Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[C:16]3[CH2:19][CH2:20][CH2:21][C:15]=3[N:14]([CH3:22])[C:13]2=[O:23])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]>C(O)(C)(C)C>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[C:16]3[CH2:19][CH2:20][CH2:21][C:15]=3[N:14]([CH3:22])[C:13]2=[O:23])=[CH:7][C:3]=1[C:4]([O:6][C:3]([CH3:7])([CH3:4])[CH3:2])=[O:5]
Reactant: Cn1c2c(c(=O)n(-c3cc(C(=O)O)c(Cl)cc3F)c1=O)CCC2
Solvent: CC(C)(C)O
Product: Cn1c2c(c(=O)n(-c3cc(C(=O)OC(C)(C)C)c(Cl)cc3F)c1=O)CCC2

Procedure:
using 2-chloro-4-fluoro-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoic acid via the corresponding acid chloride and tert.butanol there is obtained tert.butyl 2-chloro-4-fluoro-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d]-pyrimidin-3-yl)-benzoate, 1H-NMR (CDCl3, 400 MHz) 7.76 ppm (d, 1H), 7.31 ppm (d, 1H), 3.41 ppm (s, 3H), 2.94 ppm (m, 2H), 2.81 ppm (m, 2H), 2.17 ppm (m, 2H), 1.57 ppm (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[N:21][CH:22]=3)[CH:14]=[C:13]([NH:25][C:26]3[CH:31]=[N:30][CH:29]=[CH:28][N:27]=3)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1.[F-].[K+].C([OH:38])(C)(C)C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([NH2:24])=[O:38])=[N:21][CH:22]=3)[CH:14]=[C:13]([NH:25][C:26]3[CH:31]=[N:30][CH:29]=[CH:28][N:27]=3)[N:12]=2)[CH3:9])=[CH:6][CH:7]=1
Reactant: C[C@H](Nc1nc(Nc2cnccn2)cc(-c2ccc(C#N)nc2)n1)c1ccc(F)cc1
Reactant: CC(C)(C)O
Agent: [F-]
Agent: [K+]
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(-c2ccc(C(N)=O)nc2)n1)c1ccc(F)cc1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To 38 mg of (S)-5-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}picolinonitrile, was added t-butanol, and 60 mg of potassium fluoride supported on activated alumina was added thereto, and the mixture was stirred at 90° C. for 4 hours. The reaction solution was filtrated to remove precipitates, and then the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 25 mg of the objective compound as an amorphous solid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[CH:11][C:10](B2OC(C)(C)C(C)(C)O2)=[CH:9][N:8]=1.Cl[C:23]1[N:28]=[C:27]([NH2:29])[CH:26]=[N:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:8]=[CH:9][C:10]([C:23]2[N:28]=[C:27]([NH2:29])[CH:26]=[N:25][CH:24]=2)=[CH:11][N:12]=1
Reactant: Nc1cncc(Cl)n1
Reactant: C[C@H]1CCCN1c1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H]1CCCN1c1ncc(-c2cncc(N)n2)cn1
Temperature: 90 °C
Yield: 59.1 %

Procedure:
A flask was charged with (S)-2-(2-methylpyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (7.1 g, 24.55 mmol), 6-chloropyrazin-2-amine (2.89 g, 22.32 mmol), Pd(PPh3)4 (2.58 g, 2.232 mmol) and 1,4-dioxane (74.4 mL). The reaction mixture was purged with nitrogen for several minutes before aqueous 2M sodium carbonate (22.32 mL, 44.6 mmol) solution was added. The reaction mixture was then purged with nitrogen for another 10 minutes at 25° C. before it was heated to 90° C. under nitrogen overnight. 1,4-Dioxane was removed in vacuo and the crude mixture was diluted with EtOAc. The product was washed with water and brine. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified on silica gel chromatography to yield 3.38 g (13.2 mmol, 84%) of the title product as a light brown solid. ESI-MS (EI+, m/z): 258.26, 1H NMR (Chloroform-d) δ: 8.92 (d, J=5.3 Hz, 2H), 8.25 (s, 1H), 7.88 (s, 1H), 4.60 (s, 2H), 4.39 (d, J=5.8 Hz, 1H), 3.81-3.68 (m, 1H), 3.68-3.55 (m, 1H), 2.24-1.95 (m, 3H), 1.78 (s, 1H), 1.31 (d, J=6.3 Hz, 3H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:14][CH2:13][C:12]3[N:11]=[C:10]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[NH:9][C:8](=[O:22])[C:7]=3[C:6]=2[CH:23]=1.N1C=CC=CC=1.BrN1C(=O)CCC1=O>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:14]=[CH:13][C:12]3[N:11]=[C:10]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:18])[CH3:19])[NH:9][C:8](=[O:22])[C:7]=3[C:6]=2[CH:23]=1
Reactant: CC(C)(C)C(=O)Nc1nc2c(c(=O)[nH]1)-c1cc(Br)ccc1CC2
Agent: O=C1CCC(=O)N1Br
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(C)(C)C(=O)Nc1nc2ccc3ccc(Br)cc3c2c(=O)[nH]1

Procedure:
A mixture of N-(9-bromo-1,2,5,6-tetrahydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide (1.09 g, 2.9 mmoles) and pyridine (0.28 ml, 3.5 mmoles) in dry benzene (100 ml) was stirred and heated to reflux under a nitrogen atmosphere. N-Bromosuccinimide (0.57 g, 3.2 mmoles) was added in a single portion, and the mixture was vigorously stirred and refluxed for 1.5 hours. After cooling, benzene and excess pyridine were removed under reduced pressure, leaving a light yellow residue which was then triturated with methanol:methylene chloride (1:I), filtered and dried to give N-(9-bromo-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide. (0.4 g, 37%) 1H NMR (DMSO-d6, 200 MHz) δ: 1.26(s, 9H, t-butyl); 7.58(d, J=9.0 Hz, 1H, Ar); 7.74(dd, J=8.7, 2.1 Hz, 1H, Ar); 7.98(d, J=8.8 Hz, 1H, Ar); 8.25(d, J=9.0 Hz, 1H, Ar); 9.92(d, J=2.0 Hz, 1H, Ar); 11.35(br s, 1H, NH); 12.35(br s, 1H, NH).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[C:27]([CH3:28])=[CH:26][S:25][CH:24]=4)=[C:19]([CH3:29])[CH:18]=3)[O:14][N:13]=2)=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>>[OH:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[C:27]([CH3:28])=[CH:26][S:25][CH:24]=4)=[C:19]([CH3:29])[CH:18]=3)[O:14][N:13]=2)=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(-c2noc(-c3ccc(-c4cscc4C)c(C)c3)n2)ccc1O
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(-c2nc(-c3ccc(O)c(C(=O)O)c3)no2)ccc1-c1cscc1C

Procedure:
The title compound was prepared following procedure described for example 4, step 2, but starting from methyl 2-hydroxy-5-{5-[3-methyl-4-(4-methyl-3-thienyl)phenyl]-1,2,4-oxadiazol-3-yl}benzoate, obtained in step 1 and using 25 eq. of NaOH at 60° C. for 6 h. Solvents were concentrated and DCM (20 mL) was added. It was washed with HCl 1M. The organic layer was then dried over magnesium sulfate, filtered and concentrated to afford the title compound as a slightly orange solid. 1H NMR (DMSO-d6, 300 MHz) δ 8.52 (d, J=2.0 Hz, 1H), 8.15-8.12 (m, 2H), 8.06-8.03 (m, 1H), 7.46-7.39 (m, 2H), 7.35-7.34 (m, 1H), 7.10 (d, J=8.6 Hz, 1H), 2.24 (s, 3H), 2.01 (s, 3H). LC/MS (Method A): 390.9 (M−H)−. HPLC (Method A) Rt 5.39 min (Purity: 97.1%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:16][C:17]1[C:22]([C:23]([O:26][C:27](=[O:29])[CH3:28])([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=1)[CH2:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[CH:10][N:9]=1.C[Si]([N:34]=[C:35]=[O:36])(C)C>CC(O)C>[CH3:14][C:13]1[C:8]([CH2:7][N:6]([CH2:16][C:17]2[C:22]([C:23]([O:26][C:27](=[O:29])[CH3:28])([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:35]([NH2:34])=[O:36])=[N:9][CH:10]=[C:11]([CH3:15])[CH:12]=1
Reactant: CC(=O)OC(C)(C)c1cccnc1CN(CCCCN)Cc1ncc(C)cc1C
Reactant: C[Si](C)(C)N=C=O
Solvent: CC(C)O
Product: CC(=O)OC(C)(C)c1cccnc1CN(CCCCNC(N)=O)Cc1ncc(C)cc1C
Yield: 91.8 %

Procedure:
A solution of acetic acid 1-(2-{[(4-amino-butyl)-(3,5-dimethyl-pyridin-2-ylmethyl)-amino]-methyl}-pyridin-3-yl)-1-methyl-ethyl ester (223 mg, 0.56 mmol) in i-PrOH (3.7 mL) and treated with trimethylsilylisocyanate (110 μL, 0.78 mmol) at room temperature for 16 hours. The solution was then concentrated under reduced pressure and dried in vacuo. The crude material was then purified by column chromatography with silica gel (20:1:1 CH2Cl2/MeOH/NH4OH) to give almost pure acetic acid 1-(2-{[(3,5-dimethyl-pyridin-2-ylmethyl)-(4-ureido-butyl)-amino]-methyl}-pyridin-3-yl)-1-methyl-ethyl ester as a colorless oil (227 mg, 92%).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[C:20]([Cl:26])[N:19]=2)[CH2:14][CH2:13]1)=[O:10].Cl.[NH2:28][OH:29]>CO>[NH2:25][C:24](=[N:28][OH:29])[C:22]1[CH:21]=[C:20]([Cl:26])[N:19]=[C:18]([N:15]2[CH2:14][CH2:13][CH:12]([NH:11][C:9]([C:3]3[NH:4][C:5]([CH3:8])=[C:6]([Cl:7])[C:2]=3[Cl:1])=[O:10])[CH2:17][CH2:16]2)[CH:23]=1
Reactant: NO
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cc(C#N)cc(Cl)n3)CC2)c(Cl)c1Cl
Agent: Cl
Solvent: CO
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(N)=NO)cc(Cl)n3)CC2)c(Cl)c1Cl

Procedure:
3,4-Dichloro-N-[1-(6-chloro-4-cyanopyridin-2-yl)piperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide (Example 95; 150 mg, 0.362 mmol) was dissolved in MeOH (5 ml) and TEA (100 μl, 0.724 mmol) was added. Hydroxylamine hydrochloride (25.2 mg, 0.362 mmol) was added and the mixture was refluxed for 1 h. The solvent was removed in vacuo and the resulting precipitate was dissolved in DMSO and purified by semi preparative reverse phase HPLC eluting with CH3CN/H2O (0.1% TFA). (80 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:26]2[C:31](=[O:32])[NH:30][C:29](=[O:33])[CH:28]=[N:27]2)[CH:5]=[C:6]([CH3:25])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)O)[CH:10]=1.CS(O)(=O)=O.C([SiH](CC)CC)C.O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:26]2[C:31](=[O:32])[NH:30][C:29](=[O:33])[CH:28]=[N:27]2)[CH:5]=[C:6]([CH3:25])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH2:16][C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH:10]=1
Reactant: Cc1cc(-n2ncc(=O)[nH]c2=O)cc(Cl)c1Oc1ccc(O)c(C(O)c2ccc(F)cc2)c1
Agent: CC[SiH](CC)CC
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: O
Product: Cc1cc(-n2ncc(=O)[nH]c2=O)cc(Cl)c1Oc1ccc(O)c(Cc2ccc(F)cc2)c1

Procedure:
To a stirred solution of 2-(3-chloro-4-{3-[(4-fluoro-phenyl)-hydroxy-methyl]-4-hydroxy-phenoxy}-5-methyl-phenyl)-2H-[1,2,4]triazine-3,5-dione (0.4 g) in dichloromethane (25 mL) were added methanesulfonic acid (0.7 mL) and triethylsilane (1.5 mL) portionwise over 1 h. After a total of 1.5 h, water was added, the layers separated and the aqueous layer extracted with dichloromethane. The combined organic layers were washed with saturated sodium bicarbonate, dried (Na2SO4), concentrated in vacuo and flash chromatographed on silica gel (10-50% THF/hexanes) to afford the title compound of this EXAMPLE as a colorless foam, 56 mg. MS Calc.:453.9; Found:452.
Reaction SMILES: [CH:1]1([O:7][C:8]([O:10][CH2:11][CH2:12][O:13][C:14]([C:16]2[N:17]=[C:18]([C:47]([F:50])([F:49])[F:48])[N:19]3[CH2:24][CH2:23][N:22]([C:25](=[O:46])[CH2:26][C@H:27]([NH:38]C(OC(C)(C)C)=O)[CH2:28][C:29]4[CH:34]=[C:33]([F:35])[C:32]([F:36])=[CH:31][C:30]=4[F:37])[CH2:21][C:20]=23)=[O:15])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:51]>C(OCC)(=O)C>[ClH:51].[CH:1]1([O:7][C:8]([O:10][CH2:11][CH2:12][O:13][C:14]([C:16]2[N:17]=[C:18]([C:47]([F:48])([F:49])[F:50])[N:19]3[CH2:24][CH2:23][N:22]([C:25](=[O:46])[CH2:26][C@H:27]([NH2:38])[CH2:28][C:29]4[CH:34]=[C:33]([F:35])[C:32]([F:36])=[CH:31][C:30]=4[F:37])[CH2:21][C:20]=23)=[O:15])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)OCCOC(=O)OC3CCCCC3)c2C1)Cc1cc(F)c(F)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)OCCOC(=O)OC3CCCCC3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 96.1 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid (1-cyclohexyloxycarbonyloxy)-ethyl ester 38a (0.25 g, 0.347 mmol) and 5 mL of ethyl acetate were added into the reaction flask. A solution of 6.5 N hydrochloric acid in 3 mL of ethyl acetate was added to the flask under stirring. The reaction mixture was stirred at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid (1-cyclohexyloxycarbonyloxy)-ethyl ester hydrochloride 38 (0.22 g, yield 96.1%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[CH3:17][C:18]1[CH:22]=[C:21]([CH3:23])[N:20]([CH2:24][C:25](O)=[O:26])[N:19]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.[NH4+].[Cl-]>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][N:13]([C:25](=[O:26])[CH2:24][N:20]2[C:21]([CH3:23])=[CH:22][C:18]([CH3:17])=[N:19]2)[CH2:12][CH2:11]1
Reactant: Cc1cc(C)n(CC(=O)O)n1
Reactant: COC(=O)c1ccccc1N1CCNCC1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1N1CCN(C(=O)Cn2nc(C)cc2C)CC1
Reaction time: 8 h
Yield: 85.7 %

Procedure:
To a vial containing the 2-piperazin-1-yl-benzoic acid methyl ester (0.667 g, 3.03 mmol) is added a pre-mixed solution containing (3,5-dimethyl-pyrazol-1-yl)-acetic acid (0.428 g, 2.78 mmol) and carbonyl dimidazole (0.567 g, 3.50 mmol). The mixture is stirred overnight and then diluted with 200 mL of EtOAc followed by 200 mL of saturated NH4Cl. The organic phase is washed with 2×200 mL of H2O and 1×200 mL of brine, dried (MgSO4), filtered and concentrated to give 0.849 g of 2-{4-[2-(3,5-dimethyl-pyrazol-1-yl)-acetyl]-piperazin-1-yl}-benzoic acid methyl ester in 86% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=O)[CH2:8][CH2:7]2.[CH2:13]([NH2:16])[C:14]#[CH:15]>>[Br:1][C:2]1[C:11]2[C:10]3[CH:15]=[CH:14][CH:13]=[N:16][C:9]=3[CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCc2cccc(Br)c2C1
Reactant: C#CCN
Product: Brc1cccc2c1-c1cccnc1CC2
Yield: 49 %

Procedure:
The title compound is prepared from 8-bromo-2-tetralone and propargylamine following a procedure analogous to that described in Step 1 of Intermediates 1 and 2. Yield: 49% of theory; LC (method 1): tR=2.68 min; Mass spectrum (ESI+): m/z=260/262 (Br) [M+H]+.
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)(Cl)Cl>[O:30]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([F:31])[CH:37]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3-c2cccc(F)c2)CC1
Yield: 35 %

Procedure:
The title compound was synthesized in analogy to example 66, from [2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 1), 3-fluorophenylboronic acid, copper(II) acetate, pyridine and using chloroforme instead of dichloromethane as solvent, to give the desired product as a colorless foam (35%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([NH:22][CH3:23])(=[O:21])=[O:20]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:19]([NH:22][CH3:23])(=[O:21])=[O:20])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: CNS(=O)(=O)c1ccccc1N
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: ClC(Cl)Cl
Product: CNS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 61 °C

Procedure:
2,4-Dichloro-5-nitro-pyrimidine (1.94 g, 10 mmol) and 2-amino-N-methyl-benzenesulfonamide (1.86 g, 10 mmol) are dissolved in CHCl3 (30 mL). The reaction mixture is heated at 61° C. for 2 h. The solvent is evaporated and the residue is washed with ether to give the title product.
Reaction SMILES: Cl[C:2]1[C:10]2[C:6](=[N:7][O:8][N:9]=2)[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][CH:3]=1.[CH2:14]([C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:35][C:36]2[S:37][C:38]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][NH:46][CH3:47])=[N:39][N:40]=2)(=[O:34])=[O:33])=[CH:28][CH:27]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C([O-])(O)=O.[Na+]>CO>[CH2:14]([C:26]1[CH:27]=[CH:28][C:29]([S:32]([NH:35][C:36]2[S:37][C:38]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][N:46]([CH3:47])[C:2]3[C:10]4[C:6](=[N:7][O:8][N:9]=4)[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][CH:3]=3)=[N:39][N:40]=2)(=[O:33])=[O:34])=[CH:30][CH:31]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: O=[N+]([O-])c1ccc(Cl)c2nonc12
Reactant: CCCCCCCCCCCCc1ccc(S(=O)(=O)Nc2nnc(CCCCCNC)s2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCCCCc1ccc(S(=O)(=O)Nc2nnc(CCCCCN(C)c3ccc([N+](=O)[O-])c4nonc34)s2)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
4-Chloro-7-nitro-2,1,3-benzoxadiazole (NBD-Cl) (18 mg, 0.085 mmol) was dissolved in methanol (1 mL). After the addition of 4-dodecyl-N-(5-(5-(methylamino)pentyl)-1,3,4-thiadiazol-2-yl)benzenesulfonamide (43 mg, 0.085 mmol) and NaHCO3 (7 mg, 0.085 mmol) in methanol (2 mL), the solution was stirred for 2 h at 40° C. The reaction mixture was evaporated to dryness under reduced pressure and the residue was chromatographed on silica gel 60 (70-230 mesh) eluted with CH2Cl2:MeOH 49:1. Product 137 was obtained in 53% yield (30 mg, 0.045 mmol), mp 102-104° C. 1H NMR (300 MHz, CDCl3) δ 0.87 (t, 3, J=7.2 Hz), 1.25 (m, 18), 1.51-1.57 (m, 4), 1.79-1.85 (m, 4), 2.63 (t, 2, J=6.6 Hz), 2.84 (t, 2, J=7.5 Hz), 3.45 (s, 3), 4.14 (s, 2), 6.11 (d, 1, J=9.3 Hz), 7.27 (d, 2, J=8.1 Hz), 7.79 (d, 2, J=8.4 Hz), 8.44 (d, 1, J=9.0 Hz); 13C NMR (75 MHz, CDCl3) δ 14.1, 22.6, 25.7, 27.7, 29.2, 29.3, 29.4, 29.5, 29.6, 30.4, 31.1, 31.9, 35.9, 55.6, 101.2, 126.5, 128.9, 135.4, 138.3, 145.3, 148.5, 154.7, 158.3, 163.8, 167.9; HRMS (ESI+, m/z) calculated for C32H46N7O5S2 672.3002, observed 672.2996 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C@:9]([NH2:16])([CH3:15])[C:10]([F:14])([F:13])[CH2:11][OH:12])=[O:5])[CH3:2].[N:17]#[C:18]Br.C(#N)C>C(O)C>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C@:9]1([CH3:15])[C:10]([F:14])([F:13])[CH2:11][O:12][C:18]([NH2:17])=[N:16]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1C[C@@H]1[C@@](C)(N)C(F)(F)CO
Reactant: N#CBr
Solvent: CCO
Solvent: CC#N
Product: CCOC(=O)[C@H]1C[C@@H]1[C@@]1(C)N=C(N)OCC1(F)F
Temperature: 75 °C
Reaction time: 6 h
Yield: 67 %

Procedure:
A mixture of (1S,2S)-rel-2-((R)-1-amino-2,2-difluoro-3-hydroxy-1-methyl-propyl)-cyclopropane-carboxylic acid ethyl ester (542 mg, 2.28 mmol) and cyanogen bromide in acetonitrile (5M; 685 μl, 3.43 mmol) in ethanol (14 ml) was heated at 75° C. for 7 hours. In order to complete the reaction another volume of cyanogen bromide in acetonitrile (5M; 228 μl, 1.14 mmol, Eq: 0.50) was added and heating continued at 75° C. for 6 hours, and again cyanogen bromide in acetonitrile (228 μl, 1.14 mmol, Eq: 0.50) was added and heating continued at 75° C. for 24 hours. For the workup, the solution was evaporated, the residual oil was washed once with a solution of sodium carbonate (2M) and twice with ethyl acetate, then dried over sodium sulphate, filtered and concentrated at reduced pressure. The light yellow oil (731 mg) was purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 50:50 as the eluent. The (1S,2S)-rel-2-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-cyclopropanecarboxylic acid ethyl ester (404 mg, 67% yield) was obtained as a colorless oil. MS (ISP): m/z=263.2 [M+H]+.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH3:5][O:6][C:7]1[N:12]=[C:11]([CH3:13])[C:10]([NH2:14])=[C:9]([CH3:15])[N:8]=1>O1CCCC1.C(=O)([O-])O.[Na+]>[N:14]([C:10]1[C:9]([CH3:15])=[N:8][C:7]([O:6][CH3:5])=[N:12][C:11]=1[CH3:13])=[C:1]=[S:2]
Reactant: S=C(Cl)Cl
Reactant: COc1nc(C)c(N)c(C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nc(C)c(N=C=S)c(C)n1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 88 %

Procedure:
Thiophosgene (1.8 mL, 23.6 mmol) was added dropwise to a stirred mixture of 2-methoxy-4,6-dimethylpyrimidin-5-amine (2.82 g, 18.4 mmol) in tetrahydrofuran (25 mL) and saturated aqueous sodium hydrogen carbonate (25 mL) at 0° C., and the mixture was stirred at 0° C. for 40 minutes. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with diisopropyl ether/n-hexane to give the title compound as a pale yellow powder (3.16 g, 16.2 mmol, 88%).
Reaction SMILES: [N+:1](=[CH2:3])=[N-:2].[Br:4][C:5]1[CH:6]=[C:7]([CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH3:15])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].C(O)(=O)C>CCOCC.C(OCC)(=O)C>[Br:4][C:5]1[CH:6]=[C:7]([CH:13]2[CH2:3][N:1]=[N:2][C:14]2([CH3:15])[N+:16]([O-:18])=[O:17])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: C=[N+]=[N-]
Reactant: COc1ccc(C=C(C)[N+](=O)[O-])cc1Br
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COc1ccc(C2CN=NC2(C)[N+](=O)[O-])cc1Br
Reaction time: 28 h
Yield: 100.8 %

Procedure:
An ethereal solution of diazomethane (3.0 mL, 0.3M, 0.9 mmol) was added to 1-(3-bromo-4-methoxyphenyl)-2-nitropropene (250 mg, 0.92 mmol) dissolved in 2.5 mL of ether, and the solution was allowed to stand at room temperature for 28 h. Acetic acid (0.25 mL, 0.26 g, 4.4 mmol) was then added to the almost colorless solution, giving some gas evolution. After 15 min, the solution was diluted with 25 mL of ethyl acetate and washed with 10 mL of saturated aqueous sodium bicarbonate followed by 10 mL of saturated aqueous sodium chloride. The organic layer was dried (sodium sulfate), decanted, and evaporated to give 285 mg (99% yield) of a colorless oil which crystallized upon standing. 1H NMR (400 MHz, CDCl3): δ 7.17 (d, 1H, J=2 Hz), 6.89 (dd, 1H, J=8, 2 Hz), 6.84 (d, 1H, J=8 Hz), 5.21 (dd, 1H, J=18, 8 Hz), 4.97 (dd, 1H, J=18, 6 Hz), 3.90 (s, 3H), 3.77 (dd, 1H, J=8, 6 Hz), 1.60 (s, 3H).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([N:29]([CH2:37][CH2:38][C:39]([F:42])([F:41])[F:40])C(=O)OCCCC)[C:10]3[N:11]([C:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22](=[O:27])[NH:23][CH:24]5[CH2:26][CH2:25]5)=[C:18]([CH3:28])[CH:17]=4)=[CH:14][N:15]=3)[N:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.O>ClCCl>[CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([NH:29][CH2:37][CH2:38][C:39]([F:40])([F:41])[F:42])[C:10]3[N:11]([C:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([NH:23][CH:24]5[CH2:25][CH2:26]5)=[O:27])=[C:18]([CH3:28])[CH:17]=4)=[CH:14][N:15]=3)[N:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCCCOC(=O)N(CCC(F)(F)F)c1cc(NC2CCCC2)nn2c(-c3ccc(C(=O)NC4CC4)c(C)c3)cnc12
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cnc3c(NCCC(F)(F)F)cc(NC4CCCC4)nn23)ccc1C(=O)NC1CC1
Temperature: 23 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of 90 mg (153 μmol) ert-butyl {6-(cyclopentylamino)-3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]imidazo[1,2-b]pyridazin-8-yl}(3,3,3-trifluoropropyl)carbamate which was prepared according to intermediate example 453a in 1 mL dichloromethane were added 177 μL trifluoroacetic acid and the mixture was stirred for 2 hours at 23° C. The mixture was poured into water and extracted with dichloromethane. The organic phase was washed with sodium hydrogencarbonate solution and dried over sodium sulfate. After filtration and removal of solvent the residue was purified by chromatography to give 64.1 mg (82%) of the title compound.