Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1([CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3([C:28](OC)=[O:29])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1.O>O1CCCC1>[N:7]1([CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3([CH2:28][OH:29])[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[CH:18][CH:17]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: COC(=O)C1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Temperature: 2.5 °C
Yield: 93.3 %

Procedure:
Anhydrous tetrahydrofuran (141 ml, 10 vol) was charged rapidly onto stirred and cooled (0-5° C.) lithium aluminium hydride (6.2 g, 0.1634 mol, 0.44 wt) under nitrogen (Note: very exothermic). The resulting slurry was cooled to 0-5° C. and then a solution of methyl 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carboxylate (14.1 g, 0.04058 mol) in tetrahydrofuran (99 ml, 7 vol) was added dropwise over 30 minutes maintaining 0-5° C. On complete addition the reaction was allowed to warm to room temperature over 30 minutes and stirred at 18-25° C. for 30 minutes, LC analysis showed the reaction to be complete. The mixture was cooled to 0 to 5° C., a 1:1 mixture of tetrahydrofuran and water (18.6 ml, 1.32 vol) was added very slowly (Note: very exothermic, gas evolution, temperature maintained below 16° C., toward the end of the quench the reaction mixture sets and then becomes freer with continued stirring.). The mixture was further quenched with 20% w/v sodium hydroxide solution (6.2 ml, 0.44 vol) and water (18.6 ml, 1.32 vol) and the resulting white suspension stirred vigorously for 30 minutes at 18-25° C. The slats were removed by filtration and rinsed with tetrahydrofuran (3×150 ml). The combined filtrates were evaporated to dryness at 40° C. to yield title compound (12.1 g, 94%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.25 (d, 2H), 6.90 (d, 2H), 4.05 (t, 2H), 3.80 (dt, 2H), 3.55 (td, 2H), 2.60 (t, 2H), 2.62-2.41 (m, 4H), 2.10 (dt, 2H), 2.00 (p, 2H), 2.00-1.85 (m, 2H), 1.95-1.72 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]3[CH:20]=[CH:19][C:18](Br)=[CH:17][N:16]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH3:22][S:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[CH3:22][S:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([C:27]5[CH:28]=[CH:29][C:24]([S:23][CH3:22])=[CH:25][CH:26]=5)=[CH:17][N:16]=4)[CH2:10][CH2:9]3)=[N:6][CH:7]=2)=[CH:26][CH:25]=1
Reactant: Brc1ccc(N2CCCN(c3ccc(Br)cn3)CC2)nc1
Reactant: CSc1ccc(B(O)O)cc1
Product: CSc1ccc(-c2ccc(N3CCCN(c4ccc(-c5ccc(SC)cc5)cn4)CC3)nc2)cc1
Yield: 43.7 %

Procedure:
Following the procedure of Example 1, crude crystals were obtained from the 1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (206.0 mg, 0.500 mmol) synthesized in Reference Example 1 and 4-methylthiophenylboronic acid (202.0 mg, 1.20 mmol). The crude crystals were recrystallized from chloroform-hexane to yield the title compound as pale yellow needles (melting point: 252.0–255.0° C.) (109.0 mg, yield: 43%).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][NH2:4].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[CH2:16]Br>CS(C)=O>[F:1][C:2]([F:6])([F:5])[CH2:3][NH:4][CH2:16][C:9]1[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:8]=1[Br:7]
Reactant: NCC(F)(F)F
Reactant: COc1ccc(Br)c(CBr)c1
Solvent: CS(C)=O
Product: COc1ccc(Br)c(CNCC(F)(F)F)c1
Temperature: 32.5 °C
Reaction time: 18 h
Yield: 115.6 %

Procedure:
2,2,2-Trifluoroethylamine (24 g, 242 mmol) was added rapidly to a stirred solution of 4-bromo-3-bromomethylanisole (33.6 g, 120 mmol) in anhydrous DMSO (125 mL) at RT. The reaction warmed to approximately 30-35° C. After stirring for 18 hr, the reaction was diluted with ice-cold 1 N NaOH (200 mL) and extracted with Et2O (2×300 mL). The combined organic layers were washed with brine (300 mL), dried (MgSO4), and concentrated to give the title compound (41.35 g, 96%) as a pale yellow oil: TLC (toluene) Rf 0.32; 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J=9 Hz, 1H), 6.97 (d, J=3 Hz, 1H), 6.71 (dd, 1H), 3.93 (br s, 2H), 3.80 (s, 3H), 3.18 (m, 2H), 1.86 (br s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])[C@H:3]1[C:13]([OH:15])=[O:14].[C:17]([C@@H:19](O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=1)#[N:18]>>[CH3:16][C:2]1([CH3:1])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])[C@H:3]1[C:13]([O:15][C@H:19]([C:17]#[N:18])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:21]=1)=[O:14]
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Reactant: CC(C)OC(=O)/C=C\[C@H]1[C@@H](C(=O)O)C1(C)C
Product: CC(C)OC(=O)/C=C\[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Yield: 69.6 %

Procedure:
Using the procedure of Step D of Example 1, 900 mg of the product of Step C and 900 mg of (S)α-cyano-3-phenoxy-benzyl alcohol were reacted to obtain 1.8 g of raw product which was chromatographed over silica gel. Elution with a 9-1 cyclohexane-ethyl acetate mixture yielded 1.2 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[Z-2-(isopropoxycarbonyl)-ethenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+54°±2° (c=0.4% in benzene).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:19]=3)=[O:17])[CH:12]=[CH:11][C:10]=2[CH3:30])[CH:5]=[CH:4][N:3]=1.[CH2:31]([NH:34][CH3:35])[CH:32]=[CH2:33]>>[CH2:31]([N:34]([C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:19]=3)=[O:17])[CH:12]=[CH:11][C:10]=2[CH3:30])[CH:5]=[CH:4][N:3]=1)[CH3:35])[CH:32]=[CH2:33]
Reactant: C=CCNC
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1Nc1ccnc(Cl)n1
Product: C=CCN(C)c1nccc(Nc2cc(NC(=O)c3ccnc(N4CCOCC4)c3)ccc2C)n1
Temperature: 75 °C

Procedure:
A mixture of 2-chloro-4-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)anilino]pyrimidine (0.2 g) and N-allyl-N-methylamine (0.25 ml) was stirred and heated to 75° C. for 3 hours. The mixture was cooled to ambient temperature and purified by column chromatography on silica using a 9:1 mixture of methylene chloride and methanol as eluent. The resultant oil was triturated under a mixture of isohexane and diethyl ether. There was thus obtained the title compound as a solid (0.055 g); NMR Spectrum: (DMSOd6) 2.17 (s, 3H), 2.95 (s, 3H), 3.5 (m, 4H), 3.7 (m, 4H), 4.1 (d, 2H), 5.04 (m, 2H), 5.75 (m, 1H), 5.91 (m, 1H), 7.07 (m, 1H), 7.17 (m, 2H), 7.19 (m, 1H), 7.86 (m, 1H), 7.98 (m, 1H), 8.25 (m, 1H), 8.42 (s, 1H), 10.17 (s, 1H); Mass Spectrum: M+H+ 460.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[Na].C1C=CC=CC=1.[CH2:19]([OH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:5]=[CH:4][N:3]=1
Reactant: OCc1ccccc1
Reactant: Nc1ncnc(Cl)c1[N+](=O)[O-]
Agent: [Na]
Solvent: c1ccccc1
Product: Nc1ncnc(OCc2ccccc2)c1[N+](=O)[O-]
Temperature: 130 °C

Procedure:
4-Amino-6-chloro-5-nitropyrimidine (Boon et al., J. Chem. Soc., 96-102 (1951)) (1.5 g, 8.6 mmol) was added to a solution of sodium (0.23 g, 9.9 mmol) in benzyl alcohol (14 mL). The solution was heated in a 130° C. oil bath for 3.5 h, and was poured into benzene (50 mL). A yellow solid was collected by filtration and washed with benzene. Crystallization from benzene/ether afforded an analytically pure sample of 3a: yield, 0.71 g (34%); mp 149-150° C.; UV (pH 1) 1max 284 nm (e=0.368×104), 333 (0.488×104); (pH 6.9) 284 (0.329×104), 336 (0.470×104); (pH 13) 290 (0.344×104), 333 (0.494×104); 1H NMR d 5.50 (s, 2 H, ArCH2), 7.33-7.49 (m, 5 H, ArH), 8.12-8.24 (br d, 2 H, NHa and NHb, exchange with D2O), 8.24 (s, 1 H, H-2); MS (EI) calcd. m/z for C11H10N4O3 246.0752, found 246.0751; Anal. (C11H10N4O3) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH2:7][C:8]([F:11])([F:10])[F:9])[N:6]=1.[CH:12]1[C:25]2[CH:24]([C:26](Cl)=[O:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[O:17][C:16]=2[CH:15]=[CH:14][CH:13]=1>>[F:10][C:8]([F:9])([F:11])[CH2:7][N:5]1[N:4]=[N:3][C:2]([NH:1][C:26]([CH:24]2[C:25]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[O:17][C:18]3[C:23]2=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:27])=[N:6]1
Reactant: Nc1nnn(CC(F)(F)F)n1
Reactant: O=C(Cl)C1c2ccccc2Oc2ccccc21
Product: O=C(Nc1nnn(CC(F)(F)F)n1)C1c2ccccc2Oc2ccccc21

Procedure:
The title compound, white solid, m.p. 209-210 and MS: (neg. ions): m/e=374.1 (M+−H) was prepared in accordance with the general method of example 1 from 5-amino-2-(2,2,2-trifluoroethyl)-2H-tetrazole and 9H-xanthene-9-carbonyl chloride.
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].[CH3:5][O:6][CH:7]([O:10][CH3:11])[CH2:8]Br>>[CH3:5][O:6][CH:7]([O:10][CH3:11])[CH2:8][O:4][CH2:1][CH:2]=[CH2:3]
Reactant: C=CCO
Reactant: COC(CBr)OC
Product: C=CCOCC(OC)OC

Procedure:
Perkin Elmer 8310 GC (8% carbowax+2% KOH on chromasorb 80-100 mesh, 80°-200° C. in 20 min. Product retention 5.775 minutes, allyl alcohol 3.61 min, bromo-acetaldehyde dimethyl acetal 5.44 min. FID detection.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([C:16]3[N:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][C:17]=3B3OC(C)(C)C(C)(C)O3)[CH:12]=[CH:13][C:14]=2[Cl:15])=[CH:5][CH:4]=1.Br[C:38]1[C:43]([Cl:44])=[CH:42][C:41]([CH3:45])=[CH:40][N:39]=1>>[Cl:44][C:43]1[C:38]([C:17]2[C:16]([C:11]3[CH:12]=[CH:13][C:14]([Cl:15])=[C:9]([O:8][CH2:7][C:6]4[CH:35]=[CH:36][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH:10]=3)=[N:21][C:20]([C:22]([O:24][CH3:25])=[O:23])=[CH:19][CH:18]=2)=[N:39][CH:40]=[C:41]([CH3:45])[CH:42]=1
Reactant: Cc1cnc(Br)c(Cl)c1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc(Cl)c(OCc3ccc(OC)cc3)c2)n1
Product: COC(=O)c1ccc(-c2ncc(C)cc2Cl)c(-c2ccc(Cl)c(OCc3ccc(OC)cc3)c2)n1
Yield: 63.8 %

Procedure:
The Suzuki-Myaura coupling performed between 1 g (1.96 mmol) of methyl 6-[3-[(4-methoxybenzyl)oxy]-4-chlorophenyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxylate and 526 mg (2.55 mmol) of 2-bromo-3-chloro-5-methylpyridine according to Example 1.6 gives 637 mg of methyl 3-chloro-2′-{4-chloro-3-[(4-methoxybenzyl)oxy]phenyl}-5-methyl-2,3′-bipyridine-6′-carboxylate in the form of an oil.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C@@H:14]([CH2:25][C:26]([O:28][CH2:29][CH2:30][OH:31])=[O:27])[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:32]([O:39][C:40]([NH:42][C:43]1[CH:51]=[CH:50][C:46]([C:47](O)=[O:48])=[CH:45][CH:44]=1)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:1]1[C:13]2[N:12]([C@@H:14]([CH2:25][C:26]([O:28][CH2:29][CH2:30][O:31][C:47](=[O:48])[C:46]3[CH:45]=[CH:44][C:43]([NH:42][C:40]([O:39][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:41])=[CH:51][CH:50]=3)=[O:27])[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(C[C@@H](C(=O)OCc1ccccc1)n1c2ccccc2c2ccccc21)OCCO
Reactant: O=C(Nc1ccc(C(=O)O)cc1)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(C[C@@H](C(=O)OCc1ccccc1)n1c2ccccc2c2ccccc21)OCCOC(=O)c1ccc(NC(=O)OCc2ccccc2)cc1
Yield: 59.6 %

Procedure:
(S)-1-benzyl 4-(2-hydroxyethyl) 2-(9H-carbazol-9-yl)succinate 17 (0.500 g, 1.20 mmol) was added to a solution of 4-(benzoyloxycarbonylamino)benzoic acid 10 (0.389 g, 1.44 mmol), EDCHCl (0.304 g, 1.58 mmol) and DMAP (0.043 g, 0.35 mmol) in CH2Cl2 (10 mL). After the reaction mixture was refluxed for 24 h, the solution was extracted with CH2Cl2 (100 mL) and water (100 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using CH3OH:CH2Cl2 (1:99) to afford (S)-1-benzyl 4-(2-(4-(benzyloxycarbonylamino)benzoyloxy)ethyl) 2-(9H-carbazol-9-yl)succinate 18 (0.480 g, 60%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.[Br:11][C:12]1[CH:13]=[N+:14]([O-])[CH:15]=[CH:16][CH:17]=1>C(OC(=O)C)(=O)C>[Br:11][C:12]1[CH:17]=[CH:16][C:15](=[C:6]2[C:7](=[O:8])[O:9][C:2]([CH3:10])([CH3:1])[O:3][C:4]2=[O:5])[NH:14][CH:13]=1
Reactant: [O-][n+]1cccc(Br)c1
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: CC(=O)OC(C)=O
Product: CC1(C)OC(=O)C(=C2C=CC(Br)=CN2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.8 %

Procedure:
Meldrum's acid (6.63 g, 45.98 mmol) was added to a solution of 3-bromopyridine N-oxide (8 g, 45.98 mmol) in acetic anhydride (50 mL), and the mixture was stirred at room temperature overnight. Then, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate and ethyl acetate) to give the target compound (4.53 g, 33%).
Reaction SMILES: [Li]CCCC.[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22](Br)=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([C:41]2[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=2)=[O:40])=[CH:35][CH:34]=1>C1COCC1>[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22]([C:39]([C:36]3[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=3)([C:41]3[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=3)[OH:40])=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reactant: O=C(c1ccc(F)cc1)c1cccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3ccc(F)cc3)c3cccnc3)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 0.095 mL, 0.238 mmol) was added dropwise by syringe to a solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (105.5 mg, 0.246 mmol, Intermediate 16) in dry THF (2.5 mL) in a dry ice-acetone bath. After 1.5 minutes, a solution of commercially available (4-fluorophenyl)(pyridin-3-yl)methanone (58.7 mg, 0.292 mmol) in dry THF (0.2 mL) was added dropwise. The reaction mixture was stirred for 5 minutes in a dry ice-acetone bath, then the reaction flask was placed into an ice-water bath. After 10 minutes, the mixture was warmed to room temperature and the reaction was quenched with methanol and water. The mixture was partitioned between water and ethyl acetate. The separated aqueous phase was further extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 10-50% EtOAc-Hexanes followed by 0-10% MeOH-DCM) to provide the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.50-8.48 (m, 1H), 8.43 (dd, J=4.8, 1.6 Hz, 1H), 8.02 (d, J=2.1 Hz, 1H), 7.83 (d, J=2.4 Hz, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.67-7.64 (m, 2H), 7.55-7.52 (m, 2H), 7.50 (dd, J=8.8, 2.2 Hz, 1H), 7.33 (d, J=8.6 Hz, 2H), 7.26-7.20 (m, 3H), 7.03-6.96 (m, 2H), 6.42-6.40 (m, 1H), 4.28 (s, 2H), 4.07 (s, 3H); MS m/e 551.2 [M+H]+.
Reaction SMILES: [C:1]([O:4][CH3:5])(=[O:3])[CH3:2].[C:6](OC)(=O)[CH3:7].[CH3:11][OH:12]>>[C:1]([O:4][CH2:5][CH:6]=[CH2:7])(=[O:3])[CH3:2].[CH3:11][OH:12]
Reactant: COC(C)=O
Solvent: CO
Product: C=CCOC(C)=O
Yield: 92 %

Procedure:
The tandem tube reactors are operated as in Example 1, with substitution of 740 grams per hour of pure methyl acetate for the methyl acetate-methanol azeotrope. Analysis of the condensed phases indicates the collection per hour of 254 grams of methyl acetate (34% unconverted), 607 grams of allyl acetate (92% yield based on 66% conversion) and 191 grams of methanol (90% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH2:9].[CH2:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1)[CH3:11]>>[CH2:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:9][CH2:8][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:21])=[CH:15][CH:14]=1)[CH3:11]
Reactant: CCOc1ccc(N=C=O)cc1
Reactant: NCCc1ccccn1
Product: CCOc1ccc(NC(=O)NCCc2ccccn2)cc1
Yield: 95 %

Procedure:
Prepared in a similar manner to example 158 using 2-(pyridine-2-yl)ethanamine and 1-ethoxy-4-isocyanatobenzene. Yield: 95%. mp: 163-164° C. 1H NMR (500 MHz, CDCl3): δ 1.43 (t, 3H), 3.03 (t, 2H), 3.68 (t, 2H), 4.03 (q, 2H), 5.69 (br s, 1H), 6.45 (br s, 1H), 6.84 (m, 2H), 7.14 (m, 3H), 7.20 (d, 1H), 7.64 (dt, 1H), 8.43 (dd, 1H). MS (M+H,286).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12](=[O:14])[CH3:13])(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1cccc(Br)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NS(=O)(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.3 %

Procedure:
3-Bromobenzenesulfonamide (470 mg, 2.0 mmol) was dissolved in pyridine (1 mL). To this solution was added DMAP (7.3 mg, 0.060 mmol) and then acetic anhydride (570 μL, 6.0 mmol). The reaction was stirred for 3 h at room temperature during which time the reaction changed from a yellow solution to a clear solution. The solution was diluted with ethyl acetate, and then washed with aqueous NH4Cl solution (×3) and water. The organic layer was dried over MgSO4 and concentrated. The resulting oil was triturated with hexanes and the precipitate was collected by filtration to obtain N-(3-bromophenylsulfonyl)-acetamide as a shiny white solid (280 mg, 51%). 1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.01 (t, J=1.8 Hz, 1H), 7.96-7.90 (m, 2H), 7.61 (t, J=8.0 Hz, 1H), 1.95 (s, 3H); HPLC ret. time 1.06 min; ESI-MS 278.1 m/z (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:22][CH2:23][N:24]3[C@H:29]4[CH2:30][CH2:31][C@@H:25]3[CH2:26][CH:27]([N:32]3[C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=5[N:34]=[C:33]3[CH3:41])[CH2:28]4)[CH2:13][CH2:12][N:11]([C:14](=[O:21])[C:15]([CH3:20])([NH2:19])[CH:16]([CH3:18])[CH3:17])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:42][C:43]([CH3:48])([CH3:47])[C:44](Cl)=[O:45].CCN(C(C)C)C(C)C>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:22][CH2:23][N:24]3[C@H:29]4[CH2:30][CH2:31][C@@H:25]3[CH2:26][CH:27]([N:32]3[C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=5[N:34]=[C:33]3[CH3:41])[CH2:28]4)[CH2:13][CH2:12][N:11]([C:14]([C:15]([NH:19][C:44](=[O:45])[C:43]([CH3:48])([CH3:47])[CH3:42])([CH3:20])[CH:16]([CH3:17])[CH3:18])=[O:21])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)C(C)(N)C(C)C)CC1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)C(C)(NC(=O)C(C)(C)C)C(C)C)CC1
Yield: 67.3 %

Procedure:
N-{1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-1,2-dimethylpropyl}-2,2-dimethylpropanamide was obtained from treating 1,1-dimethylethyl {1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-1,2-dimethylpropyl}carbamate, example 915, (0.623 g, 0.94 mmol) with HCl as outlined in the procedure for Example 890 to form 1-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)-2,3-dimethyl-1-oxo-2-butanamine (0.524 g, 99%). 1-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)-2,3-dimethyl-1-oxo-2-butanamine (0.050 g, 0.09 mmol), 2,2-Dimethyl-propionyl chloride (0.011 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in Example 890 to give the title compound, N-{1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl) carbonyl]-1,2-dimethylpropyl}-2,2-dimethylpropanamide (0.039 g, 67%) as an oil. ES-LCMS m/z 643 (M+1).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:27]=1[SH:33]>C(O)CCC.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>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][N:12]([C:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([S:33][C:27]4[C:28]([CH3:32])=[CH:29][CH:30]=[CH:31][C:26]=4[Cl:25])[CH:11]=3)[CH:6]=[CH:7][N:8]=2)[CH2:13][CH2:14]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc3ccc(Br)cc23)CC1
Reactant: Cc1cccc(Cl)c1S
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCO
Product: Cc1cccc(Cl)c1Sc1ccc2ccnc(N3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 110 °C
Yield: 86.7 %

Procedure:
A mixture of 4-(7-bromo-isoquinoline-1-yl)-piperazine-1-carboxylic acid, tert-butyl ester (0.5 g, 1.3 mmol), 2-chloro-6-methyl-thiophenol (0.206 g, 1.3 mmol), NatBuO (0.44 g, 4.5 mmol), Pd(PPh3)4 (74 mg, 0.065 mmol) in nBuOH (10 mL) was heated at 110° C., 3 h. The reaction mixture was filtered. The filtrate was concentrated and the residue was dissolved in ethyl acetate. The organic phase was washed with water (50 mL×3), separated and dried (MgSO4), filtered. The volatiles were evaporated and the residue was purified by flash column chromatography (SiO2, n-heptane: ethyl acetate 8:2) to give 530 mg of the title compound as colourless oil (yield 86.4%). 1H NMR (CDCl3) δ 8.05 (d, 1H), 7.65 (d, 1H), 7.20-7.45 (m, 5H), 7.15 (d, 1H), 3.26-3.40 (m, 4H), 3.10-3.20 (m, 4H), 2.5 (s, 3H), 1.38 (s, 9H).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:26][CH:25]=2)[CH2:18]1)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Li+].[OH-:39]>COCCOC>[C:1]([NH:8][C@@H:9]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C@@H:17]([OH:39])[CH2:18][C@@H:19]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:28][CH:29]=1)[C:20]([OH:21])=[O:22])([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H]1C[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)O1
Agent: [Li+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H](O)C[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O

Procedure:
Analogously to Example 1 h), 2.4 g (4.728 mmol) of 5(S)-[1(S)-(Boc-amino)-2-cyclohexylethyl]-3(R)-(4-benzyloxy-benzyl)-dihydrofuran-2-(3H)-one in 10 ml of 1,2-dimethoxyethane are reacted with 9.45 ml of 1M LiOH solution to give the title compound. The title compound is purified by crystallisation from hexane. TLC Rf (E)=0.33; tRet (III)=18 min; FAB-MS (M+H+)=526.