Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([S:15][C:16]4[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=4[C:18](O)=[O:19])=[N:11][N:10]3[CH:25]=2)=[O:5])[CH2:3][CH2:2]1.CN.O1CCCC1.F[P-](F)(F)(F)(F)F.[N:40]1(OC(N(C)C)=[N+](C)C)[C:44]2N=CC=CC=2N=N1>CN(C)C=O>[CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([S:15][C:16]4[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=4[C:18]([NH:40][CH3:44])=[O:19])=[N:11][N:10]3[CH:25]=2)=[O:5])[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccccc1Sc1ccc2nc(NC(=O)C3CC3)cn2n1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)c1ccccc1Sc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 35 %

Procedure:
A mixture of 2-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}thio)benzoic acid (120 mg, 0.35 mmol), a solution of methylamine in tetrahydrofuran (2M, 1 mL, 2.0 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (200 mg, 0.53 mmol) and N,N-dimethylformamide (4 mL) was stirred at room temperature for 5 hr. The mixture was evaporated under reduced pressure, ethyl acetate/tetrahydrofuran and water were added to the residue, and the aqueous layer was extracted with ethyl acetate/tetrahydrofuran (×4). Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=40/60→90/10) to give the title compound (45 mg, 41%) as a pale-yellow solid.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:54])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH2:52][CH3:53])[CH2:45]2)[CH:7]([CH3:55])[CH2:6][CH2:5][C:4]1=[O:56])[CH3:2].C(N(C(C)C)CC)(C)C.[N+:66]([C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][C:70]=1[S:75](Cl)(=[O:77])=[O:76])([O-:68])=[O:67]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:54])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][S:75]([C:70]3[CH:71]=[CH:72][CH:73]=[CH:74][C:69]=3[N+:66]([O-:68])=[O:67])(=[O:76])=[O:77])[CH:46]([O:51][CH2:52][CH3:53])[CH2:45]2)[CH:7]([CH3:55])[CH2:6][CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1O
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1OS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-ethoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (200 mg, Example 46) in dry methylene chloride (2 ml) is added diisopropylethylamine (150 μl) followed by 2-nitrobenzenesulonyl chloride (60 mg), then 4-dimethylaminopyridine (27 mg). The yellow solution is stirred at room temperature under nitrogen atmosphere for 4 h, then quenched with sat'd aqueous sodium bicarbonate solution. The organic layer is washed (water, sat'd NaHCO3, sat'd NaCl), dried (anhydrous Na2SO4) and the solvent is removed in vacuo. Chromatography on silica gel gives the title compound.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([C:7](Cl)=[O:8])[N:6]=1.[CH2:10]([N:12](CC)CC)C.CN>ClCCl.C1COCC1>[CH3:10][NH:12][C:7]([C:5]1[N:6]=[C:2]([Cl:1])[S:3][CH:4]=1)=[O:8]
Reactant: O=C(Cl)c1csc(Cl)n1
Reactant: CCN(CC)CC
Agent: CN
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)c1csc(Cl)n1

Procedure:
To 445 mg (2.44 mmol) 2-chloro-thiazole-4-carbonyl chloride in 8.0 mL dichloromethane is added a mixture of 0.38 mL (2.69 mmol) triethylamine and 1.35 mL (2.69 mmol) 2 molars solution of methylamine in THF. The mixture is stirred over night, concentrated and the residue is treated with water and NaHCO3 solution. After extraction with ethylacetate the organic phases are combined, dried (Na2SO4) and concentrated to yield the desired product
Reaction SMILES: C1C2C(COC([NH:18][C@@H:19]([C:24]([NH:26][CH2:27][C:28]([O:30]C)=O)=[O:25])[CH2:20][CH2:21][CH2:22][CH3:23])=O)C3C(=CC=CC=3)C=2C=CC=1.ClCCl.N1CCCCC1>ClCCl>[CH2:20]([C@H:19]1[NH:18][C:28](=[O:30])[CH2:27][NH:26][C:24]1=[O:25])[CH2:21][CH2:22][CH3:23]
Reactant: CCCC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCC(=O)OC
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CCCC[C@H]1NC(=O)CNC1=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of methyl N-{[(9H-fluoren-9-ylmethyl)oxy]carbonyl}-D-norleucylglycinate from step (a) above (2 g, 4.7 mmol) in a 7:3 mixture of dichloromethane/piperidine (30 mL) was stirred at room temperature for 0.75 h. The reaction mixture was diluted with dichloromethane (200 mL) and solid which precipitated was filtered, washed with cold DCM (2×50 mL) and dried in vacuo to give the title compound as a white solid. MS (ESI, positive ion) m/z: 171 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=2)[N:17]=1)=[O:11].O[Li].O.Cl>CO.O>[N+:24]([C:20]1[CH:19]=[C:18]([C:16]2[N:17]=[C:13]([NH:12][C:10](=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:27])=[O:2])[S:14][CH:15]=2)[CH:23]=[CH:22][CH:21]=1)([O-:26])=[O:25]
Reactant: COC(=O)CCCCCCC(=O)Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CO
Product: O=C(O)CCCCCCC(=O)Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.3 %

Procedure:
To a solution of compound 14 (0.391 g, 1.0 mmol) in a mixture of MeOH (10 ml) and water (10 ml) was added LiOH—H2O (0.839 g, 20.0 mmol), and the mixture was stirred at room temperature for 3 hour. Then the reaction mixture was acidified with 1N HCl dropwise to pH 5 and extracted with EtOAc. The organic layer was washed with water and saturated brine and dried over Na2SO4. The solvent was evaporated to give compound 18 (0.322 g, 85.6%). 1H NMR (300 MHz, DMSO-d6) δ12.3 (1H, s), 8.72 (1H, s), 8.33 (1H, d, J=7.6 Hz), 8.16 (1H, dd, J=7.9, 2.8 Hz), 7.91 (1H, s), 7.72 (1H, t, J=8.0 Hz), 2.45 (2H, t, J=6.5 Hz), 2.19 (2H, t, J=5.7 Hz), 1.60 (2H, brs), 1.49 (2H, t, J=6.3 Hz), 1.30-1.18 (4H, m). 13C NMR (75 MHz, DMSO-d6) M75.3, 172.5, 159.2, 149.1, 147.1, 136.6, 132.5, 131.2, 123.0, 120.9, 111.2, 35.7, 34.4, 31.2, 29.1, 25.3, 25.1.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11](C(OC(C)(C)C)=O)[NH:12]C(OC(C)(C)C)=O)[CH:9]=2)[CH2:4][CH:3]=1.[C:27]([O:33]CC)(=O)[CH2:28][C:29]([CH3:31])=O.Cl>C(O)C.O>[CH3:31][C:29]1[CH2:28][C:27](=[O:33])[N:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[CH2:4][CH2:3][CH:2]3[CH3:1])[N:12]=1
Reactant: CC1=CCc2ccc(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc21
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC1=NN(c2ccc3c(c2)C(C)CC3)C(=O)C1
Temperature: 25 °C
Yield: 15.6 %

Procedure:
Di-tert-butyl 1-(3-methyl-inden-5-yl)hydrazine-1,2-dicarboxylate 38e (1.05 g, 2.9 mmol) was dissolved in 16 mL of a solvent mixture of ethanol and water (V:V=5:3) under stirring, followed by successive addition of ethyl acetoacetate (0.377 mL, 2.9 mmol) and 1.45 mL of 6 N hydrochloric acid. The reaction mixture was heated to reflux and reacted for 1.5 hours under nitrogen atmosphere. The mixture was cooled to room temperature and the mixture was concentrated under reduced pressure to remove ethanol. The aqueous layer was extracted with dichloromethane (15 mL×3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 5-methyl-2-(3-methyl-indan-5-yl)-2,4-dihydro-pyrazol-3-one 38f (103 mg, yield 15.6%) as a yellow oil.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Br[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]2[C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[N:27](C(OC(C)(C)C)=O)[CH:26]=[CH:25]3)=[CH:7][CH:6]=1>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:3])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]2[C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][CH:26]=[CH:25]3)=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)n1ccc2cc(-c3nc4ccccc4c(=O)n3-c3ccc(Br)cc3)ccc21
Reactant: CNC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CN(C)c1ccc(-n2c(-c3ccc4[nH]ccc4c3)nc3ccccc3c2=O)cc1
Yield: 33.2 %

Procedure:
Dimethylamine (0.3 mL, 0.58 mmol) was added to a solution of tert-butyl 5-(3-(4-bromophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-indole-1-carboxylate (0.200 g, 0.38 mmol), NatOBu (0.112 g, 1.20 mmol), Pd(OAc)2 (0.013 g, 0.06 mmol) and (t-Bu)3PHBF4 (0.034 g, 0.12 mmol) were added to toluene (5 mL). The mixture was microwaved at 300 W (max. power) and 90° C. for 30 min, before the mixture was concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 20% to 60% EtOAc in hexanes, afforded the title compound as a brown-yellow solid (0.048 g, 33%). 1H-NMR (300 MHz, DMSO-d6): δ11.14 (s, 1H), 8.16 (d, J=7.7 Hz, 1H), 7.83-7.88 (m, 1H), 7.67-7.73 (m, 2H), 7.52-7.57 (m, 1H), 7.33 (s, 1H), 7.18 (d, J=8.7 Hz, 1H), 7.03-7.08 (m, 3H), 6.54 (d, J=8.8 Hz, 2H), 6.39 (s, 1H), 2.83 (s, 6H). MS (APCI) m/z: 381 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH:7]=[C:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[C:5]([N+:16]([O-])=O)[CH:4]=1.[H][H]>CCO.[Pd]>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[C:5]([CH:4]=1)[NH2:16]
Reactant: COc1ccc(C=C2CCOCC2)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(CC2CCOCC2)c(N)c1
Reaction time: 7 h
Yield: 93.9 %

Procedure:
4-(4-methoxy-2-nitrobenzylidene)tetrahydro-2H-pyran (1.8 g; 7.22 mmol; 1 eq) is dissolved in EtOH (100 mL) and palladium on charcoal (180 mg, 10%) is added at room temperature under argon. The solution is treated with hydrogen at atmospheric pressure. After 7 h at room temperature, the reaction is complete. The mixture is filtered through celite and the filtrate is concentrated under reduced pressure to afford 1.5 g (94%) of the title compound as an orange oil. 1H NMR (DMSO-d6) δ 6.72 (d, J=8.3 Hz, 1H), 6.18 (d, J=2.6 Hz, 1H), 6.04 (dd, J=8.3, 2.6 Hz, 1H), 4.82 (s, 2H), 3.82-3.77 (m, 2H), 3.62 (s, 3H), 3.19 (td, J=11.7, 1.8 Hz, 2H), 2.29 (d, J=6.8 Hz, 2H), 1.72-1.61 (m, 1H), 1.51-1.46 (m, 2H), 1.24-1.10 (m, 2H). HPLC (max plot) 88%; Rt 1.83 min LC/MS: (ES+): 222.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6](B(O)O)[CH:7]=1.Br[C:14]1[CH:19]=[CH:18][C:17](/[C:20](/[CH3:27])=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][CH:15]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([C:14]2[CH:19]=[CH:18][C:17](/[C:20](/[CH3:27])=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][CH:15]=2)[CH:7]=1
Reactant: CCOC(=O)/C=C(\C)c1ccc(Br)cc1
Reactant: COc1ccc(Cl)cc1B(O)O
Product: CCOC(=O)/C=C(\C)c1ccc(-c2cc(Cl)ccc2OC)cc1
Yield: 90.6 %

Procedure:
(E)-Ethyl 3-(5′-chloro-2′-methoxy-biphenyl-4-yl)-but-2-enoate (1.07 g, 91% yield) was prepared from 5-chloro-2-methoxyphenylboronic acid (1.0 g, 5.36 mmol) and (E)-ethyl 3-(4-bromophenyl)-but-2-enoate (0.96 g, 3.57 mmol) by a procedure analogous to that described in example 52a.
Reaction SMILES: [NH2:1][C:2]1([C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:22](Cl)(=[O:26])[O:23][CH2:24][CH3:25]>ClCCl>[CH2:24]([O:23][C:22]([NH:1][C:2]1([C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)[CH2:4][CH2:3]1)=[O:26])[CH3:25]
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NC1(c2ccc(C(=O)OC)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 4-(1-aminocyclopropyl)benzoate (1.84 g) and triethylamine (2.82 mL) were dissolved in dichloromethane (40 mL), ethyl chlorocarbonate (1.01 mL) was added under ice-cooling, and the mixture was stirred at the same temperature for 30 min and at room temperature for 1 hr. After completion of the reaction, the solvent was evaporated, to the residue was added 0.5N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (0.86 g).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16]([NH2:23])[C:17]3[N:22]=[N:21][NH:20][C:18]=3[N:19]=2)=[N:6]1.[CH3:28]CN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.IC>CN(C)C=O>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16]([NH2:23])[C:17]3[N:22]=[N:21][N:20]([CH3:28])[C:18]=3[N:19]=2)=[N:6]1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]nnc12
Reactant: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1nnc2c(N)nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
250 mg (0.692 mmol) of the compound from example 53 and 190 mg (0.692 mmol) of BEMP were initially charged in 12 ml of dimethylformamide, and a solution of 98 mg (0.692 mmol) of iodomethane in 3 ml of dimethylformamide was added dropwise at 0° C. within 10 min. The mixture was stirred at 0° C. for 20 min. Subsequently, the reaction solution was concentrated under reduced pressure and the residue was purified by means of preparative HPLC (eluent: methanol/aqueous 0.1% ammonia solution=65:35). The residue was stirred with acetonitrile and filtered with suction, and the solids were dried under high vacuum. 78 mg of the title compound (30% of theory) and 50 mg of example 55 were obtained (19% of theory).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH3:7])[CH:3]1[OH:8].[C:9]([O:13][C:14]([NH:16][C:17]1([C:20](O)=[O:21])[CH2:19][CH2:18]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:9]([O:13][C:14]([NH:16][C:17]1([C:20]([O:8][CH:3]2[CH:4]([CH3:7])[CH2:5][CH2:6][CH:2]2[CH3:1])=[O:21])[CH2:19][CH2:18]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC1CCC(C)C1O
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1CCC(C)C1OC(=O)C1(NC(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
To a solution of 2,5-dimethylcyclopentanol (0.55 g.), compound 1 (0.97 g), and 4-(dimethylamino)pyridine (0.06 g.) in methylene chloride (100 ml) was added dicyclohexylacarbodiimide (1.09 g.), and the resulting mixture was stirred overnight. The precipitated dicyclohexylurea was removed by filtration, and the filtrate was evaporated. Ethyl acetate was then added to the residue, and the mixture was filtered again. The filtrate was washed with 1M hydrochloric acid, saturated aqeuous sodium bicarbonate, and water, dried over magnesium sulfate, and the solvent was evaporated to a colorless oil (1.18 g. 83%). The product was purified by column chromotography on silica gel, 4:1 hexane:ethyl acetate, eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([F:19])=[CH:12][C:13]=2[O:15][CH2:16][CH2:17]Cl)[C:8]([S:20]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[N:7]1.[N-:36]=[N+:37]=[N-:38].[Na+]>CS(C)=O.O>[N:36]([CH2:17][CH2:16][O:15][C:13]1[CH:12]=[C:11]([F:19])[CH:10]=[C:9]2[C:14]=1[N:6]([CH2:5][C:4]1[CH:33]=[CH:34][CH:35]=[C:2]([Cl:1])[CH:3]=1)[N:7]=[C:8]2[S:20]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)(=[O:21])=[O:22])=[N+:37]=[N-:38]
Reactant: [N-]=[N+]=[N-]
Reactant: O=S(=O)(c1cccc2ccccc12)c1nn(Cc2cccc(Cl)c2)c2c(OCCCl)cc(F)cc12
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCCOc1cc(F)cc2c(S(=O)(=O)c3cccc4ccccc34)nn(Cc3cccc(Cl)c3)c12
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(3-chloro-benzyl)-7-(2-chloro-ethoxy)-5-fluoro-3-(naphthalene -1-sulfonyl)-1H-indazole (0.1 g, 0.19 mmoles) and sodium azide (0.014 g, 0.22 mmoles) in DMSO (3 mL) was stirred together in a round bottom flask under nitrogen at 90° C. for 3 hours. Reaction mixture was cooled to room temperature, diluted with water, extracted with EtOAC, washed with water (2×), brine (1×), dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (0.09 g, 0.17 mmoles).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[S:9][CH:10]=[C:11]([CH3:13])[N:12]=1)=[O:4].[H-].[Na+].[C:18]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19].O>CN(C=O)C>[C:18]([C:22]1[CH:23]=[CH:24][C:25]([CH2:26][N:5]([CH2:6][CH2:7][C:8]2[S:9][CH:10]=[C:11]([CH3:13])[N:12]=2)[C:3](=[O:4])[C:2]([F:14])([F:1])[F:15])=[CH:28][CH:29]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: Cc1csc(CCNC(=O)C(F)(F)F)n1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1csc(CCN(Cc2ccc(C(C)(C)C)cc2)C(=O)C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
A solution of 224 mg of 2,2,2-trifluoro-N-[2-(4-methyl-thiazol-2-yl)-ethyl]-acetamide (0.94 mmol) in 4 ml DMF was added to a suspension of 45 mg of sodium hydride (60% in mineral oil) in 4 ml DMF at 0° C. After 30 min 0.173 ml 4-tert-butyl-benzylbromide were added and the reaction mixture was allowed to warm to rt. Stirring was continued for 3 h at ambient temperature, then water was added and the mixture was extracted with EtOAc. The organic layers were dried over magnesium sulfate, filtrated and the solvent was evaporated. Chromatography (silica gel; cyclohexane/EtOAc 4:1) yielded 265 mg (73%) of N-(4-tert-butyl-benzyl)-2,2,2-trifluoro-N-[2-(4-methyl-thiazol-2-yl)-ethyl]-acetamide as a light yellow liquid. 1H NMR (CDCl3, 300 MHz): δ 1.30 (s) and 1.31 (s, 9H), 2.42 (s, 3H), 3.23 (q, J=7 Hz, 2H), 3.70 (t, J=7 Hz) and 3.79 (t, J=7 Hz, 2H), 4.48(s) and 4.62 (s, 2H), 6.77 (m, 1H), 7.10 (d, J=8 Hz) and 7.17 (d, J=8 Hz, 2H), 7.36 (d, J=8 Hz) and 7.38 (d, J=8 Hz, 2H); MS (ISP) 385.4 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]([OH:23])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:11](=[O:12])[NH:10][C:8](=[O:9])[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)O
Reactant: O=C=NC(=O)C(c1ccccc1)c1ccccc1
Product: CC(C)(C)OC(=O)NC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, light yellow solid, m.p. 160-162° C. and MS: m/e=334 (M+Na+) was prepared in accordance with the general method of example 1 from diphenylacetyl isocyanate and tert.-butyl alcohol.
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:4]1=2)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH2:29][Cl:30]>O.C(#N)C>[Cl:30][CH2:29][CH2:28][CH2:27][O:19][C:16]1[CH:17]=[CH:18][C:4]2[N:3]([CH2:1][CH3:2])[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]=2[CH:15]=1
Reactant: ClCCCBr
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCCl)ccc21
Temperature: 70 °C
Yield: 90.6 %

Procedure:
1-Ethyl-7-hydroxy-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (1.85 g, 7.1 mmol) and potassium carbonate (1.2 g, 8.5 mmol) were added to 50% water-containing acetonitrile (40 ml), and dissolved by heating to 70° C. 1-Bromo-3-chloropropane (2.1 ml, 21 mmol) was added thereto, and heating was conducted under reflux for 6 hours. The reaction mixture was cooled to room temperature. Water was added, and extraction with ethyl acetate was performed. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1→1:1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 2.18 g (yield: 91%) of 7-(3-chloropropoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione as a colorless oil.
Reaction SMILES: [N+:1]([C:4]([CH:7]([C:9]1[C:18]2[C:13](=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([C:23]([F:26])([F:25])[F:24])[CH:10]=1)[OH:8])([CH3:6])[CH3:5])([O-])=O>C(O)(=O)C.[Zn]>[NH2:1][C:4]([CH:7]([C:9]1[C:18]2[C:13](=[C:14]([C:19]([F:20])([F:21])[F:22])[CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([C:23]([F:26])([F:24])[F:25])[CH:10]=1)[OH:8])([CH3:6])[CH3:5]
Reactant: CC(C)(C(O)c1cc(C(F)(F)F)nc2c(C(F)(F)F)cccc12)[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(C)(N)C(O)c1cc(C(F)(F)F)nc2c(C(F)(F)F)cccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.4 %

Procedure:
A solution of α-(2-nitro-2-propyl)-2,8-bis(trifluoromethyl)-4-quinolinemethanol (200 mg, 0.52 mmol) in acetic acid (2 mL) was treated slowly with zinc dust, stirred at room temperature for 30 min, filtered through Celite, concentrated in vacuo and the resulting viscous oil purified by chromatography [SiO2, EtOAc] to give the title compound (63 mg, 31%) as a white solid: mp 175-176° C.; IR νmax (Nujol)/cm−1 3372, 2925, 1741, 1310,1145, 1111,756 and 684; NMR δH (400 MHz, CDC3) 0.84 (3H, s), 0.99 (3H, s), 3.37 (1H, br s), 5.69 (1H, d, J 3.9 Hz), 6.01 (1H, d, J 4.0 Hz), 7.92 (1H, t, J 8.7 Hz), 8.35 (1H, d, J 7.5 Hz) and 8.75 (1H, d, J 8.6 Hz); Anal. Calcd for C14H11ClF6N2O: C, 45.12; H, 2.97; N, 7.51. Found: C, 45.21: H, 3.29; N, 7.08.