Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH:7]2[CH2:12][NH:11][CH2:10][CH2:9][NH:8]2)=[CH:4][CH:3]=1.Cl[C:14]1[CH:23]=[C:22]2[C:17]([C:18](=[O:29])[C:19]([C:26]([OH:28])=[O:27])=[CH:20][N:21]2[CH2:24][CH3:25])=[CH:16][C:15]=1[F:30]>N1C=CC=CC=1>[Cl:1][C:2]1[S:6][C:5]([CH:7]2[NH:8][CH2:9][CH2:10][N:11]([C:14]3[CH:23]=[C:22]4[C:17]([C:18](=[O:29])[C:19]([C:26]([OH:28])=[O:27])=[CH:20][N:21]4[CH2:24][CH3:25])=[CH:16][C:15]=3[F:30])[CH2:12]2)=[CH:4][CH:3]=1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: Clc1ccc(C2CNCCN2)s1
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4ccc(Cl)s4)C3)cc21
Yield: 18.4 %

Procedure:
A mixture of 2.424 g of 2-(5-chloro-2-thienyl)piperazine and 1.076 g of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 12 ml of pyridine was refluxed under argon for 24 hours and then cooled. The solid was collected, washed with methanol and ether, then dried giving 320 mg of the desired product, mp 232°-234° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([NH2:13])=[N:8][C:9]([NH2:12])=[CH:10][CH:11]=2)[CH:3]=[N:2]1.[H-].[Na+].[CH2:16]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28]Cl)=[CH:24][CH:23]=1)[CH2:17][CH2:18][CH3:19]>CN(C)C=O>[CH2:16]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][N:1]2[CH:5]=[C:4]([C:6]3[C:7]([NH2:13])=[N:8][C:9]([NH2:12])=[CH:10][CH:11]=3)[CH:3]=[N:2]2)=[CH:24][CH:23]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCOCc1ccc(CCl)cc1
Reactant: Nc1ccc(-c2cn[nH]c2)c(N)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCOCc1ccc(Cn2cc(-c3ccc(N)nc3N)cn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a solution of 3-(1H-pyrazol-4-yl)-pyridin-2,6-diamine (20 mg, 0.11 mmol) described in Manufacturing Example 36-1-2 in N,N-dimethylformamide (4 mL) was added sodium hydride (5.9 mg, 0.15 mmol, 60% in oil) under nitrogen atmosphere on an ice bath (0° C.) Following 30 minutes of stirring at room temperature, 1-butoxymethyl-4-chloromethyl-benzene (26.7 mg, 0.13 mmol) described in Manufacturing Example 33-1-4 was added and stirred for 30 minutes at room temperature. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1, then ethyl acetate) to obtain the title compound (29.0 mg, 72%).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1.Br[C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([CH3:26])[CH:25]=1)[C:21]#[N:22]>>[CH3:1][C:2]1([CH3:16])[O:3][C:4](=[O:15])[NH:5][C:6]2[CH:11]=[CH:10][C:9]([C:18]3[CH:19]=[C:20]([CH:23]=[C:24]([CH3:26])[CH:25]=3)[C:21]#[N:22])=[CH:8][C:7]1=2
Reactant: Cc1cc(Br)cc(C#N)c1
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Product: Cc1cc(C#N)cc(-c2ccc3c(c2)C(C)(C)OC(=O)N3)c1

Procedure:
3-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-methyl-benzonitrile was prepared, from (4,4-dimethyl-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and 3-bromo-5-methylbenzonitrile according to the procedure of Example 5, as a white solid: mp 256-258° C.; 1H-NMR (DMSO-d6) δ10.4 (s, 1H), 7.99 (s, 1H), 7.86 (s, 1H), 7.67-7.62 (m, 3H), 6.97 (d, 1H, J=8.11 Hz), 2.42 (s, 3H), 1.68 (s, 6H); MS (APCI) m/z 293 ([M+H]+, 100%); Anal. Calc. For C18H16N2O2: C, 73.96; H, 5.52; N, 9.58. Found: C, 73.26; H, 5.46; N, 9.24.
Reaction SMILES: [N:1]1([C:10]2[N:15]=[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:13]([C:25]([O:27]CC)=[O:26])=[CH:12][N:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[N:1]1([C:10]2[N:15]=[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:13]([C:25]([OH:27])=[O:26])=[CH:12][N:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cnc(N2CCc3ccccc32)nc1OCc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1cnc(N2CCc3ccccc32)nc1OCc1ccc(F)cc1
Temperature: 25 °C
Yield: 101.1 %

Procedure:
To a suspension of ethyl 2-(2,3-dihydro-1H-indol-1-yl)-4-[(4-fluorobenzyl)oxy]-5-pyrimidinecarboxylate (5.0 g, 13 mmol) in ethanol (25 mL) were added 10% aqueous sodium hydroxide solution (15 mL) and tetrahydrofuran (15 mL) and the mixture was heated under reflux for 30 min. The reaction mixture was allowed to cool to room temperature and 1N hydrochloric acid was added to adjust the reaction mixture to pH 5. The precipitated crystals were collected by filtration, washed several times with water, dried with heating under vacuum to give 2-(2,3-dihydro-1H-indol-1-yl)-4-[(4-fluorobenzyl)oxy]-5-pyrimidinecarboxylic acid (4.8 g, 100%) as crystals. To the obtained suspension of the obtained carboxylic acid (183 mg, 0.5 mmol), t-butyl glycine (89 mg, 0.53 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (102 mg, 0.53 mmol) in dichloromethane (2 mL) was added triethylamine (0.21 mL, 1.5 mmol) and the mixture was stirred at room temperature for 18 h. Water and ethyl acetate were added to the reaction mixture and the organic layer was concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography and eluted with ethyl acetate to give the title compound (210 mg, 88%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:24])=[CH:4][C:5]([Cl:23])=[C:6]([C:8]2[C:9](=[O:22])[N:10]([CH2:20][CH3:21])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH3:19])[CH:12]=3)[CH:7]=1.C([O-])(O)=O.[Na+].Cl[C:31]([O:33][C:34]([CH3:36])=[CH2:35])=[O:32]>CCOC(C)=O>[Cl:23][C:5]1[C:6]([C:8]2[C:9](=[O:22])[N:10]([CH2:20][CH3:21])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH3:19])[CH:12]=3)=[CH:7][C:2]([NH:1][C:31](=[O:32])[O:33][C:34]([CH3:36])=[CH2:35])=[C:3]([F:24])[CH:4]=1
Reactant: C=C(C)OC(=O)Cl
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(NC)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(NC)cc3n(CC)c2=O)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
A suspension of Example A5 (0.154 g, 0.444 mmol) in EtOAc (2.5 mL) was treated with satd. NaHCO3 (2.5 mL) and isopropenyl chloroformate (0.046 mL, 0.422 mmol) and the biphasic mixture stirred vigorously at RT for 3.5 h. Additional isopropenyl chloroformate (20 μL) was added and the mixture was stirred at RT overnight. The mixture was diluted with additional EtOAc and satd. NaHCO3 and the layers separated. The organic layer was washed with brine, dried over MgSO4 and concentrated to dryness. The resulting residue was dissolved in pyridine (1.5 mL), cooled to 0° C., treated with isopropenyl chloroformate (15 μL) and allowed to warm to RT. The mixture was re-cooled to 0° C., treated with additional isopropenyl chloroformate (7 μL) and allowed to warm to RT. The mixture was once again cooled to 0° C., treated with isopropenyl chloroformate (5 μL), allowed to warm to RT and stirred overnight. The mixture was concentrated to dryness, treated with brine and extracted with EtOAc (2×). The combined organics were dried over MgSO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford prop-1-en-2-yl (4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)carbamate (141 mg, 74% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.80 (s, 1H), 8.40 (s, 1H), 7.75 (s, 1H), 7.64 (s, 1H), 7.55 (d, J=10.5 Hz, 1H), 7.05 (d, J=5.0 Hz, 1H), 6.23 (s, 1H), 4.73 (m, 2H), 4.13 (q, J=7.1 Hz, 2H), 2.85 (d, J=4.9 Hz, 3H), 1.91 (s, 3H), 1.20 (t, J=7.0 Hz, 3H), MS (ESI) m/z: 431.1 [M+H]+.
Reaction SMILES: C([O:14][C:15]([CH2:17][O:18][N:19]=[C:20]([C:51]1[N:52]=[C:53]([NH2:56])[S:54][CH:55]=1)[C:21]([NH:23][CH:24]1[C:49](=[O:50])[N:26]2[C:27]([C:33]([O:35]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:34])=[C:28]([CH:31]=[CH2:32])[CH2:29][S:30][C@H:25]12)=[O:22])=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.Cl.C(OC(C)C)(C)C>C(O)=O>[C:15]([CH2:17][O:18][N:19]=[C:20]([C:51]1[N:52]=[C:53]([NH2:56])[S:54][CH:55]=1)[C:21]([NH:23][CH:24]1[C:49](=[O:50])[N:26]2[C:27]([C:33]([OH:35])=[O:34])=[C:28]([CH:31]=[CH2:32])[CH2:29][S:30][C@H:25]12)=[O:22])([OH:16])=[O:14]
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(c3ccccc3)c3ccccc3)c3csc(N)n3)[C@H]2SC1
Agent: Cl
Solvent: O=CO
Solvent: CC(C)OC(C)C
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Yield: 86.7 %

Procedure:
To a solution of benzhydryl 7-[2-benzhydryloxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (3 g) in formic acid (12 ml) was added 35% hydrochloric acid (1 ml) at 0° C. After stirring at ambient temperature for an hour, the reaction mixture was poured into diisopropyl ether. The precipitates were collected by filtration, washed with diisopropyl ether and then dissolved in water (15 ml). The aqueous solution was adjusted to pH 3.5 with 5% aqueous sodium bicarbonate. The precipitates were collected by filtration and dried to give 7-[2-carboxymethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (1.5 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]12[O:15][C:12]([CH3:16])([CH:13]=[CH:14]1)[CH2:11][C:10](=[O:17])[CH2:9]2>C(OCC)C>[CH3:16][C:12]12[O:15][C:8]([CH3:7])([CH:14]=[CH:13]1)[CH2:9][CH:10]([OH:17])[CH2:11]2
Reactant: CC12C=CC(C)(CC(=O)C1)O2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC12C=CC(C)(CC(O)C1)O2
Temperature: 0 °C
Reaction time: 2 h
Yield: 128.3 %

Procedure:
To a stirred suspension of lithium aluminum hydride (4.6 g of a 57% oil suspension) in dry diethyl ether (300 ml) was added a solution of 1,5-dimethyl-8-oxabicyclo[3.2.1]oct-6-en-3-one (10.0 g) in diethyl ether (50 ml) over 0.5 hour at 20° C. The reaction mixture was held for 2 hours at 20° C., cooled to 0° C., and washed successively with water (2.5 ml), 15% aqueous sodium hydroxide (2.5 ml) and water (7.5 ml), and filtered. The filter cake was washed with diethyl ether, and the combined ether filtrates were dried (MgSO4), filtered and concentrated to give 13.0 g of oil. The oil was eluted through a column of florisil first with hexane and then diethyl ether. The ether fractions were combined and concentrated to give the desired product (10.0 g) as a 66:34 mixture of epimers.
Reaction SMILES: C([O:5][C:6]([CH2:8][O:9][C:10]1[CH:40]=[CH:39][C:13]2[C:14]([NH:27][C:28]([C@H:30]3[CH2:35][CH2:34][C@H:33]([N:36]([CH3:38])[CH3:37])[CH2:32][CH2:31]3)=[O:29])=[C:15]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][N:21]=3)=[O:18])[O:16][C:12]=2[CH:11]=1)=[O:7])(C)(C)C>Cl.O1CCOCC1.C(OCC)C>[ClH:26].[C:6]([CH2:8][O:9][C:10]1[CH:40]=[CH:39][C:13]2[C:14]([NH:27][C:28]([C@H:30]3[CH2:35][CH2:34][C@H:33]([N:36]([CH3:37])[CH3:38])[CH2:32][CH2:31]3)=[O:29])=[C:15]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][N:21]=3)=[O:18])[O:16][C:12]=2[CH:11]=1)([OH:7])=[O:5]
Reactant: CN(C)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3cc(OCC(=O)OC(C)(C)C)ccc23)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CN(C)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3cc(OCC(=O)O)ccc23)CC1
Temperature: 25 °C
Reaction time: 28 h

Procedure:
Trans-6-t-butoxycarbonylmethyloxy-3-[4-(dimethylamino)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)-benzofuran-2-carboxamide (21 mg) obtained in Example 153 is suspended in 4N hydrogen chloride in dioxane (8 ml), and the mixture is stirred at room temperature for 28 hours. The reaction solution is diluted with diethyl ether, and the precipitates are collected by filtration, washed several times with diethyl ether, and dried to give the title compound (17 mg).
Reaction SMILES: O[N:2]([CH2:14][CH2:15][CH3:16])[CH:3]1[CH2:12][C:11]2[N:10]=[CH:9][C:8]([CH3:13])=[CH:7][C:6]=2[CH2:5][CH2:4]1.Cl>[Cl-].[Cl-].[Cl-].[Ti+3].CO>[CH3:13][C:8]1[CH:9]=[N:10][C:11]2[CH2:12][CH:3]([NH:2][CH2:14][CH2:15][CH3:16])[CH2:4][CH2:5][C:6]=2[CH:7]=1
Reactant: CCCN(O)C1CCc2cc(C)cnc2C1
Agent: [Ti+3]
Agent: Cl
Agent: [Cl-]
Solvent: CO
Product: CCCNC1CCc2cc(C)cnc2C1

Procedure:
This compound was prepared from the product of Step 3 (4.45 g, 20 mmol), titanium trichloride, 20 wt. % solution in 20 wt. % hydrochloric acid (23 ml, 30 mmol), and methanol (50 ml) using the procedure described in Example 11. The crude amine (4.0 g) was converted directly into the product of Step 5.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][OH:6])[CH3:2].C(N(C)CCO)C.[O:16]=[C:17]1[C:23]2[CH:24]=[CH:25][C:26]([CH:28]([CH3:37])[C:29](OCCN(C)C)=[O:30])=[CH:27][C:22]=2[CH:21]=[CH:20][C:19]2[CH:38]=[CH:39][CH:40]=[CH:41][C:18]1=2>>[CH2:1]([N:3]([CH2:4][CH2:5][O:6][C:29](=[O:30])[CH:28]([C:26]1[CH:25]=[CH:24][C:23]2[C:17](=[O:16])[C:18]3[CH:41]=[CH:40][CH:39]=[CH:38][C:19]=3[CH:20]=[CH:21][C:22]=2[CH:27]=1)[CH3:37])[CH2:7][CH3:8])[CH3:2]
Reactant: CC(C(=O)OCCN(C)C)c1ccc2c(=O)c3ccccc3ccc2c1
Reactant: CCN(CC)CCO
Agent: CCN(C)CCO
Product: CCN(CC)CCOC(=O)C(C)c1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
In similar manner substituting diethylethanolamine and N-ethyl-N-methylethanolamine for the dimethylethanolamine, there is obtained β-N-N-diethylaminoethyl-2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionate as an oil (hydrochloride salt: m.p. 117°-123° C; see Example XIV) and β-N-ethyl-N-methylaminoethyl 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)-propionate [an oil; n.m.r. spectrum in deuterochloroform relative to tetramethylsilane: 0.94 (triplet, CH2CH3); 1.53 (doublet, CHCH3); 2.08 (singlet, N--CH3); 4.17 (triplet, OCH2) and 7.03 ppm (singlet, 10H,11H); mass spectrum: 363 (M+), 305, 233, 205].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([OH:14])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].Cl[O-].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:15])[C:5](=[O:14])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)C(O)CCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: CCOC(=O)C(=O)CCc1ccccc1
Temperature: 5 °C
Yield: 97 %

Procedure:
A 500 ml flask was charged a solution dissolving 41.6 g (200 mmol) of 2-hydroxy-4-phenylbutyric acid ethyl ester in methylene chloride (100 ml) and 148.8 g (purity 12%, 240 mmol) of sodium hypochlorite, and cooled at 5° C. To the reaction mixture was added 86 mg (0.4 mmol) of 4-acetoxy-2,2,6,6-tetramethylpiperidinyl-1-oxy and further added 3.02 g (36 mmol) of sodium hydrogen carbonate. The gradual exothermal reaction proceeded, and the starting material of 2-hydorxy-4-phenylbutyric acid ethyl ester was disappeared in 1.5 hours. The reaction was terminated by adding 100 ml of 5% sodium thiosulfate aqueous solution and was separated. The organic phase was washed with 50 ml of 5% sodium thiosulfate aqueous solution and then 100 ml of 1% sodium carbonate aqueous solution, followed by the removal of the solvent by a rotary evaporator. The residue was subjected to distillation under reduced pressure to obtain 40 g of 2-keto-4-phenylbutyric acid ethyl ester having a boiling point of 103° C. at 0.3 mmHg. The yield was 92%.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7]1([Li])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(OC(N[C@H](C(O)=O)C)=O)C.C1([Mg]Br)C=CC=CC=1>CCOCC.O1CCCC1>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccccc1
Reactant: [Li]c1ccccc1
Agent: Br[Mg]c1ccccc1
Agent: CCOC(=O)N[C@@H](C)C(=O)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: c1ccc(-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
The techniques which resulted in successful amido acylation of benzene using phenyllithium were next applied to the Grignard reaction. N-ethoxycarbonylalanine was treated with 300 mol percent of phenylmagnesium bromide at -78° C. and allowed to warm to room temperature. The desired ketone was not observed. Several hours of refluxing in ether and tetrahydrofuran yielded biphenyl and starting material which was optically intact.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([O:55][Si:56]([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57])[CH2:5][C:4]1=[O:63])[CH3:2].FC(F)(F)S(O)(=O)=O.[CH2:72](OC(=N)C(Cl)(Cl)Cl)[CH:73]=[CH2:74].C1CCCCC1>C(Cl)Cl>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:74][CH:73]=[CH2:72])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([O:55][Si:56]([C:59]([CH3:60])([CH3:61])[CH3:62])([CH3:58])[CH3:57])[CH2:5][C:4]1=[O:63])[CH3:2]
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCCCC1
Product: C=CCOC1CCC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O[Si](C)(C)C(C)(C)C)C2C)C(OC)CC3C)CC1OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (820 mg in 9 ml 33% methylene chloride in cyclohexane allyl trichloroacetimidate (366 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (16 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 17 hours the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×15 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ether: hexane (2:3)) gave the title compound (800 mg). (1H NMR was consistent with the desired structure).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.ClC1C=[C:21](C)[N:20]=[C:19]([N:24]2[CH2:29][CH2:28][N:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:26][CH2:25]2)N=1>>[CH3:33][S:30]([N:27]1[CH2:26][CH2:25][N:24]([C:19]2[CH:3]=[C:8]([CH3:7])[N:9]=[C:21]([NH:15][C:5]3[CH:6]=[CH:7][C:8]([N:9]4[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]4)=[C:3]([O:2][CH3:1])[CH:4]=3)[N:20]=2)[CH2:29][CH2:28]1)(=[O:31])=[O:32]
Reactant: Cc1cc(Cl)nc(N2CCN(S(C)(=O)=O)CC2)n1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2nc(C)cc(N3CCN(S(C)(=O)=O)CC3)n2)ccc1-n1cnc(C)c1
Yield: 4 %

Procedure:
Prepared in analogy to example 81b) from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and 4-chloro-2-(4-methanesulfonyl-piperazin-1-yl)-6-methyl-pyrimidine. The title compound was isolated as a yellowish solid in a yield of 4%. MS ISP (m/e): 458.3 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.32 (s, 1H), 7.90 (s, 1H), 7.63 (d, 1H), 7.24 (d, 1H), 7.18 (d, 1H), 7.01 (s, 1H), 6.28 (s, 1H), 3.78 (s, 3H), 3.80-3.70 (m, 4H), 3.19 (t, 4H), 2.91 (s, 3H), 2.23 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: C(O[C@H]1[C@H](OCC2C=CC=CC=2)[C@@H](OCC2C=CC=CC=2)[C@]2(C3C=CC(Cl)=C(CC4C=CC(OCC)=CC=4)C=3)O[C@@]1(CF)CO2)C1C=CC=CC=1.C([O:59][C@H:60]1[C@H:66]([O:67]CC2C=CC=CC=2)[C@@H:65]([O:75]CC2C=CC=CC=2)[C@:64]2([C:84]3[CH:89]=[CH:88][C:87]([Cl:90])=[C:86]([CH2:91][C:92]4[CH:97]=[CH:96][C:95]([O:98][CH2:99][CH3:100])=[CH:94][CH:93]=4)[CH:85]=3)[O:83][C@@:61]1([CH2:101][Cl:102])[CH2:62][O:63]2)C1C=CC=CC=1.C(O)=O.C(OCC)(=O)C>C(O)C.O1CCCC1.[Pd]>[Cl:90][C:87]1[CH:88]=[CH:89][C:84]([C@@:64]23[O:83][C@@:61]([CH2:101][Cl:102])([CH2:62][O:63]2)[C@@H:60]([OH:59])[C@H:66]([OH:67])[C@H:65]3[OH:75])=[CH:85][C:86]=1[CH2:91][C:92]1[CH:93]=[CH:94][C:95]([O:98][CH2:99][CH3:100])=[CH:96][CH:97]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](CCl)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Agent: [Pd]
Agent: CCOc1ccc(Cc2cc([C@]34OC[C@](CF)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O=CO
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](CCl)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of a mixture of (1S,2S,3S,4R,5S)-2,3,4-tris-benzyloxy-5-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-1-fluoromethyl-6,8-dioxa-bicyclo[3.2.1]octane and (1S,2S,3S,4R,5S)-2,3,4-tris-benzyloxy-5-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-1-chloromethyl-6,8-dioxa-bicyclo[3.2.1]octane (50 mg, 0.07 mmol) and palladium black (50 mg, 0.38 mmol, Aldrich® high surface area) in ethanol (0.5 mL) and tetrahydrofuran (0.1 mL) was added formic acid (0.10 mL, 2.80 mmol) and the resulting mixture was stirred at room temperature for 1.5 hours. Ethyl acetate was added and the mixture was filtered through a short pad of Celite® and concentrated in vacuo. The crude material was purified by flash chromatography over silica gel using a 4 g redisep silica cartridge (eluting with a gradient of 50 to 100% ethyl acetate in heptane) to afford the title compound as a solid (8.6 mg; ˜80% pure, contaminated with some Example 8).
Reaction SMILES: Cl[C:2]1[C:3](=[O:22])[NH:4][N:5]=[C:6]([O:19][CH2:20][CH3:21])[C:7]=1[NH:8][C@@H:9]1[CH2:14][C@@H:13]2[CH2:15][C@@H:11]([C:12]2([CH3:17])[CH3:16])[C@H:10]1[CH3:18].[H][H]>CO.[C].[Pd]>[CH2:20]([O:19][C:6]1[C:7]([NH:8][C@@H:9]2[CH2:14][C@@H:13]3[CH2:15][C@@H:11]([C:12]3([CH3:16])[CH3:17])[C@H:10]2[CH3:18])=[CH:2][C:3](=[O:22])[NH:4][N:5]=1)[CH3:21]
Reactant: [H][H]
Reactant: CCOc1n[nH]c(=O)c(Cl)c1N[C@@H]1C[C@@H]2C[C@H]([C@H]1C)C2(C)C
Agent: [Pd]
Solvent: CO
Product: CCOc1n[nH]c(=O)cc1N[C@@H]1C[C@@H]2C[C@H]([C@H]1C)C2(C)C
Yield: 94 %

Procedure:
4-Chloro-6-ethoxy-5-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-3(2H)-one (200 mg, 0.614 mmol) and 10% palladium-carbon (50 wt %, 40 mg) were stirred in methanol in a hydrogen stream at room temperature for 8 days. The reaction solution was filtered through celite and concentrated under reduced pressure to give the desired product (94% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[C:9]([N:16]1[CH2:20][CH2:19][C@H:18]([NH2:21])[CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C(OCC)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:12]([O:11][C:9]([N:16]1[CH2:20][CH2:19][C@H:18]([NH:21][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=2)[CH2:17]1)=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: Cc1cc(Br)ccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1cc(N[C@H]2CCN(C(=O)OC(C)(C)C)C2)ccn1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
4-Bromo-2-methylpyridine (165 mg, 0.96 mmol), (S)-(−)-N-Boc-3-aminopyrrolidine (214 mg, 1.15 mmol), Pd(OAc)2 (8.6 mg, 0.04 mmol), (rac)-BINAP (23.9 mg, 0.04 mmol) and NaOtBu (129 mg, 1.34 mmol) in dry toluene (5 mL) were heated at 70° C. in a flask under nitrogen atmosphere for 4 hours. The reaction mixture was allowed to cool down to room temperature, taken up in diethyl ether (10 mL), washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using 15% MeOH in CH2Cl2 as eluent to afford (S)-3-(2-methyl-pyridin-4-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (255 mg, 96%) as an orange oil.