Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[F:29][C:30]1[CH:31]=[C:32]([NH:36][NH2:37])[CH:33]=[CH:34][CH:35]=1>>[F:29][C:30]1[CH:31]=[C:32]([N:36]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]5[CH2:27][CH2:26][CH2:25][CH2:24]5)(=[O:21])=[O:22])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:37]2)[CH:33]=[CH:34][CH:35]=1
Reactant: NNc1cccc(F)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)N3CCCC3)c2)ccc1=O
Product: O=c1ccn(-c2cccc(S(=O)(=O)N3CCCC3)c2)nc1-c1ccnn1-c1cccc(F)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-[3-(pyrrolidine-1-sulfonyl)-phenyl]-1H-pyridazin-4-one (A-29) and 3-fluoro-phenylhydrazine according to the method described for example 91. MS: M=466.2 (M+H)+
Reaction SMILES: [C:1]([P:5]([C:11]([F:20])([F:19])[C:12]1[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=1)([C:7]([CH3:10])([CH3:9])[CH3:8])=[O:6])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[CH:26](OCC)=[O:27].[NH4+].[Cl-]>CCOCC>[C:1]([P:5]([C:11]([F:20])([F:19])[C:12]1[CH:17]=[CH:16][C:15]([CH:26]=[O:27])=[CH:14][CH:13]=1)([C:7]([CH3:10])([CH3:9])[CH3:8])=[O:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)P(=O)(C(C)(C)C)C(F)(F)c1ccc(Br)cc1
Reactant: CCOC=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)(C)P(=O)(C(C)(C)C)C(F)(F)c1ccc(C=O)cc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To compound 27 (50 mg, 0.12 mmol ) in anhydrous ether (0.63 mL) at -78° C. under argon was added n-BuLi (1.6M in hexanes, 0.12 mL, 0.19 mmol) and the mixture was stirred at -78° C. (20 minutes). A solution of ethyl formate, 1M in ether (0.25 mmol, 2 eq.) was added and the mixture stirred (0.5 hours at -78° C.). Saturated aqueous NH4Cl (1 mL) was added and the mixture warmed to ambient temperature and extracted with ether (3×1 mL). The combined extracts were dried (MgSO4) and taken to dryness under reduced pressure, affording 43 mg of crude 28, however, contaminated with starting material 27.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])=[N:8][CH:9]=1)([O-])=O.[H][H]>CO.[Pd]>[CH3:14][N:13]([CH3:15])[CH2:12][CH2:11][O:10][C:7]1[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: CN(C)CCOc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CO
Product: CN(C)CCOc1ccc(N)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.5 %

Procedure:
2-(5-Nitropyridin-2-yloxy)-N,N-dimethylethanamine (295 mg, 1.40 mmol) was dissolved in 5 mL of methanol and placed under a nitrogen atmosphere. A catalytic amount of 10% palladium on carbon was added and a hydrogen balloon was connected to the reaction flask. The flask was flushed five times with hydrogen and stirred at room temperature under hydrogen atmosphere for 16 hours. The solid was filtered and washed with methanol. The filtrate was evaporated under reduced pressure yielding 6-[2-(dimethylamino)ethoxy]pyridin-3-amine as a brown oil (250 mg, 99%). LC/MS (m/z): 182.1 (MH+), Rt 0.36 minutes.
Reaction SMILES: [OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([C@@H:24]([N:26]2[CH2:31][CH2:30][C@:29]([CH2:38][C:39](O)([CH3:41])[CH3:40])([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:28][C:27]2=[O:43])[CH3:25])=[CH:20][CH:19]=1>O1CCCC1.C1(C)C=CC=CC=1>[Br:17][C:18]1[CH:19]=[CH:20][C:21]([C@@H:24]([N:26]2[CH2:31][CH2:30][C@@:29]([CH2:38][C:39]([CH3:41])=[CH2:40])([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[O:28][C:27]2=[O:43])[CH3:25])=[CH:22][CH:23]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=C(C)C[C@@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
(Methoxycarbonylsulfamoyl)triethylammonium hydroxide (1.38 g) is added to 3-[(S)-1-(4-bromo-phenyl)-ethyl]-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one (2.0 g) dissolved in tetrahydrofuran (30 mL) and toluene (15 mL). The resulting solution was stirred at room temperature for 0.5 h and at 75° C. for 1 h. After cooling to room temperature, the solution was concentrated and ethyl acetate was added to the residue. The resulting mixture was washed with aqueous NaHCO3 solution and brine and dried (MgSO4). The title compound was obtained after removal of the solvent. Yield: 1.9 g (quantitative). Mass spectrum (ESI+): m/z=414/416 (Br) [M+H]+
Reaction SMILES: O.C[Si]([Cl:6])(C)C.[CH3:7][N:8]([CH2:10][CH:11]1[CH2:19][CH2:18][CH:17]2[CH:13]([CH2:14][CH2:15][CH2:16]2)[C:12]1([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=1)[OH:20])[CH3:9]>CC(=O)CC>[ClH:6].[CH3:9][N:8]([CH2:10][CH:11]1[CH2:19][CH2:18][CH:17]2[CH:13]([CH2:14][CH2:15][CH2:16]2)[C:12]1([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=1)[OH:20])[CH3:7]
Reactant: C[Si](C)(C)Cl
Agent: CN(C)CC1CCC2CCCC2C1(O)c1cccc(O)c1
Solvent: O
Solvent: CCC(C)=O
Product: Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Add H2O (10 mg, 0.54 mmol) and TMSCl (35 mg, 0.33 mmol) to a solution of 5-((dimethylamino)methyl)-4-(3-hydroxyphenyl)octahydro-1H-inden-4-ol (78 mg, 0.27 mmol) in 2-butanone (10 mL). Then stir the mixture at room temperature for 12 hours. Evaporate the mixture under vacuum to give 5-((dimethylamino)methyl)-4-(3-hydroxyphenyl)octahydro-1H-inden-4-ol hydrochloride as a mixture of 4 diastereoisomers (91 mg, Yield: 100%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24].[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][NH2:39])[CH:33]=1>>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:39][CH2:38][C:34]3[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=3)=[O:19])=[CH:20][CH:21]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)(=[O:25])=[O:24]
Reactant: NCc1cccnc1
Reactant: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)c1ccccc1
Yield: 48.4 %

Procedure:
Reaction of oxalyl chloride (102 λL, 1.17 mmol) and benzoic acid 17 (280 mg, 0.78 mmol) with subsequent coupling to 3-pyridinylmethylamine (87 λL, 0.86 mmol) gave benzamide 18 (169 mg, 48%) as a white powder: mp (EtOAc) 196-198° C.; 1H NMR δ 9.20 (t, J=5.9 Hz, 1H, CONH), 8.57 (br s, 1H, H-2′), 8.46 (br s, 1H, H-6′), 8.00 (br dd, J=8.6, 1.8 Hz, 2H, H-2, H-6), 7.89 (br dd, J=8.6, 1.8 Hz, 2H, H-3, H-5), 7.80 (br d, J=8.5 Hz, 2H, H-2″, H-6″), 7.71-7.76 (m, 2H, H-4′, H-4″), 7.62 (br dd, J=8.2, 7.5 Hz, 2H, H-3″, H-5″), 7.36 (dd, J=7.8, 4.8 Hz, 1H, H-5′), 4.68 (s, 2H, CH2SO2), 4.50 (d, J=5.8 Hz, 2H, CH2N), 2.13 (s, 3H, CH3); 13C NMR δ 165.4, 157.9, 149.9, 148.8, 148.0, 138.3, 135.3, 135.0, 134.8, 133.8, 129.1 (2), 128.7, 128.1 (2), 128.0 (2), 125.8, 125.3 (2), 123.4, 52.7, 40.4, 9.5; MS m/z 448.5 (MH+, 100%). Anal. calcd for C24H21N3O4S: C, 64.41; H, 4.73; N, 9.39. Found: C, 64.23; H, 4.71; N, 9.37%.
Reaction SMILES: NC1C=C(Br)SC=1C(N)=O.Cl.N12CCC(CC1)C[C@@H]2C(O)=O.C(N(C(C)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.[Br:56][C:57]1[S:61][C:60]([C:62](=[O:64])[NH2:63])=[C:59]([NH:65][C:66]([C@H:68]2[CH2:73][CH:72]3[CH2:74][CH2:75][N:69]2[CH2:70][CH2:71]3)=O)[CH:58]=1>CN(C)C=O.O>[N:69]12[CH2:75][CH2:74][CH:72]([CH2:71][CH2:70]1)[CH2:73][C@@H:68]2[C:66]1[NH:63][C:62](=[O:64])[C:60]2[S:61][C:57]([Br:56])=[CH:58][C:59]=2[N:65]=1
Reactant: NC(=O)c1sc(Br)cc1NC(=O)[C@H]1CC2CCN1CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=c1[nH]c([C@H]2CC3CCN2CC3)nc2cc(Br)sc12
Temperature: 70 °C
Reaction time: 20 h

Procedure:
To a solution of 3-amino-5-bromothiophene-2-carboxamide (200 mg) produced in Example 1, step D, (2R)-1-azabicyclo[2.2.2]octane-2-carboxylic acid hydrochloride (173 mg), and N-ethyl-N-(1-methylethyl)propan-2-amine (0.395 mL) in N,N-dimethylformamide (4.0 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (413 mg) at 0° C., and the reaction system was stirred at 70° C. for 20 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give a mixture of (2R)—N-(5-bromo-2-carbamoylthiophen-3-yl)-1-azabicyclo[2.2.2]octane-2-carboxamide and the title compound. A mixed solution of (2R)—N-(5-bromo-2-carbamoylthiophen-3-yl)-1-azabicyclo[2.2.2]octane-2-carboxamide and the title compound produced above, and ethanol (2.0 mL) and 2M aqueous sodium hydroxide solution (1.8 mL) was stirred at 70° C. for 2 hr. The reaction mixture was neutralized with 1M hydrochloric acid at 0° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/hexane and methanol/ethyl acetate) to give the title compound (114 mg) as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[C:6]([CH3:20])[N:5]=[CH:4][N:3]=1.[NH3:21]>C(O)C>[NH2:21][C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[C:6]([CH3:20])[N:5]=[CH:4][N:3]=1
Reactant: N
Reactant: Cc1ncnc(Cl)c1C#Cc1ccc(C(F)(F)F)cc1
Solvent: CCO
Product: Cc1ncnc(N)c1C#Cc1ccc(C(F)(F)F)cc1

Procedure:
A mixture of 4-chloro-6-methyl-5-{[4-(trifluoromethyl)phenyl]ethynyl}pyrimidine and ethanol was saturated with ammonia gas and reacted under heating in a shield tube to obtain a target substance. The target substance was subjected to e.g., proton nuclear magnetic resonance spectrometry (1H-NMR) and mass spectrometry (MS) and confirmed as the titled compound. Furthermore, MS measurement result is shown.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[CH:17][C:16]=2[C:31]2[N:32]([CH3:37])[N:33]=[CH:34][C:35]=2[Br:36])[CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[Br:36][C:35]1[CH:34]=[N:33][N:32]([CH3:37])[C:31]=1[C:16]1[CH:17]=[C:18]([NH:21][C:22](=[O:30])[C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH:19]=[CH:20][C:15]=1[O:14][CH:10]1[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: Cn1ncc(Br)c1-c1cc(NC(=O)c2ccc(F)cc2)ccc1OC1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1ncc(Br)c1-c1cc(NC(=O)c2ccc(F)cc2)ccc1OC1CCCNC1
Temperature: 25 °C
Yield: 121.2 %

Procedure:
To 3-[2-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(4-fluoro-benzoylamino)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (36 mg) was added HCl in dioxane (4 M, 1 mL), the mixture was stirred at r.t. for a few hours. The solvent was concentrated in vacuo to give the title compound (36 mg) as HCl salt. 1H NMR (DMSO-d6, 400 MHz) δ 1.42-2.08 (m, 4H), 2.72-3.38 (m, 4H), 3.73 (d, 3H), 4.45 (m, 1H), 7.33-7.39 (m, 3H), 7.65 (d, J=2.53 Hz, 1H), 7.74 (t, J=3.03 Hz, 1H), 7.90-7.95 (m, 1H), 8.03-8.07 (m, 2H), 8.85-9.02 (m, 1H), 9.15-9.30 (m, 1H), 10.4 (s, 1H). Exact mass calculated for C22H22BrFN4O2 472.1. found 473.3/475.3 (MH+).
Reaction SMILES: [CH2:1]([NH2:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH2:16]([NH:19][S:20](Cl)(=[O:22])=[O:21])[CH2:17][CH3:18]>>[CH2:16]([NH:19][S:20]([NH:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])(=[O:22])=[O:21])[CH2:17][CH3:18]
Reactant: CCCNS(=O)(=O)Cl
Reactant: CCCCCCCCCCCCCCN
Product: CCCCCCCCCCCCCCNS(=O)(=O)NCCC
Yield: 55 %

Procedure:
The title compound was prepared following the method described Example 6. The starting reactants are 0.10 g (0.5 mmol) of N-tetradecylamine and 0.076 g (0.5 mmol) of N-propylsulfamoyl chloride. 0.092 g of a white solid are obtained. Yield 55%; m.p. 105-107° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:11][C:10]=2[C:21]2[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.[NH:28]1[CH:32]=[CH:31][CH:30]=[N:29]1.C(=O)([O-])[O-].[K+].[K+]>[Cu]I.CN1C(=O)CCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:11][C:10]=2[C:21]2[CH:26]=[CH:25][C:24]([N:28]3[CH:32]=[CH:31][CH:30]=[N:29]3)=[CH:23][CH:22]=2)=[CH:4][CH:3]=1
Reactant: Cn1c(-c2ccccn2)nc(-c2ccc(I)cc2)c1Sc1ccc(Cl)cc1
Reactant: c1cn[nH]c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cn1c(-c2ccccn2)nc(-c2ccc(-n3cccn3)cc2)c1Sc1ccc(Cl)cc1
Temperature: 195 °C

Procedure:
To a microwave tube were added 2-[5-[(4-chlorophenyl)thio]-4-(4-iodophenyl)-1-methyl-1H-imidazol-2-yl]pyridine (Example 61, 150 mg, 0.298 mmol), CuI (5.67 mg, 0.03 mmol), pyrazole (41 mg, 0.595 mmol), potassium carbonate (82 mg, 0.595 mmol), and 4 mL of NMP. The reaction was heated at 195° C. for 90 min via microwave. After filtration through Celite, the reaction mixture was purified by reverse phase HPLC to afford the title compound. 1H NMR (500 MHz, (CDCl3): 8.66 (d, 1H), 8.37 (d, 1H), 8.24 (d, 2H), 7.96 (d, 1H), 7.86 (dt, 1H), 7.76 (d, 2H), 7.54 (d, 2H), 7.53 (m, 1H), 7.33 (dd, 1H), 7.24 (d, 2H), 7.06 (d, 2H), 6.48 (m, 1H), 4.16 (s, 3H). LCMS: m/z 444 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[N:11]3[N:12]=[C:13]([O:18][CH3:19])[CH:14]=[C:15]([O:16][CH3:17])[C:10]3=[N:9][C:8]=2[C:20]2[CH:25]=[CH:24][C:23]([C:26]3([NH:30]C(=O)OC(C)(C)C)[CH2:29][CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)Cl.Cl.[OH-].[Na+]>CO>[CH3:19][O:18][C:13]1[CH:14]=[C:15]([O:16][CH3:17])[C:10]2[N:11]([C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:8]([C:20]3[CH:21]=[CH:22][C:23]([C:26]4([NH2:30])[CH2:27][CH2:28][CH2:29]4)=[CH:24][CH:25]=3)[N:9]=2)[N:12]=1
Reactant: COc1cc(OC)c2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)n2n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 79 %

Procedure:
To a solution of tert-butyl (1-{4-[3-phenyl-6,8-dimethoxyimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-7 (0.18 g, 0.37 mmol) in methanol (2.2 mL) and DCM (3.5 mL) was added hydrogen chloride (4 M in dioxane, 1.8 mL, 7.3 mmol, 20.0 eq), and the resulting mixture was stirred at room temperature for 20 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 dried (Na2SO4) and concentrated under reduced pressure. The resulting material was purified using MPLC (Biotage Isolera; 10 g SNAP cartridge: 100% DCM 6.0 min., gradient to 95% DCM/5% MeOH 4 min., 95% DCM/5% MeOH 5 min., gradient to 90% DCM/10% MeOH 3.5 min.) to give 1-[4-(6,8-dimethyloxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine (0.11 g, 79%):
Reaction SMILES: [C:1]([C:3]1[NH:7][C:6]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=2[Cl:19])=[N:5][C:4]=1[C:20]([OH:22])=O)#[N:2].[F-].[K+].[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26]>COCCOCCOC.ClCCl>[CH2:25]([N:27]([CH2:28][CH3:29])[C:20]([C:4]1[N:5]=[C:6]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:16])([F:18])[F:17])=[CH:10][C:9]=2[Cl:19])[NH:7][C:3]=1[C:1]#[N:2])=[O:22])[CH3:26]
Reactant: CCNCC
Reactant: N#Cc1[nH]c(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C(=O)O
Agent: [F-]
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOCCOC
Product: CCN(CC)C(=O)c1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)[nH]c1C#N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 16 %

Procedure:
5-cyano-2-(2,6-dichloro-4-trifluoromethylphenyl)-imidazole-4-carboxylic acid (1.4 g, 0.004 mol) in 2-methoxyethyl ether (11 ml) whilst maintaining the temperature at about 0° C. Potassium fluoride (0.67 g, 0.0115 mol) was added and the mixture was stirred at 0° C. for 0.5 hours, and added slowly to a solution of diethylamine (8.8 g, 12.5 ml, 0.12 mol) in dichloromethane (75 ml) whilst maintaining the temperature in the range 0°-5° C. The mixture was stirred at 0°-5° C. for 1 hour and at room temperature for 0.5 hours. The mixture was washed with saturated aqueous sodium bicarbonate solution (50 ml), dried over anhydrous sodium sulphate and evaporated to dryness. The residue was purified by mplc on silica eluting with a mixture of ethyl acetate and dichloromethane (1:2) to give N,N-diethyl 5-cyano-2-(2,6-dichloro-4-trifluoromethylphenyl)imidazole-4-carboxamide (0.26 g) m.p. 195°- 197° C. as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([CH2:12][C@@H:13]([NH:19][C:20]([N:22]2[CH2:27][CH2:26][CH:25]([N:28]3[CH2:34][CH2:33][C:32]4[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=4[NH:30][C:29]3=[O:39])[CH2:24][CH2:23]2)=[O:21])[C:14]([O:16]CC)=[O:15])=[CH:4][C:3]=1[Cl:40].O.[OH-].[Li+]>C1COCC1.O.Cl>[NH2:1][C:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][C:5]([CH2:12][C@@H:13]([NH:19][C:20]([N:22]2[CH2:23][CH2:24][CH:25]([N:28]3[CH2:34][CH2:33][C:32]4[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=4[NH:30][C:29]3=[O:39])[CH2:26][CH2:27]2)=[O:21])[C:14]([OH:16])=[O:15])=[CH:4][C:3]=1[Cl:40]
Reactant: CCOC(=O)[C@@H](Cc1cc(Cl)c(N)c(C(F)(F)F)c1)NC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1c(Cl)cc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 6.0 g (10.31 mmol) ethyl (R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-carbonyl]-amino}-propionate in 50 mL THF was added a solution of 0.64 g (15 mmol) lithium hydroxide hydrate in 100 mL of water. A further 100 mL each of water and THF were added to this suspension, and after 5 min a solution was formed. It was stirred for 1 h at RT, the THF was eliminated i.vac., diluted with 100 mL of water and 1 M HCl was added dropwise while cooling with ice until an acidic reaction was obtained. The substance precipitated was filtered, washed with water and dried in the air.
Reaction SMILES: [CH2:1]([N:6]([C:21]1[CH:30]=[CH:29][C:28]2[C:27]([CH3:32])([CH3:31])[CH2:26][CH2:25][C:24]([CH3:34])([CH3:33])[C:23]=2[CH:22]=1)[C:7](=[O:20])[NH:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[K+].C1COCC1.Cl>C(O)C.O>[CH2:1]([N:6]([C:21]1[CH:30]=[CH:29][C:28]2[C:27]([CH3:32])([CH3:31])[CH2:26][CH2:25][C:24]([CH3:33])([CH3:34])[C:23]=2[CH:22]=1)[C:7](=[O:20])[NH:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCN(C(=O)Nc1ccc(C(=O)OCC)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CCCCCN(C(=O)Nc1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 45 °C
Yield: 83.3 %

Procedure:
A solution of ethyl 4-[3-pentyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ureido]-benzoate (37) (360 mg, 0.77 mmole) in 10 mL ethanol was treated with 430 mg of potassium hydroxide in 2 mL water. THF (2 mL) was added and the mixture was heated to 45° C. for two hours. The reaction mixture was diluted with 10 mL water, the pH adjusted to 2 with concentrated HCl and then extracted with three 25 mL portions of ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo, to give a pale yellow solid. The product was purified by trituration in pentane and 280 mg of 4-[3-pentyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ureido]-benzoic acid (27) were obtained as a white solid. M.P.: 184-186° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.Cl.[CH2:16]([N:18]=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.CN>CN(C)C=O.C1COCC1.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([NH:18][CH3:16])=[O:14])[CH:6]=[CH:5]2
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccc2cc(Br)ccc2c1
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)c1ccc2cc(Br)ccc2c1
Yield: 95.6 %

Procedure:
6-Bromo-2-naphthoic acid (60.26 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (55.21 g) and 1-hydroxy-1H-benzotriazole monohydrate (44.1 g) were dissolved in dimethylformamide (960 ml) under an argon atmosphere. N-Ethyldiisopropylamine (37.23 g) was added with stirring under ice-cooling. A solution (2M; 192 ml) of methylamine in THF was added and the mixture was stirred at room temperature for 18 h. The reaction mixture was poured into water (8 L) with stirring and the precipitate was collected by filtration. The precipitate was washed successively with water and diisopropyl ether, and dried in the presence of phosphorus pentaoxide at 70° C. to give the title compound (60.6 g) as a crystalline powder.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]3[S:13][CH:12]=[C:11]([C:14]([OH:16])=O)[C:7]=3[N:8]=[CH:9][N:10]=2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:50][C:51]1[CH:52]=[C:53]([NH:58][C:59](=[O:76])[C:60]2[CH:65]=[CH:64][C:63]([N:66]3[CH2:71][CH2:70][O:69][CH2:68][CH2:67]3)=[C:62]([C:72]([F:75])([F:74])[F:73])[CH:61]=2)[CH:54]=[CH:55][C:56]=1[CH3:57]>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([NH:4][C:5]2[C:6]3[S:13][CH:12]=[C:11]([C:14]([NH:50][C:51]4[CH:52]=[C:53]([NH:58][C:59](=[O:76])[C:60]5[CH:65]=[CH:64][C:63]([N:66]6[CH2:71][CH2:70][O:69][CH2:68][CH2:67]6)=[C:62]([C:72]([F:75])([F:74])[F:73])[CH:61]=5)[CH:54]=[CH:55][C:56]=4[CH3:57])=[O:16])[C:7]=3[N:8]=[CH:9][N:10]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1csc2c(NC3CC3)ncnc12
Reactant: Cc1ccc(NC(=O)c2ccc(N3CCOCC3)c(C(F)(F)F)c2)cc1N
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
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)c2ccc(N3CCOCC3)c(C(F)(F)F)c2)cc1NC(=O)c1csc2c(NC3CC3)ncnc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
4-(Cyclopropylamino)thieno[3,2-d]pyrimidine-7-carboxylic acid (23 mg, 0.10 mmol) was dissolved in dimethylformamide 1.0 mL, HATU (76 mg, 0.20 mmol) and N,N-diisopropylethylamine (0.081 mL, 0.47 mmol) was added thereto, and the mixture was stirred at room temperature for 30 minutes. N-(3-amino-4-methylphenyl)-4-morpholino-3-(trifluoromethyl)benzoamide (25 mg, 0.066 mmol) was added to the reaction mixture and subjected to a reaction at 45° C. for 17 hours. After cooling to room temperature the reaction mixture was diluted with ethyl acetate (5 mL) and washed with an aqueous sodium hydrogen carbonate solution (5 mL). The organic layer was washed with brine (5 mL×3), dried with sodium sulfate, and the solvent was distilled under reduced pressure. The concentrated reactant was crystallized using ethyl acetate (1 mL) and n-hexane (10 mL) to obtain the title compound as a bright brown solid (34 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)[CH3:2].C(N(CC)CC)C.[C:18](OC(=O)C)(=[O:20])[CH3:19].Cl>ClCCl>[CH2:1]([O:3][C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:18](=[O:20])[CH3:19])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOc1ccc(N)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1ccc(NC(C)=O)cc1
Reaction time: 1 h

Procedure:
4-Ethoxyaniline (40 g, 0.29 mol) and triethylamine (61 mL, 0.44 mol) were dissolved in dichloromethane (200 mL). Acetic anhydride (30 mL, 0.32 mol) was added in drops thereto, and the mixture was stirred for 1 h at 0° C. to room temperature. 1N hydrochloric acid solution was added, and the reaction mixture was extracted with ethyl acetate, washed with sodium chloride solution, and dried over anhydrous magnesium sulfate to give the title compound.