Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH3:30])[NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH:25]=[O:26])[CH:22]=[C:21]([C:27]#[N:28])[CH:20]=2)[C:12]=1[F:29])=[O:8].[BH4-].[Na+].C(=O)(O)[O-].[Na+]>CO.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([CH3:30])[NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH2:25][OH:26])[CH:22]=[C:21]([C:27]#[N:28])[CH:20]=2)[C:12]=1[F:29])=[O:8]
Reactant: Cc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(C#N)cc(C=O)c3)c2F)[nH]1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(C#N)cc(CO)c3)c2F)[nH]1
Temperature: 25 °C
Yield: 75.4 %

Procedure:
To a solution of 4-chloro-N-({4-chloro-3-[(3-cyano-5-formylphenyl)oxy]-2-fluorophenyl}methyl)-2-methyl-1H-imidazole-5-carboxamide (0.178 g, 0.398 mmol) in methanol (5 ml) at 0° C. was added sodium borohydride (0.015 g, 0.398 mmol) and the reaction mixture was allowed to warm to rt over 30 minutes. The reaction mixture was neutralized with saturated sodium bicarbonate, diluted with EtOAc, and the organic layer was separated. The solvent was evaporated and the crude material was purifed via silica gel chromatography to give 4-chloro-N-[(4-chloro-3-{[3-cyano-5-(hydroxymethyl)phenyl]oxy}-2-fluorophenyl)methyl]-2-methyl-1H-imidazole-5-carboxamide (0.135 g, 0.300 mmol, 76% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.39 (s, 1H), 7.27-7.38 (m, 2H), 7.18 (s, 1H), 7.08 (s, 1H), 4.60 (s, 2 H), 4.58 (s, 2H), 2.32 (s, 3H). LC-MS (ES+) m/z 448.94, [M+H].
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.[CH3:7][N:8]1[C:17]2[NH:16][C:15]3[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:14]=3[N:13]([C:23]([CH:25]3[CH2:30][CH2:29][CH:28]([CH2:31][NH:32][C:33](=[O:41])[CH2:34][CH:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)[CH2:27][CH2:26]3)=[O:24])[CH2:12][C:11]=2[CH:10]=[N:9]1>ClCCl.C(N(CC)CC)C>[CH3:7][N:8]1[C:17]2[NH:16][C:15]3[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:14]=3[N:13]([C:23]([CH:25]3[CH2:26][CH2:27][CH:28]([CH2:31][NH:32][C:33](=[O:41])[CH2:34][CH:35]4[CH2:36][CH2:37][N:38]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:39][CH2:40]4)[CH2:29][CH2:30]3)=[O:24])[CH2:12][C:11]=2[CH:10]=[N:9]1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)C1CCC(CNC(=O)CC2CCNCC2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)C1CCC(CNC(=O)CC2CCN(S(C)(=O)=O)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methanesulfonyl chloride (0.57 mg, 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of N-[4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-cyclohexylmethyl]-2-piperidin-4-yl-acetamide hydrochloride from Example E17 (2.57 mg, 0.005 mmol) in dichloro-methane (0.05 ml) and triethylamine (0.0035 ml). The mixture was stirred at room temperature for 1 h then sol-vents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=557.4
Reaction SMILES: CS(C)=O.Br[CH:6]1[C:15]2[C:10](=[CH:11][C:12]([Cl:16])=[CH:13][N:14]=2)[N:9]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[C:8](=[O:30])[C:7]1([CH3:32])[CH3:31].C(=O)([O-])[OH:34].[Na+]>O>[Cl:16][C:12]1[CH:11]=[C:10]2[C:15]([C:6](=[O:34])[C:7]([CH3:32])([CH3:31])[C:8](=[O:30])[N:9]2[CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[N:14][CH:13]=1
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)N1CCC(N2C(=O)C(C)(C)C(Br)c3ncc(Cl)cc32)CC1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)C(C)(C)C(=O)c3ncc(Cl)cc32)CC1
Temperature: 100 °C
Reaction time: 6 h
Yield: 83.5 %

Procedure:
To a dimethylsulfoxide solution (8 ml) of tert-butyl 4-(4-bromo-7-chloro-3,3-dimethyl-2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)piperidine-1-carboxylate (375 mg) was added sodium hydrogen carbonate (871 mg), followed by stirring at 100° C. for 6 hours. Water was added to the reaction solution, and extracted with ethyl acetate. The collected organic layer was washed sequentially with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After the resulting residue was dissolved in dichloromethane (14 ml), manganese dioxide (684 mg) was added and stirred for 50 minutes, and further manganese dioxide (690 mg) was added and stirred for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford tert-butyl 4-(7-chloro-3,3-dimethyl-2,4-dioxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)piperidine-1-carboxylate (270 mg).
Reaction SMILES: C([O:3][P:4]([C:9]([C:36]#[N:37])([CH3:35])[CH2:10][C:11]([CH3:34])=[CH:12][CH2:13][C:14]1[C:15]([O:27]CC[Si](C)(C)C)=[C:16]2[C:20](=[C:21]([CH3:25])[C:22]=1[O:23][CH3:24])[CH2:19][O:18][C:17]2=[O:26])(=[O:8])[O:5]CC)C.C[Si](Br)(C)C.N1C(C)=CC=CC=1C>CN(C=O)C.C(Cl)Cl>[C:36]([C:9]([P:4](=[O:3])([OH:5])[OH:8])([CH3:35])[CH2:10][C:11]([CH3:34])=[CH:12][CH2:13][C:14]1[C:15]([OH:27])=[C:16]2[C:20](=[C:21]([CH3:25])[C:22]=1[O:23][CH3:24])[CH2:19][O:18][C:17]2=[O:26])#[N:37]
Reactant: CCOP(=O)(OCC)C(C)(C#N)CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Product: COc1c(C)c2c(c(O)c1CC=C(C)CC(C)(C#N)P(=O)(O)O)C(=O)OC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.5 %

Procedure:
To a solution of {1-cyano-5-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-1,3-dimethyl-pent-3-enyl}-phosphonic acid diethyl ester (18 mg, 0.04 mmol) in DMF (0.5 mL) and DCM (0.5 mL) was added TMSBr (51 μL, 0.4 mmol) and 2,6-lutidine (46 μL, 0.4 mmol). The reaction solution was allowed stir at room temperature overnight before quenching with MeOH. The reaction mixture was dried under reduced pressure and the residue was purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 4.5 mg (33%) of the desired product. 1H NMR (300 MHz, CD3OD) δ 1.37 (d, 3H), 1.87 (s, 3H), 2.13 (s, 3H), 2.26 (m, 1H), 2.64 (m, 1H), 3.39 (m, 2H), 3.75 (s, 3H), 5.18 (s, 2H), 5.34 (m, 1H) ppm; 31P (121.4 MHz, CD3OD) δ 21.47 ppm; MS (m/z) 422 [M−H]−, 424 [M+H]+.
Reaction SMILES: [CH2:1]([N:4]1[C:8]([CH2:9][CH2:10][CH3:11])=[CH:7][CH:6]=[C:5]1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]([NH2:22])=[O:21])[CH:14]=1)[CH2:2][CH3:3]>C(O)(=O)C>[CH2:1]([N:4]1[C@H:8]([CH2:9][CH2:10][CH3:11])[CH2:7][CH2:6][C@@H:5]1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]([NH2:22])=[O:21])[CH:14]=1)[CH2:2][CH3:3].[CH2:1]([N:4]1[C@@H:8]([CH2:9][CH2:10][CH3:11])[CH2:7][CH2:6][C@@H:5]1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]([NH2:22])=[O:21])[CH:14]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(Cc2cccc(NC(N)=O)c2)n1CCC
Solvent: CC(=O)O
Product: CCC[C@@H]1CC[C@H](Cc2cccc(NC(N)=O)c2)N1CCC
Product: CCC[C@H]1CC[C@H](Cc2cccc(NC(N)=O)c2)N1CCC
Reaction time: 2 h
Yield: 5 %
Yield: 39 %

Procedure:
A solution of 4.6 g (15 mmol) of 1,5-dipropyl-2-(3'-ureidobenzyl)pyrrole in 150 ml of glacial acetic acid was hydrogenated at 45 p.s.i. in the presence of 3.5 g of 5% rodium on activated alumina as catalyst, during 2 hours. The catalyst was then separated by filtration and the filtrate evaporated in vacuo. The residue was suspended in 100 ml of methylene chloride and 20 ml of ammonium hydroxide were added (to adjust pH to alkaline). Anhydrous sodium sulfate was added and the solvent evaporated under reduced pressure. The residue was purified by t.l.c. using an (80:20) mixture of chloroform [chloroform-methanol-ammonium hydroxide (60:10:1)] as the eluant, thus obtaining 1.83 g (39%) of the less polar cis-1,5-dipropyl-2-(3'-ureidobenzyl)pyrrolidine isomer (as an oil), and 214 mg (5%) of the more polar trans-1,5-dipropyl-2-(3'-ureidobenzyl)pyrrolidine isomer, which was recrystallized from ether-hexane.
Reaction SMILES: [O:1]=[C:2]([C@@H:23]([C:25]1[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=1)[CH3:24])/[CH:3]=[CH:4]/[C@H:5]1[C@H:12]([O:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][C@H:10]2[C@@H:6]1[CH2:7][C:8](=[O:22])[O:9]2.B(Cl)([C@H]1[C@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1)[C@H]1[C@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1.CC(C)=O.C(=O)([O-])O.[Na+]>C1COCC1>[OH:1][C@@H:2]([C@@H:23]([C:25]1[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=1)[CH3:24])/[CH:3]=[CH:4]/[C@H:5]1[C@H:12]([O:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][C@H:10]2[C@@H:6]1[CH2:7][C:8](=[O:22])[O:9]2
Reactant: Cc1cccc([C@@H](C)C(=O)/C=C/[C@@H]2[C@H]3CC(=O)O[C@H]3C[C@H]2OC(=O)c2ccccc2)c1
Agent: C[C@@H]1[C@H]2C[C@@H](C[C@H]1B(Cl)[C@@H]1C[C@@H]3C[C@H]([C@H]1C)C3(C)C)C2(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: Cc1cccc([C@@H](C)[C@H](O)/C=C/[C@@H]2[C@H]3CC(=O)O[C@H]3C[C@H]2OC(=O)c2ccccc2)c1
Yield: 440 %

Procedure:
A solution of enone{(1S,5R,6R,7R)-6-[(1E,4R)-3-oxo-4-(m-tolyl)-1-pentenyl]-7-benzoyloxy-2-oxabicyclo[3.3.0]octan-3-one} (147.0 g) synthesized in Example 3 in THF (1480 mL) was cooled to −40° C., (−)-B-chlorodiisopinocampheylborane (1.7 M hexane solution) (721 mL) was added, and the mixture was stirred under ice-cooling for 20 hr. Acetone (183 mL) was added and the mixture was stirred for 3 hr. Aqueous sodium hydrogen carbonate was added, and the mixture was extracted with t-butyl methyl ether. The extract was dried over magnesium sulfate, and concentrated under reduced pressure to give a crude title compound (649.9 g).
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[C:8]2[CH:14]=[CH:13][O:12][C:9]2=[CH:10][N:11]=1)=[O:5])C.[O-]CC.[Na+].[C:19]([O:22][CH2:23][CH3:24])(=[O:21])[CH3:20].C(O)(=O)C>C1(C)C=CC=CC=1.O>[O:5]=[C:4]([C:6]1[CH:7]=[C:8]2[CH:14]=[CH:13][O:12][C:9]2=[CH:10][N:11]=1)[CH2:20][C:19]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)c1cc2ccoc2cn1
Reactant: CCOC(C)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)CC(=O)c1cc2ccoc2cn1
Temperature: 80 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
5-Ethoxycarbonylfuro[2,3-c]pyridine(956 mg, 5.0 mmol) was dissolved in 10 mL of toluene, 510 mg (7.5 mmol) of sodium ethoxide was added at room temperature to the solution, and 661 mg (7.5 mmol) of ethyl acetate was then added dropwise at room temperature with stirring. After all the ethyl acetate had been added, the reaction mixture was heated to 80° C., and a reaction was carried out for 4 hours. The reaction solution was then cooled to 5° C. and was neutralized with 450 mg (7.5 mmol) of acetic acid as the temperature was held 5-10° C., the solution was stirred for 30 minutes as the temperature was maintained, 1 mL water was then added, and the solution was returned to room temperature. The organic layer was separated, the aqueous layer was extracted twice with 5 mL of methylene chloride, and the combined organic layer was dried with anhydrous magnesium sulfate and then concentrated in a rotary evaporator, and the resulting solids were recrystallized from a mixed solvent of toluene-hexane, giving 840 mg (72% yield) of ethyl β-oxo-5-furo[2,3-c]pyridinepropionate in a purity of 99% by HPLC.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([O:15][CH3:16])[CH:14]=1)[CH2:10]O.N1C=CC=CC=1>CCOCC>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([O:15][CH3:16])[CH:14]=1)[CH2:10][Cl:3]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(CO)cc(OC)c1
Solvent: CCOCC
Solvent: c1ccncc1
Product: COc1cc(CCl)cc(OC)c1
Reaction time: 3 h
Yield: 86.5 %

Procedure:
Over a period of 20 minutes a solution of 150 g (1.26 moles) of thionyl chloride in 0.65 l of ether was added to 100 g (0.59 moles) of 3,5-dimethoxybenzyl alcohol and 6.6 ml of pyridine in 1.35 l of ether. After stirring for 3 hr the solution containing the product was separated from the residual dark oil, concentrated, and the crude product was redissolved in 1 l of ether, washed with water (3×250 ml), dried (brine, magnesium sulfate), filtered, and reconcentrated to give a dark oil which was vacuum distilled: b.p. 115°-118° C. at 0.4 mm Hg. Upon standing, fractions containing the desired compound solidified to give 95.3 g (86%) of white solid, m.p. 43°-45° C.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1.O>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.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>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:2]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2cccnc2)C1
Yield: 96.2 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.605 mmol), a solution of 3-pyridineboronic acid (112 mg, 0.912 mmol) in ethanol (0.7 ml), 2N aqueous sodium carbonate solution (2.5 ml), and tetrakis(triphenylphosphine)palladium(0) (84.0 mg, 0.0730 mmol) in toluene (5 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (190 mg, 96.4%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][N:3]=1.[CH3:10][CH:11]([NH2:13])[CH3:12]>>[CH3:10][CH:11]([N:13]=[CH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[N:7]=1)[CH3:12]
Reactant: CC(C)N
Reactant: Nc1nccc(C=O)n1
Product: CC(C)N=Cc1ccnc(N)n1

Procedure:
2-Aminopyrimidine-4-carboxaldehyde and 2-propyl amine were reacted by the procedure of example 1(c) to afford the title compound as a yellow oil.
Reaction SMILES: C(N[C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][N:6]=1)(=O)C.Cl[C:16]([F:21])([F:20])C([O-])=O.[Na+].C1OCCOCCOCCOCCOCC[O:25]C1.OS([O-])(=O)=O.[K+]>CC#N>[F:20][CH:16]([F:21])[N:6]1[C:5](=[O:25])[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7]1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: COC(=O)c1ccc(NC(C)=O)nc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1ccc(=O)n(C(F)F)c1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
A mixture of methyl 6-acetamidonicotinate (1.93 g, 9.94 mmol), sodium chlorodifluoroacetate (1.818 g, 11.93 mmol, Alfa Aesar Avocado Lancaster) and 18-crown-6 (0.525 g, 1.988 mmol, Aldrich) in MeCN (40 mL) was heated to 90° C. (reflux) under nitrogen. After 5 h, a solution of KHSO4 (1% in H2O, 10 mL) was added and the mixture was refluxed for 21 h. The mixture was then cooled to room temperature and concentrated. The mixture was diluted with EtOAc (250 mL), washed with 10% aqueous hydrochloric acid (100 mL), and then with saturated aqueous NaHCO3 (100 mL), and finally with brine (100 mL). The mixture was dried (MgSO4) and concentrated in vacuo. The residue was dissolved in DCM (5 mL), and the solution was purified by silica gel flash column chromatography (5-30% EtOAc/hexane) to afford the title compound as a white solid. MS (ESI, positive ion) m/z: 204 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][C:3]=1[N:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.CC(C)=O.C(=O)=O.B(Br)(Br)Br>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1
Reactant: COc1ccc(C)c(-n2cccc2)c1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: Cc1ccc(O)cc1-n1cccc1

Procedure:
A solution of 86.6 g (0.46 mole) of 4-methyl-3-(pyrrol-1-yl)-anisole in 1.5 liters of absolute methylene chloride is cooled to -78° with acetone/dry ice. At this temperature, 231.7 g (0.92 mole) of boron tribromide are added dropwise. Subsequently, the cooling bath is removed and the reaction mixture is heated to from 0° to 5°, then poured into 2 liters of ice/water, and the methylene chloride phase is removed and washed with saturated sodium chloride solution. The aqueous phases are then extracted a further twice with methylene chloride. The organic phases are combined, dried over sodium sulphate and concentrated in a vacuum rotary evaporator. Distillation of the residue in a high vacuum yields 4-methyl-3-(pyrrol-1-yl)-phenol, b.p. 105°-107°/0.03 torr, Rf (toluene/ethyl acetate=10:1): 0.38.
Reaction SMILES: [OH-].[Li+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:13][CH2:14][N:15]([CH3:38])[C:16](=[O:37])[CH2:17][CH2:18][C:19]2[CH:36]=[CH:35][C:22]([O:23][CH2:24][C:25]3[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=3[C:27]([O:29]C)=[O:28])=[CH:21][CH:20]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]>O.C1COCC1>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:13][CH2:14][N:15]([CH3:38])[C:16](=[O:37])[CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:23][CH2:24][C:25]3[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=3[C:27]([OH:29])=[O:28])=[CH:35][CH:36]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COC(=O)c1ccccc1COc1ccc(CCC(=O)N(C)CCc2ccc(OC)c(OC)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CCN(C)C(=O)CCc2ccc(OCc3ccccc3C(=O)O)cc2)cc1OC
Yield: 87.5 %

Procedure:
Lithium hydroxide (12 mg, 0.488 mmol) in water (1 ml) was added to methyl 2-[(4-{3-[[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino]-3-oxopropyl}phenoxy)methyl]benzoate (120 mg, 0.244 mmol) dissolved in THF (2 ml). The mixture was then irradiated in a microwave oven (Smith Synthesizer) at 150° C. for 7 minutes and then evaporated to remove THF. The residue was acidified with 1% hydrochloric acid, pH˜4, and extracted with ethyl acetate (×2). The organic extracts were combined and washed with brine and dried with magnesium sulphate and then evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 2 g/6 ml) using DCM, then MeOH/DCM (1:99) as eluant gave 102 mg the desired product, yield 87.5%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:21])=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13].[N:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:21][C:35]2[CH:36]=[CH:37][N:32]=[CH:33][CH:34]=2)=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)=[O:13]
Reactant: OB(O)c1ccncc1
Reactant: COc1c(C)c(Cc2ccc(O)c(C(=O)N3CCCCC3)c2)c(OC)c(OC)c1OC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(C)c(Cc2ccc(Oc3ccncc3)c(C(=O)N3CCCCC3)c2)c(OC)c(OC)c1OC
Yield: 31.1 %

Procedure:
N-[5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-hydroxybenzoyl]piperidine (0.150 g, 0.350 mmol) was dissolved in methylene chloride (3.5 ml) and after adding thereto in sequence copper acetate (0.064 g, 0.350 mmol), 4-pyridylboronic acid (0.086 g, 0.700 mmol), Molecular Sieves 4A (0.150 g), triethylamine (0.088 g, 0.874 mmol) and pyridine (0.069 g, 0.874 mmol), the solution was stirred at room temperature for 12 hours. The reaction solution was filtered and the filtrate was poured into water and then extracted with methylene chloride. The extract was washed with saturated brine, then dried and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=9:1) to obtain the titled compound (0.055 g, 0.109 mmol, 31%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:16])[CH2:11][CH2:10]2)[CH:4]=1)#[N:2].[N+:23]([CH2:26][CH3:27])([O-])=[O:24].C1(N=C=O)C=CC=CC=1>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH3:27][C:26]1[N:2]=[C:1]([C:3]2[CH:8]=[CH:7][N:6]=[C:5]([N:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:16])[CH2:13][CH2:14]3)[CH:4]=2)[O:24][N:23]=1
Reactant: CC[N+](=O)[O-]
Reactant: CC(C)(C)COC(=O)N1CCN(c2cc(C#N)ccn2)CC1
Solvent: Cc1ccccc1
Solvent: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1noc(-c2ccnc(N3CCN(C(=O)OCC(C)(C)C)CC3)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.9 %

Procedure:
2,2-Dimethylpropyl 4-(4-cyanopyridin-2-yl)piperazine-1-carboxylate (301 mg) obtained in Example 2 was dissolved in toluene (5 mL), and nitroethane (82.6 mg), triethylamine (one drop) and phenyl isocyanate (0.238 mL) were added thereto, stirred at room temperature for 1 hour, and then heated under reflux for 2 hours. The reaction liquid was filtered, the filtrate was evaporated, and the resulting residue was isolated and purified through thin-layer silica gel chromatography (hexane/ethyl acetate=1/1) to obtain 114 mg of the entitled compound as a yellow solid.
Reaction SMILES: C1N=CN([C:6]([N:8]2[CH:12]=N[CH:10]=[CH:9]2)=[O:7])C=1.[O:13]1[CH2:18][CH2:17][CH:16](C(O)=O)[CH2:15][CH2:14]1.[Cl:22][C:23]1[C:35]([CH2:36][N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:34][CH:33]=[CH:32][C:24]=1[O:25][C@H:26]1[CH2:29][C@H](CN)[CH2:27]1>C1COCC1>[ClH:22].[Cl:22][C:23]1[C:35]([CH2:36][N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:34][CH:33]=[CH:32][C:24]=1[O:25][C@H:26]1[CH2:29][C@H:10]([CH2:9][N:8]([CH3:12])[C:6]([CH:16]2[CH2:15][CH2:14][O:13][CH2:18][CH2:17]2)=[O:7])[CH2:27]1
Reactant: O=C(O)C1CCOCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NC[C@H]1C[C@H](Oc2cccc(CN3CCCC3)c2Cl)C1
Solvent: C1CCOC1
Product: CN(C[C@H]1C[C@H](Oc2cccc(CN3CCCC3)c2Cl)C1)C(=O)C1CCOCC1
Product: Cl

Procedure:
CDI (110 mg, 0.70 mmol) was added to a solution of tetrahydropyran-4-yl-carboxylic acid CAS 5337-03-1 (132 mg, 1.0 mmol) in THF (2 ml) at RT under stirring, the mixture was stirred at RT for 1 h. Example 386, ({trans-3-[2-Chloro-3-(pyrrolidin-1-ylmethyl)phenoxy]cyclobutyl}methyl) amine (200 mg, 0.7 mmol) was added to the mixture and the solution was stirred at RT for 20 h and evaporated. The residue was purified by chromatography (silica gel, 63-100 μm, 5 g, hexane/CHCl3 20:80→0:100, then CHCl3/MeOH 100:0→95:5). The residue was dissolved in ether (1 mL). 4N HCl/dioxane (0.20 mL) was added, and the reaction mixture was evaporated to dryness. The obtained crystals were washed with ether and dried in vacuo to give the title compound (162 mg, 53% yield). LC/MS data: 407.1 (M+H) (calculated for C22H31ClN2O3 406.96). 1H NMR-data (DMSO-d6): 10.31 (br. s, 1H, NH+); 7.73-8.12 (m, 1H, NH); 7.30-7.44 (m, 2H, Ar—H); 6.94-7.04 (m, 1H, Ar—H); 4.78-4.95 (m, 1H), 4.42-4.58 (m, 2H); 3.79-3.91 (m, 2H); 3.41-3.49 (m, 2H+ H2O); 3.25-3.34 (m, 2H); 3.09-3.24 (m, 4H); 2.24-2.45 (m, 4H); 1.98-2.19 (m, 4H); 1.83-1.94 (m, 2H); 1.83-1.94 (m, 4H).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[O:26]1[CH2:30]C[C@@H:28](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:27]1>>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH:21]1[CH2:28][CH2:27][O:26][CH2:30]1
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CCOC2)cc1
Product: Cl
Product: Clc1ccc2c(c1SC1CCOC1)CCNCC2

Procedure:
Use a method similar to the Example 332, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and (R)-toluene-4-sulfonic acid tetrahydro-furan-3-yl ester to give, after deprotection using a method similar to the General Procedure 1-4, the title compound as an off-white solid. MS (APCI+) m/z: 284 (M+H); [α]20D +32.5° (c 0.5, CH3OH); ee=95.7% [Chiral HPLC: Column: YMC ODS-AQ 120 Å 4.6×50 mm [S-3μm]; eluent: gradient from 95:5 to 5:95 A/B; solvent A: water, 0.01% HFBA, 1% isopropanol; solvent B: acetonitrile, 0.01% HFBA, 1% isopropanol; flow rate 2 mL/min].