Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[N:15]O)[C:10]2([CH3:14])[CH3:13])=[CH:5][CH:4]=1.C(NCC)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[H][H].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.[Cl-].[Na+].O.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6](=[CH:5][CH:4]=1)[CH2:7][C@H:8]1[NH:15][C@H:9]1[C:10]2([CH3:14])[CH3:13]
Reactant: COc1ccc2c(c1)C(C)(C)C(=NO)CC2
Reactant: [H][H]
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)C(C)(C)[C@@H]1N[C@@H]1C2
Temperature: 0 °C
Yield: 71 %

Procedure:
To a solution of 7-methoxy-1,1-dimethyl-3,4-dihydro-1H-napthalen-2-one oxime (15.3 g, 70 mmol) in THF (240 mL) was added diethylamine (18 mL). The reaction mixture was cooled to 0° C. and a 2.0 M solution of lithium aluminum hydride in THF (100 mL, 200 mmol) was added slowly over 20 min to control the rate of hydrogen evolution. The reaction mixture was heated to 70° C. for 1 h, cooled to 0° C. and Na2SO410H2O (20 g), brine (60 mL), and EtOAc (300 mL) were added. The solid were washed with EtOAc (4×100 mL); the combined organic layers were washed with water (4×100 mL) and brine (100 mL), dried with Na2SO4, and concentrated to give crude title product (14.3 g). The crude product was dissolved in EtOAc (500 mL), extracted with 0.1 N HCl (100 mL), then with 0.3 N HCl (225 mL). Sodium carbonate (8 g, 75 mmol) was added to the aqueous layer which was extracted with EtOAc (4×200 mL). Organic layers were combined, dried with Na2SO4 and concentrated to give the title compound as an oil (10.1 g) which crystallized on standing to a tan solid. (m/z): [M+H]+ calcd for C13H17NO 204.14. found 204.2
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:24])[CH2:9][NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=3)[CH2:12]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].[C:38]([OH:45])(=[O:44])/[CH:39]=[CH:40]\[C:41]([OH:43])=[O:42]>C(C(C)=O)C>[C:38]([OH:45])(=[O:44])/[CH:39]=[CH:40]\[C:41]([OH:43])=[O:42].[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:24])[CH2:9][NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]3[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=3)[O:23][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1cccc([C@@H]2CCC[C@@H](NC[C@H](O)c3cccc(Cl)c3)C2)c1
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1cccc([C@@H]2CCC[C@@H](NC[C@H](O)c3cccc(Cl)c3)C2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A methyl ethyl ketone mixture liquid of 1 equivalent of (1R)-1-(3-chlorophenyl)-2-[(1R,3R)-3-(3-hydroxyphenyl)cyclohexylamino]ethanol 1/3 toluene-solvate and from 3.0 equivalents of potassium carbonate was heated under reflux for 2 hours. With heating, a methyl ethyl ketone solution of 1.2 equivalents of ethyl bromoacetate was dropwise added to the mixture liquid, and further heated under reflux for 3 hours. A part of the reaction liquid was sampled, and subjected to HPLC analysis. After cooled, this was filtered through Celite, and a methyl ethyl ketone solution of 1.0 equivalent of maleic acid was put into the obtained solution, and stirred at room temperature for 30 minutes, and then, with cooling with ice, for 30 minutes. The precipitated crystal was taken out through filtration, then washed with methyl ethyl ketone, and dried through aeration to obtain ethyl 3-[(1R,3R)-3-[(2R)-2-(3-chlorophenyl)-2-hydroxyethylamino]cyclohexyl]phenoxyacetate maleate. The obtained crystal was subjected to HPLC analysis, in which the content of (1R)-1-(3-chlorophenyl)-2-[(1R,3R)-3-(3-hydroxyphenyl)cyclohexylamino]ethanol (starting compound) and the content of ethyl 3-[(1R,3R)-3-[(2R)-2-(3-chlorophenyl)-2-hydroxyethylamino]cyclohexyl]phenoxyacetate (target product) in the crystal were determined according to the above-mentioned relative area percentage method.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:11]1([Mg]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:6])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Br)c1F
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1cccc(Br)c1F
Temperature: -78 °C

Procedure:
To a solution of 3-bromo-2-fluorobenzaldehyde (0.150 g, 0.739 mmol) in THF (3.21 mL) cooled to −78° C. was added phenylmagnesium bromide (0.887 mL, 0.887 mmol). The reaction mixture was maintained at −78° C. for at least 1 hr and then allowed to warm to room temperature slowly over 3 hr. The reaction was quenched with a saturated aqueous solution of NH4Cl. The reaction mixture was diluted with CH2Cl2 and the layers were separated. The aqueous phase was extracted twice with CH2Cl2. The organic layers were combined, dried over Na2SO4, filtered, and concentrated to afford the title compound as a colorless residue.
Reaction SMILES: [Li].[CH2:2]([O:4][C:5]1[CH:10]=[C:9]([C:11](OCC)=[O:12])[CH:8]=[C:7]([O:16][CH2:17][CH3:18])[C:6]=1[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[CH3:3]>C1COCC1>[CH2:2]([O:4][C:5]1[CH:10]=[C:9]([CH2:11][OH:12])[CH:8]=[C:7]([O:16][CH2:17][CH3:18])[C:6]=1[C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[CH3:3]
Reactant: CCOC(=O)c1cc(OCC)c(-c2ccc(F)cc2)c(OCC)c1
Agent: [Li]
Solvent: C1CCOC1
Product: CCOc1cc(CO)cc(OCC)c1-c1ccc(F)cc1
Reaction time: 2 h

Procedure:
A solution of lithium aluminumhydride (34 ml, 34 mmol) in THF was added dropwise over 30 min to a stirred solution of Compound 2 (14 g, 42 mmol) in THF (120 mL) at room temperature. After 2 h, TLC showed no starting material left. The reaction mixture was stored in the fridge overnight and was quenched by the sequential addition of water (4 mL), aq NaOH (0.5 M, 4 mL) and water (4 mL). The mixture was filtered through CELITE (diatomaceous earth), washed thoroughly with EtOAc and the filtrate was concentrated to give Compound 3 as white solid. H NMR (500 MHz, CDCl3, ppm): 1.3 (t, 6H), 1.8 (t, 1H), 4.0 (q, 4H), 4.7 (d, 2H), 6.7 (s, 2H), 7.1 (m, 2H), 7.4 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]3=[O:24])[CH2:8][CH2:7]2)[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][N:3]1[CH2:31][C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38]C)=[O:37])=[CH:34][CH:33]=1.O.[OH-].[Li+]>CO.O>[O:1]=[C:2]1[C:6]2([CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]3=[O:24])[CH2:10][CH2:11]2)[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][N:3]1[CH2:31][C:32]1[CH:33]=[CH:34][C:35]([C:36]([OH:38])=[O:37])=[CH:40][CH:41]=1
Reactant: COC(=O)c1ccc(CN2CN(c3ccccc3)C3(CCN(CCCn4c(=O)[nH]c5ccccc54)CC3)C2=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(CN2CN(c3ccccc3)C3(CCN(CCCn4c(=O)[nH]c5ccccc54)CC3)C2=O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 4-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.4 g, 0.72 mmol) in methanol (6 mL) was added lithium hydroxide monohydrate (0.061 g, 1.44 mmol) in water (2 mL). After stirring at room temperature for 18 h, the reaction mixture was concentrated in vacuo and isolated by reverse phase HPLC to obtain the title compound as an acetate salt (0.05 g, 13%); 1H NMR (DMSO-d6): δ 1.60 (d, 2H, J=6.8 Hz), 1.82 (t, 2H, J=6.8 Hz), 2.35 (t, 2H, J=6.8 Hz), 2.50-2.71 (m, 7H), 3.85 (t, 2H, J=6.8 Hz), 4.55-4.56 (m, 4H), 6.75 (t, 1H, J=7.2 Hz), 6.84 (d, 2H, J=8.4 Hz), 6.96 (d, 3H, J=2.4 Hz), 7.17-7.26 (m, 5H), 7.85 (d, 2H, J=8 Hz); MS for C31H33N5O4 m/z 540.05 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=[C:19]([F:21])[F:20])[N:13]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[H][H]>CCOC(C)=O.[Pd]>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH:19]([F:21])[F:20])[N:13]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: [H][H]
Reactant: COC(=O)c1cc(-c2cccc(C=C(F)F)n2)ccc1Cl
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2cccc(CC(F)F)n2)ccc1Cl

Procedure:
To a solution of methyl 2-chloro-5-(6-(2,2-difluorovinyl)pyridin-2-yl)benzoate (Preparation 33, 105 mg, 0.34 mmol) in EtOAc (1 mL) was added 10% palladium on alumina (36 mg, 0.03 mmol) and stirred at room temperature under 15 psi of hydrogen for 2 hours. The reaction was filtered and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-20% EtOAc in heptanes to afford the title compound.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[NH:12][NH2:13].N1C=CC=CC=1>ClCCl>[NH:12]([C:11]([O:15][CH2:16][CH3:17])=[O:14])[NH:13][C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCOC(=O)NN
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)NNC(=O)Oc1ccccc1
Yield: 90.4 %

Procedure:
Phenyl chloroformate (32.34 g, 0.207M) in dichloromethane (100 ml) was reacted with ethyl carbazate (20.8 g, 0.2M) in dichloromethane (150 ml) and pyridine (16.63 g, 0.21M) to give ethyl phenyl hydrazine-1,2-dicarboxylate (40.5 g). After chromatography on silica gel using dichloromethane and ethyl acetate, recrystallization from toluene gave colourless solid m.p. 89.5-90.5. (Found C 53.8%, H 5.5%, N 12.7%; C10H12N2O4 requires C 53.6%, H 5.4%, N 12.5%). The infra-red spectrum (0.5% in dichloromethane) showed bands at 3360 cm-1 (NH), 1775 and 1745 cm-1 (>C=O), and 1600 cm-1 (aromatic ring). Oxidation of the diester (5 g) in dichloromethane (25 ml) with t-butyl hypochlorite and evaporation of the solvent gave a red oil which was extracted with petroleum spirit (b.p. 30°-40° C.) to isolate ethyl phenyl azodicarboxylate (4 g). (Found C 53.9%, H 4.6%, N 12.4%, C10H10N2O4 requires C 54.1%, H 4.5%, N 12.6%). The infra-red spectrum (0.4% in dichloromethane) showed bands at 1792 with a shoulder at circa 1780 cm-1 (>C=O) and 1600 cm-1 (aromatic ring) and no >NH band at 3360 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:23]1([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH2:36])[CH:27]=[CH:26][N:25]=[CH:24]1.O>O1CCCC1.C(OCC)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)=[O:8])=[CH:9][CH:10]=1
Reactant: NCCCCCCCCn1ccnc1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCCCCCCCCn1ccnc1)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1.58 g of 6-chloronicotinic acid and 1.62 g of 1,1'-carbonyldiimidazole in 30 ml of tetrahydrofuran was stirred at room temperature for 3 hours. Then 1.95 g of 1H-imidazole-1-octanamine was added and the mixture was stirred at room temperature for 16 hours. The mixture was heated at reflux for 5 hours, 10 ml of water was added and heating was continued for one hour longer. The mixture was concentrated to remove tetrahydrofuran. Then 5 ml of 1N sodium hydroxide and dichloromethane was added. The mixture was shaken and the organic layer was separated, washed twice with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and gave an oil. The oil was treated with diethyl ether to crystallize the desired compound as white crystals, mp 79°-81° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:21]([CH2:23]O)[N:22]=3)[CH2:14][C@H:13]2[O:30][CH3:31])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].CCN(S(F)(F)[F:38])CC>ClCCl.[Cl-].[Na+].O>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:21]([CH2:23][F:38])[N:22]=3)[CH2:14][C@H:13]2[O:30][CH3:31])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)nc1CO
Reactant: CCN(CC)S(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)nc1CF
Reaction time: 0.5 h
Yield: 58.4 %

Procedure:
Ethyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-(hydroxymethyl)-1,3-thiazole-5-carboxylate obtained by the method described in Example (27b) (0.14 g, 0.30 mmol) was dissolved in dichloromethane (5 mL). A solution of DAST (0.05 mL, 0.38 mmol) in dichloromethane (2 mL) was added dropwise at −40° C. The mixture was stirred at that temperature for 30 minutes. Brine was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was washed with brine and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=4/1, 3/1, 1/1) to obtain 83 mg of the title compound as a colorless oily substance (59%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([O:21]C)[N:16]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:5][C:4]=1[CH3:23]>CO>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[NH:16][C:17](=[O:21])[N:18]=[CH:19][CH:20]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:5][C:4]=1[CH3:23]
Reactant: COc1nccc(-c2cccnc2-c2ccc(F)c(C)c2)n1
Agent: Cl
Solvent: CO
Product: Cc1cc(-c2ncccc2-c2ccnc(=O)[nH]2)ccc1F
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 70.3 %

Procedure:
Aqueous HCl (2N, 20 mL) was added to the stirring solution of 4-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-2-methoxypyrimidine (1.3 g) in MeOH (10 mL) and heated at 90° C. for 12 h. The reaction mixture was concentrated by rotary evaporator under reduced pressure and neutralized the resultant pale yellow viscous material with aq. NaHCO3 solution. The slurry thus formed upon neutralization was stirred at room temperature for 20 min. The solid was collected by filtration, washed with water, suction dried. After 6 h, the solid was further dried over P2O5 under high vacuum to provide 6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)pyrimidin-2(1H)-one as a white solid (0.87 g). 1H NMR (300 MHz, DMSO-d6): δ 11.92 (s, 1H), 8.74 (dd, J=4.8, 1.7 Hz, 1H), 7.98 (dd, J=7.8, 1.7 Hz, 1H), 7.80 (app d, J=6.0 Hz, 1H), 7.51 (dd, J=7.8, 4.8 Hz, 1H), 7.43 (dd, J=7.7, 2.1 Hz, 1H), 7.24-7.02 (m, 2H), 5.96 (d, J=6.0 Hz, 1H), 2.22 (app s, 3H). 19F NMR (282 MHz, DMSO-d6) δ −117.63.
Reaction SMILES: [CH3:1][C:2]([CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]2[CH2:10][CH2:11][O:12][C:8]=2[CH:7]=1.ClC1C=CC=C(C(OO)=[O:29])C=1>C(Cl)Cl>[O:29]1[C:18]([CH3:20])([CH3:19])[CH:17]1[CH2:16][CH2:15][C:2]([CH3:1])=[CH:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]2[CH2:10][CH2:11][O:12][C:8]=2[CH:7]=1
Reactant: CC(C)=CCCC(C)=CCOc1ccc2c(c1)OCC2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(=CCOc1ccc2c(c1)OCC2)CCC1OC1(C)C
Reaction time: 2 h

Procedure:
18 g. of 6-[(3,7-dimethyl-2,6-octadienyl)-oxy]-2,3-dihydrobenzofuran are dissolved in 180 ml. of methylene chloride and, with stirring and ice cooling at 0°-5° C., 14.3 g. of 80% m-chloroperbenzoic acid are added portionwise. The mixture is then stirred for a further 2 hours with ice cooling. The mixture is subsequently diluted with 360 ml. of diethyl ether and washed successively with ice-cold 1-N aqueous sodium hydroxide and water. The organic phase is dried over sodium sulfate and evaporated. By chromatography on silica gel with hexane/diethyl ether (7:3 parts by volume) there is obtained pure 6-[(6,7-epoxy-3,7-dimethyl-2-octenyl)-oxy]-2,3-dihydrobenzofuran of boiling point ca. 150° C./0.001 mmHg; nD20 = 1.5346.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[CH2:7]1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:17][O:16][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([CH2:4][OH:3])[CH2:15][CH2:14]2
Reactant: CCOC(=O)C1CCc2cc(OC)ccc2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCC(CO)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
(RS)-6-methoxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid ethyl ester (1.39 g, 5.93 mmol) in THF (20 ml) was added dropwise to a suspension of LiAlH4 (473 mg, 12.46 mmol) at 0-10° C. over 15 min. The reaction was stirred for 1 hr at RT, then quenched by the addition of 4N NaOH (15 ml) and water (20 ml). After stirring vigorously for 15 min the mixture was extracted with EtOAc (25 ml), the aqueous phase was further extracted with EtOAc (2×25 ml), the combined organic extracts were washed with satd. NaCl solution (30 ml), dried (Na2SO4) filtered and evaporated to give the crude product as a clear oil. Chromatographic purification over SiO2 (Merck 230-400 mesh) eluting with EtOAc-nHexane (1:3) produced (RS)-(6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-methanol as a colourless oil (989 mg, 5.14 mmol, 86%), MS m/e=192.1 (M−+).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:20])[C@H:6]([CH2:16][CH:17]([CH3:19])[CH3:18])[NH:7][C:8](=[O:15])[C@H:9]([CH:12]([CH3:14])[CH3:13])[N:10]=[O:11]>CO>[O:11]=[N:10][C@H:9]([C:8]([NH:7][C@H:6]([C:5]([OH:20])=[O:4])[CH2:16][CH:17]([CH3:18])[CH3:19])=[O:15])[CH:12]([CH3:14])[CH3:13]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N=O)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@@H](N=O)C(C)C)C(=O)O
Reaction time: 1 h
Yield: 71.8 %

Procedure:
113.5 ml of a 2N sodium hydroxide solution were added to a solution of 22.1 g of the ketovalylleucine methyl ester obtained in Example 10 in 200 ml of methanol, and the mixture was stirred for 1 hour. The methanol solvent was subsequently removed under reduced pressure, and the resulting aqueous solution was buffered with saturated ammonium chloride solution. After the mixture had been adjusted to pH 2 with 6N hydrochloric acid, it was extracted with dichloromethane. The collected organic phases were dried over sodium sulfate, and after filtration, the solvent was removed under reduced pressure. 15.0 g of the title compound were obtained in the form of an oil. The compound proved to have properties identical to those of the product obtained in Example 8.
Reaction SMILES: [N:1]([Si](C)(C)C)=[N+:2]=[N-:3].[Br:8][C:9]1[CH:10]=[C:11]2[C:22]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])(O)[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([I:30])[CH:20]=3)[O:15][C:12]2=[N:13][CH:14]=1>C1(C)C=CC=CC=1>[N:1]([C:22]1([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:11]2[C:12](=[N:13][CH:14]=[C:9]([Br:8])[CH:10]=2)[O:15][C:16]2[C:21]1=[CH:20][C:19]([I:30])=[CH:18][CH:17]=2)=[N+:2]=[N-:3]
Reactant: CCOC(=O)CC1(O)c2cc(I)ccc2Oc2ncc(Br)cc21
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1(N=[N+]=[N-])c2cc(I)ccc2Oc2ncc(Br)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Azidotrimethylsilane (1.102 ml, 8.32 mmol) was added to a suspension of ethyl 2-(3-bromo-5-hydroxy-7-iodo-5H-chromeno[2,3-b]pyridin-5-yl)acetate (2.33 g, 4.75 mmol) in toluene (31.7 ml). The reaction mixture was cooled to 0° C. and (diethyloxonio) trifluoroborate (0.753 ml, 5.94 mmol) was added slowly. The reaction mixture was allowed to warm to RT. After 30 min, the reaction mixture was quenched with MeOH (5 mL) followed by aqueous, saturated NaHCO3 solution (10 mL). The reaction mixture was extracted twice with EtOAc. The combined organic phases were washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford ethyl 2-(5-azido-3-bromo-7-iodo-5H-chromeno[2,3-b]pyridin-5-yl)acetate as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1
Reactant: C1=COCCC1
Reactant: Brc1cccc2[nH]ncc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: Brc1cccc2c1cnn2C1CCCCO1
Yield: 82 %

Procedure:
A solution of 4-bromo-1H-indazole (1.82 g, 9.24 mmol), 3,4-dihydro-2H-pyran (1.55 g, 18.48 mmol) and toluene-4-sulfonic acid (0.26 g, 1.39 mmol) in anhydrous tetrahydrofuran (40 mL) was heated at 80° C. overnight under nitrogen. The solvent was removed under reduced pressure and the residue was purified on silica gel column (3% ethyl acetate in petroleum ether) to give the title compound (2.13 g, 81% yield) as a yellow solid. MS (ESI): m/z 280.9 [M+1]+.
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][CH2:17][CH2:18][N:19]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>>[C:30]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][O:16][CH2:17][CH2:18][NH2:19])[CH2:12][CH2:13]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C1c2ccccc2C(=O)N1CCOCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: NN
Solvent: O
Product: NCCOCCN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
Batch size: 27 g (55.6 mmol) 2-{2-[2-(4-diphenylmethyl-piperazinyl)-ethoxy]-ethyl}-isoindol-1,3-dione and 5.4 ml (110 mmol) hydrazine-hydrate.
Reaction SMILES: [CH2:1]([NH:10][C@@H:11]([CH3:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([Li])CCC.[C:24]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])(=[O:33])[CH:25]=[CH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:1]([N:10]([C@@H:11]([CH3:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C@@H:26]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:25][C:24]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)C=Cc1ccccc1
Reactant: C[C@H](NCC=Cc1ccccc1)c1ccccc1
Agent: [Li]CCCC
Product: C[C@@H](c1ccccc1)N(CC=Cc1ccccc1)[C@H](CC(=O)OC(C)(C)C)c1ccccc1
Yield: 93.8 %

Procedure:
(S)-N-cinnamyl-α-methylbenzylamine (4) (0.100 g, 0.42 mmol), 1.6M butyllithium (0.242 ml, 0.39 mmol) and t-butyl cinnamate (7) (0.072 g, 0.35 mmol) were reacted according to the procedure of Example 1. Flash chromatography of the product on silica gel [ethyl acetate/petroleum ether (1:49)] afforded the title compound (Rf 0.3) as a colourless oil (0.145 g, 78%). δH (300 MHz; CDCl3) 7.50-7.18 (15H, m, Ph), 6.42 (1H, d, J=16.0, PhCH=CH), 6.11 (1H, dt, J=16.0 and 6.2; CH=CHPh), 4.53 (1H, dd, J=8.7 and 6.4, PhCHCH2), 4.07 (1H, q, J=6.7, PhCHCH3), 3.32 (2H, dd, J=6.2 and 1.1, NCH2), 2.83 (1H, dd, J=14.6 and 6.4, CH2CO2), 2.62 (1H, dd, J=14.6 and 8.7, CH2CO2), 1.31 (9H, s, (CH3)3C), 1.27 (3H, d, J=6.7, PhCHCH3).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[O:6][C:7]2[C:13]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)=[O:4].CC1C=CC(S(O[CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[N:35]=2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:41][O:40][C:36]1[N:35]=[C:34]([CH2:33][CH2:32][N:17]2[CH2:18][CH2:19][N:14]([C:13]3[C:7]4[O:6][C:5]([C:3]([N:2]([CH3:20])[CH3:1])=[O:4])=[CH:9][C:8]=4[CH:10]=[CH:11][CH:12]=3)[CH2:15][CH2:16]2)[CH:39]=[CH:38][CH:37]=1
Reactant: CN(C)C(=O)c1cc2cccc(N3CCNCC3)c2o1
Reactant: COc1cccc(CCOS(=O)(=O)c2ccc(C)cc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cccc(CCN2CCN(c3cccc4cc(C(=O)N(C)C)oc34)CC2)n1
Temperature: 80 °C

Procedure:
A reaction mixture of N,N-dimethyl-7-(piperazin-1-yl)benzofuran-2-carboxamide (0.090 g, 0.33 mmol) (Example 39d), 2-(6-methoxypyridin-2-yl)ethyl 4-methylbenzenesulfonate (0.10 g, 0.33 mmol) and potassium carbonate (0.046 g, 0.33 mmol) in dry acetonitrile (10 mL) was heated at 80° C. for over night. After cooling, the mixture was filtered and the solvent removed in vacuo. The product was purified by preparative HPLC to give the title compound. Yield: 0.048 g (36%).