time: 1 h
Yield: 23.7 %

Procedure:
6-Methyl-2,3-dihydro-4H-1-benzothiopyran-4-one (2g, 10.9 mmol) was dissolved in 80% ethanol (73 mL) and to this was added hydroxylamine hydrochloride (840 mg, 12.05 mmol) and sodium acetate (990 mg, 12.03 mmol). This mixture was heated at reflux for 3 hours. Water (150 mL) was added and then extracted with dichloromethane (3×100 mL), washed with brine (75 mL), water (75 mL), dried (sodium sulfate) and concentrated to residue. The residue was taken up in polyphosphoric acid (10 mL) and heated at reflux for 1 hour. Ice chips were added and water was added (100 mL) this was stirred for 1 hour. A solid formed and was filtered and purified by flashcolumn chromatography on 20 g of silica gel, eluting with (50%, 60%, and 70%) ethyl acetate in hexanes to give 7-methyl-2,3,4,5-tetrahydrobenzo[b]1,4-thiazepin-4-one (500 mg, 30%). 1H NMR (CDCl3, 300 MHz): δ7.87 (s-broad, 1H), 7.47 (d, 1H, J=7.7 Hz), 6.98 (d, 1H, J=8.1 Hz), 6.91 (s, 1H), 3.42 (t, 2H, J=6.9 Hz), 2.62 (t, 2H, J=6.9 Hz), 2.35 (s, 3H) ppm.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5](=[O:13])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:8]=1)[CH3:2].Br[CH2:15][CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>>[CH2:1]([C:3]1[N:4]([CH2:15][CH2:16][O:17][C:18]2[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=2)[C:5](=[O:13])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[N:8]=1)[CH3:2]
Reactant: O=Cc1ccc(OCCBr)cc1
Reactant: CCc1nc(C(F)(F)F)cc(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1nc(C(F)(F)F)cc(=O)n1CCOc1ccc(C=O)cc1
Yield: 39 %

Procedure:
The title compound (138 mg, 40%) was prepared from 2-ethyl-4-trifluoromethyl-1,6-dihydro-6-pyrimidone (200 mg, 1.04 mmol) and 4-[2-bromoethoxy]benzaldehyde (238.5 mg, 1.04 mmol) in presence of K2CO3 (287.5 mg, 2.08 mmol) as base by a similar procedure to that described in preparation 1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][CH:6]([C:12](=[O:19])[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH2:7][C:8]([O:10][CH3:11])=[O:9].[C:20]([NH:23][CH2:24][CH2:25][C:26](O)=[O:27])(=[O:22])[CH3:21].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>ClCCl>[C:20]([NH:23][CH2:24][CH2:25][C:26]([NH:1][CH2:2][CH2:3][S:4][CH2:5][CH:6]([C:12](=[O:19])[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:27])(=[O:22])[CH3:21]
Reactant: CC(=O)NCCC(=O)O
Reactant: COC(=O)CC(CSCCN)C(=O)c1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)CC(CSCCNC(=O)CCNC(C)=O)C(=O)c1cccnc1
Yield: 75 %

Procedure:
A solution of methyl 3-[(2-aminoethylthio)methyl]-4-oxo-4-(3-pyridyl)butanoate (747 mg), 3-(acetylamino)propanoic acid (302 mg), dicyclohexylcarbodiimide (433 mg), 1-hydroxybenzotriazole (567 mg) and N-methylmorpholine (402 mg) in dichloromethane (10 mL) were stirred at room temperature overnight. The solution was concentrated and purified by flash chromatography (SiO2, chloroform:methanol=9:1) to give the title compound in 75% yield; ESMS (M+1)+353.
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([CH3:15])([CH3:14])[C:7](=[O:13])[N:8]2[CH3:12])=[CH:4][CH:3]=1.[C:16](O)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1>>[F:11][C:10]1[C:2]([NH:1][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=2)=[CH:3][CH:4]=[C:5]2[C:9]=1[N:8]([CH3:12])[C:7](=[O:13])[C:6]2([CH3:15])[CH3:14]
Reactant: CN1C(=O)C(C)(C)c2ccc(N)c(F)c21
Reactant: O=C(O)c1cccnc1
Product: CN1C(=O)C(C)(C)c2ccc(NC(=O)c3cccnc3)c(F)c21

Procedure:
Prepared in analogy to example 26 from 6-amino-7-fluoro-1,3,3-trimethylindolin-2-one (example 13d) and nicotinic acid. The title compound was obtained as off-white crystals.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:23]=[C:22]([O:24][CH2:25][C:26]([O:28]C)=[O:27])[N:21]([CH3:30])[N:20]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCCC1.CO>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:23]=[C:22]([O:24][CH2:25][C:26]([OH:28])=[O:27])[N:21]([CH3:30])[N:20]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)COc1cc(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)nn1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1nc(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)cc1OCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.3 %

Procedure:
A mixture of methyl [(3-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}-1-methyl-1H-pyrazol-5-yl)oxy]acetate (0.573 g, 1.38 mmol) and 1 M sodium hydroxide solution (5 mL) in tetrahydrofuran (20 mL) and methanol (20 mL) was stirred at room temperature for 3 h. Solvent was removed and 1 M hydrochloric acid solution added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to purify the residue by HPLC (Gilson Preparative HPLC System; column: YMC Combiprep ODS-A, S-5 μm, 50×20 mm; solvent: A; water containing 0.1% TFA, B; acetonitrile containing 0.1% TFA; gradient cycle: 0.00 min (A/B=90/10), 1.00 min (A/B=90/10), 4.20 min (A/B=10/90), 5.40 min (A/B=10/90), 5.50 min (A/B=90/10), 5.60 min (A/B=90/10); flow rate: 25 mL/min; detect: UV 220 nm). Solvent was removed to afford a solid (0.3 g, 54%).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[CH:3]1[C:9](N)=[O:10].[OH-:13].[Na+].Cl>CO>[CH3:1][C:2]1([CH3:12])[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[CH:3]1[C:9]([OH:13])=[O:10]
Reactant: CC1(C)CCC(C)(C)C1C(N)=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC1(C)CCC(C)(C)C1C(=O)O
Temperature: 80 °C
Yield: 94 %

Procedure:
3.38 g of (2,2,5,5-tetramethylcyclopentane-1-yl)carboxamide was dissolved in 30 ml of methanol, and 15 ml of an aqueous 3N sodium hydroxide solution was added thereto. Then, the mixture was heated at 80° C. for 5 hours. After cooling, 40 ml of 2N hydrochloric acid was added thereto, and the mixture was extracted with 100 ml and 50 ml of ethyl acetate. The organic layers were combined, washed with 100 ml of water and 50 ml of aqueous saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. After removal of magnesium sulfate by filtration, the filtrate was concentrated under reduced pressure, whereby 3.20 g of 2,2,5,5-tetramethylcyclopentanecarboxylic acid was obtained. Yield 94%. (m.p. 113.6° C.)
Reaction SMILES: I[C:2]1[CH:33]=[CH:32][CH:31]=[CH:30][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:19](=[O:20])[CH2:18][C:17](=[O:21])[NH:16][C:15]3[C:22]4[C:27]([CH:28]=[CH:29][C:14]2=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:9][CH:8]=1)=[O:5].[CH2:34]([Sn](CCCC)(CCCC)CCCC)[CH:35]=[CH2:36].C(#N)C>C1(C)C=CC=CC=1>[CH:34]([C:2]1[CH:33]=[CH:32][CH:31]=[CH:30][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:19](=[O:20])[CH2:18][C:17](=[O:21])[NH:16][C:15]3[C:22]4[C:27]([CH:28]=[CH:29][C:14]2=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:9][CH:8]=1)=[O:5])=[CH:35][CH3:36]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: O=C1CC(=O)N(c2ccc(NC(=O)c3ccccc3I)cc2)c2ccc3ccccc3c2N1
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CC=Cc1ccccc1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Temperature: 110 °C
Reaction time: 16 h
Yield: 67.7 %

Procedure:
5-[4-(2-Iodobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (70 mg, 0.128 mmol), allyltributyltin (98 mg, 0.32 mmol), and tetrakistriphenylphosphine palladium(0) (15 mg, 12.8 μmol) were dissolved in anhydrous toluene (0.6 mL), and the solution was stirred at 110° C. for 16 hours. The reaction mixture was left to cool, and then added with acetonitrile, the mixture was washed with petroleum ether, and the solvent of the acetonitrile layer was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=100/1) to obtain the title compound (40 mg, yield 68%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[NH2:11][C:12]1[C:13]([F:43])=[CH:14][C:15]([F:42])=[C:16]([C:18]2[C:19](=[O:41])[N:20]([CH2:39][CH3:40])[C:21]3[C:26]([CH:27]=2)=[CH:25][N:24]=[C:23]([N:28]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[CH3:29])[CH:22]=3)[CH:17]=1.[N-]=C=O>C1COCC1.CCOC(C)=O>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:28]([CH3:29])[C:23]2[CH:22]=[C:21]3[C:26]([CH:27]=[C:18]([C:16]4[C:15]([F:42])=[CH:14][C:13]([F:43])=[C:12]([NH:11][C:9]([NH:8][C:4]5[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=5)=[O:10])[CH:17]=4)[C:19](=[O:41])[N:20]3[CH2:39][CH3:40])=[CH:25][N:24]=2)=[CH:36][CH:35]=1
Reactant: O=C=Nc1cccc(F)c1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2F)cc2cnc(N(C)Cc3ccc(OC)cc3)cc21
Agent: [N-]=C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3cccc(F)c3)c(F)cc2F)cc2cnc(N(C)Cc3ccc(OC)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
3-Fluorophenyl isocyanate (81 mg, 0.444 mmol) was added to a solution of Example A7 (200 mg, 0.444 mmol) in THF (5 mL) and the mixture was stirred at RT overnight. The reaction was treated with additional isocyanate (10 mg) and stirred at RT for a further 4 h. The mixture was diluted with EtOAc, washed successively with water, satd. NaHCO3, and brine, dried (Na2SO4), concentrated in vacuo, purified by reverse phase chromatography (MeCN/water with 0.1% TFA) and partially concentrated to give an aqueous solution. The solution was diluted with satd. NaHCO3, extracted with EtOAc (2×) and the combined organics were washed with brine, dried (Na2SO4) and evaporated at reduced pressure to give 1-(5-(7-((4-methoxybenzyl)(methyl)amino)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-(3-fluorophenyl)urea (207 mg, 79% yield, ˜75% pure) as a light yellow solid, which was used without further purification. MS (ES-API) m/z: 588.2 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([CH2:17][NH:18][NH:19][C:20]([C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)=[O:21])[CH:11]=[CH:10]2)[CH2:4][CH3:5])[CH3:2].S(Cl)([Cl:33])=O>CN(C)C=O.C(OCC)C>[CH2:1]([N:3]([CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([CH2:17][NH:18][NH:19][C:20]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([Cl:33])=[O:27])=[CH:24][CH:23]=1)=[O:21])[CH:11]=[CH:10]2)[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)Cc1ccc2cc(CNNC(=O)c3ccc(C(=O)O)cc3)ccc2c1
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCN(CC)Cc1ccc2cc(CNNC(=O)c3ccc(C(=O)Cl)cc3)ccc2c1
Yield: 99.3 %

Procedure:
A solution of 4-[6-(diethylaminomethyl)naphth-2-ylmethylaminocarbamoyl]benzoic acid (3.1 g, 7.6 mmol) and thionyl chloride (1.1 ml, 15.2 mmol) in dimethylformamide (30 ml) was stirred overnight at room temperature, then the suspension was diluted with diethyl ether and the solid was filtered and dried yielding 3.2 g of crude 4-[6-(diethylaminomethyl)naphth-2-ylmethylaminocarbamoyl]benzoyl chloride. This compound was added as solid to a solution of hydroxylamine hydrochloride (0.6 g, 8.5 mmol) and sodium bicarbonate (1.2 g, 14 mmol) and 1N sodium hydroxide (8.5 ml, 8.5 mmol) in water (30 ml) and THF (40 ml). The mixture was stirred at room temperature for 2 hours, then the mixture was saturated with sodium chloride and the organic phase was separated and the aqueous phase was extracted with THF. The combined organic phases were dried foyer anhydrous sodium sulphate and the solvent was removed under reduced pressure. Crude was dissolved in hot THF (150 ml) and the insoluble material was filtered off. The solution was cooled at room temperature and treated with 1.5 N etheric solution of HCl. The solid product was filtered and dried yielding 1.2 g (yield 38%) of pure 4-[6-(diethylaminomethyl)naphth-2-ylmethylaminocarbamoyl]-benzohydroxamic acid hydrochloride as white solid; m.p.=167-168° C. (dec.)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8]([OH:11])(=O)=[O:9])[CH:5]=[N:6][CH:7]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:13].P(Cl)(Cl)(Cl)=O.C([O-])(O)=O.[Na+].[Na+].[Cl-]>C(OC)(C)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([Cl:13])(=[O:11])=[O:9])[CH:5]=[N:6][CH:7]=1
Reactant: O=S(=O)(O)c1cncc(Br)c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O=P(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1cncc(Br)c1
Temperature: 0 °C
Yield: 98.4 %

Procedure:
A mixture of 5-bromo-pyridine-3-sulfonic acid (Example B.2 step 1) (7.14 g, 30 mmol), phosphorus pentachloride (9.68 g, 47 mmol) and phosphorus oxychloride (20 mL) was heated to reflux for 4 h (according to J. Org. Chem. 1989, 54(2), 389). The reaction mixture was concentrated to dryness to give a yellow semisolid, dissolved in ice water and tert-butyl-methyl-ether, and cautiously added sat. NaHCO3-sol. until neutralized, saturated with solid NaCl, separated phases, dried organic layer over Na2SO4. Removal of the solvent in vacuum gave the title compound as a yellow solid (7.57 g, 98%). MS (EI) 254.9 [(M)+], 256.9 [(M+2)+] and 258.9 [(M+4)+]; mp 64° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[CH:17]=[CH2:18].O>CC(C)=O>[CH2:18]([O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[Br:1])[CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: Oc1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C=CCOc1ccc(F)cc1Br
Yield: 100 %

Procedure:
To a mixture of 2-bromo-4-fluorophenol (9.75 g, 0.051 mol) and potassium carbonate (7.76 g, 0.056 mol) in acetone (125 mL) was added allyl bromide (4.64 mL, 0.054 mol) and the reaction mixture heated to reflux for 3.5 hours. The cooled reaction mixture was then poured into water and the resulting oily suspension extracted with dichloromethane (2×500 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford 11.79 g (100%) of 1-(allyloxy)-2-bromo-4-fluorobenzene as a yellow oil. MS (ESI) m/z 229.9 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=O)=[CH:5][CH:4]=1.[NH2:21][CH2:22][C:23]([OH:25])=[O:24]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:21]([CH2:22][C:23]([OH:25])=[O:24])[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: NCC(=O)O
Reactant: COc1ccc(C(=O)CCC(=O)c2ccccc2)cc1
Solvent: CC(=O)O
Product: COc1ccc(-c2ccc(-c3ccccc3)n2CC(=O)O)cc1
Temperature: 100 °C

Procedure:
A mixture of 1-(4-methoxy-phenyl)-4-phenyl-butane-1,4-dione (2.90 g, 10.8 mmol) and glycine 4 (1.62 g, 21.6 mmol) in 100 mL of glacial acetic acid is heated at 100° C. The reaction is monitored by TLC, when the starting material is consumed, the mixture is washed with 5% H2SO4 (200 mL) and then extracted with ethyl acetate (2×200 mL). The organics are combined, dried over sodium sulfate, filtered and concentrated to yield [2-(4-Methoxy-phenyl)-5-phenyl-pyrrol-1-yl]-acetic acid as a green solid (3.40 g, crude), characterized by LCMS (Obs: 308.54, Cal: 307.34).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1>CN(C=O)C.CCOCC>[C:14]([Si:11]([CH3:13])([CH3:12])[O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2)([CH3:17])([CH3:16])[CH3:15]
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
A suspension of 5-hydroxy-indol (5 g, 38 mmol), tert-butyldimethylsilyl chloride (6.1 g, 39.4 mmol) and imidazole (5.4 g, 68 mmol) in DMF (50 ml) was stirred for 20 h at RT. The reaction mixture was taken up in ether and washed with 1N HCl and water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give 9.4 g (38 mmol, quant.) 5-(tert-butyl-dimethyl-silanyloxy)-1H-indole.