Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]2[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=2)[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[N:4][CH:5]=[CH:6][CH:7]=1.[OH:21]O>ClCCl.C[Re](=O)(=O)=O>[C:14]([O:13][C:11]([C:10]1[CH:9]=[C:8]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N+:4]=2[O-:21])[CH:20]=[CH:19][CH:18]=1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: Cc1cccnc1-c1cccc(C(=O)OC(C)(C)C)c1
Reactant: OO
Agent: C[Re](=O)(=O)=O
Solvent: ClCCl
Product: Cc1ccc[n+]([O-])c1-c1cccc(C(=O)OC(C)(C)C)c1
Reaction time: 16 h
Yield: 57 %

Procedure:
tert-Butyl 3-(3-methylpyridin-2-yl)benzoate (49.6 g, 184 mmol) was dissolved in a mixture of 75 mL of dichloromethane and 40 mL of 30% hydrogen peroxide. Methyltrioxorhenium (VII) (2.35 g, 9.44 mmol) was added and the reaction mixture was stirred vigorously for 16 hours. The layers were then separated and the organic layer was treated with sodium sulfite and then dried over sodium sulfate. The crude product was then poured onto a pad of silica gel and washed with ethyl acetate. The product was then eluted from the silica gel pad with a mixture of 10% (v/v) methanol in ethyl acetate to yield 2-(3-(tert-butoxycarbonyl)phenyl)-3-methylpyridine 1-oxide (29.8 g, 57%) as a white solid. ESI-MS m/z calc. 285.1, found 286.1 (M+1)+. Retention time 1.22 minutes.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7](/[C:10](=[N:16]\[OH:17])/[C:11]([O:13]CC)=[O:12])=[CH:6][CH:5]=1.Cl[CH2:19][C:20]1[CH:39]=[CH:38][C:23]([O:24][CH2:25][C:26]2[N:27]=[C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:29][C:30]=2[CH3:31])=[CH:22][CH:21]=1.Cl.C(=O)(O)[O-].[Na+]>CN(C)C=O>[F:3][C:4]1[CH:5]=[CH:6][C:7](/[C:10](=[N:16]\[O:17][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:29][C:30]=3[CH3:31])=[CH:38][CH:39]=2)/[C:11]([OH:13])=[O:12])=[CH:8][CH:9]=1
Reactant: CCOC(=O)/C(=N/O)c1ccc(F)cc1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(/C(=O)O)c2ccc(F)cc2)cc1
Reaction time: 1 h
Yield: 53.8 %

Procedure:
Sodium hydride (60% in oil, 209 mg) was added under a nitrogen atmosphere to a solution of ethyl E-2-(4-fluorophenyl)-2-hydroxyiminoacetate (920 mg) and 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.37 g) in N,N-dimethylformamide (10 ml) at room temperature and the mixture was stirred for 1 hour. After adding 1N HCl (7 ml), aqueous sodium bicarbonate was added, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain an oil from a fraction eluted with ethyl acetate-hexane (1:3, v/v). This oil was dissolved in tetrahydrofuran (20 ml)-methanol (10 ml), and 1N aqueous solution of sodium hydroxide (10 ml) was added and the mixture was stirred at 40° C. for 2 hours. 1N HCl (10.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residual crystal was recrystallized from ethyl acetate to obtain E-2-(4-fluorophenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetic acid (1.08 g, yield 54 to) as colorless crystals. m.p. 150-151° C. (decomposition)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][NH2:5].C(N(CC)CC)C.[IH:14].[O:15]=[C:16]1[N:21]([CH2:22][C:23]#[CH:24])[N:20]=[N:19][C:18]2=[C:25]([C:28](SC)=[NH:29])[N:26]=[CH:27][N:17]12>CC#N>[IH:14].[CH3:1][O:2][C:3](=[O:6])[CH2:4][NH:5][C:28]([C:25]1[N:26]=[CH:27][N:17]2[C:16](=[O:15])[N:21]([CH2:22][C:23]#[CH:24])[N:20]=[N:19][C:18]=12)=[NH:29]
Reactant: C#CCn1nnc2c(C(=N)SC)ncn2c1=O
Reactant: COC(=O)CN
Agent: I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C#CCn1nnc2c(C(=N)NCC(=O)OC)ncn2c1=O
Reaction time: 0.17 h

Procedure:
Glycine methyl ester (0.14 mmol) was suspended in dry MeCN (1 mL). Triethylamine (0.14 mmol) was added and the solution stirred for 10 minutes. Methyl 4-oxo-3-(prop-2-ynyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbimidothioate hydroiodide (0.13 mmol) was then added and the reaction stirred at room temperature for 2 hours. The resulting precipitate was then filtered and washed with MeCN and ether. δH (DMSO-d6) 9.70 (2H, bs), 9.22 (1H, s), 5.76 (1H, s), 5.24 (2H, d, J=2.4), 4.45 (2H, s), 3.74 (3H, s), 3.60 (1H, t, J=2.4).
Reaction SMILES: [C:1]1([C:7]2([CH2:15][CH2:16][C:17]([OH:19])=O)[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]2=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>S(=O)(=O)(O)O>[NH:9]1[C:10](=[O:13])[CH2:11][CH2:12][C:7]2([C:1]3[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:17](=[O:19])[CH2:16][CH2:15]2)[C:8]1=[O:14]
Reactant: O=C(O)CCC1(c2ccccc2)CCC(=O)NC1=O
Agent: O=S(=O)(O)O
Product: O=C1CCC2(CCC(=O)c3ccccc32)C(=O)N1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.4 %

Procedure:
Two hundred (200) grams (0.76 M) of 3-phenyl-2,6-dioxopiperidine-3-propionic acid, prepared by the method of Koelsch, J. Org. Chem., 25, 164 (1960), and 500 ml of concentrated sulfuric acid were heated on a steam bath with stirring for 1.5 hours. The mixture was cooled to room temperature and poured over crushed ice with stirring. The light tan colored precipitate which separated was water washed and filtered. This material was combined with a second crop which separated on standing and both were stirred in water and treated with five percent sodium carbonate solution until just alkaline. The precipitate was collected and water washed. The precipitate was recrystallized from acetone to give a total of 144.6 grams (82.4%) of 2,3-dihydrospiro-[naphthalene-1(4H), 3'-piperidine]-2',4,6'-trione, melting point 198°-200° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[C@:9]3([CH2:26][CH2:25][C@H:24]4[C@@H:14]([CH2:15][CH:16]=[C:17]5[C@:22]4([CH3:23])[CH2:21][CH2:20][C@H:19]([OH:27])[CH2:18]5)[C@@H:11]3[CH2:12][CH:13]=2)[CH3:10])[N:7]=1.Br>>[CH3:1][NH:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[C@:9]3([CH2:26][CH2:25][C@H:24]4[C@@H:14]([CH2:15][CH:16]=[C:17]5[C@:22]4([CH3:23])[CH2:21][CH2:20][C:19](=[O:27])[CH2:18]5)[C@@H:11]3[CH2:12][CH:13]=2)[CH3:10])[N:7]=1
Reactant: CNc1nc(C2=CC[C@H]3[C@@H]4CC=C5C[C@@H](O)CC[C@]5(C)[C@H]4CC[C@]23C)cs1
Agent: Br
Product: CNc1nc(C2=CC[C@H]3[C@@H]4CC=C5CC(=O)CC[C@]5(C)[C@H]4CC[C@]23C)cs1

Procedure:
In an analogous manner to example 2 the title compound is prepared from (3β)-17-[2-(methylamino)-4-thiazolyl]-androsta-5,16-dien-3-ol.HBr prepared in example 3.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[S:13])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])=[O:4].O.[NH2:18][NH2:19].O>O1CCCC1>[NH:18]([C:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:6]([N+:14]([O-:16])=[O:15])[CH:7]=1)=[S:13])[NH2:19]
Reactant: COC(=O)c1ccc(N=C=S)cc1[N+](=O)[O-]
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=S)NN)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 84.7 %

Procedure:
A solution of the above synthesized 4-methoxycarbonyl-3-nitrophenyl isothiocyanate (149 mg, 0.62 mmol) in tetrahydrofuran (2.2 ml) was added dropwise to a solution of hydrazine monohydrate (94 mg, 1.87 mmol) in tetrahydrofuran (4.0 ml) at 0° C. over 20 minutes. After stirring at 0° C. for further 40 minutes, water was added, and the precipitated solid was filtered to obtain 142 mg of the desired product as a colorless solid (yield 85%).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH2:13]Cl.[C:15]([O-:18])(=[O:17])[CH3:16].[K+].CN(C=O)C>O>[C:15]([O:18][CH2:13][C:3]1[N:4]=[C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][N:6]2[C:7](=[O:8])[C:2]=1[Br:1])(=[O:17])[CH3:16]
Reactant: CC(=O)[O-]
Reactant: O=c1c(Br)c(CCl)nc2ccccn12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCc1nc2ccccn2c(=O)c1Br
Temperature: 40 °C
Reaction time: 3.5 h

Procedure:
A mixture of 3-bromo-2-(chloromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (4.53 g, 15.76 mmol), potassium acetate (1.5 equiv.) and DMF (60 mL) was stirred at 40° C. for 3.5 h, at this point the reaction was completed by LCMS. The mixture was cond under reduced pressure. To the residue was added water (100 mL) and the resulting precipitate was collected by filtration, washed with water (100 mL) and dried to give the (3-bromo-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)methyl acetate as a brown solid, which was carried forward without further purification: 1HNMR (400 MHz, DMSO-d6): δ 8.96-8.98 (dd,1H), 8.03-8.08 (m,1H), 7.74-7.76 (dd,1H), 7.43-7.48 (m,1H), 5.2 (s,2H), 2.1 (s,3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].[CH2:16]([N:23]1[CH2:27][C@@H:26]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=2)[C@H:25]([NH:36][CH3:37])[CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:16]([N:23]1[CH2:27][C@@H:26]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=2)[C@H:25]([N:36]([CH3:37])[C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:5]=2)[CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1ccc(C(=O)Cl)cc1C(F)(F)F
Reactant: CN[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)N(C)[C@@H]2CN(Cc3ccccc3)C[C@H]2c2ccc(Cl)c(Cl)c2)cc1C(F)(F)F
Reaction time: 4 h
Yield: 86 %

Procedure:
A solution of 4-methoxy-3-trifluoromethyl-benzoyl chloride (commercially available) (0.88 g, 2.76 mmol) in CH2Cl2 (10 ml) was added drop wise to a stirred solution of rac-[(3S,4R)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-amine (0.80 g, 2.38 mmol) and ethyl-diisopropyl-amine (0.61 ml, 3.58 mmol) in CH2Cl2 (10 ml). The reaction mixture was stirred 4 h, concentrated under vacuo and purification by flash chromatography (SiO2, CH2Cl2/MeOH, 99:1) yielded 1.09 g (86%) of the title product as colorless oil. ES-MS m/e: 537.5 (M+H+).
Reaction SMILES: [CH2:1]([N:3]([CH2:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([CH3:15])[CH:14]=1)[C:9]([OH:11])=O)[CH3:4])[CH3:2].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH2:58]([O:65][C:66]1[C:75]([CH3:76])=[CH:74][C:69]([C:70]([NH:72][NH2:73])=O)=[CH:68][C:67]=1[CH2:77][CH3:78])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1.CC(=O)OCC>[CH2:58]([O:65][C:66]1[C:75]([CH3:76])=[CH:74][C:69]([C:70]2[O:11][C:9]([C:8]3[CH:7]=[C:6]([CH:14]=[C:13]([CH3:15])[CH:12]=3)[CH2:5][N:3]([CH2:1][CH3:2])[CH3:4])=[N:73][N:72]=2)=[CH:68][C:67]=1[CH2:77][CH3:78])[C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=1
Reactant: CCc1cc(C(=O)NN)cc(C)c1OCc1ccccc1
Reactant: CCN(C)Cc1cc(C)cc(C(=O)O)c1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1cc(-c2nnc(-c3cc(C)cc(CN(C)CC)c3)o2)cc(C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
To a solution of 3-[(ethyl-methyl-amino)-methyl]-5-methyl-benzoic acid (750 mg, 3.62 mmol) in THF (10 mL), DIPEA (940 mg, 7.24 mmol) and PyBOP (1.88 g, 3.62 mmol) was added. The mixture was stirred at rt for 1 h before 4-benzyloxy-3-ethyl-5-methyl-benzoic acid hydrazide (2.06 g, 3.62 mmol) was added. The mixture was stirred at rt for 1 h and was then diluted with EA and washed with sat. aq. NaHCO3 solution. The org. phase was collected, dried over MgSO4, filtered and concentrated. The residue was dissolved in THF and Burgess reagent (1.03 g, 4.34 mmol) was added. The mixture was stirred at 110° C. under microwave irradiation for 12 min. The mixture was cooled to rt, diluted with EA and washed with water. The org. phase was separated and concentrated. The crude product is purified by CC on silica gel eluting with DCM:MeOH 9:1 to 5:1 to give {3-[5-(4-benzyloxy-3-ethyl-5-methyl-phenyl)-[1,3,4]oxadiazol-2-yl]-5-methyl-benzyl}-ethyl-methyl-amine as a pale yellow oil (1.48 g). LC-MS: tR=0.96 min; [M+1]+=456.13.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][C:14](=O)[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:5]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[N:6][CH:7]=1.[OH-].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[N:13]=[C:14]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[N:8]([CH2:9][CH:10]3[CH2:12][CH2:11]3)[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)CC(=O)Nc1cc(Br)cnc1NCC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)Cc1nc2cc(Br)cnc2n1CC1CC1
Yield: 81.8 %

Procedure:
A mixture of N-{5-bromo-2-[(cyclopropylmethyl)amino]pyridin-3-yl}-3,3-dimethylbutanamide (5.04 g, 14.8 mmol, step E) and 2 N sodium hydroxide solution (10 mL) in ethanol (90 mL) was stirred under reflux for 21 h. After concentration, the residue was dissolved in water (50 mL) and the mixture was extracted with ethyl acetate (30 mL×2). The organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=9:1 as eluent) to give the title compound (3.9 g, 82%) as a pale pink solid.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.CC1(C)C(C)(C)OB([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[CH:25]=[C:24]([NH:29][C:30]([C:32]2[CH:36]=[CH:35][S:34][CH:33]=2)=[O:31])[CH:23]=[CH:22]3)O1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>[Pd].O>[NH:6]1[C:7]2[C:3](=[C:2]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[CH:25]=[C:24]([NH:29][C:30]([C:32]3[CH:36]=[CH:35][S:34][CH:33]=3)=[O:31])[CH:23]=[CH:22]4)[CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: Brc1cccc2[nH]ccc12
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)c4ccsc4)ccc3c2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1ccc2cc(-c3cccc4[nH]ccc34)ccc2c1)c1ccsc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 22 %

Procedure:
4-bromo-1H-indole (31.0 mg, 0.158 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)thiophene-3-carboxamide (114.5 mg, 0.302 mmol), Fibercat palladium catalyst (Johnson-Matthey, 34.5 mg), and K2CO3 (2 M in water, 0.45 ml, 0.90 mmol) were combined in a microwave reaction vessel and 1,4-dioxane (1.5 ml) was added. The reaction tube was sealed and heated in the microwave (CEM microwave) at 60 Watts and 80 C, first for 10 minutes, and then for 20 minutes. The reaction was cooled to room temperature, diluted with water (5 ml), and extracted with EtOAc (10 ml, 2×5 ml). The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on HPLC (10%->95% MeCN/water with 0.1% TFA). The fractions with product were purified on silica gel (3:1->1:1 hexanes/EtOAc) to afford title compound (12.8 mg, 22%). MS (ESI pos. ion) m/z: 369 (M+H). Calc'd Exact Mass for C23H16N2OS: 368.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][CH:6]1[C:15]2[CH:14]=[C:13]([O:16][CH2:17][CH2:18][NH2:19])[CH:12]=[CH:11][C:10]=2[CH2:9][CH2:8][CH:7]1[N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.[CH3:28][N:29]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30]1>ClCCl.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][CH:6]1[C:15]2[CH:14]=[C:13]([O:16][CH2:17][CH2:18][NH:19][S:34]([C:31]3[CH:32]=[CH:33][N:29]([CH3:28])[CH:30]=3)(=[O:36])=[O:35])[CH:12]=[CH:11][C:10]=2[CH2:9][CH2:8][CH:7]1[N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NCCOc1ccc2c(c1)C(Cc1cccc(F)c1)C(N1CCCC1)CC2
Reactant: Cn1ccc(S(=O)(=O)Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cn1ccc(S(=O)(=O)NCCOc2ccc3c(c2)C(Cc2cccc(F)c2)C(N2CCCC2)CC3)c1
Temperature: 25 °C

Procedure:
2-(8-(3-Fluorobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethanamine (50 mg, 0.136 mmol) was dissolved in dichloromethane (2 mL). N,N-Dimethyl-4-aminopyridine (49.7 mg, 0.407 mmol) and 1-methyl-1H-pyrrole-3-sulfonyl chloride (24.4 mg, 0.136 mmol) were added successively. The reaction mixture was stirred at room temperature over night. The reaction was diluted with dichloromethane and washed with water. The organic phase was dried (MgSO4) and the solvent was evaporated in vacuo. The crude product was purified by flash chromatography (silica gel, dichloromethane, methanol). Yield: 31 mg (0.061 mmol, 45%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:16]=[C:15]([C:24]([OH:26])=O)[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C([N:48]3[CH2:52][C:51](=[O:53])[NH:50][CH2:49]3)=O)C=2)C=C(F)C=1.Cl.N1C=CNC1=O>>[F:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:16]=[C:15]([C:24]([N:48]3[CH2:52][C:51](=[O:53])[NH:50][CH2:49]3)=[O:26])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:10])([F:12])[F:11])[CH:7]=1
Reactant: O=C(O)c1cc(-c2cc(F)cc(OC(F)(F)F)c2)n(-c2cccnc2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Agent: Cl
Agent: O=c1[nH]cc[nH]1
Product: O=C1CN(C(=O)c2cc(-c3cc(F)cc(OC(F)(F)F)c3)n(-c3cccnc3)n2)CN1

Procedure:
100 mg (0.27 mmol) of the compound of Example 34A is reacted analogously to the synthesis of the compound of Example 1 with 37 mg (0.30 mmol) of 4-imidazolinone-hydrochloride. 98 mg (83% of theory) of the title compound is obtained.
Reaction SMILES: [Br: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][S:14](Cl)(=[O:16])=[O:15].[CH:18]1([NH2:21])[CH2:20][CH2:19]1>>[CH:18]1([NH:21][S:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])(=[O:16])=[O:15])[CH2:20][CH2:19]1
Reactant: O=S(=O)(Cl)CCCCCCCCCCCCBr
Reactant: NC1CC1
Product: O=S(=O)(CCCCCCCCCCCCBr)NC1CC1
Yield: 96.6 %

Procedure:
The reaction was carried out in the same manner as in Preparation Example 3 except for using 12-bromododecanesulfonyl chloride (2.92g, 8.4 mmol) in place of 6-bromohexanesulfonyl chloride, and cyclopropylamine (1.08g, 18.5 mmol), to give N-cyclopropyl-12-bromododecanesulfonamide (2.99 g) as colorless crystals.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[N:11]([CH3:12])[N:10]=[C:9]([CH3:13])[CH:8]=1.S(Cl)(Cl)=O>>[Cl:6][C:7]1[N:11]([CH3:12])[N:10]=[C:9]([CH3:13])[C:8]=1[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: Cc1cc(Cl)n(C)n1
Reactant: O=S(=O)(O)Cl
Solvent: O=S(Cl)Cl
Product: Cc1nn(C)c(Cl)c1S(=O)(=O)Cl
Temperature: 5 °C
Reaction time: 8 h

Procedure:
Into 150 xl of chlorosulfonic acid was added dropwise under cooling at 5° C. or lower, 30 g (0.23 ml) of 5-chloro-1,3-dimethylpyrazole. After the addition, the mixture was stirred at 100° C. for 8 hours. Then, the reaction mixture was cooled to 80° C., followed by dropwise addition of 36 g of thionyl chloride over 30 minutes After the addition, the mixture was stirred at 100° C. for an additional 2 hours. The reaction mixture was cooled on ice and poured carefully into ice-water, whereby crude 5-chloro-1,3-dimethylpyrazole-4-sulfonylchloride (50 g) was formed as crystals. Subsequently, into a solution of 40 g of dimethylamine in 250 ml of THF, the above compound was added under cooling and the reaction mixture was stirred at room temperature for 3 hours. After the reaction, THF was evaporated under reduced pressure and into the residue was added ether and washed with water. After drying and evaporating the etherial solution, there was obtained 47 g of the title compound m.p. 53 -55° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C1COCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:27]([NH:26][C:23]4[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=4)=[O:28])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)N2CCN(c3ccnc4cc(Cl)ccc34)CC2)cc1

Procedure:
7-Chloro-4-(piperazin-1-yl)quinoline (316 mg, 1.28 mmol) and 4-methoxyphenyl isocyanate (194 μL, 1.50 mmol) in THF (10 mL) are reacted according to method C yielding the title product as a colorless needles after column chromatography with hexane-EtOAc and recrystallization from ether.
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].[OH:26][NH:27][C:28](=N)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([C:28]1[N:2]=[C:1]([N:3]2[CH2:4][CH2:5][CH:6]([N:9]([CH:23]3[CH2:25][CH2:24]3)[C:10](=[O:22])[C:11]3[CH:12]=[CH:13][C:14]([C:17]4[O:21][CH:20]=[N:19][CH:18]=4)=[CH:15][CH:16]=3)[CH2:7][CH2:8]2)[O:26][N:27]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: N=C(Cc1ccccc1)NO
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2nc(Cc3ccccc3)no2)CC1

Procedure:
The title compound is prepared from N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide and N-hydroxy-2-phenyl-acetamidine following a procedure analogous to that described in Example 1. LC (method 6): tR=1.69 min; Mass spectrum (ESI+): m/z=470 [M+H]+.
Reaction SMILES: [C:1]([CH:5]1[C:10]2[NH:11][C:12](=[O:14])[S:13][C:9]=2[CH2:8][CH2:7][CH2:6]1)([O:3][CH3:4])=[O:2].C(=O)([O-])N.[K+].[P:20](Cl)([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])=[S:21]>CC(C)=O>[CH2:23]([O:22][P:20]([O:14][C:12]1[S:13][C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([C:1]([O:3][CH3:4])=[O:2])[C:10]=2[N:11]=1)([O:25][CH2:26][CH3:27])=[S:21])[CH3:24]
Reactant: CCOP(=S)(Cl)OCC
Reactant: COC(=O)C1CCCc2sc(=O)[nH]c21
Agent: NC(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOP(=S)(OCC)Oc1nc2c(s1)CCCC2C(=O)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.9 %

Procedure:
A mixture of 4 g of 4-carbomethoxy-2,3,4,5,6,7-hexahydrobenzothiazoline-2-one, 3 g of potassium carbamate and 50 ml of acetone was refluxed for 1 hour and after the addition of 4 g of O,O-diethyl chlorothiophosphate, the mixture was refluxed for another hour. The mixture was stirred for 18 hours at room temperature and the mineral salts formed were filtered off. The filtrate was distilled to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with an 8-2 cyclohexane-ethyl acetate mixture yielded 1.5 g of 2-(diethoxythiophosphoryloxy)-4-carbomethoxy-4,5,6,7-tetrahydrobenzothiazole with a refractive index nD26 = 1.5261.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[CH2:14][C:13]=3[CH:25]=2)[CH:5]=[CH:6][C:7]=1[NH2:8]>C(O)(=O)C>[CH3:22][O:21][C:19]([NH:15][C:14]1[NH:8][C:7]2[CH:6]=[CH:5][C:4]([C:9]3[CH:10]=[CH:11][C:12]4[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[CH2:14][C:13]=4[CH:25]=3)=[CH:3][C:2]=2[N:1]=1)=[O:20]
Reactant: C=CCOC(=O)N1CCOc2ccc(-c3ccc(N)c(N)c3)cc2C1
Solvent: CC(=O)O
Product: C=CCOC(=O)N1CCOc2ccc(-c3ccc4[nH]c(NC(=O)OC)nc4c3)cc2C1
Temperature: 80 °C
Yield: 205.8 %

Procedure:
Prop-2-en-1-yl 7-(3,4-diaminophenyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (2.7 g, 7.96 mmol) was taken into glacial acetic acid (15 mL) followed by addition of 1,3-(dimethoxycarbonyl)-2-methyl-2-thiopseudourea (1.81 g, 8.8 mmol) and the mixture was heated to 80° C. for 30 minutes then concentrated to a thick residue. The residue was treated with saturated aqueous sodium bicarbonate and the aqueous mixture basified with portionwise addition of solid sodium bicarbonate with pH 8-9. The aqueous mixture was then partitioned with hexanes then filtered. The filter cake was washed with water then hexanes and dried to give prop-2-en-1-yl 7-(2-{[(methyloxy)carbonyl]amino}-1H-benzimidazol-5-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (3.46 g, 100% yield) as a pale yellow solid.