Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]3)=[CH:15][CH:14]=2)[N:3]=1.[C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][C:39]([O:41][CH3:42])=[O:40])#[CH:31].CCN(CC)CC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=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.[Cu]I>[CH3:42][O:41][C:39](=[O:40])[CH2:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[C:30]#[C:31][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]3)=[CH:15][CH:14]=2)[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)C1
Reactant: C#Cc1ccccc1CC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(C3CN(C(=O)OC(C)(C)C)C3)cc2)ncc1C(F)(F)F
Temperature: 120 °C

Procedure:
A suspension of tert-butyl 3-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)azetidine-1-carboxylate (A78) (500 mg, 1.16 mmol), methyl 2-(2-ethynylphenyl)acetate (K1) (244 mg, 1.39 mmol), Et3N (0.60 mL), PdCl2(PPh3)2 (0.041 g, 0.058 mmol), CuI (0.022 g, 0.117 mmol) and PPh3 (0.031 g, 0.117 mmol) in DMF (4 mL) were heated under microwave irradiation at 120° C. for 15 minutes. The resulting mixture was adsorbed onto silica gel and purified using column chromatography (CombiFlash Rf, 40 g SiO2 cartridge, 0-30% EtOAc in cyclohexane) to give the title compound A79 as a yellow foam (0.570 g, 86%); 1H NMR (300 MHz, d6-DMSO) δ 8.65 (s, 1H), 7.70 (d, J=7.7 Hz, 1H), 7.64 (d, J=8.5 Hz, 2H), 7.48-7.33 (m, 6H), 4.35 (t, J=8.6 Hz, 2H), 4.01-3.96 (m, 4H), 3.75-3.72 (m, 4H), 1.49 (s, 9H). LCMS-B: rt 9.160 min; m/z 567 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.N1C=CC=CC=1.[I:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>C1COCC1>[Cl:19][C:6]1[CH:5]=[C:4]([NH:20][S:34]([C:31]2[CH:32]=[CH:33][C:28]([I:27])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1
Reactant: Nc1cc(Cl)c(Sc2ccc3ccccc3c2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)c(Sc2ccc3ccccc3c2)c(Cl)c1)c1ccc(I)cc1
Yield: 92.2 %

Procedure:
The title compound was prepared using the method of example 94, starting with 3,5-dichloro-4-(naphthalen-2-ylsulfanyl)-phenylamine (90) (150 mg, 0.47 mmol), pyridine (Aldrich, 0.19 mL, 2.34 mmol) and 4-iodobenzenesulfonyl chloride (Acros, 155 mg, 0.52 mmol) in THF. 254 mg (93%) of 101 was obtained as a pale yellow solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[N:8][O:9][C:10]=1[CH3:11])=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:7]1[C:6]([CH2:4][OH:3])=[C:10]([CH3:11])[O:9][N:8]=1
Reactant: CCOC(=O)c1c(-c2ccccc2F)noc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1onc(-c2ccccc2F)c1CO
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 56.8 %

Procedure:
To a solution of 3-(2-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester (73.6 g, 295 mmol) in THF (977 mL) was added portionwise lithiumaluminiumhydride (6.48 g, 162 mmol) over 20 min, at 0° C., and the reaction mixture was stirred at room temperature for 2.5 h. The mixture was then cooled to 0° C. and water (7.5 mL) added followed by sodium hydroxide (15% solution, 7.5 mL) and then again with water (21 mL). The precipitate was then filtered off and washed with THF. The combined washings and filtrate were then evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=75:25) afforded the title compound (34.7 g, 57%) which was obtained as a light yellow oil. MS: m/e=208.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C@@H:10]([CH3:14])[CH2:11][O:12][CH3:13])[N:3]=1.[NH2:15][C:16]1[C:17](=[O:27])[NH:18][C:19]2[C:24]([N:25]=1)=[C:23]([OH:26])[CH:22]=[CH:21][CH:20]=2>>[NH2:15][C:16]1[C:17](=[O:27])[NH:18][C:19]2[C:24]([N:25]=1)=[C:23]([O:26][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C@@H:10]([CH3:14])[CH2:11][O:12][CH3:13])[N:3]=1)[CH:22]=[CH:21][CH:20]=2
Reactant: Nc1nc2c(O)cccc2[nH]c1=O
Reactant: COC[C@H](C)Nc1nc(Cl)cc(Cl)n1
Product: COC[C@H](C)Nc1nc(Cl)cc(Oc2cccc3[nH]c(=O)c(N)nc23)n1

Procedure:
The reaction of (S)-4,6-dichloro-N-(1-methoxypropan-2-yl)pyrimidin-2-amine from step (a) above (0.62 g, 2.63 mmol) with 3-amino-5-hydroxyquinoxalin-2(1H)-one (0.47 g, 3 mmol, prepared as described in WO 2004/014871) under the conditions of Example 105(a) provided the title compound as an off-white solid. MS (ESI, pos. ion.) m/z: 377 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[CH:11][CH:10]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH:2]([C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]2[C:18]([F:24])=[CH:19][CH:20]=[CH:21][C:22]=2[F:23])=[CH:11][CH:10]=1)=[O:1]
Reactant: O=C(Nc1ccc(C2=C(CO)CCCC2)cc1)c1c(F)cccc1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=CC1=C(c2ccc(NC(=O)c3c(F)cccc3F)cc2)CCCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 76.9 %

Procedure:
To the solution of Compound 22 (55 mg, 0.16 mmol) in DCM (4 mL) was added Dess-Martin reagent (100 mg, 0.24 mmol). The solution was stirred at room temperature for 20 min before it was concentrated and chromatographed to afford Compound 100 (42 mg, 78%). 1H NMR (300 MHz, CDCl3) δ 9.52 (s, 1H), 7.68-7.65 (m, 3H), 7.47-7.41 (m, 1H), 7.25 (d, J=8.4 Hz, 2H), 7.02 (t, J=8.1 Hz, 2H), 2.55-2.51 (m, 2H), 2.37-2.31 (m, 2H), 1.79-1.71 (m, 4H); ESMS cacld (C20H17F2NO2): 341.1; found: 342.1 (M+H).
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:19](O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([O:16][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:15])=[CH:17][CH:18]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 60.6 %

Procedure:
To a mixture of 4-(N-Boc-aminomethyl)benzoic acid (500 mg, 1.99 mmol), DMAP (catalytic amount), benzyl alcohol (226 μl, 2.19 mmol) and dichloromethane (20 ml) was added dicyclohexylcarbodiimide (1M solution in dichloromethane, 2.19 ml, 2.19 mmol) and the mixture stirred at room temperature for 60 hours. The precipitate was removed by filtration and the filtrate concentrated in vacuo. Diethyl ether (50 ml) was added to the residue, the resulting precipitate removed by filtration and the filtrate concentrated in vacuo. Purification by flash column chromatography (petrol/EtOAc, 3:1) gave the title compound (412 mg, 61%) as a solid.
Reaction SMILES: CO[CH:3]1[CH:7]([CH:8]=[O:9])[CH2:6][CH:5](OC)O1.Cl.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1>O>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH:5]=[CH:6][C:7]([CH:8]=[O:9])=[CH:3]2)=[CH:17][CH:16]=1
Reactant: COc1ccc(N)cc1
Reactant: COC1CC(C=O)C(OC)O1
Agent: Cl
Solvent: O
Product: COc1ccc(-n2ccc(C=O)c2)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
2,5-Dimethoxytetrahydrofuran-3-carbaldehyde (7.31 g) and p-anisidine hydrochloride (7.28 g) were added to water (100 ml) and stirred at 60° C. for three hours. The precipitated yellow solid were filtered at the same temperature, washed with water (50 ml), saturated aqueous solution of sodium bicarbonate (50 ml), and further water (50 ml) to give 1-(4-methoxyphenyl)pyrrole-3-carb aldehyde.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:23](Cl)=[N:22][C:21]([Cl:25])=[CH:20][N:19]=1)(=[O:16])=[O:15]>>[Cl:6][C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:23]([O:5][CH2:4][CH2:3][S:2][CH3:1])=[N:22][C:21]([Cl:25])=[CH:20][N:19]=1)(=[O:16])=[O:15]
Reactant: O=S(=O)(Nc1ncc(Cl)nc1Cl)c1cccc(Cl)c1Cl
Reactant: CSCCO
Product: CSCCOc1nc(Cl)cnc1NS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 31 using 2-methylsulphanylethanol (0.05 g) and 2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (0.1 g). Yield 0.06 g.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>C(#N)C>[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH:31][CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]3[C:15]4[S:16][CH:17]=[CH:18][C:14]=4[O:13][N:12]=3)[CH:6]=2)=[CH:28][CH:27]=1
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Reactant: NCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Clc1ccc(CNCCOc2cccc(-c3noc4ccsc34)c2)cc1

Procedure:
The title compound is prepared from 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, 4-chlorobenzylamine and acetonitrile essentially as described above in example 18 except that the column is eluted using a gradient of 40% ethyl acetate in heptane, to 100% ethyl acetate. Purity by LC/MS (APCI)=100%, [M+H]+=385.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7]3[N:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]([CH:16]([F:18])[F:17])(C=O)[C:4]=2[CH:3]=1.[CH:21]([O:30][CH:31]([CH3:33])[CH3:32])([O:26][CH:27]([CH3:29])[CH3:28])OC(C)C.CC1C=CC(S(O)(=O)=O)=CC=1.O.CCOC(C)=O.CCCCCC>C(O)(C)C>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7]3[N:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]([CH:16]([F:18])[F:17])([CH:21]([O:26][CH:27]([CH3:28])[CH3:29])[O:30][CH:31]([CH3:32])[CH3:33])[C:4]=2[CH:3]=1
Reactant: O=CC1(C(F)F)c2cc(Cl)ccc2Nc2ncccc21
Reactant: CC(C)OC(OC(C)C)OC(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: CCCCCC
Solvent: O
Product: CC(C)OC(OC(C)C)C1(C(F)F)c2cc(Cl)ccc2Nc2ncccc21
Reaction time: 1.5 h
Yield: 33.3 %

Procedure:
Method MMM To a stirred solution of 7-chloro-5-(difluoromethyl)-5-formyl-5,10-dihydrobenzo[b][1,8]naphthyridine (93) (294 mg, 1.0 mmol) in anhydrous triisopropyl orthoformate (8.24 mL, 36.98 mmol) and anhydrous isopropanol (5 mL) at room temperature was added p-TsOH.H2O (380 mg, 2.0 mmol). After 1.5 h at room temperature, the reaction was concentrated in vacuo. Flash chromatography (SiO2, 30% EtOAc-hexane) afforded 94 (132 mg, 34% yield) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:20]=[C:19]([CH3:21])[C:13]2[N:14]=[C:15]([NH2:18])[N:16]=[N:17][C:12]=2[CH:11]=1.Br[C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH2:32][CH2:33][CH2:34][N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)(=[O:31])=[O:30])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C(Cl)Cl.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:20]=[C:19]([CH3:21])[C:13]2[N:14]=[C:15]([NH:18][C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH2:32][CH2:33][CH2:34][N:35]4[CH2:36][CH2:37][CH2:38][CH2:39]4)(=[O:31])=[O:30])=[CH:25][CH:24]=3)[N:16]=[N:17][C:12]=2[CH:11]=1
Reactant: O=S(=O)(CCCN1CCCC1)c1ccc(Br)cc1
Reactant: COc1ccc(Cl)c(-c2cc(C)c3nc(N)nnc3c2)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: ClCCl
Product: COc1ccc(Cl)c(-c2cc(C)c3nc(Nc4ccc(S(=O)(=O)CCCN5CCCC5)cc4)nnc3c2)c1
Yield: 89.1 %

Procedure:
In a dry 25 mL round bottom flask, 7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamine (0.0361 g, 0.122 mmol, 1 equiv), 1-[3-(4-bromo-benzenesulfonyl)-propyl]-pyrrolidine (0.061 g, 0.184 mmol, 1.5 equiv), cesium carbonate (0.120 g, 0.367 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.014 g, 0.0244 mmol, 0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.012 g, 0.0122 mmol, 0.1 equiv) were combined. The reactants were flushed with argon, diluted with dioxane (6 mL) and outfitted with reflux condenser. The reaction was heated to reflux for 18 hours, filtered hot, diluted with ethyl acetate and washed with brine. The brine layer was back extracted once with fresh ethyl acetate. The organic phases were combined and dried over sodium sulfate (Na2SO4). Filtration followed by evaporation provided crude product, which was dissolved in minimum amount of DCM and precipitated out with excess hexanes. Solids were filtered off and dried to yield a yellow powder (0.06 g, 91% yield).
Reaction SMILES: [I-].[C:2]1([S+:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:21](OC)([O:25][CH3:26])([O:23][CH3:24])=[O:22]>>[CH3:24][O:23][PH:21](=[O:22])[O:25][CH3:26].[C:15]1([S+:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COP(=O)(OC)OC
Agent: [I-]
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Product: CO[PH](=O)OC
Temperature: 130 °C
Reaction time: 3 h

Procedure:
A mixture of triphenylsulfonium iodide (390 mg; 1 mmol) and trimethyl phosphate (1 g) was stirred at 130° C. for 3 hours. Subsequently, the homogenous solution was cooled, and the thus-obtained solid matter was washed with IPA, to thereby yield 280 mg of the target compound as white crystals (yield: 72.2%). The anion content of the resultant compound was determined by ion chromatography. The iodide anion content was determined to be not greater than 50 ppm.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([O:13][C@H:14]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]2)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].[NH:26]([C:28](OCC)=[O:29])[NH2:27].C1CCN2C(=NCCC2)CC1>CN1C(=O)CCC1>[O:29]=[C:28]1[NH:26][N:27]=[C:1]([C:3]2[N:4]=[C:5]([O:13][C@H:14]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]3)[C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:2]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C#N)cc3ccccc23)C1
Reactant: CCOC(=O)NN
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(-c3n[nH]c(=O)[nH]3)cc3ccccc23)C1
Temperature: 170 °C

Procedure:
(S)-tert-Butyl 3-((3-cyanoisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate (4.670 g, 13.76 mmol), ethyl hydrazinecarboxylate (7.160 g, 68.80 mmol), DBU (1.037 mL, 6.88 mmol) and NMP (34.6 mL) were mixed in a 200 mL high pressure reaction vessel. The resulting suspension was heated at 170° C. overnight and was then cooled to room temperature. Crushed ice was added and the mixture was stirred. A yellow precipitate was collected by vacuum filtration, washed with additional water, and dried in a vacuum oven at 45° C. overnight to give the title compound, which was used in the next step without further purification (5.47 g). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.33-1.51 (m, 9H), 2.09-2.38 (m, 2H), 3.39-3.60 (m, 3H), 3.75 (dd, J=12.20, 4.88 Hz, 1H), 6.03-6.22 (m, 1H), 7.62-7.71 (m, 1H), 7.81 (td, J=7.57, 1.46 Hz, 1H), 7.95-8.05 (m, 1H), 8.11-8.29 (m, 2H), 11.78 (s, 1H), 12.03 (br s, 1H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.O[CH2:33][C@@H:34]([NH:38][C:39]([NH:41][C:42]1[CH:43]=[N:44][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:46][CH:47]=1)=[O:40])[CH:35]([CH3:37])[CH3:36]>C1COCC1>[CH3:36][CH:35]([C@H:34]1[CH2:33][N:41]([C:42]2[CH:43]=[N:44][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:46][CH:47]=2)[C:39](=[O:40])[NH:38]1)[CH3:37]
Reactant: CC(C)[C@@H](CO)NC(=O)Nc1ccc(C(F)(F)F)nc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)[C@H]1CN(c2ccc(C(F)(F)F)nc2)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
Triphenylphosphine (770 mg) and diethyl azodicarboxylate (2.2 M solution in toluene, 1.3 mL) were added to a solution of 1-[(2S)-1-hydroxy-3-methylbutan-2-yl]-3-[6-(trifluoromethyl)pyridin-3-yl]urea (640 mg) in THF (10 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, the residue was purified by column chromatography (silica gel cartridge and NH silica gel cartridge, hexane/ethyl acetate), and the resulting solid was washed with isopropyl ether to afford the title compound (500 mg). This product contained by-products originating in reaction reagents.
Reaction SMILES: Br[C:2]1[C:3]([F:25])=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]4[N:16]([CH:21]([CH3:23])[CH3:22])[N:17]=[C:18]([CH3:20])[N:19]=4)=[CH:10]3)[C:6]=2[CH:24]=1.[CH:26]([B-](F)(F)F)=[CH2:27].[K+].C(N(CC)CC)C>C(O)CC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:25][C:3]1[C:2]([CH:26]=[CH2:27])=[CH:24][C:6]2[C:7]3[N:11]([CH2:12][CH2:13][O:14][C:5]=2[CH:4]=1)[CH:10]=[C:9]([C:15]1[N:16]([CH:21]([CH3:23])[CH3:22])[N:17]=[C:18]([CH3:20])[N:19]=1)[N:8]=3
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(Br)c(F)cc2OCC3)n(C(C)C)n1
Reactant: C=C[B-](F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CCCO
Product: C=Cc1cc2c(cc1F)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Yield: 87.8 %

Procedure:
A degassed solution of 9-bromo-8-fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene from Example 8 (5.0 g, 12.31 mmol), potassium vinyltrifluoroborate (2.47 g, 18.46 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (1.01 g, 1.23 mmol) and triethylamine (8.58 mL, 61.55 mmol) in nPrOH (50 mL) was heated to 100° C. for 2 h. The reaction mixture was concentrated in vacuo; the residue was taken up in EtOAc and filtered through celite. Organics were washed with water and brine, dried (Na2SO4) and concentrated in vacuo to give the title compound (3.82 g, 10.81 mmol, 88%) as a peach solid. The product was taken on without further purification. LCMS (Method J): RT=3.35 min, [M+H]+ =354.
Reaction SMILES: [OH-].[Na+].[CH:3]1([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[S:17]([NH2:20])(=[O:19])=[O:18])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH:21]1([N:27]=[C:28]=[S:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(OCC)(=O)C>O.O.CC(C)=O.C(N(CC)CC)C.CO>[CH:3]1([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[S:17]([NH:20][C:28]([NH:27][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[S:29])(=[O:19])=[O:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: S=C=NC1CCCCC1
Reactant: NS(=O)(=O)c1cnccc1NC1CCCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=S(=O)(NC(=S)NC1CCCCC1)c1cnccc1NC1CCCCCC1
Yield: 50 %

Procedure:
0.01 mol of NaOH dissolved in a minimum of water is added to a solution of 0.01 mol of (4-(cycloheptylamino)pyrid-3-yl)sulfonamide in 80 ml of a water/acetone mixture (1:1). The mixture is stirred with a magnetic rod, and 0.015 mol of cyclohexylisothiocyanate is added. Stirring is continued, while the reaction is followed by TLC (silica gel 60F254; mobile phase: ethyl acetate 9, methanol 1, triethylamine 0.2). Gentle heating can accelerate the reaction. The mixture is evaporated under reduced pressure and the residue is taken up in 100 ml of 0.2N NaOH. Any insoluble material is filtered out and the solution is corrected to pH 6.5-7 and left to crystallize for 1 hour in the refrigerator. The precipitate collected is suspended in 100 ml of a water/acetone mixture (4:1) saturated with NaHCO3. The mixture is stirred for 1 hour and then filtered, and the filtrate, brought back to pH 6.5-7, is left to crystallize in the refrigerator. The crystals are collected, washed in cold water and dried under vacuum at normal temperature. Yield is around 50-60%. Melting point: 195°-197° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]Cl)=[C:6]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:5]=1)([O-:3])=[O:2].[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([SH:24])[N:18]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([S:24][S:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[C:12]([Cl:15])([Cl:14])[Cl:13])[N:18]=1
Reactant: O=[N+]([O-])c1ccc(SCl)c(C(Cl)(Cl)Cl)c1
Reactant: Cc1cc(C)nc(S)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(C)nc(SSc2ccc([N+](=O)[O-])cc2C(Cl)(Cl)Cl)n1
Reaction time: 12 h
Yield: 91.4 %

Procedure:
61.4 g of 4-nitro-2-trichloromethylbenzenesulfenyl chloride, dissolved in 500 ml of glacial acetic acid, are mixed with 28 g of 4,6-dimethyl-2-mercaptopyrimidine and 16.4 g of sodium acetate at 20° C. After 12 hours, the precipitate is filtered off, washed with water and dried over potassium hydroxide. 75 g (91% of theory) of 4,6-dimethylpyrimidin-2-yl-dithio-(4-nitro-2-trichloromethylbenzene), of melting point 151° C., are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[CH:10]([CH2:13][CH2:14][CH:15]([OH:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:9]2[C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.N.[H][H].ClCCl.CO>C(O)C.[Ni]>[NH2:28][CH2:27][C:26]1[CH:29]=[CH:30][C:23]([CH:9]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:11](=[O:12])[CH:10]2[CH2:13][CH2:14][CH:15]([OH:22])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:24][CH:25]=1
Reactant: N#Cc1ccc(C2C(CCC(O)c3ccccc3)C(=O)N2c2ccc(F)cc2)cc1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: NCc1ccc(C2C(CCC(O)c3ccccc3)C(=O)N2c2ccc(F)cc2)cc1

Procedure:
930 mg of 4-[1-(4-fluorophenyl)-3-(3-hydroxy-3-phenylpropyl)-4-oxo-azetidin-2-yl]-benzonitrile, dissolved in 100 ml of ethanol, are admixed with 4 ml of conc. ammonia and hydrogenated for 20 hours over Raney Ni, at room temperature and a hydrogen pressure of 20 bar. The catalyst is filtered off and the filtrate is concentrated under reduced pressure, giving, after chromatography (SiO2, dichloromethane/methanol=0:1), the product of molecular weight 404.5 (C25H25FN2O2); MS (DCl+): 405 (M+H+), 387 (M+H+−H2O).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[C:15]2([OH:19])[CH2:18][CH2:17][CH2:16]2)[CH2:3][CH2:2]1.[CH3:20][C:21]([CH3:29])([C:23]1[N:27]=[C:26]([CH3:28])[O:25][N:24]=1)[NH2:22]>>[CH3:20][C:21]([NH:22][C:12]([C:10]1[CH:9]=[CH:8][C:7]([C:15]2([OH:19])[CH2:18][CH2:17][CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([C:23]1[N:27]=[C:26]([CH3:28])[O:25][N:24]=1)[CH3:29]
Reactant: O=C(O)c1ccc(C2(O)CCC2)c(OCC2CC2)n1
Reactant: Cc1nc(C(C)(C)N)no1
Product: Cc1nc(C(C)(C)NC(=O)c2ccc(C3(O)CCC3)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(1-hydroxy-cyclobutyl)-pyridine-2-carboxylic acid and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials, MS (EI): m/e=387.2 [M+H]+.