Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH2:22][CH:23]([F:25])[F:24])[C:6]=1[N:7]1[CH2:13][CH2:12][CH2:11][C@H:10]([N:14]([CH3:21])[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:9][CH2:8]1.[Br:26][C:27]1[S:28][C:29]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[C:30]([C:32](O)=[O:33])[N:31]=1>>[Br:26][C:27]1[S:28][C:29]([NH:35][C:36](=[O:37])[O:38][C:39]([CH3:41])([CH3:40])[CH3:42])=[C:30]([C:32](=[O:33])[NH:1][C:2]2[CH:3]=[N:4][N:5]([CH2:22][CH:23]([F:25])[F:24])[C:6]=2[N:7]2[CH2:13][CH2:12][CH2:11][C@H:10]([N:14]([CH3:21])[C:15](=[O:20])[C:16]([F:18])([F:17])[F:19])[CH2:9][CH2:8]2)[N:31]=1
Reactant: CN(C(=O)C(F)(F)F)[C@H]1CCCN(c2c(N)cnn2CC(F)F)CC1
Reactant: CC(C)(C)OC(=O)Nc1sc(Br)nc1C(=O)O
Product: CN(C(=O)C(F)(F)F)[C@H]1CCCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2CC(F)F)CC1

Procedure:
Following the procedure for Intermediate 7 starting from (S)—N-(1-(4-amino-1-(2,2-difluoroethyl)-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoro-N-methylacetamide and 2-bromo-5-(tert-butoxycarbonylamino)-thiazole-4-carboxylic acid afforded (S)-tert-butyl 2-bromo-4-(1-(2,2-difluoroethyl)-5-(4-(2,2,2-trifluoro-N-methylacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as a pale pink gum (80 mg 57%). 1H NMR (400 MHz, CDCl3) δ 10.27 (s, 1H), 8.31 and 8.27 (2s, 1H), 7.88 and 7.85 (2s, 1H), 6.34-6.05 (m, 1H), 4.41-4.31 (m, 2H), 3.42-3.29 (m, 5H), 3.10 and 2.95 (2s, 3H), 2.08-1.75 (m, 4H), 1.40-1.15 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH3:11])[CH:3]=1.C(Cl)(=O)C(Cl)=O.CN.[CH2:20]([N:22](CC)CC)C>C(Cl)Cl.CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:22][CH3:20])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: CCN(CC)CC
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(Br)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
N,N-Dimethylformamide (10 uL) was added to a mixture of 4-bromo-2-methylbenzoic acid (1.0 g, 0.0046 mol) in oxalyl chloride (2.0 mL, 0.023 mol). The mixture was stirred at r.t. overnight. The volatiles were removed under reduced pressure. The residue was dissolved in methylene chloride (2 mL). To the solution was added to a mixture of methylamine (0.41 mL, 0.0093 mol) and triethylamine (1.3 mL, 0.0093 mol) in DCM (10 ml). After 30 min, the reaction mixture was quenched with aqueous sodium carbonate (10 mL) and extracted with DCM (3×20 mL). The organic layers were washed with brine, dried over Na2SO4, filtered. The solvents were removed under reduced pressure to give a crude product (980 mg, 92.4%). LCMS (M+H)+: m/z=228.1/230.2.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[S:3]([C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([NH2:13])[C:7]=1[OH:14])(=[O:5])=[O:4].[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]=[C:24]=[S:25]>C(O)C>[Cl:12][C:11]1[CH:10]=[CH:9][C:8]([NH:13][C:24]([NH:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[Br:16])=[S:25])=[C:7]([OH:14])[C:6]=1[S:3]([N:2]([CH3:15])[CH3:1])(=[O:5])=[O:4]
Reactant: S=C=Nc1ccccc1Br
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(N)c1O
Solvent: CCO
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=S)Nc2ccccc2Br)c1O
Yield: 22.1 %

Procedure:
A solution of N,N-dimethyl-3-amino-6-chloro-2-hydroxybenzene sulfonamide (480 mg, 3.58 mmol) and 2-bromophenylisothiocyanate (0.53 μL, 3.94 mmol) in 10 mL of ethanol was stirred at room temperature for overnight. Purification by column chromatography on silica gel, eluting with ethyl acetate/hexane (gradient elution) gave the desired product (368 mg, 22%). EI-MS (m/z) 463.67, 465.66, 467.65, 468.64 (M+).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.C1N=C[N:13](C(N2C=NC=C2)=O)C=1.[OH-].[NH4+]>CCOC(C)=O>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([NH2:13])=[O:10])[CH2:4][CH2:3]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C[C@H]1CC[C@H](C(=O)O)CC1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: C[C@H]1CC[C@H](C(N)=O)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of trans-4-methylcyclohexane carboxylic acid (1.00 g, 7.03 mmol) in EtOAc (15 mL) was treated with CDI (1.425 g, 8.79 mmol) and stirred at RT for 20 minutes. Ammonium hydroxide (˜14M, 5.00 mL, ˜70.0 mmol) was added, the mixture stirred for 20 minutes, then concentrated to dryness. The material was treated with satd. NaHCO3 and the solids collected via filtration and dried to afford trans-4-methylcyclohexanecarboxamide (842 mg, 85%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.13 (s, 1H), 6.61 (s, 1H), 1.94 (m, 1H), 1.70 (m, 4H), 1.25 (m, 3H), 0.84 (m, 5H); MS (ESI) m/z: 142.1 (M+H+).
Reaction SMILES: [CH3:1][C@@H:2]([CH2:8][CH2:9][CH2:10][C:11]([CH3:14])([OH:13])[CH3:12])/[CH:3]=[CH:4]\[CH2:5][CH2:6][OH:7].[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][C@@H:2]([CH2:8][CH2:9][CH2:10][C:11]([CH3:14])([OH:13])[CH3:12])[CH2:3][CH2:4][CH2:5][CH2:6][OH:7]
Reactant: [H][H]
Reactant: C[C@H](/C=C\CCO)CCCC(C)(C)O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@H](CCCCO)CCCC(C)(C)O
Yield: 100.7 %

Procedure:
To a solution of diol 13 (55 mg, 0.27 mmol) in ethyl acetate (10 mL) was added Pd/C (10%, 50 mg). The reaction mixture was stirred for 18 hours under a continuous stream of hydrogen at room temperature. The mixture was then filtered, and the solvent was evaporated under reduced pressure. The crude oily product was chromatographed on silica Sep-Pak cartridge eluted with hexane/EtOAc (8:2) to give an oily diol 14 (55 mg, 45%).
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:18]=[CH:17][C:6]2[NH:7][C:8](C(OC(C)(C)C)=O)=[N:9][C:5]=2[CH:4]=1.Br[C:22]1[N:27]=[C:26]2[N:28]([CH2:32][CH:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[C:29](=[O:31])[NH:30][C:25]2=[N:24][CH:23]=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:7]1[C:6]2[CH:17]=[CH:18][C:3]([C:22]3[N:27]=[C:26]4[N:28]([CH2:32][CH:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)[C:29](=[O:31])[NH:30][C:25]4=[N:24][CH:23]=3)=[CH:4][C:5]=2[N:9]=[CH:8]1
Reactant: O=c1[nH]c2ncc(Br)nc2n1CC1CCOCC1
Reactant: CC(C)(C)OC(=O)c1nc2cc([Sn](C)(C)C)ccc2[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: O=c1[nH]c2ncc(-c3ccc4[nH]cnc4c3)nc2n1CC1CCOCC1
Yield: 10.5 %

Procedure:
6-(1H-Benzo[d]imidazol-5-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazol-[4,5-b]pyrazin-2(3H)-one hydrochloride. tert-Butyl 5-(trimethylstannyl)-1H-benzo[d]imidazole-2-carboxylate (640 mg, 1.7 mmol), 6-bromo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (See Example 101.B) (420 mg, 1.3 mmol), dichlorobis(triphenylphosphine)palladium(II) (90 mg, 0.13 mmol) in DMF (25 mL) were reacted for 1.5 h at 90° C. The product was purified by reverse-phase semi-preparatory HPLC (30-100% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). The desired fractions were concentrated, treated with 4N hydrochloric acid in diethyl ether (few drops), and sonicated. This procedure was repeated twice more to provide 6-(1H-benzo[d]imidazol-5-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (48 mg, 10% yield) as the hydrochloride salt. 1H NMR (400 MHz, DMSO-d6) 12.07 (s, 1H), 8.55 (s, 1H), 8.52 (s, 1H), 8.33 (s, 1H), 8.06 (dd, J=8.0, 1.6, 1H), 7.80 (d, J=8.8, 1H), 3.81 (m, 2H), 3.80 (d, J=7.2, 2H), 3.27 (d, J=11.6, 2H), 2.14 (m, 1H), 1.59 (m, 2H), 1.33 (m, 2H); MS (ESI) m/z 351.2 [M+1]+.
Reaction SMILES: [F:1][C@@H:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:4]([OH:7])[CH2:5][OH:6].O([Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])S(C(F)(F)F)(=O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Si:30]([O:7][CH:4]([CH2:5][O:6][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C@H:2]([F:1])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)N[C@H](C(O)CO)[C@@H](F)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C(CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C)[C@H](F)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 117.6 %

Procedure:
To a 500 mL RBF containing tert-butyl (1S,2R)-1-fluoro-3,4-dihydroxy-1-phenylbutan-2-ylcarbamate (98.00 mg, 327 μmol) was added DCM (5 mL) and the mixture was allowed to stir at 0° C. for 5 min. At this time, TEA (274 μl, 1964 μmol) and tert-butyldimethylsilyl triflate (188 μl, 818 μmol) was added to the mixture via syringe. The reaction was allowed to stir for 30 min and then queched with sodium bicarbonate (50 ml, sat). The aq. layer was extracted with DCM (3×25 ml). The combined organics were washed with brine, dried with sodium sulfate and passed through a plug of silica gel and concentrated to give 203 mg of a yellow oil that was taken directly to the next step.
Reaction SMILES: N[C@H](C(O)=O)CC(=O)O.N[C@H](C(O)=O)CCC(=O)N.N[C@H](C(N)=O)CC(=O)N.N1C(=O)CC[C@H]1C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(NCC(NCC(NCC(N[C@H:79]([C:82]([NH:84][C@H:85]([C:90]([OH:92])=[O:91])[CH2:86][C:87](=[O:89])[NH2:88])=[O:83])[CH2:80][OH:81])=O)=O)=O)=O)CCC(=O)N)=O)CO)=O)CCCCN)=O)C)=O.[NH:93]1[C:97](=[O:98])[CH2:96][CH2:95][C@H:94]1[C:99]([NH:101][C@H:102]([C:104]([NH:106][C@H:107]([C:113]([NH:115][C@H:116]([C:119]([NH:121][C@H:122]([C:128]([NH:130][CH2:131][C:132]([NH:134][C@H:135]([C:138]([NH:140][C@H](C(O)=O)CC(=O)N)=[O:139])CO)=[O:133])=[O:129])[CH2:123][CH2:124][C:125](=[O:127])[NH2:126])=[O:120])[CH2:117][OH:118])=[O:114])[CH2:108][CH2:109][CH2:110][CH2:111][NH2:112])=[O:105])[CH3:103])=[O:100]>>[NH:93]1[C:97](=[O:98])[CH2:96][CH2:95][C@H:94]1[C:99]([NH:101][C@@H:102]([C:104]([NH:106][C@H:107]([C:113]([NH:115][C@H:116]([C:119]([NH:121][C@H:122]([C:128]([NH:130][CH2:131][C:132]([NH:134][CH2:135][C:138]([NH:140][C@H:79]([C:82]([NH:84][C@H:85]([C:90]([OH:92])=[O:91])[CH2:86][C:87](=[O:89])[NH2:88])=[O:83])[CH2:80][OH:81])=[O:139])=[O:133])=[O:129])[CH2:123][CH2:124][C:125](=[O:127])[NH2:126])=[O:120])[CH2:117][OH:118])=[O:114])[CH2:108][CH2:109][CH2:110][CH2:111][NH2:112])=[O:105])[CH3:103])=[O:100]
Reactant: C[C@H](NC(=O)[C@@H]1CCC(=O)N1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)O
Reactant: C[C@H](NC(=O)[C@@H]1CCC(=O)N1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)NCC(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)O
Agent: NC(=O)CC[C@H](N)C(=O)O
Agent: NC(=O)C[C@H](N)C(N)=O
Agent: N[C@@H](CC(=O)O)C(=O)O
Product: C[C@@H](NC(=O)[C@@H]1CCC(=O)N1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)O

Procedure:
Asn9 is replaced by: Asp, Gln, -Ala-NH, and Asn-NH2, and the polypeptides, PyroGlu-Ala-Lys-Ser-Gln-Gly-Gly-Gly-Ser-Asn, and PyroGlu-Ala-Lys-Ser-Gln-Gly-Ser-Asn.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([NH:18][C:19](=[O:27])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)=[CH:16][CH:15]=[C:14]([C:28]([F:31])([F:30])[F:29])[N:13]=2)[CH2:8][CH2:7]1)C.O1CCCC1.CO.[OH-].[Li+]>O>[Cl:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C:17]1[C:12]([N:9]2[CH2:8][CH2:7][CH:6]([CH2:5][C:4]([OH:32])=[O:3])[CH2:11][CH2:10]2)=[N:13][C:14]([C:28]([F:30])([F:29])[F:31])=[CH:15][CH:16]=1)=[O:27]
Reactant: CCOC(=O)CC1CCN(c2nc(C(F)(F)F)ccc2NC(=O)c2cccc(Cl)c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC1CCN(c2nc(C(F)(F)F)ccc2NC(=O)c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
To a mixture of 0.230 g (0.489 mmol) of [3′-(3-chloro-benzoylamino)-6′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid ethyl ester in a 2:1 mixture of tetrahydrofuran:methanol (12 mL) is added 0.058 g (2.4 mmol) of lithium hydroxide as a solution in water (2 mL). The mixture is stirred at room temperature for 2 hours then concentrated under reduced pressure. The residue is diluted with water and the pH of the mixture is adjusted to pH 2 by the addition of concentrated hydrochloric acid causing a solid to precipitate from solution. The formed precipitate is collected by filtration and dried to provide 0.21 g (quant) of [3′-(3-chloro-benzoylamino)-6′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid as a white solid.
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>ClCCl>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:6]2[CH:7]=[C:2]([F:1])[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]2=[O:8])(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: CN(C)C=Nc1nc(O)ncc1F
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C=Nc1nc(=O)n(S(=O)(=O)c2ccc(Cl)cc2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.8 %

Procedure:
To a 25 mL screw-cap vial were added dichloromethane (CH2Cl2; 10 mL), N′-(5-fluoro-2-hydroxy-pyrimidin-4-yl)-N,N-dimethylformamidine (250 mg, 1.36 mmol), and triethylamine (Et3N, 300 mg, 3 mmol). To this mixture was added 4-chlorobenzenesulfonyl chloride (315 mg, 1.5 mmol), and the resulting mixture was shaken at room temperature for 3 h. The crude reaction mixture was partitioned between CH2Cl2 and brine, dried over MgSO4, filtered, and evaporated. The residue was purified by reverse phase chromatography to yield the title compound as a white solid (321 mg, 66%): mp 207-210° C.; 1H NMR (300 MHz, CDCl3) δ 8.75 (s, 1H), 8.08-8.02 (m, 3H), 7.53-7.47 (m, 2H), 3.23 (s, 3H), 3.21 (s, 3H); ESIMS m/z 360 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][C:14]([OH:16])=O.O>FC(F)(F)S(O)(=O)=O>[Br:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[C:4]2[C:3]=1[CH2:12][CH2:13][C:14]2=[O:16]
Reactant: O=C(O)CCc1cccc(C(F)(F)F)c1Br
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Product: O=C1CCc2c1ccc(C(F)(F)F)c2Br
Temperature: 85 °C

Procedure:
3-(2-Bromo-3-trifluoromethyl-phenyl)-propionic acid (3.0 g, 10.1 mmol) is suspended in trifluoromethanesulfonic acid (30 mL)) under argon and heated at 85° C. for 4 hours. The mixture is added dropwise to iced water and then extracted with ethyl acetate. The organic extract is washed with saturated sodium bicarbonate solution, dried and concentrated under vacuum. The residue is purified by flash chromatography (Eluent 0-5% EtOAc in cyclohexane) to give the title compound.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:37])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]4[N:17]=[C:18]([S:28][C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=5)[CH:19]=[C:20]([NH:21][CH2:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:15]4=[N:14][CH:13]=3)=[CH:8][C:7]=2[CH3:36])[CH2:3][CH2:2]1.C(#N)C1C=CN=CC=1.OO.S([O-])([O-])(=[O:50])=S.[Na+].[Na+]>ClCCl.C[Re](=O)(=O)=O>[CH:1]1([NH:4][C:5](=[O:37])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]4[N:17]=[C:18]([S:28]([C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=5)=[O:50])[CH:19]=[C:20]([NH:21][CH2:22][CH2:23][C:24]([F:26])([F:27])[F:25])[C:15]4=[N:14][CH:13]=3)=[CH:8][C:7]=2[CH3:36])[CH2:2][CH2:3]1
Reactant: Cc1cc(-c2cnc3c(NCCC(F)(F)F)cc(Sc4cccc(F)c4)nn23)ccc1C(=O)NC1CC1
Reactant: O=S([O-])([O-])=S
Agent: C[Re](=O)(=O)=O
Agent: N#Cc1ccncc1
Agent: OO
Solvent: ClCCl
Product: Cc1cc(-c2cnc3c(NCCC(F)(F)F)cc(S(=O)c4cccc(F)c4)nn23)ccc1C(=O)NC1CC1
Temperature: 23 °C
Reaction time: 48 h
Yield: 8 %

Procedure:
To a solution of 50 mg (121 μmol) N-cyclopropyl-4-{6-[(3-fluorophenyl) sulfanyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide, which was prepared according to intermediate example 209 in 1.0 mL dichloromethane were added 0.71 mg methyl(trioxo)rhenium, 1.77 mg isonicotinonitrile and 58 μL aqueous hydrogen peroxide (30%). The mixture was stirred for two days at 23° C., poured into sodium thiosulfate solution and extracted with dichloromethane. The organic phase was dried over sodium sulfate. After filtration and removal of solvent the residue was purified by chromatography to give 14.9 mg (53%) of the title compound A and 4.5 mg (8%) of the title compound B.
Reaction SMILES: [O:1]([C:8]1[N:13]=[C:12]([C:14](Cl)=[O:15])[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([N:27]2[CH2:31][CH:30]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH2:29][NH:28]2)=[O:26])=[CH:20][CH:19]=1.[OH-].[Na+]>C(Cl)Cl.O.C(Cl)Cl>[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([N:27]2[CH2:31][CH:30]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH2:29][N:28]2[C:14]([C:12]2[CH:11]=[CH:10][N:9]=[C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:13]=2)=[O:15])=[O:26])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccnc(Oc2ccccc2)n1
Reactant: O=C(Cc1ccc(F)cc1)N1CC(N2CCOCC2)CN1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=C(Cc1ccc(F)cc1)N1CC(N2CCOCC2)CN1C(=O)c1ccnc(Oc2ccccc2)n1
Reaction time: 18 h
Yield: 23 %

Procedure:
2-Phenoxypyrimidine-4-carbonyl chloride, 18, (0.07 g, 0.28 mmol) in methylene chloride (1.5 mL) is added dropwise to a suspension of 2-(4-fluorophenyl)-1-(4-morpholin-4-yl-pyrazolidin-1-yl)ethanone, 13, (0.06 g, 0.18 mmol) in a 2:5 water/CH2Cl2 solution (7 mL) containing NaOH (0.0112 g, 0.28 mmol) at room temperature. The solution is stirred 18 hours and diluted with additional 2:5 water/CH2Cl2. The layers are allowed to separate and the aqueous phase extracted with additional methylene chloride. The organic layers are combined, dried, filtered and concentrated in vacuo to afford a tan solid which is purified by preparative HPLC to provide 0.021 g (23% yield) of the desired product as an oily solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH:12]([C:14]1[NH:18][C:17]([CH3:19])=[C:16]([C:20]([OH:22])=[O:21])[C:15]=1[CH3:23])=O.N1CCCC1>C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:14]1[NH:18][C:17]([CH3:19])=[C:16]([C:20]([OH:22])=[O:21])[C:15]=1[CH3:23]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Solvent: CCO
Solvent: C1CCNC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)O
Temperature: 25 °C
Yield: 93.3 %

Procedure:
A mixture of 5-fluoro-1,3-dihydroindol-2-one (A2) (20 g, 132 mmol), 5-formyl-2,4-dimethylpyrrole-3-carboxylic acid (A1) (21.1 g, 126 mmol), pyrrolidine (5 ml) and absolute ethanol (400 mL) were heated to reflux for 3 hours. Then the mixture was cooled to room temperature and the solid was collected by filtration, washed with ethanol (100 mL). The solid was stirred in ethanol (350 ml) at reflux for 0.5 h again. The mixture was cooled to room temperature and the solid was collected by filtration, washed with ethanol (100 ml) and dried under vacuum overnight to give (Z)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (A3) (35.3 g, 93%) as orange solid. LC-MS observed [M−H]+: 299.2.
Reaction SMILES: [C:1]1([S:7][CH2:8][C:9]2[CH:18]=[CH:17][C:12]([C:13](OC)=[O:14])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[C:1]1([S:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:13][OH:14])=[CH:17][CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(CSc2ccccc2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(CSc2ccccc2)cc1
Reaction time: 0.67 h
Yield: 95.4 %

Procedure:
Methyl 4-(phenylsulfanylmethyl)benzoate (1.07 g) was dissolved in THF (14 mL), added with lithium aluminum hydride (200 mg) in small portions under ice cooling, and stirred for 40 minutes at the same temperature. Under ice cooling, sodium sulfate decahydrate was added in small portions and filtered through Celite. The solvent was evaporated under reduced pressure. The residues were suspended in hexane and collected by filtration to obtain the title compound (910 mg) as a white powder.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[O:27]1[CH2:30][CH:29]([CH2:31][C:32](OC)=[O:33])[CH2:28]1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:32](=[O:33])[CH2:31][CH:29]5[CH2:30][O:27][CH2:28]5)[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: COC(=O)CC1COC1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(CC1COC1)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (66 mg, 62%), MS (ISP) m/z=427.4 [(M+H)+], mp 197° C., was prepared in accordance with the general method of example 81 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and methyl 2-(oxetan-3-yl)acetate.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[N:11]3[N:12]=[C:13]([O:20][CH2:21][C:22]4[N:26]=[CH:25][NH:24][N:23]=4)[C:14]4[C:19]([C:10]3=[N:9][N:8]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:3]=1.[H-].[Na+].I[CH:30]([CH3:32])[CH3:31].O>CN(C)C=O>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[N:11]3[N:12]=[C:13]([O:20][CH2:21][C:22]4[N:26]=[CH:25][N:24]([CH:30]([CH3:32])[CH3:31])[N:23]=4)[C:14]4[C:19]([C:10]3=[N:9][N:8]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:3]=1
Reactant: CC(C)I
Reactant: Cc1cc(-c2nnc3c4ccccc4c(OCc4nc[nH]n4)nn23)no1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4ncn(C(C)C)n4)nn23)no1
Temperature: 0 °C
Reaction time: 8 h
Yield: 22.1 %

Procedure:
To a stirred solution of 3-(5-methylisoxazol-3-yl)-6-(1,2,4-triazol-3-yl)methyloxy-1,2,4-triazolo[3,4-a]phthalazine (100 mg, 0.29 mmol) in N,N-dimethylformamide (6 ml) at room temperature under nitrogen was added sodium hydride (17 mg, 0.41 mmol). The mixture was cooled to 0° C. and 2-iodopropane (0.04 ml, 0.36 mmol) added after 0.25 h. The mixture was left to stir at room temperature overnight, water was added and the precipitate filtered off. The crude product was flash chromatographed on silica gel, eluting with ethyl acetate→4% methanol/ethyl acetate, to give the title-product (25 mg, 22%), mp 179-181° C.; 1H NMR (360 MHz, CDCl3) δ 1.58 (6H, d, J=6.7 Hz, 2 of CH3), 2.59 (3H, s, CH3), 4.58 (1H, septet, J=6.7 Hz, CH), 5.72 (2H, s, CH2), 7.01 (1H, s, Ar—H), 7.78 (1H, t, J=7.2 Hz, Ar—H), 7.94 (1H, t, J=7.6 Hz, Ar—H), 8.13 (1H, s, Ar—H), 8.28 (1H, d, J=7.9 Hz, Ar—H), 8.80 (1H, d, J=7.4 Hz, Ar—H); MS (ES30) m/e 391 [MH]+; Anal. Found. C, 56.81; H, 4.68; N, 27.89; C19H18N8O2.0.7H2O requires C, 56.62; H, 4.85; N, 27.80%.
Reaction SMILES: [N+:1]([N:4]=[C:5]1[NH:9][CH2:8][CH2:7][NH:6]1)([O-:3])=[O:2].[CH:10](=O)[CH2:11][CH3:12].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O>CN(C)C=O.C(OCC)(=O)C>[CH:10]([N:6]1[CH2:7][CH2:8][NH:9][C:5]1=[N:4][N+:1]([O-:3])=[O:2])=[CH:11][CH3:12]
Reactant: O=[N+]([O-])N=C1NCCN1
Reactant: CCC=O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC=CN1CCNC1=N[N+](=O)[O-]
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 65.8 %

Procedure:
5.0 g of 2-nitroiminoimidazolidine and 4.5 g of propionaldehyde were dissolved in 25 ml of N,N-dimethylformamide, and 4.0 g of phosphorus pentoxide was added thereto with cooling with ice over a period of 20 minutes and thereafter stirred for 10 minutes at 10° C. 20 ml of water and 20 ml of ethyl acetate were added to the reaction mixture, and the crystals thus precipitated out were filtrated and dried to give 4.3 g of 1-(1-propenyl)-2-nitroiminoimidazolidine.