Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].N1(C2C=CC=CN=2)CCC(NC(=O)NCCNC(C2N=C3C(N=CN3[C@@H]3C[C@H](NC(=O)C)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)=O)CC1.[NH2:64][C@@H:65]1[CH2:69][CH2:68][N:67]([C:70]2[N:78]=[C:77]3[C:73]([N:74]=[CH:75][N:76]3[C@@H:79]3[CH2:83][C@H:82]([NH:84][C:85](=[O:88])[CH2:86][CH3:87])[C@@H:81]([OH:89])[C@H:80]3[OH:90])=[C:72]([NH:91][CH2:92][CH:93]([C:100]3[CH:105]=[CH:104][CH:103]=[CH:102][CH:101]=3)[C:94]3[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=3)[N:71]=2)[CH2:66]1.C(Cl)(=O)C.[N:110]([C:113]1[CH:114]=[N:115][CH:116]=[CH:117][CH:118]=1)=[C:111]=[O:112]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:94]1([CH:93]([C:100]2[CH:101]=[CH:102][CH:103]=[CH:104][CH:105]=2)[CH2:92][NH:91][C:72]2[N:71]=[C:70]([N:67]3[CH2:68][CH2:69][C@@H:65]([NH:64][C:111]([NH:110][C:113]4[CH:114]=[N:115][CH:116]=[CH:117][CH:118]=4)=[O:112])[CH2:66]3)[N:78]=[C:77]3[C:73]=2[N:74]=[CH:75][N:76]3[C@@H:79]2[CH2:83][C@H:82]([NH:84][C:85](=[O:88])[CH2:86][CH3:87])[C@@H:81]([OH:89])[C@H:80]2[OH:90])[CH:95]=[CH:96][CH:97]=[CH:98][CH:99]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O
Reactant: O=C=Nc1cccnc1
Agent: CC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NC4CCN(c5ccccn5)CC4)nc32)[C@H](O)[C@@H]1O
Solvent: CC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
This compound is prepared analogously to 9-((1R,2S,3R,4S)-4-acetylamino-2,3-dihydroxy-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid {2-[3-(3,4,5,6-tetra-hydro-2H-[1,2′]bipyridinyl-4-yl)-ureido]-ethyl}-amide trifluoroacetate (Ex. 42) by replacing 9-((1R,2S,3R,4S)-4-amino-2,3-dihydroxy-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid {2-[3-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-ureido]-ethyl}-amide dihydrochloride (an intermediate for preparing Example 38) with N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (Example 36) and by replacing acetyl chloride with 3-isocyanato-pyridine.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1I)[CH3:2].FC1C=CC(B(O)O)=CC=1.[N+:31]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)([O-:33])=[O:32]>>[CH2:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1[C:38]1[CH:37]=[CH:36][CH:35]=[C:34]([N+:31]([O-:33])=[O:32])[CH:39]=1)[CH3:2]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: CCc1c(I)[nH]c(C=O)c1C(=O)OCc1ccccc1
Agent: OB(O)c1ccc(F)cc1
Product: CCc1c(-c2cccc([N+](=O)[O-])c2)[nH]c(C=O)c1C(=O)OCc1ccccc1

Procedure:
Following the procedures described in Example 5, replacing methyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate with benzyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate and 4-fluorophenylboronic acid with 3-nitrophenylboronic acid, the title compound was obtained. Proton NMR for the product was consistent with the title compound. HRMS (ES) exact mass calculated for C21H19N2O5 (M+H): 379.1289. Found 379.1290
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[CH2:6]([O:8][P:9]([CH2:14][C:15]1[N:19]2[C:20]3[C:25]([NH:26][C:27](=[O:28])[C:18]2=[N:17][N:16]=1)=[CH:24][C:23]([C:29]([F:32])([F:31])[F:30])=[CH:22][CH:21]=3)([O:11][CH2:12][CH3:13])=[O:10])[CH3:7]>S(=O)(=O)(O)O>[CH2:12]([O:11][P:9]([CH2:14][C:15]1[N:19]2[C:20]3[C:25]([NH:26][C:27](=[O:28])[C:18]2=[N:17][N:16]=1)=[CH:24][C:23]([C:29]([F:30])([F:32])[F:31])=[C:22]([N+:1]([O-:4])=[O:2])[CH:21]=3)([O:8][CH2:6][CH3:7])=[O:10])[CH3:13]
Reactant: CCOP(=O)(Cc1nnc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n12)OCC
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOP(=O)(Cc1nnc2c(=O)[nH]c3cc(C(F)(F)F)c([N+](=O)[O-])cc3n12)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
Powdered potassium nitrate (1.82 g, 18 mmol) was added to a stirred solution of 1-[(diethoxyphosphoryl)methyl]-7-trifluoromethyl[1,2,4]triazolo [4,3-a]quinoxalin-4(5H)-one (3.7 g, 9.15 mmol) in 50 ml of conc. sulfuric acid at 0° C. The mixture was stirred at room temperature overnight, and quenched in ice/water (300 g). The aqueous phase was extracted with ethyl acetate (5×100 ml), and the combined organic extracts were dried with anhydrous sodium sulfate, and evaporated. The residue was triturated with ether to give 3.25 g (79%) of the title compound, m.p. 222°-228° C.; 1H-NMR (DMSO-d6): δ 1.20 (t, 6H), 4.10 (quint, 4H), 4.39 (d, 2H), 7.88 (s, 1H), 8.96 (s, 1H), 12.67 (br s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][CH2:21][O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:18]3[CH:28]=[CH:29][CH:30]=[CH:31][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[IH:32].C(OCC)C>CO>[IH:32].[F:27][C:24]([F:25])([F:26])[CH2:23][O:22][CH2:21][CH2:20][N:19]1[C:18]2[CH:28]=[CH:29][CH:30]=[CH:31][C:17]=2[N:16]=[C:15]1[N:11]1[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCOCC(F)(F)F)CC1
Agent: I
Solvent: CCOCC
Solvent: CO
Product: FC(F)(F)COCCn1c(N2CCCNCC2)nc2ccccc21
Reaction time: 4 h

Procedure:
Combine 1-t-butoxycarbonyl-4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (0.47 g, 1.1 mmol) and aqueous hydriodic acid (0.70 mL, 9,42 mmol) in methanol (10 mL). After 4 hours, evaporate to remove most of the methanol to give a residue. Combine the residue and diethyl ether (50 mL) and stir to give a solid. Collect the solid by filtration to give, after drying, the title compound: Rf =0.39 (silica gel, 10% methanol/dichloromethane/5% acetic acid).
Reaction SMILES: C([O:3][C:4](=[O:39])[CH:5]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:17][C:18]3[N:19]([CH2:34][C:35]([F:38])([F:37])[F:36])[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=4)[CH:22]=3)[CH:14]=2)[CH:9]=[CH:8]1)[CH3:6])C.[Li+].[OH-]>>[F:37][C:35]([F:36])([F:38])[CH2:34][N:19]1[C:18]([CH2:17][O:16][C:13]2[CH:14]=[C:15]3[C:10]([CH:9]=[CH:8][N:7]3[CH:5]([CH3:6])[C:4]([OH:39])=[O:3])=[CH:11][CH:12]=2)=[CH:22][C:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([F:32])([F:31])[F:33])=[CH:25][CH:24]=2)=[N:20]1
Reactant: CCOC(=O)C(C)n1ccc2ccc(OCc3cc(-c4ccc(OC(F)(F)F)cc4)nn3CC(F)(F)F)cc21
Agent: [Li+]
Agent: [OH-]
Product: CC(C(=O)O)n1ccc2ccc(OCc3cc(-c4ccc(OC(F)(F)F)cc4)nn3CC(F)(F)F)cc21

Procedure:
In analogy to the procedure described in example 1 f], [rac]-2-{6-[2-(2,2,2-trifluoro-ethyl)-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-propionic acid ethyl ester was treated with LiOH to obtain [rac]-2-{6-[2-(2,2,2-trifluoro-ethyl)-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-propionic acid as colorless foam.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[N:4]=[CH:5][C:6]2[N:11]=[C:10]([N:12]=[C:13](SC)SC)[S:9][C:7]=2[N:8]=1.Cl.Cl.[NH2:21][CH2:22][C@@:23]1([OH:31])[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][N:2]([CH3:18])[C:3]1[N:4]=[CH:5][C:6]2[N:11]=[C:10]([NH:12][C:13]3[O:31][C@:23]4([CH2:22][N:21]=3)[CH:28]3[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]3)[CH2:24]4)[S:9][C:7]=2[N:8]=1
Reactant: NC[C@]1(O)CN2CCC1CC2
Reactant: CSC(=Nc1nc2cnc(N(C)C)nc2s1)SC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)c1ncc2nc(NC3=NC[C@@]4(CN5CCC4CC5)O3)sc2n1
Temperature: 100 °C
Yield: 74.9 %

Procedure:
A mixture of dimethyl 5-(dimethylamino)thiazolo[5,4-d]pyrimidin-2-ylcarbonimidodithioate (90 mg, 0.301 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (83 mg, 0.361 mmol) and cesium carbonate (196 mg, 0.60 mmol) in DMF (1.0 mL) was heated to 100° C. for 1.5 hours. The reaction mixture was cooled to ambient temperature, poured into water and extracted with chloroform (4×). The combined organics were washed with brine, dried over sodium sulfate, filtered, concentrated in vacuo, and the crude residue was purified by silica gel chromatography (2-40% 9:1 methanol:ammonium hydroxide-chloroform) to afford (R)—N5,N5-dimethyl-N2-(4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]-2-yl)thiazolo[5,4-d]pyrimidine-2,5-diamine (81 mg, 71% yield) as a tan solid. 1H NMR (400 MHz, CDCl3) δ ppm 9.07 (br. s., 1 H) 8.50 (s, 1 H) 4.01 (d, J=9.54 Hz, 1 H) 3.67 (d, J=9.54 Hz, 1 H) 3.39 (dd, J=14.93, 1.63 Hz, 1 H) 3.23 (s, 6 H) 2.71-3.10 (m, 5 H) 2.10-2.24 (m, 2 H) 1.68-1.84 (m, 1 H) 1.46-1.68 (m, 2 H). MS (LC/MS) R.T.=0.87; [M+H]+=360.23.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:13]=[C:14]1[O:18][C:16](=[O:17])[CH2:15]1>Cl>[C:16]([O:5][CH2:4][CH:1]1[CH2:3][CH2:2]1)(=[O:17])[CH2:15][C:14]([CH3:13])=[O:18]
Reactant: C=C1CC(=O)O1
Reactant: OCC1CC1
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)OCC1CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
To 13.2 g (179 millimole) of cyclopropyl-carbinol dissolved in 18.1 g (179 millimole) of triethylamine was slowly added 14 ml (179 millimole) of diketene at 0° C. The mixture was stirred at 0° C. for 10 minutes and at room temperature for 30 minutes, diluted with 3% aqueous HCl solution and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under the reduced pressure to obtain 24 g of cyclopropylmethyl acetoacetate as an oil.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1.[Cl:14][C:15]1[CH:16]=[C:17]([C:25](=O)[CH3:26])[CH:18]=[CH:19][C:20]=1[O:21][CH:22]([F:24])[F:23]>O1CCCC1>[Br:13][C:9]1[CH:8]=[C:7]([C:25]([C:17]2[CH:18]=[CH:19][C:20]([O:21][CH:22]([F:23])[F:24])=[C:15]([Cl:14])[CH:16]=2)=[CH2:26])[CH:12]=[CH:11][CH:10]=1
Reactant: Brc1cccc(Br)c1
Reactant: CC(=O)c1ccc(OC(F)F)c(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C(c1cccc(Br)c1)c1ccc(OC(F)F)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of n-butyllithium (1.6 M in hexane, 16.4 mL, 26.2 mmol, 1.16 eq.) was added dropwise over 20 min to a solution of 1,3-dibromobenzene (3.00 mL, 24.8 mmol, 1.1 eq) in 25 mL of dry tetrahydrofuran at −78° C. and under an inert atmosphere. The white suspension formed was stirred at −78° C. for 30 min. A solution of 1-(3-chloro-4-difluoromethoxy-phenyl)-ethanone (7 g, 31.7 mmol, 1.0 eq.) in 25 mL of tetrahydrofuran was then added dropwise and the reaction stirred for 1 h. The reaction mixture was examined by LC-MS which showed the complete formation of tertiary alcohol. The solution was quenched with a saturated solution of ammonium chloride and water. 2 N HCl was then added to reach pH=5. The two phases were separated; the organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The crude (tertiary alcohol) and a catalytic amount of p-toluenesulfonic acid were dissolved in 70 mL toluene (Dean-Stark apparatus) and the mixture was heated to reflux for 3 h. The solution was examined by TLC (cyclohexane) which showed consumption of starting material but many side products formed. Solvent was evaporated under reduced pressure and the crude residue was purified by flash chromatography eluting with cyclohexane. The desired product was obtained as yellow oil (2.2 g, Yield: 27%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[C:9](Br)[CH:10]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].[F:18][C:19]([F:31])([F:30])[O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>CN(C)C=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>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[C:9]([C:24]2[CH:23]=[CH:22][C:21]([O:20][C:19]([F:18])([F:30])[F:31])=[CH:26][CH:25]=2)[CH:8]=[N:7][CH:6]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)c1cncc(Br)c1
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: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cncc(-c2ccc(OC(F)(F)F)cc2)c1
Temperature: 80 °C
Yield: 54.5 %

Procedure:
81 mg (0.07 mmol)Pd(PPh3)4 was added under argon at room temperature to a solution of 1.0 g (4.63 mmol) methyl-5-bromo-pyridine-3-carboxylate in 23 ml N,N-dimethylformamide and the mixture was heated to 80° C. Then 2.26 g (6.94 mmol) cesium carbonate and 1.05 g (5.09 mmol) of 4-(trifluoromethoxy)phenyl boronic acid were added and the mixture was stirred at 80° C. over night. The reaction mixture was cooled to room temperature, filtered, and the filtrate evaporated. The residue was taken up with ethyl acetate, washed twice with water, dried over sodium sulphate and evaporated. Chromatography on silica (eluent: ethyl acetate/n-heptane 1:3) gave 0.75 g (49%) of 5-(4-Trifluoromethoxy-phenyl)-nicotinic acid methyl ester
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[C:10](=[O:15])[C:11]([F:14])([F:13])[F:12].N1C=CN=C1.FC(F)(F)S(O[Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])(=O)=O>CN(C=O)C>[NH2:1][C:2]1[C:7]([O:8][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[C:10](=[O:15])[C:11]([F:14])([F:12])[F:13]
Reactant: Nc1c(O)cc(Cl)cc1C(=O)C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cc(Cl)cc(C(=O)C(F)(F)F)c1N
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a stirred, cooled (0° C.) solution of 29.3 g (122 mmol) of 2′-amino-5′-chloro-3′-hydroxy-2,2,2-trifluoroacetophenone in 280 mL of DMF was added 23.8 g (350 mmol) of imidazole followed by 66 g (250 nmol) of t-butyldimethylsilyl trifluoromethanesulfonate over 10 min. The reaction was stirred 5 h at 0° C. and diluted with 800 mL of 1:1 ether-hexanes. The solution was washed twice with water and once with brine, dried (MgSO4) and concentrated under reduced pressure to give a dark oil. The crude product was rapidly passed through an 800 g plug of silica gel (elution with hexanes followed by 6:1 hexanes-ether) to afford, after evaporation of solvent, 42.5 g (98%) of 2′-amino-5′-chloro-3′-(t-butyldimethylsilyloxy)-2,2,2-trifluoroacetophenone as a yellow oil. The product solidified after extended evacuation at 0.01 torr to give a yellow solid, mp 45-46.5° C. 1H NMR (300 MHz, CDCl3) δ7.34-7.36(m, 1H); 6.85(d, 1H, J=2.2 Hz); 6.7-6.8(br. s, 2H); 1.03(s, 9H); 0.30(s, 6H). High resolution mass spec: calculated for C14H20NO2ClF3Si(M+H)+: 354.0904, found: 354.0900. Analysis calculated for C14H19NO2ClF3Si: C, 47.52; H, 5.41; N, 3.97; Cl, 10.02. Found: C, 47.71; H, 5.36; N, 3.87; Cl, 10.02.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[CH3:21][C:22]1[S:23][C:24]2[CH:30]=[C:29]([CH:31]=O)[CH:28]=[CH:27][C:25]=2[N:26]=1>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:31][C:29]2[CH:28]=[CH:27][C:25]3[N:26]=[C:22]([CH3:21])[S:23][C:24]=3[CH:30]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Reactant: Cc1nc2ccc(C=O)cc2s1
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1ccc2nc(C)sc2c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with 2-methylbenzo[d]thiazole-6-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.83 min.; [M+H]+: 411.03 g/mol.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1.[Li+].[OH-]>O.CO>[C:13]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]=[CH:4][C:3]([OH:21])=[O:2])=[CH:7][CH:8]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)C=Cc1ccc(NC(=O)c2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C=Cc1ccc(NC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
(Method H5) A mixture of 3-(4-benzoylamino-phenyl)-acrylic acid methyl ester (4b) (1.650 g, 5.87 mmol) and LiOH (0.630 g, 15 mmol) in water (30 ml) and methanol (30 ml) was stirred at ambient temperature for 24 hours. Methanol was evaporated and the residue was treated with hydrochloric acid to pH 4. The resulting precipitate was filtered off, washed with water (3×20 ml), and dried to give the title compound as a white solid (1.443 g, 92%). 1H NMR (DMSO-d6, HMDSO), δ: 6.44 (1H, d, J=16.0 Hz); 7.33-8.11 (10H, m); 10.40 (1H, s).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]1.[CH2:9]=[C:10]1[O:14][C:12](=[O:13])[CH2:11]1>O1CCCC1>[OH:8][CH2:7][CH:3]1[CH2:4][CH2:5][CH2:6][N:1]([C:12](=[O:13])[CH2:11][C:10](=[O:14])[CH3:9])[CH2:2]1
Reactant: OCC1CCCNC1
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)N1CCCC(CO)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A solution of 25 g (0.22 mol) of 3-piperidinemethanol in 200 ml tetrahydrofuran was added dropwise to a solution of 18 g of diketene (0.2 mol) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue purified by column chromatography. This gave 31.50 g (0.16 mol, 74% yield) of a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[N:6]=[C:5]2Cl.[CH2:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[H-].[Na+].O>O1CCCC1>[CH2:14]([O:21][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[N:8]=[C:7]([Cl:12])[N:6]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OCc1ccccc1
Reactant: Clc1nc(Cl)c2cc(Br)ccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Clc1nc(OCc2ccccc2)c2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a cooled solution of 6-bromo-2,4-dichloroquinazoline (1.39 g, 5 mmol) in tetrahydrofuran (50 mL) was added a solution of benzyl alcohol (0.52 mL, 5 mmol) and sodium hydride (210 mg, 5.25 mmol, 60% in mineral oil) in tetrahydrofuran (15 mL) dropwise at 0° C. After being stirred at room temperature for 2 hours, the reaction mixture was poured into cold water (10 mL) and then extracted with ethyl acetate (50 mL). The organic layer was dried over magnesium sulfate and concentrated in vacuo to afford 1.73 g of the desired product as a yellow solid (yield was 99%).
Reaction SMILES: [CH:1]1([N:4]([CH2:12][C:13]2[CH:14]=[C:15]([CH:23]=[CH:24][C:25]([O:27][CH3:28])=[O:26])[CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:3][CH2:2]1>CCOC(C)=O.[Pd]>[CH:1]1([N:4]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)[C:5]([O:7][C:8]([CH3:10])([CH3:11])[CH3:9])=[O:6])[CH2:3][CH2:2]1
Reactant: COC(=O)C=Cc1cc(CN(C(=O)OC(C)(C)C)C2CC2)c2ncccc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CCc1cc(CN(C(=O)OC(C)(C)C)C2CC2)c2ncccc2c1

Procedure:
To a solution of methyl 3-{8-[(cyclopropyl{[(1,1-dimethylethyl)oxy]carbonyl}amino)methyl]-6-quinolinyl}-2-propenoate (1 eq.) from the previous step in EtOAc (0.1 M) was added palladium (10% (w/w) over carbon, 0.1 eq.). The resulting suspension was evacuated and back-filled repeatedly with hydrogen. Finally, the reaction suspension was allowed to stir under a hydrogen-filled balloon atmosphere for 3 h. The reaction was quenched with the addition of dichloromethane and filtered through a bed of celite. The filtrate was then concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a yellow oil.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH3:21])=[CH:11][C:10]=2[CH:22]=1)=[O:5].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([Mg]Br)=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:4]([C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([CH2:14][CH2:15][N:16]4[CH2:20][CH2:19][CH2:18][C@H:17]4[CH3:21])=[CH:11][C:10]=3[CH:22]=2)=[O:5])=[CH:27][CH:26]=1
Reactant: CON(C)C(=O)c1ccc2oc(CCN3CCC[C@H]3C)cc2c1
Reactant: Clc1ccc([Mg]Br)cc1
Product: C[C@@H]1CCCN1CCc1cc2cc(C(=O)c3ccc(Cl)cc3)ccc2o1

Procedure:
The product from Example 71E and 4-chlorophenylmagnesium bromide were processed as described in Example 71F to provide the title compound. 1HNMR (300 MHz, CD3OD) δ 1.18 (d, 3H, J=6.1 Hz), 1.46 (m, 1H), 1.78 (m, 2H), 2.01-2.36 (m, 2H), 2.50 (m, 2H), 3.03 (m, 2H), 3.23 (m, 2H), 6.67 (s, 1H), 7.57 (m, 3H), 7.78 (m, 3H), 7.97 (s, 1H); MS (ESI) m/z 368.1 (M++1).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([F:28])([F:27])[C:17]([F:26])([F:25])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])[CH:5]=[CH:4][C:3]=1I.FC1C(F)=C(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C=CC=1[B:56]([OH:58])[OH:57]>>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([F:28])([F:27])[C:17]([F:26])([F:25])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])[CH:5]=[CH:4][C:3]=1[B:56]([OH:58])[OH:57]
Reactant: OB(O)c1ccc(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(F)c1F
Reactant: Fc1c(I)ccc(OCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c1F
Product: OB(O)c1ccc(OCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(F)c1F
Yield: 89 %

Procedure:
2,3-Difluoro-4-(7,7,8,8,9,9,10,10,10-nonafluoro-decyloxy)-phenylboronic acid (11B) was prepared from 2,3-difluoro-1-iodo-4-(7,7,8,8,9,9,10,10,10-nonafluoro-decyloxy)-benzene (10B) as described in the preparation 2,3-difluoro-4-(5,5,6,6,7,7,8,8,8-nonafluoro-octyloxy)-phenylboronic acid (11A), yielding 2,3-difluoro-4-(7,7,8,8,9,9,10,10,10-nonafluoro-decyloxy)-phenylboronic acid (11B) as a colorless oil (89%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[N:19]([CH:23]([CH3:25])C)[CH:20](C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.N1CCC1>CN(C=O)C.C(Cl)Cl>[N:19]1([C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:16])[CH2:20][CH2:25][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: C1CNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCC2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 106.5 %

Procedure:
1-(tert-Butoxycarbonyl)piperidine-4-carboxylic acid (0.40 g, 1.75 mmol) was dissolved in dry DMF (5 mL) and to the solution were added DIPEA (1.22 mL, 7.0 mmol), TBTU (0.67 g, 2.1 mmol) and azetidine (0.12 g, 2.1 mmol). The reaction mixture was stirred at RT for 12 h. The mixture was diluted with methylene chloride and then washed with an aqueous solution of HCl (2 M) and then with an aqueous solution of NaHCO3 (sat.). The phases were separated by means of a phase separator column and the solvent was removed by evaporation. There was obtained 0.50 g (100%) of tert-butyl 4-(azetidin-1-ylcarbonyl)piperidine-1-carboxylate as a crude solid. 1H NMR (500 MHz, CDCl3): 1.4-1.5 (s, 9H), 1.6-1.9 (m, 5H), 2.2-2.4 (m, 3H), 2.6-2.8 (m, 2H), 3.9-4.2 (m, 5H).