Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:29]=[CH:28][C:17]4[O:18][CH2:19][C:20]5[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=5[CH:22]([SH:23])[C:16]=4[CH:15]=3)=[N:9]2)=[CH:4][CH:3]=1.Br[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37]>>[C:36]([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][S:23][CH:22]1[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[CH2:19][O:18][C:17]2[CH:28]=[CH:29][C:14]([O:13][CH2:12][C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=3)=[CH:15][C:16]1=2)([OH:38])=[O:37]
Reactant: SC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21
Reactant: CCOC(=O)CCCCCBr
Product: O=C(O)CCCCCSC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21

Procedure:
2-(7-Chloroquinolin-2-yl)methoxy-11-mercapto-6,11-dihydrodibenz[b,e]oxepine and ethyl 6-bromohexanoate were used and reacted in the same manner as in Example 24 to obtain the title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([OH:22])[CH2:11][C:12]1([S:15]([O:18][CH:19]([CH3:21])[CH3:20])(=[O:17])=[O:16])[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23](Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O.CC(OC)(C)C>CN(C=O)C.[Na+].[I-]>[CH2:23]([O:22][C@@H:10]([CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:11][C:12]1([S:15]([O:18][CH:19]([CH3:20])[CH3:21])(=[O:16])=[O:17])[CH2:13][CH2:14]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)OS(=O)(=O)C1(C[C@@H](O)COCc2ccccc2)CC1
Reactant: ClCc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: COC(C)(C)C
Product: CC(C)OS(=O)(=O)C1(C[C@H](COCc2ccccc2)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 91.1 %

Procedure:
Under a Nitrogen atmosphere was mixed NAH (91.5 g) in DMF (2 L) and (R)-isopropyl 1-(3-(benzyloxy)-2-hydroxypropyl)cyclopropane-1-sulfonate (715 g) in DMF (1 L) at a temperature between −5° C. and 5° C. for 140 minutes. After stirring for a further 5 minutes, NaI (5.1 g) was added. After BnCl (289.5 g) in DMF (300 mL) was added gradually, the reaction mixture was warmed slowly to room temperature and stirred for approximately 16 hours until HPLC analysis showed the reaction was complete. The reaction mixture was cooled to −5° C. and water (4 L) was added followed by MTBE (2 L (×2)) with stirring for 20 minutes. The organic layer was separated, washed with water (2 L (×2)), brine (2 L), dried over Na2SO4 and concentrated to give 830 g of product.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=2)=[CH:7][C:6]=1[C:22]1[CH:31]=[CH:30][C:29]2[C:28]([CH3:33])([CH3:32])[CH2:27][CH2:26][C:25]([CH3:35])([CH3:34])[C:24]=2[CH:23]=1.[CH:36]1([NH2:39])[CH2:38][CH2:37]1>C(O)C>[CH:36]1([NH:39][CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=3)=[CH:7][C:6]=2[C:22]2[CH:31]=[CH:30][C:29]3[C:28]([CH3:33])([CH3:32])[CH2:27][CH2:26][C:25]([CH3:35])([CH3:34])[C:24]=3[CH:23]=2)[CH2:38][CH2:37]1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCBr)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Reactant: NC1CC1
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2ccc(OCCNC3CC3)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Yield: 61.2 %

Procedure:
In a manner similar to that of Example 1c, by reaction of 600 mg (1.15 mmol) of ethyl 4′-(2-bromoethoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate with 800 μl (11.5 mmol) of cyclopropylamine in 100 ml of ethanol. 360 mg of ethyl 4′-(2-cyclopropylaminoethoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate are obtained in the form of a white solid (m.p.=141° C., yield=63%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([S:12](Cl)(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH4+:16].[OH-]>C(Cl)Cl>[NH2:16][S:12]([C:8]1[CH:9]=[C:10]([Cl:11])[C:2]([Cl:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])(=[O:14])=[O:13]
Reactant: [NH4+]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)cc(Cl)c1Cl
Agent: [OH-]
Solvent: ClCCl
Product: NS(=O)(=O)c1cc(Cl)c(Cl)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a 20 ml scintillation vial was added 2,3-dichloro-5-(chlorosulfonyl)benzoic acid (170 mg, 0.587 mmol). To this was added 1.5 ml of DCM and 7 ml of 7M NH4OH. The reaction mixture was stirred vigorously at room temperature overnight. After consumption of the starting material, the reaction solution was concentrated to half volume with a rotary evaporator and acidified with 6M HCl to ˜pH 4.5. The resulting solution was left at room temperature until the product precipitated. The product was collected by vacuum filtration and air dried, yielding 5-(aminosulfonyl)-2,3-dichlorobenzoic acid (80 mg, 50%) as light yellow solid.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[C:9]2[N:10]=[C:11]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][CH2:31][CH3:32])=[O:29])=[CH:23][CH:22]=3)[N:12]=[C:13]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]3[CH3:20])[C:8]=2[CH2:7][CH2:6][N:5]1[CH:33]([CH3:35])[CH3:34])#[N:2].C(CC1C2N=C(C3C=CC(NC(NCC)=O)=CC=3)N=C(N3CCOC[C@@H]3C)C=2CCN1)#N.CN(C)C=O.C(N(CC)C(C)C)(C)C.C(I)(C)C>>[C:1]([CH2:3][C@@H:4]1[C:9]2[N:10]=[C:11]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][CH2:31][CH3:32])=[O:29])=[CH:23][CH:22]=3)[N:12]=[C:13]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]3[CH3:20])[C:8]=2[CH2:7][CH2:6][N:5]1[CH:33]([CH3:34])[CH3:35])#[N:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(C)C)[C@H]3CC#N)cc1
Agent: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3CC#N)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)I
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(C)C)[C@@H]3CC#N)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
and 1-(4-((S)-8-(cyanomethyl)-7-isopropyl-4-((S)-3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)-3-ethylurea (xu2): 1-(4-(8-(cyanomethyl)-4-((S)-3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)-3-ethylurea (0.0947 g, 0.217 mmol) in dry N,N-Dimethylformamide (1.600 mL, 20.66 mmol) was added N,N-Diisopropylethylamine (0.1200 mL, 0.6888 mmol) followed by Isopropyl iodide (0.0460 mL, 0.460 mmol). The reaction mixture was heated at 50° C. and stirred overnight. The reaction mixture was heated at 80° C. and stirred overnight. The reaction mixture was heated at 90° C. overnight. Added Isopropyl iodide (0.1150 mL, 1.150 mmol) and N,N-Diisopropylethylamine (0.1200 mL, 0.6889 mmol). The reaction mixture was heated at 120° C. and stirred for 4 days. The reaction mixture was concentrated and chromatographed through silica gel (40 g, 0-5% MeOH in dichloromethane), purified by HPLC, and the diastereomers were separated out by SFC. Diastereomer 1 LC/MS-m/z+478.3 (M+H)+; Diastereomer 2 LC/MS-m/z+478.2 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:17])=[C:6]([O:15][CH3:16])[C:7]2[O:11][CH:10]=[CH:9][C:8]=2[C:12]=1[O:13][CH3:14])(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([C:4]1[C:5]([OH:17])=[C:6]([O:15][CH3:16])[C:7]2[O:11][CH2:10][CH2:9][C:8]=2[C:12]=1[O:13][CH3:14])(=[O:3])[CH3:2]
Reactant: COc1c(C(C)=O)c(O)c(OC)c2occc12
Agent: [Pd]
Solvent: CO
Product: COc1c(O)c(C(C)=O)c(OC)c2c1OCC2
Yield: 96.2 %

Procedure:
10 g of 5-acetyl-6-hydroxy-4,7-dimethoxybenzofuran in 100 ml of methanol are hydrogenated using 2 g of Pd/C (10%) at room temperature and under slightly superatmospheric pressure. When the absorption of hydrogen is complete, the mixture is filtered and the solvent is distilled off. 9.7 g of the desired product of melting point 100°-101° C. are obtained.
Reaction SMILES: [N+](=[CH:3][C:4](=[O:8])[CH2:5][CH2:6][CH3:7])=[N-].[CH3:9][C:10]1[C:15]([CH3:16])=[C:14]([CH3:17])[CH:13]=[C:12]([CH3:18])[C:11]=1[S:19]([OH:22])(=[O:21])=[O:20]>CCOCC>[O:8]=[C:4]([CH2:5][CH2:6][CH3:7])[CH2:3][O:22][S:19]([C:11]1[C:12]([CH3:18])=[CH:13][C:14]([CH3:17])=[C:15]([CH3:16])[C:10]=1[CH3:9])(=[O:20])=[O:21]
Reactant: CCCC(=O)C=[N+]=[N-]
Reactant: Cc1cc(C)c(S(=O)(=O)O)c(C)c1C
Solvent: CCOCC
Product: CCCC(=O)COS(=O)(=O)c1c(C)cc(C)c(C)c1C
Yield: 60 %

Procedure:
A 1.0 g quantity of 1-diazo-2-pentanone is reacted with 2.3 g of 2,3,4,6-tetramethyl-benzene-sulfonic acid in 30 ml of ether until nitrogen no longer evolves. The reaction mixture is washed with water, dried and distilled in a vacuum to remove the ether. The residue is recrystallized from ethanol/water, affording 1.6 g of 2-oxopentyl-2,3,4,6-tetramethylbenzene sulfonate (Compound 95), m.p. 49° to 50° C. Yield 60.0%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:22][C:23]([CH3:25])=[CH2:24])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17](N)=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10].C([OH:28])C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:22][C:23]([CH3:25])=[CH2:24])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([OH:28])=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: C=C(C)COc1ccc(Cl)cc1CN(CC)c1ccc(C(N)=O)nn1
Reactant: CCO
Product: C=C(C)COc1ccc(Cl)cc1CN(CC)c1ccc(C(=O)O)nn1

Procedure:
A mixture of 6-[N-(5-Chloro-2-(2-methylprop-2-en-1-yloxy)benzyl)-N-ethylamino]-pyridazine-3-carboxamide (example 18) (10.5 g, 29.3 mol) and caustic liquor, 40% w/v (10 ml, 100 mmol) in ethanol (150 ml) was stirred at reflux for 16 hours. The solvent was evaporated at reduced pressure and the residue partitioned between 2N hydrochloric acid (70 ml) and dichloromethane (200 ml). The organic layer was dried over anhydrous magnesium sulphate, filtered and evaporated to give a brown gum (10.0 g), which was redissolved in ether (200 ml) and allowed to crystallise slowly over 12 hours to give the title compound as a pale yellow solid (4.6 g, 45%) m.p. 130-131° C.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5](Cl)=[C:4]2[CH:9]=[N:10][C:11]([CH3:15])=[C:12]([O:13][CH3:14])[C:3]=12.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[CH3:15][C:11]1[N:10]=[CH:9][C:4]2=[C:5]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:6]=[N:7][C:2]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[C:3]2[C:12]=1[O:13][CH3:14]
Reactant: COc1c(C)ncc2c(Cl)nnc(Cl)c12
Reactant: C1COCCN1
Product: COc1c(C)ncc2c(N3CCOCC3)nnc(N3CCOCC3)c12

Procedure:
0.5 part by weight of 1,4-dichloro-7-methyl-8-methoxypyrido[3,4-d]pyridazine and 3.6 parts by weight of morpholine are heated together at 80°C for 1.5 hour and, then, the excess morpholine is distilled off. To the residue is added water, whereupon an oily precipitate is obtained. This oil is triturated with a small amount of methanol to obtain crystals of 7-methyl-8-methoxy-1,4-dimorpholinopyrido[3,4-d]pyridazine. Recrystallization from a mixture of methanol and water (1:3) yields crystals melting at 145°-146°C. Yield 0.5 part by weight.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].Br[C:22]1[O:26][N:25]=[C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:23]=1[CH3:32].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:22]2[O:26][N:25]=[C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:23]=2[CH3:32])[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:10])[F:11]
Reactant: CC1(C)OB(c2ccc(C(F)(F)F)c(F)c2)OC1(C)C
Reactant: CCOC(=O)c1noc(Br)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1noc(-c2ccc(C(F)(F)F)c(F)c2)c1C
Temperature: 100 °C
Yield: 51.2 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (139 mg, 0.121 mmol) was added to a suspension of 2-(3-fluoro-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (350 mg, 1.21 mmol), ethyl 5-bromo-4-methylisoxazole-3-carboxylate (282 mg, 1.21 mmol) and potassium carbonate (334 mg, 2.413 mmol) in DME and water mix. The reaction mixture was sealed in a microwave vial and heated at 100° C. for 2 hours, after which time, the reaction was allowed to cool. The reaction mixture was then diluted with ethyl acetate and washed with water. The aqueous layer was then extracted with ethyl acetate, the organics combined, washed with brine and dried over magnesium sulfate, filtered and concentrated in vacuo. the resulting residue was purified by silica gel chromatography, eluting with heptane to 40% ethylacetate in heptane, to afford ethyl 5-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methylisoxazole-3-carboxylate (196 mg, 0.62 mmol).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][CH:25]=O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(O)(=O)C.N1CCCCC1.[BH4-].[Na+].Cl>ClCCl.COC(C)(C)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][CH:6]2[C:7](=[O:8])[O:9][C:2]([CH3:10])([CH3:1])[O:3][C:4]2=[O:5])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CCC2C(=O)OC(C)(C)OC2=O)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
To a solution of meldrums acid (1.68 g, 11.66 mmol) and 4-(2-oxo-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (2.21 g, 9.72 mmol) in dichloromethane (40 mL) was added acetic acid (0.055 mL, 0.972 mmol) and piperidine (0.096 mL, 0.972 mmol). The mixture was heated at reflux for 3 h, and then allowed to attain room temperature. After being diluted with tert-butyl methyl ether, the mixture was washed with NaHCO3 (sat.) and brine. The organic phase was dried, filtered and concentrated. The residue was dissolved in a mixture of EtOH (40 mL) and acetic acid (20 mL). The solution was cooled to 0° C., and NaBH4 (0.554 g, 14.6 mmol) was added in portions after which the solution was allowed to stir for 30 min at rt and then acidified to pH 3 with 1 M HCl. The solution was extracted several times with dichloromethane. The combined organic phases were dried, filtered, concentrated and filtered through a pad of silica gel (dichloromethane). The solvent was evaporated to give 4-[2-(2,2-Dimethyl-4,6-dioxo-[1,3]dioxan-5-yl)-ethyl]-piperidine-1-carboxylic acid tert-butyl ester as a colorless oil (2.30 g, 65%) which solidified on standing.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([OH:20])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21]1(I)[CH2:25][CH2:24][CH2:23][CH2:22]1>CN(C=O)C.CCOCC.[Ag-]=O>[CH:21]1([O:18][C:17](=[O:19])[CH:16]([O:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: IC1CCCC1
Reactant: O=C(O)C(O)Cc1ccc(OCc2ccccc2)cc1
Agent: O=[Ag-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(OC1CCCC1)C(Cc1ccc(OCc2ccccc2)cc1)OC1CCCC1
Temperature: 55 °C
Yield: 17 %

Procedure:
A mixture of 3-(4-benzyloxy-phenyl)-2-hydroxy-propionic acid (1.0 g, 3.67 mmol), cyclopentyl iodide (7.2 g, 36.7 mmol) and silver (I) oxide (4.25 g, 18.3 mmol) in DMF (15 mL) was heated at 55° C. under N2 for 72 h. The reaction mixture was cooled, diluted with Et2O and filtered through hyflo. The filtrate was extracted with water and the organic layer was dried (MgSO4) and the solvent removed in vacuo to afford crude product that was purified by flash chromatography using 10:1 hexanes:acetone to afford 0.255 g (17%) 3-(4-benzyloxy-phenyl)-2-cyclopentyloxy-propionic acid cyclopentyl ester. Rf=0.67 (1:1 hexanes:acetone). 1H NMR.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])=[NH:10])[CH:5]=[CH:4][CH:3]=1.[Br-].[CH2:22]([Zn+])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])(=O)C>[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O.C(#N)C>[CH2:22]([C:2]1[N:7]=[C:6]([NH:8][C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])=[NH:10])[CH:5]=[CH:4][CH:3]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: [Zn+]Cc1ccccc1
Reactant: COc1ccccc1CNC(=N)Nc1cccc(Br)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: COc1ccccc1CNC(=N)Nc1cccc(Cc2ccccc2)n1
Reaction time: 8 h
Yield: 7.4 %

Procedure:
The preparation was carried out analogously to Example 67, using 0.200 g (0.597 mmol) N-(6-bromopyridin-2-yl)-N′-(2-methoxybenzyl)guanidine and 2.98 mL (1.491 mmol) of the benzyl zinc bromide solution (0.5 M in tetrahydrofuran) under Pd catalysis with 20 mg (0.055 mmol) [1,1′-bis-(diphenylphosphino)ferrocene]palladium(II) chloride-methylene chloride. The mixture was likewise heated under a nitrogen atmosphere, first under reflux for 9 hr, and then after repeated additions of 2.98 mL (1.491 mmol) of the 0.5 M benzyl zinc bromide solution and 20 mg (0.055 mmol) Pd catalyst the mixture was heated for an additional 8 hr and stirred for an additional 8 hr. After appropriate workup and purification via two preparative HPLC procedures (1× via Waters, XTerra RP-18 and Merck, 1× Chromolith RP-18 100×25 mm, each eluent: water/acetonitrile/0.1 M acetic acid), 18 mg (0.044 mmol, 7%) N-(6-benzylpyridin-2-yl)-N′-(2-methoxybenzyl)guanidine was obtained in the form of the acetate salt (base/acetate in a ratio of 1:1).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:16]([O:18][CH3:19])=[O:17].Cl>O>[CH3:19][O:18][C:16]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][OH:1])[CH2:4][CH2:5]1)=[O:17]
Reactant: COC(=O)Cl
Reactant: OCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)N1CCC(CO)CC1
Temperature: 0 °C
Yield: 94.2 %

Procedure:
4-Hydroxymethylpiperidine (1.0 g, 8.6 mmol) was dissolved in water (15 mL) and cooled to 0° C. To this solution was added dropwise a solution of potassium carbonate (4.8 g, 34.7 mmol) in water (10 mL), followed by methyl chloroformate (2.68 mL, 34.7 mmol). The mixture was stirred vigorously and allowed to warm to room temperature over 2 h. After stirring overnight (16 h), the reaction mixture was acidified with 6M aqueous hydrochloric acid and extracted with dichloromethane (3×60 mL). The extracts were combined, dried over sodium sulfate and filtered. The filtrate was evaporated to yield the title intermediate (1.4 g, 8.1 mmol, 93%) as a colorless oil. (m/z): C8H15NO3 calcd. 173.11. found 156.2 [M−H2O+H]+. 1H NMR (300 MHz, DMSO-d6): δ (ppm) 0.98 (m, 2H), 1.52 (m, 1H), 1.63 (br d, 2H), 2.72 (br m, 2H), 3.23 (d, 2H), 3.56 (s; 3H), 3.95 (br d, 2H), 4.48 (br s, 1H).
Reaction SMILES: C(OC(N1C2C(=CC(C3C=CC=CC=3OC)=CC=2)C(C(O)C)=CC1(C)C)=O)(C)(C)C.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]1[CH:40]=[C:41]2[C:46](=[CH:47][CH:48]=1)[NH:45][C:44]([CH3:50])([CH3:49])[CH:43]=[C:42]2[CH:51]([O:53][CH2:54]/[CH:55]=[CH:56]/[CH2:57]C)[CH3:52].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1.BrCC=CCC>[CH2:54]([O:53][CH:51]([C:42]1[C:41]2[C:46](=[CH:47][CH:48]=[C:39]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[O:32][CH3:31])[CH:40]=2)[NH:45][C:44]([CH3:50])([CH3:49])[CH:43]=1)[CH3:52])/[CH:55]=[CH:56]/[CH3:57]
Reactant: CC/C=C/COC(C)C1=CC(C)(C)Nc2ccc(-c3ccccc3OC)cc21
Agent: CCC=CCBr
Agent: COc1ccccc1-c1ccc2c(c1)C(C(C)O)=CC(C)(C)N2C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Product: C/C=C/COC(C)C1=CC(C)(C)Nc2ccc(-c3ccccc3OC)cc21
Yield: 92.8 %

Procedure:
6-(2-Methoxyphenyl)-2,2-dimethyl-4-{1-[((E)-pent-2-enyl)oxy]ethyl}-1,2-dihydroquinoline 4-(1-Hydroxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylic acid tert-butyl ester (70 mg) was treated with 220 μL of 1 M solution of sodium bis(trimethylsilyl)amide in THF and 26 μL of 1-bromo-2-pentene to give the alkylated product, which was deprotected to yield 30 mg of the title compound as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][C:9]1[N:10]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:11](=[O:29])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([C:25]([NH2:28])=[N:26]O)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:42][O:43][C:44](=[O:47])[CH2:45][CH3:46].O>C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:7][CH2:8][C:9]1[N:10]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:11](=[O:29])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([C:25]1[NH:28][CH:46]=[C:45]([C:44]([O:43][CH3:42])=[O:47])[N:26]=1)=[CH:14][CH:13]=2)=[O:34])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(C(N)=NO)ccc2c1=O
Reactant: CCC(=O)OC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1c[nH]c(-c2ccc3c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c4ccccc4)c3c2)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 41.5 %

Procedure:
To a mixture of tert-butyl{6-[amino(hydroxyimino)-methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl}methylcarbamate (0.47 g, 1.0 mmol) and triethylamine (0.17 mL, 1.2 mmol) in ethyl acetate (10 mL) was added methylpropionate (0.10 g, 1.2 mmol), and the mixture was stirred at room temperature for 17 h. The reaction mixture was poured into water (5 mL), and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue was added p-xylene (10 mL), the mixture was refluxed for 40 h. The reaction mixture was diluted with ethyl acetate (100 mL), and the solution was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1 (v/v)) to give methyl 2-(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)-1H-imidazole-4-carboxylate (0.22 g, 42%) as an orange powder.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:34]([O:38][C:39](=[O:53])[NH:40][C@@H:41]([CH2:51]O)[CH2:42][O:43][C:44]1[CH:45]=[N:46][CH:47]=[C:48]([Br:50])[CH:49]=1)([CH3:37])([CH3:36])[CH3:35]>C1COCC1.CC#N.C1COCC1>[C:34]([O:38][C:39]([N:40]1[CH2:51][C@H:41]1[CH2:42][O:43][C:44]1[CH:45]=[N:46][CH:47]=[C:48]([Br:50])[CH:49]=1)=[O:53])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)COc1cncc(Br)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H]1COc1cncc(Br)c1
Temperature: 4 °C
Reaction time: 0.25 h
Yield: 105.5 %

Procedure:
Ph3P (1.13 g, 4.32 mmol) was dissolved in 9:1 THF/CH3CN (30 mL) and cooled to 4° C. with an ice/water bath. DIAD (850 μL, 4.32 mmol) was added slowly. After stirring 15 min, a solution of Example 273B (1.0 g, 2.88 mmol) in THF (4 mL) was added slowly. The solution was allowed to warm to rt and stirred for over night. The solution was concentrated and the residual oil was purified by flash chromatography (20-40% EtOAc in hexane) to give the desired product (1.0 g, 75%). MS (DCI) m/z 329, 331 (M+1)+.
Reaction SMILES: [Cl:1][CH:2]=[C:3]([O:9]C1C=CC=CC=1)[C:4]([CH3:8])([CH3:7])[CH:5]=[CH2:6]>C(O)(=O)C>[Cl:1][CH2:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH:5]=[CH2:6]
Reactant: C=CC(C)(C)C(=CCl)Oc1ccccc1
Solvent: CC(=O)O
Product: C=CC(C)(C)C(=O)CCl
Yield: 81.2 %

Procedure:
22.2 g (0.1 mol) of 1-chloro-3,3-dimethyl-2-phenoxy-1,4-pentadiene are heated under reflux in 100 ml of acetic acid, during the course of 4 hours. The working-up corresponding to Example B1(a) yields 11.9 g of 1-chloro-3,3-dimethyl-pent-4-en-2-one, which are 81% of theory.