Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7](=O)[CH2:8]Br)=[CH:5][CH:4]=1)#[N:2].[CH3:13][C@@H:14]([NH:19][C:20]([NH2:22])=[S:21])[C:15]([F:18])([F:17])[F:16].C(=O)(O)[O-].[Na+]>C(O)C>[CH3:13][C@@H:14]([NH:19][C:20]1[S:21][CH:8]=[C:7]([C:6]2[CH:11]=[CH:12][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[N:22]=1)[C:15]([F:18])([F:17])[F:16]
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: C[C@@H](NC(N)=S)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: C[C@@H](Nc1nc(-c2ccc(C#N)cc2)cs1)C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 50.8 %

Procedure:
Dissolve 4-cyanophenacyl bromide (1.82 g, 8.14 mmol), (R)-(1-methyl-2,2,2-trifluoroethyl)-thiourea (1.4 g, 8.14 mmol) and sodium bicarbonate (0.68 g, 8.14 mmol) in absolute ethanol. Heat at reflux 2 h, cool to room temperature and let stand over 2 days. Filter and collect the resulting crude product as a tan solid. Purify by chromatography on silica gel (34 g) eluting with hexane/EtOAc (19:1 to 4:1 over 30 min, 4:1 over 10 min; 40 mL/min) to obtain the desired intermediate as a white solid (1.23 g, 52%). MS (ES+) m/z: 298 (M+H)+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([N:9]([CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH:22]([O-])=[O:23].[Na+]>CN(C=O)C>[CH:22]([C:2]1[CH:3]=[C:4]([N:9]([CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8])=[O:23]
Reactant: O=C[O-]
Reactant: CCS(=O)(=O)N(Cc1cccnc1)c1ccc(C)c(I)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)N(Cc1cccnc1)c1ccc(C)c(C=O)c1
Temperature: 100 °C

Procedure:
A mixture of N-(3-iodo-4-methylphenyl)-N-(ethylsulfonyl)pyrid-3-ylmethylamine (0.415 g, 0.997 mmol), sodium formate (0.102 g, 1.50 mmol), and dichloro-bis(triphenylphosphine)palladium (0.014 g, 0.020 mmol) were combined in 1.0 mL DMF and purged with anhydrous CO gas. The mixture was heated to 100° C. for 1.5 h. The reaction was poured into saturated NaHCO3 solution and extracted with EtOAc. The combined fractions were washed with H2O and brine, dried over MgSO4, filtered and concentrated. The mixture was chromatographed on silica gel with 1:1 EtOAc/DCM to give the title compound as a clear oil. 1H NMR: 10.11 (s,1H), 8.38 (br s,1H), 8.26 (br s,1H). 7.60 (m,2H), 7.13 (m,1H), 7.00 (s,2H), 4.80 (s,2H), 3.00 (q,J=7.3 Hz, 2H), 2.52 (s,3H), 2.35 (t,J=7.3 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[C:14]([Cl:15])=[CH:13][C:12]([N+:16]([O-])=O)=[CH:11][C:10]=1[Cl:19])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+]>C(O)C.O.[Fe]>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[C:14]([Cl:15])=[CH:13][C:12]([NH2:16])=[CH:11][C:10]=1[Cl:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)COc1c(Cl)cc(N)cc1Cl

Procedure:
A soution of (4-nitro-2,6-dichloro-phenoxy)-acetic acid tert-butyl ester (1 g) in ethanol (17 mL) and water (8.6 mL) is treated with iron powder (0.861 g) and ammonium chloride (86 mg) and the mixture is heated to reflux for approximately 1 hour. The mixture is then filtered and concentrated under reduced pressure. The resulting oil is partitioned between water and ethyl acetate, and the organic phase is then washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to provide the desired compound as a pale yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1.[S:14]1[CH2:18][C:17](=[O:19])[NH:16][C:15]1=[O:20]>>[N:13]1[CH:12]=[CH:11][N:10]2[C:5]([S:4][CH2:3][CH2:2][N:16]3[C:17](=[O:19])[CH2:18][S:14][C:15]3=[O:20])=[CH:6][CH:7]=[CH:8][C:9]=12
Reactant: O=C1CSC(=O)N1
Reactant: ClCCSc1cccc2nccn12
Product: O=C1CSC(=O)N1CCSc1cccc2nccn12

Procedure:
Using 2.29 g (10.8 mmol) of 5-(2-chloroethylthio)-imidazo[1,2-a]pyridine, 1.27 g (10.8 mmol) of thiazolidine-2,4-dione and 1.62 ml (10.8 mmol) of 1,8-diazabicyclo-[5.4.0]-7-undecene, the same procedure as in Reference Example 2 was followed, to yield 1.49 g (38.7%, light orange crystal) of the desired product.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[F:19][C:20]1[CH:21]=[C:22]([CH:33]=[C:34]([F:36])[CH:35]=1)[CH2:23][NH:24][C:25](=[O:32])[C:26]([CH3:31])([CH3:30])[C:27](O)=[O:28]>>[F:19][C:20]1[CH:21]=[C:22]([CH:33]=[C:34]([F:36])[CH:35]=1)[CH2:23][NH:24][C:25](=[O:32])[C:26]([CH3:31])([CH3:30])[C:27]([NH:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:28]
Reactant: CC(C)(C(=O)O)C(=O)NCc1cc(F)cc(F)c1
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Product: CN1C(=O)C(NC(=O)C(C)(C)C(=O)NCc2cc(F)cc(F)c2)c2ccccc2-c2ccccc21

Procedure:
The title compound, MS: m/e=478.2 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and N-(3,5-difluoro-benzyl)-2,2-dimethyl-malonamic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][N:20]=1)[C:15](O)=[O:16].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:11][C:12]1[CH:13]=[C:14]([C:15]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[CH2:5][CH2:6]2)=[O:16])[CH:18]=[CH:19][N:20]=1
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: Fc1ccc2c(c1)CCN2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1ccnc(Cl)c1)N1CCc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
174 mg (1.27 mmol) 5-fluoro-2,3-dihydro-1H-indole were added to 198 mg (1.26 mmol) 2-chloroisonicotinic acid, 351 μL (2.50 mmol) triethylamine and 434 mg (1.35 mmol) TBTU in 3 mL DMF. The reaction mixture was stirred overnight at RT. Purification was carried out by preparative HPLC. The product fractions were combined and evaporated down i. vac.
Reaction SMILES: CI.[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][NH:18][C:19]2[C:29]([NH:30][C:31]([NH:33][CH2:34][CH3:35])=S)=[CH:28][CH:27]=[CH:26][C:20]=2[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:13][CH:12]=1)#[N:4].Cl>C(O)C>[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:19]3[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=[CH:28][C:29]=3[N:30]=[C:31]2[NH:33][CH2:34][CH3:35])=[CH:13][CH:12]=1)#[N:4]
Reactant: CCNC(=S)Nc1cccc(C(=O)OCC)c1NCc1ccc(-c2ccccc2C#N)cc1
Agent: Cl
Solvent: CI
Solvent: CCO
Product: CCNc1nc2cccc(C(=O)OCC)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.6 %

Procedure:
Methyl iodide (4.5 g) was added to a solution of ethyl 2-[[(2′-cyanobiphenyl-4-yl)methyl]amino]-3-(ethylthioureido)benzoate (1.8 g) in ethanol (50 ml), and the mixture was heated under reflux for 12 hours. To the reaction mixture was added 1N—HCl (60 ml) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated to dryness and the concentrate was dissolved in ethyl acetate. The solution was washed with an aqueous solution of sodium hydrogen carbonate and water and dried. The solvent was evaporated to dryness and the residue was purified by column chromatography on silica gel to afford yellow syrup (0.96 g, 58%).
Reaction SMILES: [CH2:1]([C:3]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[C:4]=1[CH2:5][O:6][C:7]1[C:8]([N+:26]([O-])=O)=[N:9][CH:10]=[C:11]([CH:25]=1)[C:12](OCC1C(C)=CC=CC=1CC)=[O:13])[CH3:2].[NH3:34]>CO>[NH2:26][C:8]1[C:7]([O:6][CH2:5][C:4]2[C:29]([CH3:33])=[CH:30][CH:31]=[CH:32][C:3]=2[CH2:1][CH3:2])=[CH:25][C:11]([C:12]([NH2:34])=[O:13])=[CH:10][N:9]=1
Reactant: N
Reactant: CCc1cccc(C)c1COC(=O)c1cnc([N+](=O)[O-])c(OCc2c(C)cccc2CC)c1
Solvent: CO
Product: CCc1cccc(C)c1COc1cc(C(N)=O)cnc1N
Temperature: 35 °C
Reaction time: 96 h
Yield: 31 %

Procedure:
2-ethyl-6-methylbenzyl 5-(2-ethyl-6-methylbenzyloxy)-6-nitronicotinate (0.7 g, 2 mmol) was added to a solution of ammonia in methanol (5-10%)(40 ml) and the mixture was stirred at 35° C. for 96 h. The solvent was evaporated under reduced pressure. Purification of the residue twice by column chromatography on silica gel using ethylacetate:methylene chloride (1:1) and methanol:methylene chloride (1:9) as eluent gave 0.14 g (31%) of the title compound.
Reaction SMILES: CO[C:3](=[O:17])[C:4]([C:6]1[CH:7]=[C:8]([CH3:16])[CH:9]=[C:10]2[C:14]=1[N:13]([CH3:15])[CH:12]=[CH:11]2)=O.[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH2:27][C:28]([NH2:30])=[O:29])=[CH:19]1.CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[CH3:15][N:13]1[C:14]2[C:10](=[CH:9][C:8]([CH3:16])=[CH:7][C:6]=2[C:4]2[C:3](=[O:17])[NH:30][C:28](=[O:29])[C:27]=2[C:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[NH:18][CH:19]=2)[CH:11]=[CH:12]1
Reactant: NC(=O)Cc1c[nH]c2ccccc12
Reactant: COC(=O)C(=O)c1cc(C)cc2ccn(C)c12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(C2=C(c3c[nH]c4ccccc34)C(=O)NC2=O)c2c(ccn2C)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 56.3 %

Procedure:
To a mixture of (1,5-dimethyl-1H-indol-7-yl)-oxo-acetic acid methyl ester (0.51 g, 2.21 mmol) and 2-(1H-indol-3-yl-acetamide (0.35 g, 2 mmol) in DMF (20 mL) was added a solution of potassium tert-butoxide in THF (1.0 M, 8.0 mL, 8.0 mmol) at room temperature. The reaction mixture was heated at 50° C. for 18 h, cooled to room temperature, and quenched with hydrochloric acid (1.0 N). After 30 min at room temperature, the mixture was extracted with ethyl acetate and the extract washed with water, saturated aqueous sodium bicarbonate and brine, dried (sodium sulfate), filtered and concentrated. Flash column chromatography on silica gel eluting with chloroform and acetone gave 3-(1,5-dimethyl-1H-indol-7-yl)-4-(1H-indol-3-yl]-pyrrole-2,5-dione (400 mg, 56.3%). 1HNMR (DMSO-d6, 400 MHz) 2.28 (s, 3H), 3.64 (s, 3H), 6.39 (d, J=3.07 Hz, 1H), 6.50 (t, J=7.66 Hz, 1H), 6.53 (t, J=7.00 Hz, 1H), 6.74 (d, J=1.4 Hz, 1H), 7.0 (t, J=7.47 Hz, 1H), 7.20 (d, J=3.09 Hz, 1H), 7.35 (d, J=8.11 Hz, 1H), 7.41 (s, 1H), 7.88 (d, J=3.0 Hz, 1H), 11.13 (s, 1H), 11.84 (s, 1H); MS (ES, m/z): C22H17N3O2: 356.2 (M++1); 354.2 (M+−1).
Reaction SMILES: [C:1]1([C:7]2[N:11]3[N:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]3=[N:9][C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([C:24]3([NH:28]C(=O)OC(C)(C)C)[CH2:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.O1CCOCC1.[OH-].[Na+]>C(Cl)Cl.CO>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]2[N:11]([C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:8]([C:18]3[CH:19]=[CH:20][C:21]([C:24]4([NH2:28])[CH2:25][CH2:26][CH2:27]4)=[CH:22][CH:23]=3)[N:9]=2)[N:12]=1
Reactant: COc1ccc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)n2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83 %

Procedure:
To a mixture of tert-butyl (1-{4-[3-phenyl-6-methoxyimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-5 (550 mg, 1.17 mmol) in DCM (7.5 mL) and MeOH (0.8 mL) was added a 4 M hydrogen chloride solution in dioxane (5.8 mL, 23.4 mmol, 20.0 eq), and the resulting mixture was stirred at room temperature for 12 h. The resulting mixture was added to ice water, made alkaline with aqueous sodium hydroxide (2 N), and extracted with EtOAc (3×25 mL). The combined organic phases were washed, dried (Na2SO4 anh.) and concentrated under reduced pressure. The resulting material was purified using MPLC (Biotage Isolera; 100 g SNAP cartridge: 100% DCM 3.5 min., gradient to 95% DCM/5% MeOH 1 min., 95% DCM/5% MeOH 3.5 min., gradient to 90% DCM/10% MeOH 1 min., 90% DCM/10% MeOH 4.5 min.) to give 1-[4-(6-methyloxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine (379 mg, 83% yield):
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:12]12[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH:17]C(=O)O[C:13]2=[O:14]>>[C:13]([O:11][C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=1)(=[O:14])[C:12]1[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH2:17]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CC(C)(C)c1ccc(O)cc1
Product: CC(C)(C)c1ccc(OC(=O)c2ccccc2N)cc1

Procedure:
To 112.5 g. of p-tert-butylphenol heated at 100°-120° C. there was added in portions 123 g. of isatoic anhydride during about 0.75 hour. The reaction mixture was allowed to cool and was then extracted with hot ethyl alcohol from which the crude ester crystallized upon cooling. Recrystallization from n-heptane afforded the crystalline ester mp 142°-143° C.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH2:9](Cl)[C:10](=[CH2:12])[CH3:11]>>[CH3:11][C:10](=[CH2:9])[CH2:12][S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8]
Reactant: C=C(C)CCl
Reactant: Oc1ccccc1S
Product: C=C(C)CSc1ccccc1O
Yield: 65 %

Procedure:
This compound was prepared in 65% yield from 2-mercaptophenol and methallyl chloride according to the procedure for 16b in Example VII. Brown Oil; 1H NMR (CDCl3): δ 1.86 (s, 3H), 3.26 (s, 2H), 4.52 (s, 1H), 4.73 (s, 1H), 6.68 (s, 1H), 6.85 (dt, J=1.35 Hz, J=7.40 Hz, 1H), 6.97 (dd, J=1.1, J=8.0 Hz, 1H), 7.25 (dt, J=1.4, J=7.7, 1H), 7.39 (dd, J=1.7 Hz, J=7.7 Hz, 1H); 13C NMR (CDCl3): δ 20.91, 44.49, 114.74, 114.92, 118.84, 120.67, 131.25, 136.31, 140.32, 157.08.
Reaction SMILES: ON[C:3]([CH:5]1[CH:11]([CH2:12][O:13]C(=O)C)[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)(=[O:19])=[O:18])=[O:4].[Li+].[OH-:29]>CO.O>[OH:13][CH2:12][CH:11]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)(=[O:18])=[O:19])[CH:5]1[C:3]([OH:4])=[O:29]
Reactant: COc1ccc(S(=O)(=O)N2CCCCC(COC(C)=O)C2C(=O)NO)cc1
Reactant: [OH-]
Agent: [Li+]
Solvent: CO
Solvent: O
Product: COc1ccc(S(=O)(=O)N2CCCCC(CO)C2C(=O)O)cc1
Reaction time: 0.5 h

Procedure:
To a solution of Acetic acid 2-hydroxycarbamoyl-1-(4-methoxy-benzenesulfonyl)-azepan-3-ylmethyl ester in 1.1 mL methanol was added 0.1 mL of 1.0 M LiOH in water at ambient temperature. The reaction was stopped after 30 minutes by evaporating the solvent under reduced pressure. The residue was taken up in water and washed twice with diethyl ether, followed by acidification of the water to pH=1 with 1N HCl. The water layer was extracted twice with ethyl acetate which was dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure and was purified with column chromatography (silica: 2% to 8% methanol in dichloromethane) to yeild a thin film which was freeze-dried to yield 3-Hydroxymethyl-1-(4-methoxy-benzenesulfonyl)-azepane-2-carboxylic acid hydroxamide as a white lyopholate; MS: (M-H)- =357.
Reaction SMILES: [O:1]1[C:5]2([CH2:15][CH2:14][C:8]3([CH2:12][CH2:11][NH:10][C:9]3=[O:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Br[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1>>[F:24][C:23]([F:26])([F:25])[C:20]1[CH:21]=[CH:22][C:17]([N:10]2[CH2:11][CH2:12][C:8]3([CH2:14][CH2:15][C:5]4([O:4][CH2:3][CH2:2][O:1]4)[CH2:6][CH2:7]3)[C:9]2=[O:13])=[CH:18][CH:19]=1
Reactant: O=C1NCCC12CCC1(CC2)OCCO1
Reactant: FC(F)(F)c1ccc(Br)cc1
Product: O=C1N(c2ccc(C(F)(F)F)cc2)CCC12CCC1(CC2)OCCO1

Procedure:
The title compound was prepared in analogy to example 133, step 4 from 1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one (described in example 133 step 3) and 1-bromo-4-(trifluoromethyl)benzene as white crystalline solid. MS (m/e): 356.146 [(M-H2O)H+].
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[S:25]([CH3:28])(=[O:27])=[O:26])[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:29][C:30]1[CH:34]=[CH:33][N:32]([CH2:35][C:36]([CH3:39])([OH:38])[CH3:37])[N:31]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[S:25]([CH3:28])(=[O:27])=[O:26])[CH:13]=[N:12]2)[C:8]([NH:29][C:30]2[CH:34]=[CH:33][N:32]([CH2:35][C:36]([OH:38])([CH3:37])[CH3:39])[N:31]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: CS(=O)(=O)c1ccccc1Oc1cnn(C(CC2CCCC2)C(=O)O)c(=O)c1
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3ccccc3S(C)(=O)=O)cc2=O)n1
Yield: 54 %

Procedure:
Using the method described in Example 17, 3-cyclopentyl-2-[4-(2-methanesulfonyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 48) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[4-(2-methanesulfonyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionamide as a white solid (0.74 g, 54%); ES+-HRMS m/e calcd for C26H33N5O6S [M+Na+] 566.2044 found 566.2045. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.10 (m, 1H), 1.28-1.76 (m, 8H), 1.92 (m, 1H), 2.28 (m, 1H), 3.36 (s, 3H), 3.89 (s, 2H), 4.67 (s, 1H), 5.48 (dd, J=4.4, J=10.9 Hz, 1H), 5.96 (d, J=2.8 Hz, 1H), 6.41 (d, J=2.2 Hz, 1H), 7.53 (d, J=2.2 Hz, 1H), 7.56-7.66 (m, 2H), 7.87 (m, 1H), 8.00 (dd, Jo=8.0 Hz, Jm=1.6 Hz, 1H), 8.21 (d, J=2.8 Hz, 1H), 10.83 (s, 1H).
Reaction SMILES: [C:1]1([C:7]2([C:12](=[N+]=[N-])[CH3:13])[O:11]CCO2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][CH2:17][C:18](=[O:43])[C@:19]1([OH:42])[C@:36]2([CH3:37])[C@H:22]([C@H:23]3[C@:33]([F:39])([C@@H:34]([OH:38])[CH2:35]2)[C@:31]2([CH3:32])[C:26](=[CH:27][C:28](=[O:40])[CH:29]=[CH:30]2)[CH2:25][CH2:24]3)[CH2:21][C@H:20]1[OH:41]>CO>[Cl:16][CH2:17][C:18](=[O:43])[C@:19]1([OH:42])[C@:36]2([CH3:37])[C@H:22]([C@H:23]3[C@:33]([F:39])([C@@H:34]([OH:38])[CH2:35]2)[C@:31]2([CH3:32])[C:26](=[CH:27][C:28](=[O:40])[CH:29]=[CH:30]2)[CH2:25][CH2:24]3)[CH2:21][C@H:20]1[O:41][CH:12]([C:7](=[O:11])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:13]
Reactant: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](O)[C@](O)(C(=O)CCl)[C@@]3(C)C[C@H](O)[C@@]12F
Reactant: CC(=[N+]=[N-])C1(c2ccccc2)OCCO1
Solvent: CO
Product: CC(O[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CCl)C(=O)c1ccccc1
Temperature: 0 °C

Procedure:
A solution of 2-phenyl-2-(1-diazoethyl)dioxolane in 3:2 ether-pentane is diluted with methanol and cooled to 0°C. 21-Chloro-9-fluoro-11β,16α,17-trihydroxypregna-1,4-diene-3,20-dione, 16,17-cycloborate is added in portions until nitrogen evolution ceases. The solvent is removed in vacuo.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[O:11]=[C:12]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14][NH:13]1>>[CH3:7][N:6]1[C:2]([N:13]2[C:12](=[O:11])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: Cn1ncc([N+](=O)[O-])c1Br
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)CC1
Product: Cn1ncc([N+](=O)[O-])c1N1CCN(C(=O)OC(C)(C)C)CCC1=O
Yield: 33 %

Procedure:
Following the procedure for Intermediate 202 starting from 5-bromo-1-methyl-4-nitro-1H-pyrazole and tert-butyl 5-oxo-1,4-diazepane-1-carboxylate gave tert-butyl 4-(1-methyl-4-nitro-1H-pyrazol-5-yl)-5-oxo-1,4-diazepane-1-carboxylate as a brown gum (136 mg, 33%). 1H NMR (400 MHz, d4-MeOD) δ 8.18 (s, 1H), 4.04-3.72 (m, 5H), 3.90-3.62 (m, 4H), 3.02-2.86 (m, 2H), 1.52 (s, 9H).
Reaction SMILES: [F:1][C:2]1[C:31]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:30][C:5]2[NH:6][C:7]([C:9]3[C:13]([NH:14][C:15](=[O:23])[N:16]([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])=[CH:12][N:11](C4CCCCO4)[N:10]=3)=[N:8][C:4]=2[CH:3]=1>Cl>[F:1][C:2]1[C:31]([N:32]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)=[CH:30][C:5]2[NH:6][C:7]([C:9]3[C:13]([NH:14][C:15](=[O:23])[N:16]([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:18])[CH3:19])=[CH:12][NH:11][N:10]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: CC(C)N(C(=O)Nc1cn(C2CCCCO2)nc1-c1nc2cc(F)c(N3CCOCC3)cc2[nH]1)C(C)C
Agent: Cl
Product: CC(C)N(C(=O)Nc1c[nH]nc1-c1nc2cc(F)c(N3CCOCC3)cc2[nH]1)C(C)C
Yield: 39.8 %

Procedure:
A solution of 550 mg of 3-[3-(5-fluoro-6-morpholin-4-yl-1H-benzimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]-1,1-diisopropylurea in 8.5 mL of concentrated hydrochloric acid is stirred at ambient temperature for 12 hours and the medium is concentrated under vacuum in a rotary evaporator. The reaction crude is purified by preparative LC/MS, elution being carried out with a mixture of water and acetonitrile containing respectively 0.07% of trifluoroacetic acid. 183 mg of 3-[3-(5-fluoro-6-morpholin-4-yl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-diisopropylurea in the form of a trifluoroacetate salt are isolated. 1H NMR (400 MHz, DMSO-d6, δ in ppm): 1.35 (d, J=7.0 Hz, 12H); 3.00 (m, 4H); 3.78 (m, 4H); 4.07 (m, 2H); 7.08 (broad d, J=7.5 Hz, 1H); 7.32 (broad d, J=12.0 Hz, 1H); 8.03 (s, 1H); 9.57 (s, 1H); 12.95 (broad m, 2H).
Reaction SMILES: [F:1][C:2]([F:25])([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)[C:3]1[N:7]2[N:8]=[C:9]([C:12](=O)[CH3:13])[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.[NH2:26][N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32]>CO>[F:1][C:2]([F:25])([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)[C:3]1[N:7]2[N:8]=[C:9](/[C:12](=[N:26]/[N:27]3[CH2:31][CH2:30][NH:29][C:28]3=[O:32])/[CH3:13])[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1
Reactant: CC(=O)c1ccc2nnc(C(F)(F)c3ccc4ncccc4c3)n2n1
Reactant: NN1CCNC1=O
Solvent: CO
Product: C/C(=N\N1CCNC1=O)c1ccc2nnc(C(F)(F)c3ccc4ncccc4c3)n2n1
Yield: 32.1 %

Procedure:
A solution of 1-(3-(difluoro(quinolin-6-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (20 mg, 0.059 mmol) and 1-aminoimidazolidin-2-one (12 mg, 0.12 mmol) in MeOH was stirred at room temperature for overnight. Solvent was evaporated and the crude product was purified on flash chromatography (CH2Cl2:MeOH 9:1) to give the title compound as a white solid (8 mg, 32%). 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.98 (s, 1H), 8.52 (d, 1H), 8.43 (s, 1H), 8.26 (d, 2H), 8.19 (m, 1H), 8.06 (d, 1H), 7.66 (d, 1H), 3.55 (t, 2H), 3.38 (t, 2H), 2.30 (s, 3H). LCMS (method A): [MH]+=423.0, tR=4.63 min.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][C:13]([Br:17])=[CH:14][CH:15]=2)[O:10][C:9](=[O:18])[CH:8]=1)(=O)=O.[CH3:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[F-].[K+]>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:17][C:13]1[CH:12]=[C:11]2[C:16]([C:7]([C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:21])[CH:27]=3)=[CH:8][C:9](=[O:18])[O:10]2)=[CH:15][CH:14]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: O=c1cc(OS(=O)(=O)C(F)(F)F)c2ccc(Br)cc2o1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Product: Cc1cccc(-c2cc(=O)oc3cc(Br)ccc23)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 7-bromo-2-oxo-2H-chromen-4-yl trifluoromethanesulfonate (prepared as described in U.S. Pat. No. 5,552,437) (1.1 g, 3.0 mmol) and 3-methylbenzeneboronic acid (450 mg, 3.3 mmol) in THF (12 mL), tricyclohexylphosphine (30 mg, 0.1 mmol) and potassium fluoride (574 mg, 9.9 mmol) were added. The reaction mixture was purged twice with nitrogen before palladium (II) acetate (20 mg, 0.1 mmol) was added. After 16 hours stirring at room temperature the reaction mixture was filtered over celite and the filtrate was concentrated under reduced pressure. The crude residue obtained was purified by column chromatography (CH2Cl2/hexanes, 70:30). To afford the title compound 1H NMR (400 MHz, acetone-d6): 7.67 (s, 1H), 7.53-7.33 (m, 6H), 6.40 (s, 1H), 2.46 (s, 3H).