Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@@H:8]([NH:10][C:11]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]4[C:30]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:25][CH:24]=2)[C:17]([CH3:42])=[C:16]3[CH3:43])=[O:12])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[C:50](B1OC(C)(C)C(C)(C)O1)([CH3:52])=[CH2:51]>O1CCOCC1.O.C(OCC)(=O)C.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>[CH3:42][C:17]1[N:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[C:30]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:25][CH:24]=2)[C:19]2[C:15]([C:16]=1[CH3:43])=[CH:14][C:13]([C:11](=[O:12])[NH:10][C@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:50]([CH3:52])=[CH2:51])[CH:3]=1)[CH3:9])=[CH:21][CH:20]=2
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(Br)c3)cc12
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: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: C=C(C)c1cccc([C@H](C)NC(=O)c2ccc3c(c2)c(C)c(C)n3Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c1
Temperature: 100 °C

Procedure:
A solution of (S)-tert-butyl 4′-((5-((1-(3-bromophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate (83 mg, 0.13 mmol, 1 equiv.), K2CO3 (36 mg, 0.26 mmol, 2 equiv.) and Pd(PPh3)4 (15 mg, 0.013 mmol, 0.1 equiv.) in dioxane/water (1.2 mL/0.3 mL) was degassed with argon. The isopropenylboronic acid pinacol ester (49 μL, 0.26 mmol, 2 equiv.) was added and the solution was heated at 100° C. for 1 h under microwave irradiation. The resulting solution was diluted with ethyl acetate, washed with a 0.5 N HCl solution, saturated aqueous NaHCO3 and brine, and then dried over Na2 SO4. The obtained oil was used without further purification. ESI-MS (m/z): 599 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:28]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1>O1CCCC1>[CH:28]1([C:33](=[O:34])[CH:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[C:10]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:11])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)Nc1nccs1
Reactant: O=C(Cl)C1CCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Nc1nccs1)C(C(=O)C1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 39.9 %

Procedure:
To a solution of rac-2-(3,4-dichloro-phenyl)-N-thiazol-2-yl-acetamide (185 mg, 0.64 mmol) in tetrahydrofuran (15 mL), previously cooled to −78° C., was added slowly a 1.0 M solution of lithium bis(trimethylsilyl)amide (1.3 mL, 1.3 mmol). The solution was stirred for 15 min at −78° C., then cyclopentanecarbonyl chloride (0.08 mL, 0.64 mmol) was dropwise added. The reaction mixture was stirred for an additional 60 min at −78° C. before it was quenched by the addition of a saturated ammonium chloride solution (10 mL). The mixture was then extracted with ethyl acetate (3×10 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The product was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) to afford 3-cyclopentyl-2-(3,4-dichloro-phenyl)-3-oxo-N-thiazol-2-yl-propionamide (98 mg, 40% yield) as a yellow-orange solid: EI-HRMS m/e calcd for C17H16N2O2SCl2 (M+) 382.0309, found 382.0309.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O[N:35]=[C:36]([NH2:47])[CH2:37][S:38]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)(=[O:40])=[O:39]>ClCCl>[CH:15]1([CH2:14][CH2:13][CH2:12][C@@H:8]([C:9]2[O:11][N:47]=[C:36]([CH2:37][S:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)(=[O:40])=[O:39])[N:35]=2)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NC(CS(=O)(=O)c1ccccc1)=NO
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CS(=O)(=O)c2ccccc2)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.4 %

Procedure:
A solution of (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-cyclohexylpentanoic acid (Preparation 1) (300 mg, 1.00 mmol) in dichloromethane (15m) was treated with 1,1′-carbonyidiimidazole (162 mg, 1.00 mmol) and the solution was stirred at room temperature for 2 hours. N′-hydroxy-2-(phenylsulfonyl)ethanimidamide (J.Heterocycl.Chem.; 16; 1979; 1197-1200) (214 mg, 1.00 mmol) was then added and the mixture was stirred for 17 hours. The solvent was removed under reduced pressure and the residue was heated neat at 130° C. under a nitrogen atmosphere for 2 hours. The crude product was then purified by column chromatography on silica gel eluting with dichloromethane:methanol (99:1) to afford the title compound (78 mg).
Reaction SMILES: BrC1C=CC=CC=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13](S(C)(=O)=O)=[N:14][CH:15]=2)[N:10](C2C=CC=C(CCN3C(=O)C4=CC=CC=C4C3=O)C=2)[C:9]1=[O:41].[CH3:42][O:43][C:44]1[CH:50]=[CH:49][C:47]([NH2:48])=[CH:46][CH:45]=1>Cl>[CH3:42][O:43][C:44]1[CH:50]=[CH:49][C:47]([NH:48][N:10]2[C:11]3=[N:12][CH:13]=[N:14][CH:15]=[C:16]3[CH2:17][NH:8][C:9]2=[O:41])=[CH:46][CH:45]=1
Reactant: COc1ccc(N)cc1
Reactant: CS(=O)(=O)c1ncc2c(n1)N(c1cccc(CCN3C(=O)c4ccccc4C3=O)c1)C(=O)N(c1ccccc1Br)C2
Agent: Cl
Product: COc1ccc(NN2C(=O)NCc3cncnc32)cc1
Temperature: 120 °C

Procedure:
A solution of 130 mg (0.31 mmol) of 3-(2-bromophenyl)-7-methanesulfonyl-3,4-dihydro-1-[3-(2-phthalimidoethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one from Example 50 was treated with 1 g (8 mmol) of 4-methoxyaniline. The mixture was heated to 120° C. for 2 hours. The mixture was cooled and treated with 30 ml of 2M aqueous hydrochloric acid. The suspended solid was filtered, washed with water and dried. The solid was dissolved in 20 ml of ethanol and treated with 0.2 ml of hydrazine hydrate. After 18 hours the mixture was evaporated and the product purified by column chromatography on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution. Product-containing fractions were combined, evaporated and the residue evaporated with toluene. The residue was then dissolved in 50 ml of dichloromethane, washed with 50 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to give 35 mg (31%) of 1-[3-(2-aminoethyl)phenyl]-3-(2-bromophenyl)-7-(4-methoxyanilino-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 132-133° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[C:27](Cl)(=[O:29])[CH3:28].C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:27](=[O:29])[CH3:28])[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cccc(N)c1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cccc(NC(C)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
To a solution of [4-(3-amino-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (30 mg, 0.079 mmol) and acetyl chloride (9.2 mg, 0.119 mmol) in tetrahydrofuran (3 mL) was added triethylamine (16 mg, 0.158 mmol) at 0° C. After being stirred at room temperature overnight, the mixture was concentrated in vacuo. The residue was purified by flash column (gradient elution, 0-5% methanol in dichloromethane) to afford [4-(3-acetylamino-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (24 mg, 72%) as a white solid. MS cald. for C19H24N4O5S 420, obsd. (ESI+) [(M+H)+] 421.
Reaction SMILES: [N:1]([CH2:4][C:5](=[O:18])[C:6]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([O:16][CH3:17])[CH:10]=1)([CH3:8])[CH3:7])=[N+]=[N-].[ClH:19]>CO.[Pd]>[ClH:19].[NH2:1][CH2:4][C:5](=[O:18])[C:6]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([O:16][CH3:17])[CH:10]=1)([CH3:8])[CH3:7]
Reactant: COc1cc(C(C)(C)C(=O)CN=[N+]=[N-])ccc1F
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1cc(C(C)(C)C(=O)CN)ccc1F
Reaction time: 8 h
Yield: 55.4 %

Procedure:
A pressure bottle was charged with a solution of 1-azido-3-(4-fluoro-3-methoxyphenyl)-3-methylbutan-2-one (99.5 g, 0.396 mol) in MeOH (1.0 L), 50% wet 10% Pd/C (25 g, 25% w/w.) and conc HCl (105 mL, 1.19 mol). The bottle was purged with hydrogen gas (40 psi×2), pressurized with hydrogen (45 psi) and agitated overnight. The reaction mixture was filtered through a Celite™ pad. The filtrate was evaporated to give a residue, which was triturated with Et2O to give 1-amino-3-(4-fluoro-3-methoxyphenyl)-3-methylbutan-2-one hydrochloride (57.4 g, 55%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.26 (b, 2H), 7.22 (m, 1H), 6.99 (dd, 1H), 6.89 (m, 1H), 3.87 (s, 3H), 3.81 (s, 2H), 1.50 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:27][CH2:28][C:29]#[CH:30])[C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([O:25][CH3:26])[CH:19]=2)=[O:10])=[CH:4][CH:3]=1.C[O-].[Na+].[CH2:34](Cl)[C:35]#[C:36][CH2:37][CH3:38].C(OCC)(=O)C>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:27][CH2:28][C:29]#[CH:30])[C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:34][C:35]#[C:36][CH2:37][CH3:38])=[C:20]([O:25][CH3:26])[CH:19]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: C#CCOC(C(=O)Nc1ccccc1-c1ccc(O)c(OC)c1)c1ccc(Cl)cc1
Reactant: CCC#CCCl
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C#CCOC(C(=O)Nc1ccccc1-c1ccc(OCC#CCC)c(OC)c1)c1ccc(Cl)cc1

Procedure:
A solution of 1.3 g (3.1 mmol) 2-(4-chloro-phenyl)-N-(4′-hydroxy-3′-methoxy-biphenyl-2-yl)-2-prop-2-ynyloxy-acetamide, 6.0 ml (6.0 mmol) of a 1 M solution of sodium methoxide in methanol and 0.5 g (4.7 mmol) 2-pentynyl chloride in 50 ml of methanol is heated to reflux for 3 hours. After cooling, the reaction mixture is poured into ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate and evaporated. The remaining product is subjected to flash-chromatography (ethyl acetate/hexane 4:6) to yield 2-(4-chlorophenyl)-N-(3′-methoxy-4′-pent-2-ynyloxy-biphenyl-2-yl)-2-prop-2-ynyloxy-acetamide as yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([C:9]1[N:10]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH:11]=[CH:12][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7]O)=[O:5])[CH3:2].C([O-])(=O)C.[NH4+:32]>C(O)C>[NH2:32][CH:7]=[C:6]([C:9]1[N:10]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH:11]=[CH:12][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)C(=CO)c1c(C(=O)OCC)ccn1Cc1ccc(OC)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: CCOC(=O)C(=CN)c1c(C(=O)OCC)ccn1Cc1ccc(OC)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 75.9 %

Procedure:
A mixture of ethyl 2-{1-[(ethyloxy)carbonyl]-2-hydroxyethenyl}-1-{[4-(methyloxy)phenyl]methyl}-1H-pyrrole-3-carboxylate (6.59 g), ammonium acetate (6.47 g) and ethanol (80 ml) was stirred at 60° C. under argon for 4 h, at room temperature over night then heated at 60° C. for a further hour. After cooling the solvent was evaporated and the residue partitioned between ethyl acetate and water, extracting the separated aqueous layer three times with ethyl acetate. The combined organic layers were washed with brine then dried (MgSO4), filtered and evaporated. The residue was stirred in n-hexane for 1 h and then the mixture was allowed to settle. The n-hexane was decanted off and the oil dried to afford the title compound as a brown oil (4.99 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20])[C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+]>CO.O>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([N:10]1[C:11](=[O:20])[C:12]2=[CH:19][CH:18]=[CH:17][CH:16]=[C:13]2[C:14]1=[O:15])[C:7]([O:9][CH2:11][C:12]1[CH:13]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:8]
Reactant: O=C(O)[C@H](CCCCO)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: O
Product: O=C(OCc1ccccc1)[C@H](CCCCO)N1C(=O)c2ccccc2C1=O
Yield: 198.6 %

Procedure:
6-Hydroxy-2(S)-phthalimidohexanoic acid (5.0 g) was dissolved in a mixture of 90 ml of methanol and 9 ml of water. To this solution, an aqueous 0.5M cesium carbonate solution (18 ml) was added and the mixture stirred for a few minutes. Most of the methanol was removed in vacuo and the resulting aqueous residue was freeze-dried. The lyophilized material was dissolved in DMF (70 ml) and treated with 3.08 g of benzyl bromide. After stirring under nitrogen for 6 hours, the reaction mixture was diluted with 450 ml of water and repeatedly extracted with ethyl acetate. Organic layers were then back-washed with water, dried (Na2SO4), and concentrated to give 6.58 g of benzyl 6-hydroxy-2(S)-phthalimidohexanoate. Recrystallization from ether gave a white solid, m.p. 106.5°-108°; [α]D25° =-27.6° (MeOH, c=1.77).
Reaction SMILES: ClC1C=C2C(C)(C)/C(=C\C=C(/C3C=CC=C(CCCCC(O[N:70]4[C:74](=[O:75])[CH2:73][CH2:72][C:71]4=[O:76])=O)C=3)\C=C\C3C(C)(C)C4C5C=C(S([O-])(=O)=O)C=C(S([O-])(=O)=O)C=5C=CC=4[N+]=3CCCCS([O-])(=O)=O)/N=C2N(CCCCS([O-])(=O)=O)C=1.[Na+:77].[Na+].[Na+].[C:80]([CH2:83][CH2:84][C:85]1[CH:86]=[C:87](/[C:91](=[CH:125]\[CH:126]=[C:127]2/[C:128]([CH3:146])([CH3:145])[C:129]3[C:130](=[N:144]/2)[N:131]([CH2:136][CH2:137][CH2:138][CH2:139][S:140]([O-:143])(=[O:142])=[O:141])[CH:132]=[C:133]([Cl:135])[CH:134]=3)/[CH:92]=[CH:93]/[C:94]2[C:102]([CH3:104])([CH3:103])[C:101]3[C:100]4[CH:105]=[C:106]([S:113]([O-:116])(=[O:115])=[O:114])[CH:107]=[C:108]([S:109]([O-:112])(=[O:111])=[O:110])[C:99]=4[CH:98]=[CH:97][C:96]=3[N+:95]=2[CH2:117][CH2:118][CH2:119][CH2:120][S:121]([O-:124])(=[O:123])=[O:122])[CH:88]=[CH:89][CH:90]=1)([OH:82])=[O:81].[Na+].[Na+].[Na+]>>[Cl:135][C:133]1[CH:134]=[C:129]2[C:128]([CH3:146])([CH3:145])/[C:127](=[CH:126]\[CH:125]=[C:91](/[C:87]3[CH:88]=[CH:89][CH:90]=[C:85]([CH2:84][CH2:83][C:80]([O:82][N:70]4[C:74](=[O:75])[CH2:73][CH2:72][C:71]4=[O:76])=[O:81])[CH:86]=3)\[CH:92]=[CH:93]\[C:94]3[C:102]([CH3:103])([CH3:104])[C:101]4[C:100]5[CH:105]=[C:106]([S:113]([O-:116])(=[O:114])=[O:115])[CH:107]=[C:108]([S:109]([O-:112])(=[O:110])=[O:111])[C:99]=5[CH:98]=[CH:97][C:96]=4[N+:95]=3[CH2:117][CH2:118][CH2:119][CH2:120][S:121]([O-:124])(=[O:123])=[O:122])/[N:144]=[C:130]2[N:131]([CH2:136][CH2:137][CH2:138][CH2:139][S:140]([O-:143])(=[O:142])=[O:141])[CH:132]=1.[Na+:77].[Na+:77].[Na+:77]
Reactant: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C(/C=C/C1=[N+](CCCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c2C1(C)C)c1cccc(CCC(=O)O)c1
Reactant: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C(/C=C/C1=[N+](CCCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c2C1(C)C)c1cccc(CCCCC(=O)ON2C(=O)CCC2=O)c1
Agent: [Na+]
Product: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C(/C=C/C1=[N+](CCCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c2C1(C)C)c1cccc(CCC(=O)ON2C(=O)CCC2=O)c1

Procedure:
Compound 31 is prepared analogously to compound 29 (Example 38), except that compound 30 is used as a starting material.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH:9]2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]3[O:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][CH2:37][O:38][CH3:39])[C:30]=3[CH:40]=2)=[CH:4][CH:3]=1.I[CH2:42][CH2:43][CH3:44]>>[CH3:39][O:38][CH2:37][CH2:36][CH2:35][N:31]1[C:30]2[CH:40]=[C:26]([CH2:25][O:24][CH:9]3[CH:8]([C:5]4[CH:6]=[CH:7][C:2]([O:1][CH2:42][CH2:43][CH3:44])=[CH:3][CH:4]=4)[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[O:15])[CH2:10]3)[CH:27]=[CH:28][C:29]=2[O:34][CH2:33][CH2:32]1
Reactant: CCCI
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(O)cc3)cc21
Product: CCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1

Procedure:
Analogously to Method D, 0.0618 g of benzyl 4-(4-hydroxyphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1 carboxylate and 0.0392 g of 1-iodopropane are reacted. The title compound is obtained as a colourless oil. Rf=0.35 (1:1 EtOAc-heptane); Rt=5.88.
Reaction SMILES: [OH-].[K+].O1CCCC1.[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH:23]2[O:35]C(=O)C2C=CC([N+]([O-])=O)=CC=2)=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O>[CH2:8]([O:15][C:16]1[CH:17]=[CH:18][C:19]([C@H:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[CH2:24][C@H:23]2[OH:35])=[CH:20][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCc3ccccc3)cc2)C(OC(=O)c2ccc([N+](=O)[O-])cc2)C1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(OCc3ccccc3)cc2)[C@H](O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of KOH (5.06 g, 90 mmol), water (60 ml) and tetrahydrofuran (200 ml) was added tert-butyl 4-(4-(benzyloxy)phenyl)-3-((4-nitrobenzoyl)oxy)piperidine-1-carboxylate (6 g, 11.3 mmol) and the reaction mixture was stirred at room temperature overnight. It was then diluted with 200 mL water and extracted twice with 200 mL ethyl acetate. The organic layer was washed with 1.5 N HCl solution and was then dried over Na2SO4, filtered, and evaporated to dryness. The crude product 4 g, (±)-rel-(3S,4R)-tert-butyl 4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate), was used in the next step without further purification. LCMS (method F) RT 2.44 min (95% AP), m/z 382 (M−H) (negative mode); 1H NMR (300 MHz, DMSO-d6) δ ppm 7.29-7.44 (m, 5H), 7.71 (d, J=8.4, 2H), 6.91 (d, J=8.4, 2H), 5.06 (s, 2H), 4.45 (br s, 1H), 3.80-4.20 (m, 2H), 3.70 (br s, 1H), 2.60-3.05 (m, 3H), 1.95-2.20 (m, 1H), 1.35 (s, 9H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][CH:5]=[C:6]([O:10][CH3:11])[C:7](=[O:9])[CH:8]=1.[C:12](Cl)(=[O:14])[CH3:13]>N1C=CC=CC=1>[C:12]([O:1][CH2:2][C:3]1[NH:4][CH:5]=[C:6]([O:10][CH3:11])[C:7](=[O:9])[CH:8]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)Cl
Reactant: COc1c[nH]c(CO)cc1=O
Solvent: c1ccncc1
Product: COc1c[nH]c(COC(C)=O)cc1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 8.3 g of 2-(hydroxymethyl)-5-methoxypyridin-4(1H)-one in 30 mL of pyridine, 5.7 mL of acetyl chloride was dropped under cooling with ice. After warming to room temperature, the mixture was stirred at 55 to 60° C. for 2 hours 30 minutes. After cooling to room temperature, the solvent was distilled off under reduced pressure, and the resultant residue was purified by flash silica gel column chromatography using gradient elution with chloroform:methanol=95:1 to 80:20 to obtain 6.7 g of (5-methoxy-4-oxo-1,4-dihydropyridin-2-yl)methyl acetate as a brown foam.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:28]([O:30]C)=[O:29])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][CH:16]([CH2:26][OH:27])[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[Cl-].[CH2:35]([NH+:42]([CH3:46])[CH2:43][CH2:44]Cl)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:35]([N:42]([CH3:46])[CH2:43][CH2:44][O:27][CH2:26][CH:16]1[CH2:15][N:14]2[C:13]3[CH:12]=[C:11]([C:28]([OH:30])=[O:29])[CH:10]=[CH:9][C:8]=3[C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:21]2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CO)COc1ccccc1-3
Reactant: C[NH+](CCCl)Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CN(CCOCC1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1)Cc1ccccc1
Temperature: 65 °C
Reaction time: 18 h

Procedure:
A solution of (+)-methyl 14-cyclohexyl-7-(hydroxymethyl)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (second eluting isomer) in toluene (0.04 M) was treated with 30% w/v NaOH (10 eq) and tetrabutylammonium bromide (0.25 eq) followed by N-benzyl-2-chloro-N-methylethanaminium chloride (prepared as described in example 7 step 1) (2.5 eq). The resulting solution was stirred at 65° C. for 18 h. Toluene was removed in vacuo, the residue was taken up in EtOAc and washed with 1N HCl (aq) and brine before drying (Na2SO4), filtering and concentrating in vacuo to afford the product as an oil that was used without further purification. (ES+) m/z 553 (M+H)+.
Reaction SMILES: [Eu+3:1].[C:2]([C:5]1[C:6]([CH3:75])=[C:7]([C:11]2[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[N:14]=[C:13]([CH2:20][N:21]3[CH2:29][CH2:28][N:27]([CH2:30][C:31]4[CH:36]=[C:35]([C:37]5[O:38][C:39]([CH3:46])=[C:40]([C:43]([OH:45])=[O:44])[C:41]=5[CH3:42])[CH:34]=[C:33]([C:47]([OH:49])=[O:48])[N:32]=4)[CH2:26][CH2:25][N:24]([CH2:50][C:51]4([C:72]([OH:74])=[O:73])[CH:56]=[C:55]([C:57]5[O:58][C:59]([CH3:71])=[C:60]([C:63]([NH:65][CH2:66][CH2:67][CH2:68][CH2:69][NH2:70])=[O:64])[C:61]=5[CH3:62])[CH:54]=[CH:53][NH:52]4)[CH2:23][CH2:22]3)[CH:12]=2)[O:8][C:9]=1[CH3:10])([OH:4])=[O:3].[N:76]1[C:83]([Cl:84])=[N:82][C:80](Cl)=[N:79][C:77]=1[Cl:78].O.[OH-].[Na+]>CC(O[Na])=O.CC(C)=O>[Eu+3:1].[C:2]([C:5]1[C:6]([CH3:75])=[C:7]([C:11]2[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[N:14]=[C:13]([CH2:20][N:21]3[CH2:29][CH2:28][N:27]([CH2:30][C:31]4[CH:36]=[C:35]([C:37]5[O:38][C:39]([CH3:46])=[C:40]([C:43]([OH:45])=[O:44])[C:41]=5[CH3:42])[CH:34]=[C:33]([C:47]([OH:49])=[O:48])[N:32]=4)[CH2:26][CH2:25][N:24]([CH2:50][C:51]4([C:72]([OH:74])=[O:73])[CH:56]=[C:55]([C:57]5[O:58][C:59]([CH3:71])=[C:60]([C:63]([NH:65][CH2:66][CH2:67][CH2:68][CH2:69][NH:70][C:80]6[N:82]=[C:83]([Cl:84])[N:76]=[C:77]([Cl:78])[N:79]=6)=[O:64])[C:61]=5[CH3:62])[CH:54]=[CH:53][NH:52]4)[CH2:23][CH2:22]3)[CH:12]=2)[O:8][C:9]=1[CH3:10])([OH:4])=[O:3]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Cc1oc(C2=CC(CN3CCN(Cc4cc(-c5oc(C)c(C(=O)O)c5C)cc(C(=O)O)n4)CCN(Cc4cc(-c5oc(C)c(C(=O)O)c5C)cc(C(=O)O)n4)CC3)(C(=O)O)NC=C2)c(C)c1C(=O)NCCCCN
Agent: CC(=O)O[Na]
Agent: [Eu+3]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1oc(C2=CC(CN3CCN(Cc4cc(-c5oc(C)c(C(=O)O)c5C)cc(C(=O)O)n4)CCN(Cc4cc(-c5oc(C)c(C(=O)O)c5C)cc(C(=O)O)n4)CC3)(C(=O)O)NC=C2)c(C)c1C(=O)NCCCCNc1nc(Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Compound 23 (4.5 mg, 3.9 μmol) was dissolved in 1 mL of 0.1M CH3COONa (pH 6.5). Cyanuric chloride (0.8 mg, 4.2 mmol) was dissolved in acetone (1 mL) and 0.3 mL water was added. The solutions were combined, the pH was adjusted to 6.5 with 0.1 M NaOH-solution and the mixture was stirred for 20 min at r.t. The product was precipitated by adjusting the pH to 3 with 1 M HCl. The precipitate was washed twice with 2 mL of acetone and dried in a vacuum desiccator.