Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16](I)=[C:15]([CH3:20])[CH:14]=1>>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=2)=[C:15]([CH3:20])[CH:14]=1
Reactant: Cc1cc(Br)ccc1I
Reactant: OCc1ccc(B(O)O)cc1
Product: Cc1cc(Br)ccc1-c1ccc(CO)cc1
Yield: 7.1 %

Procedure:
In accordance with Example 4-(2), but using [4-(hydroxymethyl)phenyl]boronic acid instead of (4-bromophenyl)boronic acid, and 4-bromo-1-iodo-2-methylbenzene instead of tert-butyl[2-(4-iodophenyl)ethoxy]dimethylsilane, the title compound (yield 7.1%) was afforded as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1)=O.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH:30]=O>>[F:9][C:8]([F:11])([F:10])[C:7]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:2]=1[N:1]=[CH:30][C:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:22]([F:21])([F:32])[F:33])=[C:12]2[C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1
Reactant: Nc1c(C(=O)c2cccc(O)c2)cccc1C(F)(F)F
Reactant: O=CCc1ccccc1C(F)(F)F
Product: Oc1cccc(-c2c(-c3ccccc3C(F)(F)F)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from [2-amino-3-(trifluoromethyl)phenyl]-(3-hydroxy-phenyl)methanone and (2-Trifluoromethyl-phenyl)-acetaldehyde following the procedure of Example 457: MS (ES) m/z 431.9; HRMS: calcd for C23H13F6NO+H+, 434.09741; found (ESI, [M+H]+), 434.0961.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:15][N:14]=[C:13]([NH2:16])[N:12]=3)[CH:9]=2)[NH:4][CH:3]=1.[CH:17]([NH:20][C:21]1[CH:26]=[N:25][CH:24]=[C:23]([Sn](CCCC)(CCCC)CCCC)[N:22]=1)([CH3:19])[CH3:18].N#N>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>[CH:17]([NH:20][C:21]1[N:22]=[C:23]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[O:15][N:14]=[C:13]([NH2:16])[N:12]=4)[CH:9]=3)[NH:4][CH:3]=2)[CH:24]=[N:25][CH:26]=1)([CH3:19])[CH3:18]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(NC(C)C)n1
Reactant: Nc1noc(-c2ccc3[nH]cc(I)c3c2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Product: CC(C)Nc1cncc(-c2c[nH]c3ccc(-c4nc(N)no4)cc23)n1
Temperature: 90 °C
Yield: 9.7 %

Procedure:
To a solution of 5-(3-iodo-1H-indol-5-yl)-1,2,4-oxadiazol-3-amine (0.15 g, 0.460 mmol) and isopropyl-(6-tributylstannanyl-pyrazin-2-yl)-amine (0.235 g, 0.549 mmol) was bubbled N2 gas for 15 min. To the mixture was added Cut (0.070 g, 0.366 mmol) and Pd(PPh3)4 (0.053 g, 0.043 mmol) and N2 gas was bubbled for another 15 min. The reaction was heated at 90° C. for 1 h. The mixture was cooled to RT, quenched with H2O (100 mL) and extracted with EtOAc (2×100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified with preparative HPLC (eluent: 10-60% AcCN in H2O with 0.01% TFA) to give 5-(3-(6-(isopropylamino)pyrazin-2-yl)-1H-indol-5-yl)-1,2,4-oxadiazol-3-amine (0.015 g, 10%) as a pale yellow solid. MS (ESI, pos. ion) m/z: 336.2 (M+1); 1H-NMR (400 MHz, CD3OD): δ 9.34 (s, 1H), 8.09 (s, 1H), 8.04 (d, J=0.8 Hz, 1H), 7.88 (d, J=8.4 Hz, 1H), 7.56 (d, J=8.8 Hz, 1H), 4.39 (m, 1H), 1.38 (dd, J=6.8, 1.2 Hz, 6H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[O:9])[CH2:2]2.CC(C)([O-])C.[K+].CC(O)C>CC(O)C>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([OH:9])[CH2:2]2
Reactant: O=C1CN2CCC1CC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: O[C@H]1CN2CCC1CC2
Temperature: 30 °C
Reaction time: 15 h

Procedure:
To a 100-mL autoclave were added 3-quinuclidinone (500 mg, 4.0 mmol), [RuCl(p-cymene)((R)-DM-SEGPHOS)]Cl (4.1 mg, 0.004 mmol), and (R)-DAIPEN (5.0 mg, 0.016 mmol). Under a nitrogen atmosphere, IPA (4 mL) and potassium t-butoxide/IPA solution (1.0 mol/L, 0.4 mL) were added thereto. Then, the mixture was stirred under a hydrogen pressure of 3 MPa at 30° C. for 15 hours. After analysis of the reaction solution, (R)-3-quinuclidinol was obtained at an optical purity of 90.8% ee and a conversion ratio of 99% or more.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[C:11](=[O:12])[N:10]3[C:13]([CH3:17])=[CH:14][CH:15]=[CH:16][C:9]3=[N:8][CH:7]=2)=[N:4][N:3]=[N:2]1.[CH3:18]N(C)C=O.C(=O)([O-])[O-].[K+].[K+].CI>O>[CH3:18][N:1]1[C:5]([C:6]2[C:11](=[O:12])[N:10]3[C:13]([CH3:17])=[CH:14][CH:15]=[CH:16][C:9]3=[N:8][CH:7]=2)=[N:4][N:3]=[N:2]1
Reactant: Cc1cccc2ncc(-c3nnn[nH]3)c(=O)n12
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: Cc1cccc2ncc(-c3nnnn3C)c(=O)n12
Temperature: 80 °C
Reaction time: 1 h
Yield: 66.53 %

Procedure:
A mixture of 2.3 g of 3- (1H-tetrazol-5-yl) -6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine, 50 ml of dimethylformamide, 1.38 g (0.001 mole) of anhydrous potassium carbonate and 2.85 g (0.02 moles) of methyl iodide was stirred at 80° C. for 1 hour. The reaction mixture was cooled to room temperature and diluted with 150 ml of water. The precipitating crystals were collected. 1.61 g (66.53%) of the title compound was obtained, which was crystallized from dimethylformamide, m.p.: 232°-234° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][CH2:4][C@@H:5]([CH2:9][CH:10]=[CH2:11])[C:6](O)=[O:7].Cl.[CH3:14][NH:15][O:16][CH3:17].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>ClCCl>[CH3:17][O:16][N:15]([CH3:14])[C:6](=[O:7])[C@@H:5]([CH2:4][CH2:3][CH:2]([CH3:12])[CH3:1])[CH2:9][CH:10]=[CH2:11]
Reactant: C=CC[C@H](CCC(C)C)C(=O)O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C=CC[C@H](CCC(C)C)C(=O)N(C)OC

Procedure:
A solution of Example 8D (4.54 g, 26.7 mmol), N,O-dimethyl hydroxylamine hydrochloride (5.6 g, 57 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.19 g, 27 mmol), 1-hydroxybenzotriazole (4.12 g, 30.5 mmol), and N-methylmorpholine (7.0 mL, 64 mmol) in dichloromethane (270 mL) at room temperature was stirred for 4 hours, diluted with dichloromethane, washed sequentially with aqueous NaHCO3, brine, 10% KHSO4, and brine, dried (MgSO4), filtered, and concentrated. Flash column chromatography (silica gel, 10% ethyl acetate/hexanes) provided the desired product. MS (ESI(+)) m/e 214 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[C:13](=[O:22])[CH:12]=[CH:11]2)[CH2:4][CH2:3]1.[O:23]1[C:32]2[CH:31]=[C:30]([CH:33]=O)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.CO>[O:23]1[C:32]2[CH:31]=[C:30]([CH2:33][NH:1][CH:2]3[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]4[C:19]5[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=5)[C:13](=[O:22])[CH:12]=[CH:11]4)[CH2:4][CH2:3]3)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: COc1ccc2c(=O)ccn(CCN3CCC(N)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(=O)ccn(CCN3CCC(NCc4cc5c(cn4)OCCO5)CC3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-[2-(4-aminopiperidin-1-yl)ethyl]-7-methoxyquinolin-4(1H)-one (Intermediate 8, 60 mg, 0.20 mmol) and 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (33 mg, 0.20 mmol) in dry chloroform/methanol (5 mL, 1:1) was heated over 3 Å molecular sieves at 70° C. for 3 hours. The reaction mixture was cooled to 0° C., and sodium triacetoxyborohydride (127 mg, 0.6 mmol) was added and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was then filtered through a 0.45 μm membrane, acidified with conc. HCl to pH 1 and concentrated to dryness under reduced pressure. The residue was taken up in dichloromethane (50 mL) and saturated aqueous sodium hydrogen carbonate solution (5 mL). The pH of the aqueous phase was adjusted to pH10 with 1M aqueous sodium hydroxide solution. The aqueous phase was back extracted twice with dichloromethane (2×20 mL) and the combined organic phases were dried over sodium sulfate. Chromatography on silica gel with dichloromethane/methanol (4:1), containing 0.125% ammonium hydroxide, gave the free base of the title compound as a colorless oil. The free base was taken up in dichloromethane (2 mL), ethanol (7 mL) was added, followed by addition of 1M HCl in ether (0.45 mL). The colorless precipitate was collected by filtration and gave 84 mg (81% yield) of the bis-hydrochloride salt of the product, mp 260° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1.[C:31](O)(=[O:34])[CH2:32][CH3:33].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[C:31]([NH:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1)(=[O:34])[CH2:32][CH3:33]
Reactant: CCC(=O)O
Reactant: Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(=O)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Yield: 68.1 %

Procedure:
Using N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (150 mg, 0.363 mmol), propionic acid (40 μL, 0.544 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (104 mg, 0.544 mmol), 1-hydroxybenzotriazole (73 mg, 0.544 mmol), triethylamine (76 μL, 0.544 mmol) and N,N-dimethylformamide (5 mL) as starting materials and in the same manner as in Example 380, the title compound (116 mg, 68%) was obtained as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[O:9][C:8]([CH:10]=O)=[CH:7][CH:6]=1.[NH3:17].CO>[Ni]>[F:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[O:9][C:8]([CH2:10][NH2:17])=[CH:7][CH:6]=1
Reactant: O=Cc1ccc(Oc2ccc(F)cc2F)o1
Reactant: N
Agent: [Ni]
Solvent: CO
Product: NCc1ccc(Oc2ccc(F)cc2F)o1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.7 %

Procedure:
To a solution of 5-(2,4-difluoro-phenoxy)-furan-2-carbaldehyde (2060 mg, 9.19 mmol) in 7N ammonia/methanol solution (100 mL) was added Raney nickel (5.9 g), and the mixture was stirred for 24 hours at room temperature under hydrogen atmosphere. The reaction mixture was filtered through Celite pad, and the filtrate was concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane:ethyl acetate), and the title compound (1814 mg, 88.06 mmol, 87.7%) was obtained as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[C:10]([OH:11])=[C:9]([C@H:12]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([CH3:23])=[CH:7][C:5]=2[N:6]=1.[B-](F)(F)(F)[F:25].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[Br:1][C:2]1[S:3][C:4]2[C:10]([OH:11])=[C:9]([C@H:12]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([CH3:23])=[C:7]([F:25])[C:5]=2[N:6]=1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1O
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)c(F)c2nc(Br)sc2c1O
Yield: 34.4 %

Procedure:
The reaction mixture of (S)-ethyl 2-(2-bromo-7-hydroxy-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (75A) (380 mg, 0.948 mmol), Selectfluor (1.9 g, 4.74 mmol) in acetonitrile (7 mL) was reacted at 0° C. for 5 days. The reaction mixture was washed by 1.5 M KH2PO4, extracted by EtOAc, the organic phase was dried over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-40% EtOAc in hexanes to give 75B (137 mg, 35%). LCMS-ESI+: calc'd for C16H19FNO4S: 420.0 (M+H+). Found: 420.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22](Cl)(=[O:24])=[O:23])=[C:6]1[CH3:26].[CH3:28][NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22](=[O:24])(=[O:23])[N:29]([CH3:28])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:6]1[CH3:26]
Reactant: CNc1ccccc1
Reactant: COC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)Cl)c2cc(F)ccc21
Product: COC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)N(C)c2ccccc2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 20c using [3-(2-chlorosulfonylbenzyl)-5-fluoro-2-methylindol-1-yl]acetic acid methyl ester and N-methylaniline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[N:15]=[C:16]([CH2:18][CH3:19])[CH:17]=[C:13]2[N:12]=[C:11]([CH3:20])[N:10]=1.[N+:21]([O-])([OH:23])=[O:22].CCOC(C)=O>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[N:15]=[C:16]([CH2:18][CH3:19])[C:17]([N+:21]([O-:23])=[O:22])=[C:13]2[N:12]=[C:11]([CH3:20])[N:10]=1
Reactant: CCc1cc2nc(C)nc(-c3ccc(Cl)cc3Cl)n2n1
Reactant: O=[N+]([O-])O
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CCc1nn2c(-c3ccc(Cl)cc3Cl)nc(C)nc2c1[N+](=O)[O-]
Temperature: -7.5 °C
Yield: 21.4 %

Procedure:
A solution of 4-(2,4-dichlorophenyl)-7-ethyl-2-methyl-pyrazolo[1,5-a]-1,3,5-triazine (653 mg, 2.2 mmol) in acetic anhydride (4 mL) was cooled with stirring to −5 to −10° C. A solution of fuming nitric acid (160 mg, 2.55 mmol) in acetic anhydride (2 mL) was added dropwise over 15 min. The reaction mixture was stirred at the same temperature for 3 h, then it was partitioned between water and ether three times. The combined organic layers were washed with a saturated NaHCO3 solution, dried over MgSO4 and filtered. Solvent was removed in vacuo to provide a solid. Column chromatography (EtOAc:hexanes::1:9 to 1:4) provided a solid (166 mg, 21% yield) after removal of solvent in vacuo: NMR (CDCl3, 300 MHz): δ 7.64 (d, 1H, J=8), 7.63 (d, 1H, J=2), 7.50 (dd, 1H J=8, 2), 3.19 (q, 2H, J=7), 2.94 (s, 3H), 1.32 (t, 3H, J=7).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])([OH:12])[C:9]([OH:11])=[O:10].C1N=CN(C(N2C=NC=C2)=O)C=1.[Br-:32].O[C@@H:34]1[CH:39]2[CH2:40][CH2:41][N+:36]([CH2:42][C:43](=[O:50])[NH:44][C:45]3[CH:49]=[CH:48][O:47][N:46]=3)([CH2:37][CH2:38]2)[CH2:35]1>CN(C=O)C>[Br-:32].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])([OH:12])[C:9]([O:11][C@@H:38]1[CH:39]2[CH2:40][CH2:41][N+:36]([CH2:42][C:43](=[O:50])[NH:44][C:45]3[CH:49]=[CH:48][O:47][N:46]=3)([CH2:35][CH2:34]2)[CH2:37]1)=[O:10]
Reactant: O=C(C[N+]12CCC(CC1)[C@@H](O)C2)Nc1ccon1
Reactant: O=C(O)C(O)(c1ccccc1Cl)c1ccccc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Br-]
Solvent: CN(C)C=O
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccccc1Cl)c1ccccc1Cl)C2)Nc1ccon1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a stirred solution of bis-(2-chloro-phenyl)-hydroxy-acetic acid (0.17 g, 0.572 mmol) in dry DMF (3 ml) under an inert atmosphere of Argon is added CDI (0.097 g, 0.6 mmol). After 1 hour, (R)-3-hydroxy-1-(isoxazol-3-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide (Intermediate A) (0.2 g, 0.602 mmol) is added and the reaction mixture is heated to 40° C. overnight. Purification using C-18 reverse phase column chromatography (eluent: water-acetonitrile) affords a solid which is triturated with diethyl ether to yield the titled compound as a crystalline solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:53]1[C:57]2[CH:58]=[CH:59][C:60]([C:62]3[CH:63]=[C:64]([NH2:68])[CH:65]=[CH:66][CH:67]=3)=[CH:61][C:56]=2[O:55][CH2:54]1>CN(C=O)C>[O:53]1[C:57]2[CH:58]=[CH:59][C:60]([C:62]3[CH:63]=[C:64]([NH:68][C:24]([C:19]4[C:20](=[O:23])[O:21][C:22]5[C:17]([CH:18]=4)=[CH:16][CH:15]=[CH:14][C:13]=5[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:65]=[CH:66][CH:67]=3)=[CH:61][C:56]=2[O:55][CH2:54]1
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Reactant: Nc1cccc(-c2ccc3c(c2)OCO3)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2ccc3c(c2)OCO3)c1)c1cc2cccc(OC(F)(F)F)c2oc1=O
Temperature: 25 °C
Yield: 70 %

Procedure:
DIEA (0.014 mL, 0.077 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.019 g, 0.070 mmol) and HATU (0.029 g, 0.077 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Benzo[1,3]dioxol-5-yl-phenylamine (0.015 g, 0.070 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.023 g of product in 70% yield: LCMS (ESI) m/z 470 (MH+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]([N:14]1[CH2:30][CH2:29][C:17]3([N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:20][NH:19][C:18]3=[O:28])[CH2:16][CH2:15]1)[CH2:8]2.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[ClH:2].[C:31]([N:19]1[C:18](=[O:28])[C:17]2([CH2:29][CH2:30][N:14]([CH:7]3[CH2:6][CH2:5][C:4]4[C:9](=[C:10]([Cl:13])[CH:11]=[CH:12][C:3]=4[Cl:2])[CH2:8]3)[CH2:15][CH2:16]2)[N:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20]1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCc3c(Cl)ccc(Cl)c3C1)CC2
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Product: O=C(c1ccccc1)N1CN(c2ccccc2)C2(CCN(C3CCc4c(Cl)ccc(Cl)c4C3)CC2)C1=O

Procedure:
The title compound, m.p. 220° C. dec. was prepared in accordance with the general method of example 4 from 8-(5,8-dichloro-1,2,3,4-tetrahydro-2-naphthyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one hydrochloride and benzoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:15]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:15][C:14]2[CH:17]=[CH:18][C:19]([Cl:20])=[C:12]([Cl:11])[CH:13]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccc(O)cc1Cl
Reactant: OCc1ccc(Cl)c(Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=Cc1ccc(OCc2ccc(Cl)c(Cl)c2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.4 %

Procedure:
2-Chloro-4-hydroxybenzaldehyde (324 mg, 2.07 mmol), 3,4-dichlorobenzyl alcohol (513 mg, 2.90 mmol), and triphenylphosphine (760 mg, 2.90 mmol) were dissolved in tetrahydrofuran (8 mL), and a diethyl azodicarboxylate toluene solution (2.2 M, 1.32 mL, 2.90 mmol) was slowly added dropwise thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. The solvent in the reaction solution was distilled off under reduced pressure, and the resulting residue was washed with hexane/dichloromethane (6/1 (v/v)), whereby the objective title compound was obtained as a white solid (244 mg, yield: 37%).
Reaction SMILES: I[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:12])[N:5]=[CH:4][CH:3]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[C:16]([F:23])[C:15]=1[F:24].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:12])[N:5]=[CH:4][CH:3]=2)=[C:16]([F:23])[C:15]=1[F:24]
Reactant: OB(O)c1ccc(Br)c(F)c1F
Reactant: COC(=O)c1c(I)ccnc1C
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
Solvent: O
Product: COC(=O)c1c(-c2ccc(Br)c(F)c2F)ccnc1C
Temperature: 110 °C
Yield: 43.8 %

Procedure:
In a microwave vessel, methyl 4-iodo-2-methylnicotinate (1.00 g, 3.61 mmol) was taken in a mixture of 1,4-dioxane (18 mL) and water (2 mL) under inert atmosphere. (4-bromo-2,3-difluorophenyl)boronic acid (1.03 g, 4.33 mmol) and Na2CO3 (765 mg, 7.22 mmol) were added to the reaction mixture and degassed for 5 minutes. Pd(Ph3P)4 (83 mg, 0.072 mmol) was added to the reaction mixture and heated in microwave at 110° C. for 90 min. The reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (200 mL). The organic phase was washed with brine (2×100 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (gradient of ethyl acetate and petroleum ether) to afford methyl 4-(4-bromo-2,3-difluorophenyl)-2-methylnicotinate (540 mg, 1.58 mmol, 44% yield) as a yellow liquid. LC/MS (ESI) m/e 344.0 [(M+2H)+, calcd for C14H12BrF2NO2 344.1]; LC/MS retention time (method C): tR=2.48 min.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].F[C:9](F)(F)[C:10](O)=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][C@H:40]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]1.C(Cl)(=O)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:10]([N:42]1[CH2:43][CH2:44][CH2:45][C@H:40]([CH2:39][C:38]([NH:37][C:29]2[CH:30]=[CH:31][C:32]3[NH:33][C:34]4[N:35]=[C:19]([NH:20][C:21]5[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=5)[CH2:26][CH2:27][C:28]=2[CH:36]=3)[N:18]=[CH:17][C:16]=4[Cl:15])=[O:46])[CH2:41]1)(=[O:11])[CH3:9]
Reactant: O=C(C[C@H]1CCCNC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)Cl
Product: CC(=O)N1CCC[C@H](CC(=O)Nc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)C1
Yield: 78 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3R)-piperidin-3-yl]acetamide bis(trifluoroacetate) and acetyl chloride as the starting materials in 78% yield. LCMS for C27H30ClN6O2 (M+H)+: m/z=505.0.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[CH2:4][N:3]=[N:2]1.[CH3:11][N:12]=[C:13]=[S:14]>C(O)C>[CH3:11][NH:12][C:13]([N:2]1[N:3]=[CH:4][C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[CH2:1]1)=[S:14]
Reactant: CN=C=S
Reactant: C1CC2(CCO1)CN=NC2
Solvent: CCO
Product: CNC(=S)N1CC2(C=N1)CCOCC2
Yield: 0.2 %

Procedure:
0.8 g (1 mol equiv.) 8-Oxa-2,3-diaza-spiro[4.5]dec-2-ene (synthesized as described in WO 2008/034863) and 0.54 g (1.3 mol equiv.) methyl isothiocyanate were added to 10 mL ethanol, and the reaction mixture was refluxed for 5 hours. Silica gel was added and volatiles were removed under reduced pressure. Purification by flash chromatography on silica gel (Et2O) afforded 0.52 g (35%) 8-oxa-2,3-diaza-spiro[4.5]dec-3-ene-2-carbothioic acid methylamide. 1H NMR (400 MHz, CDCl3) δ 1.52-1.59 (m, 3H), 1.82-1.90 (m, 2H), 3.17 (d, J=5.0, 3H), 3.56-3.64 (m, 2H), 3.86-3.92 (m, 2H), 4.11 (s, 2H), 6.80 (s, 1H), 7.21 (br.s., 1H).