Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[F:40][C:41]([F:53])([F:52])[O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1B(O)O>>[NH2:32][C:4]1[S:3][C:2]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[O:42][C:41]([F:40])([F:53])[F:52])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Reactant: OB(O)c1ccccc1OC(F)(F)F
Product: Cn1ncc(NC(=O)c2nc(-c3ccccc3OC(F)(F)F)sc2N)c1[C@@H]1CC[C@@H](N)[C@@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 88), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-(trifluoromethoxy)phenyl)boronic acid gave 266. 1H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 8.28-8.20 (m, 1H), 7.78 (s, 1H), 7.57-7.43 (m, 6H), 5.00-4.77 (m, 2H), 4.22-4.06 (m, 1H), 4.06-3.92 (m, 1H), 3.75 (s, 3H), 3.29-3.21 (m, 1H), 2.18-2.09 (m, 1H), 1.95-1.54 (m, 5H). LCMS (ES+) m/z 515 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([I:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl>[CH2:15]([NH:22][C:2]1[C:11]2[C:6](=[CH:7][C:8]([I:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[CH:4][N:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: COc1cc2c(Cl)nccc2cc1I
Solvent: ClCCl
Product: COc1cc2c(NCc3ccccc3)nccc2cc1I
Temperature: 140 °C
Reaction time: 8 h

Procedure:
2.82 g (8.86 mmol) of 1-chloro-6-iodo-7-methoxyisoquinoline was added to 15 ml of benzylamine, and they were stirred at 140° C. overnight. After the treatment with dichloromethane as the extraction solvent in an ordinary manner, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Br:9])[CH:3]=1.[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOCC.C(N(CC)CC)C>[Br:9][C:4]1[CH:3]=[C:2]([CH:12]=[CH:11][C:10]([O:14][CH3:15])=[O:13])[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: Fc1cc(Br)cc(Br)c1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)C=Cc1cc(F)cc(Br)c1

Procedure:
A mixture of 5.1 g (0.02 mol) of 1,3-dibromo-5- fluorobenzene (prepared according to A. Cannoni de Degiorgi and E. V. Zappi, Anales asoc. quim. argentina, 1940, 28, 72) (C. A. 34 65933), 2.2 ml (0.025 mol) of methyl acrylate, 10 ml of triethylamine, 0.044 g (0.002 mol) of palladium acetate and 0.208 g (0.0008 mol) of triphenylphosphine is heated for 24 h at 100° C. in a closed vessel with magnetic stirring. Cooling, pouring into 1N HCl, extraction with ether, washing with water, drying over Na2SO4, filtration and evaporation under vacuum are carried out. The residue is purified by chromatography on silica (eluent: 2/1 hexane/ethyl acetate). Yd.: 2.7 g (51%) M.p.=95°-6° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9](C1C=CC=CC=1O)([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[C:10]([F:13])([F:12])[F:11]>>[CH3:8][C:9]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)([C:4]1[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=1)[C:10]([F:11])([F:12])[F:13]
Reactant: CC(c1ccc(O)cc1)(c1ccccc1O)C(F)(F)F
Reactant: Oc1ccccc1
Product: CC(c1ccc(O)cc1)(c1ccc(O)cc1)C(F)(F)F

Procedure:
Repeating the process of Example 5 using 470 g (5 moles) of phenol in place of the xylenol, yielded a reaction mixture consisting of 66% of 4,4-(1-methyltrifluoroethylidene)bisphenol and 34% of 2,4'-(1-methyltrifluoroethylidene)bisphenol. After the removal of excess phenol by distillation, the mixture of the two isomers was readily separated by elution chromatography over silica, using methylene chloride as eluant. After the emergence of the 2,4'-isomer, the 4,4'-isomer was eluted. The 4,4'-isomer crystallized out readily from the concentrated solution in the form of white crystals which melted at 93°-94.5° C. and had a purity of 98.2%.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21](O)=[O:22])[N:4]=1)#[N:2].C(N1CCOCC1)C.[NH2:32][C:33]([CH3:41])([CH3:40])[CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21]([NH:32][C:33]([CH3:41])([CH3:40])[CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[O:22])[N:4]=1)#[N:2]
Reactant: N#Cc1nc(C(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Reactant: COC(=O)CCC(C)(C)N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COC(=O)CCC(C)(C)NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1-Cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid (47 mg, 0.15 mmol), N-ethylmorpholine (27 μL, 0.21 mmol), methyl 4-amino-4-methylpentanoate (crude as its acetic acid salt, 41 mg, 0.20 mmol), DCC (41 mg, 0.20 mmol) and HOBT (56 mg, 0.41 mmol) were suspended in CH2Cl2 (1 mL). The resulting mixture was stirred at room temperature for 20 hours. The reaction crude was filtered through a pad of celite and the filtrate was washed with sat'd NaHCO3 solution and H2O. The organic layer was dried over MgSO4, concentrated, and purified by flash chromatography (0-40% EtOAc/hexanes) to give the title compound in 12 mg. MS: (−) m/z 432.22 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[NH2:8].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[O:19])=[CH:13][C:12]=1[C:20]([F:23])([F:22])[F:21].O>ClCCl>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:8][C:7]2[CH:6]=[CH:5][C:4]([OH:9])=[CH:3][C:2]=2[F:1])=[O:19])=[CH:13][C:12]=1[C:20]([F:21])([F:22])[F:23]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1ccc(O)cc1F
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Nc1ccc(O)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.6 %

Procedure:
At room temperature, 3-fluoro-4-amino-phenol (500 mg, 3.93 mmol, 1 eq) was dissolved in N,N-dimethylformide (3 mL). A solution of 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene (917 mg, 4.13 mmol, 1.05 eq) in dichloromethane (3 mL) was added dropwise. The resulted mixture was stirred at room temperature for 16 h. The mixture was added with water (10 mL) and extracted with ethyl acetate (20 mL). The organic phase was washed with saturated brine (10 mL×3), and dried over anhydrous sodium sulfate. The solvent in the organic phase was removed under reduced pressure, and the resulted solid was refluxed in petroleum ether (15 mL) and ethyl acetate (5 mL) for 2 h. The mixture was cooled to room temperature and filtered to give title compound (1.2 g, purity 98%, yield 89%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:18]2[C:6](=[C:7]([CH3:21])[C:8]3[NH:9][C:10]4[CH:11]=[CH:12][C:13]([O:19]C)=[CH:14][C:15]=4[C:16]=3[CH:17]=2)[CH:5]=[CH:4][N:3]=1.Cl>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Cl:1][C:2]1[C:18]2[C:6](=[C:7]([CH3:21])[C:8]3[NH:9][C:10]4[CH:11]=[CH:12][C:13]([OH:19])=[CH:14][C:15]=4[C:16]=3[CH:17]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc2[nH]c3c(C)c4ccnc(Cl)c4cc3c2c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Product: Cc1c2ccnc(Cl)c2cc2c1[nH]c1ccc(O)cc12
Temperature: 140 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
In a 5 ml sealed tube, a mixture of 1-chloro-9-methoxy-5-methyl-6H-pyrido[4,3-b]carbazole (75 mg, 0.25 mMol) (prepared according to J. Chem. Soc. Perkin Trans. 1, 1979, 1706), benzyltriethylammonium chloride (225 mg, 1 mMol) and 37% hydrochloric acid (4 ml) is heated in an oil bath at 140° C. for 24 h. The reaction mixture is then evaporated, under vacuum, then 20 ml of water are added. The medium is then rendered basic by addition of 28% ammonium hydroxide (0.5 ml), and the solid is recovered by low-temperature filtration, then washed with water and dried using a vacuum desiccator, at a temperature of 200° C. for 18 h. 65 mg (90% yield) of Compound 10 are then obtained, the proton NMR spectrum of which is the following:
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[C-:9]#[N:10].[Na+]>CS(C)=O>[N:4]1[CH:5]=[CH:6][CH:7]=[N:8][C:3]=1[CH2:2][C:9]#[N:10]
Reactant: [C-]#N
Reactant: ClCc1ncccn1
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1ncccn1
Temperature: 50 °C

Procedure:
A solution of 6.8 g. of 2-(chloromethyl)pyrimidine is added dropwise to a solution of 5.2 g. of sodium cyanide in 100 ml. of dimethylsulfoxide. The mixture is heated at 50° C. for 2 hours, then diluted with 150 ml. of 5% aqueous sodium carbonate solution and extracted with ether. The extract is dried and concentrated to give 2-(2-pyrimidyl)acetonitrile.
Reaction SMILES: C(#N)CC.[NH2:5][C:6]1[N:13]=[CH:12][C:11](Br)=[CH:10][C:7]=1[C:8]#[N:9].[CH3:15][N:16]([CH2:21][C:22]1[N:23]([CH3:31])[C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:17](=[O:20])[CH:18]=[CH2:19].C(N(C(C)C)CC)(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[ClH:63]>CC([O-])=O.CC([O-])=O.[Pd+2]>[ClH:63].[NH2:5][C:6]1[N:13]=[CH:12][C:11](/[CH:19]=[CH:18]/[C:17]([N:16]([CH3:15])[CH2:21][C:22]2[N:23]([CH3:31])[C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:20])=[CH:10][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1cc(Br)cnc1N
Reactant: C=CC(=O)N(C)Cc1cc2ccccc2n1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1cnc(N)c(C#N)c1
Temperature: 100 °C
Reaction time: 6 h
Yield: 43 %

Procedure:
A propionitrile (15 mL) solution of 2-amino-5-bromo-nicotinonitrile (198 mg, 1 mmol), N-methyl-N-(1-methyl-1H-indol-2-ylmethyl)-acrylamide (457 mg, 2 mmol) and diisopropyl-ethylamine (523 μL, 3 mmol) was purged with Argon for 10 min. Pd(OAc)2 (23 mg, 0.1 mmol) and P(o-Tol)3 (61 mg, 0.2 mmol) was added and the Argon purge was repeated. The mixture was heated to 100° C. and stirred for 6 hr under Argon. Upon cooling, solvents were removed under vacuo and the residue was purified by Flash chromatography (silica, 2% MeOH in CH2Cl2). The purified free base was converted to its HCl salt by addition of HCl (1 mL, 1 mmol, 1M in ether). The salt was washed with ether and dried to afford 162 mg (43%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.50 (m, 2H), 7.55-6.95 (m, 4H), 6.40 and 6.17 (rotamers, 2s, 1H), 5.03 and 4.83 (rotamers, 2s, 2H), 3.71 and 3.67 (rotamers, 2s, 3H), 3.09 and 2.96 (rotamers, 2s, 3H). MS (ESI) m/e: 346.1662 (M+H)+.
Reaction SMILES: Cl.[NH:2]([C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:18]3C(=O)C4=CC=CC=C4C3=O)[CH:12]=2)[N:10]=1)[C:3]([NH2:5])=[NH:4].Cl>O.C(O)C.[OH-].[Na+]>[NH:2]([C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH2:18])[CH:12]=2)[N:10]=1)[C:3]([NH2:5])=[NH:4]
Reactant: N=C(N)Nc1nc(-c2cccc(CN3C(=O)c4ccccc4C3=O)c2)cs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N=C(N)Nc1nc(-c2cccc(CN)c2)cs1
Yield: 35.9 %

Procedure:
A mixture of 2-guanidino-4-(3-phthalimidomethylphenyl)thiazole hydrochloride (0.7 g.) in water (30 ml.) and ethanol (30 ml.) and sufficient aqueous sodium hydroxide to give pH 12 was heated under reflux for 30 minutes. The pH was adjusted to approximately 3 with concentrated hydrochloric acid and the mixture heated under reflux for a further 30 minutes. The pH was then adjusted to 12 with dilute sodium hydroxide solution and the mixture extracted with ethyl acetate (50 ml.). This extract was evaporated to dryness to give 2-guanidino-4-(3-aminomethylphenyl)thiazole (0.15 g.), m.p. 155°-160° C. (decomp.).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([O:24][CH2:25][CH2:26][CH3:27])[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([O:24][CH2:25][CH2:26][CH3:27])[CH:17]=1
Reactant: CCCOc1cc(Cl)ccc1CO
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: CCCOc1cc(Cl)ccc1COc1ccnn1-c1cc(C#N)ccn1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-chloro-2-propoxyphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 1.01 (3H, t, J=7.2 Hz), 1.77-1.86 (2H, m), 3.98 (2H, t, J=2.4 Hz), 5.24 (2H, s), 5.78 (1H, d, J=1.6 Hz), 6.90 (1H, d, J=1.6 Hz), 6.95 (1H, dd, J=2.0 Hz, 8.4 Hz), 7.34 (1H, d, J=8.4 Hz), 7.39 (1H, dd, J=0.8 Hz, 4.8 Hz), 7.58 (1H, d, J=1.6 Hz), 8.05 (1H, d, s), 8.70 (1H, d, J=4.8 Hz). [M+H] Calc'd for C19H17ClN4O2, 369; Found, 369.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH2:3][CH2:2]1.Cl[C:17]1[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19][N:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][N:12]([C:17]3[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19][N:18]=3)[C:11]2=[O:15])[CH2:3][CH2:2]1
Reactant: O=C1NCCN1c1cnccc1C1CC1
Reactant: Cc1cc(Cl)ncn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCN(c3cnccc3C3CC3)C2=O)ncn1
Yield: 20.6 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 11 above, 1-(4-cyclopropylpyridin-3-yl)imidazolidin-2-one (I-1d: 100 mg, 0.492 mmol) was reacted with 4-chloro-6-methylpyrimidine (73 mg, 0.541 mmol), 2-dicyclohexyl-phosphino-2′,4′,6′-triisopropylbiphenyl (23 mg, 0.0492 mmol), Pd2(dba)3 (23 mg, 0.024 mmol), cesium carbonate (400 mg, 1.23 mmol) and toluene (10 mL) in seal tube at 115° C. for 14 hours. Purification by column chromatography on silica gel (2% methanol in chloroform) afforded 30 mg of the product (21.1% yield).
Reaction SMILES: [CH2:1]([C:4]1([S:7]([NH:10][C:11]2[C:16]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=3[F:25])=[C:15]([CH3:26])[C:14](=[O:27])[N:13]([CH3:28])[CH:12]=2)(=[O:9])=[O:8])[CH2:6][CH2:5]1)[CH:2]=C.I([O-])(=O)(=O)=[O:30].[Na+].N1C(C)=CC=CC=1C>O1CCOCC1.O.C(Cl)Cl.[Os](=O)(=O)(=O)=O>[F:25][C:19]1[CH:20]=[C:21]([I:24])[CH:22]=[CH:23][C:18]=1[NH:17][C:16]1[C:11]([NH:10][S:7]([C:4]2([CH2:1][CH:2]=[O:30])[CH2:5][CH2:6]2)(=[O:9])=[O:8])=[CH:12][N:13]([CH3:28])[C:14](=[O:27])[C:15]=1[CH3:26]
Reactant: C=CCC1(S(=O)(=O)Nc2cn(C)c(=O)c(C)c2Nc2ccc(I)cc2F)CC1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2(CC=O)CC2)cn(C)c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-allyl-N-(4-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)cyclopropane-1-sulfonamide (98 mg, 0.19 mmol) in a mixture of dioxane (3 mL) and H2O (1 mL) is added sodium periodate (158 mg, 0.74 mmol), 2,6-lutidine (0.043 mL, 0.37 mmol) and osmium tetraoxide (0.060 mL, 4% in H2O, 0.0093 mmol). The reaction mixture is stirred at room temperature for 4 h. The solution is diluted with CH2Cl2 (20 mL), washed with aqueous HCl (20 mL, 2N), dried over MgSO4 and concentrated to give N-(4-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-oxoethyl)cyclopropane-1-sulfonamide, which is used for the next step without any purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:24])[CH2:15][C@H:16]3[O:20]C(C)(C)[O:18][C:17]3=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:25][OH:26]>CC(O)C.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:24])[CH2:15][C@@H:16]([OH:20])[C:17]([NH:25][OH:26])=[O:18])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC1(C)OC(=O)[C@@H](CC(=O)N2CCN(c3ccc(F)cc3)CC2)O1
Reactant: NO
Solvent: C1CCOC1
Solvent: CC(C)O
Product: O=C(NO)[C@H](O)CC(=O)N1CCN(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.3 %

Procedure:
To a solution of (5R)-5-{2-[4-(4-fluorophenyl)-1-piperazinyl]-2-oxoethyl}-2,2-dimethyl-1,3-dioxolan-4-one (336 mg; 1.0 mmol; 1.0 eq.) in i-PrOH/THF (25/75) (5 mL) wad added an aqueous solution of hydroxylamine (50%, 0.295 mL; 5.0 mmol; 5.0 eq.). After stirring 3 h at RT, the solvents were evaporated to give a solid. This solid was crystallized from AcOEt (by addition of Et2O and c-Hex) to give the title compound as a white powder (250 mg, 80%). M+(ESI): 312.1; M−(ESI): 310.1. 1H NMR (DMSO-d6, 300 MHz) δ 10.50 (s, 1H), 8.72 (s, 1H), 7.12-6.91 (m, 4H), 5.46 (d, J=3.0 Hz, 1H), 4.28 (q, J=6.3 Hz, 1H), 3.60 (s, 4H), 3.14-2.95 (m, 4H), 2.65 (d, J=6.3 Hz, 2H). HPLC (Condition A): Rt: 1.6 min (HPLC purity: 85.6%).
Reaction SMILES: [CH2:1]([C:8]1[O:12][C:11]([C@H:13]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:14][N:15]([O:18]CC2C=CC=CC=2)[CH:16]=[O:17])=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd]>[CH2:1]([C:8]1[O:12][C:11]([C@H:13]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:14][N:15]([OH:18])[CH:16]=[O:17])=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC[C@H](CN(C=O)OCc1ccccc1)c1nnc(Cc2ccccc2)o1
Agent: [Pd]
Product: CCCCC[C@H](CN(O)C=O)c1nnc(Cc2ccccc2)o1
Reaction time: 5.5 h
Yield: 35.7 %

Procedure:
A mixture consisting of N-[(R)-2-(5-benzyl-[1,3,4]oxadiazol-2-yl)-heptyl]-N-benzyloxy formamide (108 mg crude) with 10% palladium on carbon was stirred under an atmosphere of hydrogen for 5.5 h. The mixture was filtered and solvent removed in vacuo. Purification by preparative HPLC provided the title compound (30 mg, 38% for two steps). Mass spectrum ES+: 318 [M+H]+
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[CH:9][Se:10](=[O:11])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[OH-].[Na+].[BH4-].[Na+].Cl>>[OH:3][CH:1]([C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[CH:9][Se:10](=[O:11])[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)[Se](=O)C=N2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: CC(O)c1ccc2c(c1)[Se](=O)C=N2

Procedure:
1.2 g (0.005 mol) of 6-acetylbenzoselenazolinone are introduced together with 7.5 cm3 of 3% sodium hydroxide into a ground-necked round-bottom flask cooled in an ice bath. 0.38 g (0.001 mol) of sodium borohydride is then added slowly and with stirring. The solution is stirred at room temperature for 15 hours an the acidified with aqueous hydrochloric acid solution diluted 4-fold. The precipitate obtained is drained, washed with water and then recrystallized in a mixture of cyclohexane (1/3) and ethyl acetate (2/3).
Reaction SMILES: [H-].[Na+].C([O:10][C:11](=O)[NH:12][C@@H:13]([C@@H:27]([F:30])[CH2:28][CH3:29])[CH2:14][NH:15][C:16]1[C:21]([F:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][N:17]=1)C1C=CC=CC=1.O>C1COCC1>[F:30][C@H:27]([C@H:13]1[CH2:14][N:15]([C:16]2[C:21]([F:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][N:17]=2)[C:11](=[O:10])[NH:12]1)[CH2:28][CH3:29]
Reactant: CC[C@H](F)[C@@H](CNc1ncc(C(F)(F)F)cc1F)NC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC[C@H](F)[C@H]1CN(c2ncc(C(F)(F)F)cc2F)C(=O)N1
Temperature: 25 °C
Reaction time: 6 h
Yield: 98 %

Procedure:
Sodium hydride (about 60%, 546 mg) was added to a solution of benzyl[(2R,3S)-3-fluoro-1-{[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]amino}pentan-2-yl]carbamate (2.85 g) in THF (35 mL), and the mixture was stirred at room temperature for 6 hr. Water was added to the reaction mixture, the resulting mixture was extracted with ethyl acetate, and the organic layer was washed with brine. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, hexane/ethyl acetate=80:20-40:60) to afford the title compound (2.07 g).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[B](F)F.[CH:11]1([N:14]2[C:23]3[C:18](=[CH:19][C:20]([F:29])=[C:21](F)[C:22]=3[O:24][CH:25]([F:27])[F:26])[C:17](=[O:30])[C:16]([C:31]([OH:33])=[O:32])=[CH:15]2)[CH2:13][CH2:12]1.O>CS(C)=O>[CH:11]1([N:14]2[C:23]3[C:18](=[CH:19][C:20]([F:29])=[C:21]([N:6]4[CH2:5][CH2:4][NH:3][CH:2]([CH3:1])[CH2:7]4)[C:22]=3[O:24][CH:25]([F:26])[F:27])[C:17](=[O:30])[C:16]([C:31]([OH:33])=[O:32])=[CH:15]2)[CH2:12][CH2:13]1
Reactant: CC1CNCCN1
Reactant: O=C(O)c1cn(C2CC2)c2c(OC(F)F)c(F)c(F)cc2c1=O
Agent: F[B]F
Solvent: CS(C)=O
Solvent: O
Product: CC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2OC(F)F)CCN1
Reaction time: 8 h
Yield: 82.2 %

Procedure:
1.63 g (0.016 moles) of 2-methylpiperazine was added to a solution of 2.58 g (0.0068 mole) of 1-cyclopropyl-8-difluoromethoxy-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid boron difluoride chelate (prepared as described in Preparation 8) in 20 ml of dimethyl sulfoxide, and the mixture was allowed to stand at room temperature overnight. The reaction mixture was then poured into 100 ml of water, and the crystals which precipitated were collected by filtration and washed with water. The crystals were then dissolved in 500 ml of 80% v/v aqueous methanol containing 15 ml of triethylamine, and the solution was heated under reflux for 3 hours. At the end of this time, the solvent was removed by evaporation under reduced pressure, and the residue was washed with ethanol, to give 2.30 g of a pale yellow powder. The whole of this powder was dissolved in 50 ml of water, insoluble materials were removed by filtration, and the filtrate was adjusted to a pH value of 7.5 by the addition of a 1N aqueous solution of sodium hydroxide. The crystals which precipitated were collected by filtration and washed with water and with ethanol, in that order, to give 1.74 g of the title compound as fine pale yellow needles, melting at 223°-225° C.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[Cl:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[CH:15]=[N:14][CH:13]=[CH:12][C:11]=3[C:10](=O)[C:9]=2[C:8](F)=[CH:7][CH:6]=1>N1C=CC=CC=1>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[N:2]([CH3:1])[N:3]=[C:10]3[C:11]4[CH:12]=[CH:13][N:14]=[CH:15][C:16]=4[C:17](=[O:19])[C:18]=1[C:9]=23
Reactant: O=C1c2ccncc2C(=O)c2c(Cl)ccc(F)c21
Reactant: CNN
Solvent: c1ccncc1
Product: Cn1nc2c3c(c(Cl)ccc31)C(=O)c1cnccc1-2
Reaction time: 0.1 h
Yield: 71 %

Procedure:
A solution of methyl hydrazine (0.76M; 0.021 g) in pyridine (0.6 mL) is added dropwise over two min to a stirred solution of 9-chloro-6-fluoro benzo[g]isoquinoline-5,10-dione of Preparative Example 20 in pyridine (0.5 mL) cooled with an ice-bath. A yellow precipitate appears in the dark solution after 6 min. After 1.3 h the reaction mixture is reduced to half its volume by a gentle stream of nitrogen and quenched with ice (5 g). The pale yellow precipitate is collected by suction filtration and washed with ice-water (2×1 mL) and dried under vacuum. The yellow solid is purified by silica gel column chromatography (eluant: chloroform/methanol 96/4 v/v) to yield 5-chloro-2-methylisoquino[5,6,7-cd]indazole-6(2H)-one (0.033 g; 71% yield) as a yellow solid.