Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[N:6]#[O+].[CH:8]([C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1)=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCOCC>C(#N)C>[F:1][B-:2]([F:5])([F:4])[F:3].[CH:8]([C:16]1[CH:17]=[CH:18][C:19]([N+:22]#[N:6])=[CH:20][CH:21]=1)=[CH:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1ccc(C=Cc2ccccc2)cc1
Reactant: N#[O+]
Agent: F[B-](F)(F)F
Solvent: CCOCC
Solvent: CC#N
Product: N#[N+]c1ccc(C=Cc2ccccc2)cc1
Temperature: -30 °C
Yield: 324.3 %

Procedure:
To a 25 mL round bottom in a drybox was added nitrosonium tetrafluoroborate (0.11 g, 0.95 mmol). Acetonitrile (2 mL) was added and the flask was cooled down to −30° C. A solution of 4-STYRYLPHENYLAMINE (0.17 g, 0.86 mmol) and BHT (0.19 g, 0.86 mmol) in acetonitrile (5 mL) was added dropwise via syringe. The reaction was allowed to warm to −5° C. over 20 min. Ether (10 mL) was then added and the precipitate was filtered. The title compound was purified by re-precipitating from acetonitrile (3 mL) with ether (15 mL) to yield 0.82 g (34%) of the desired compound.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[CH2:13]([O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:27][CH2:28][C:29]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)([C:34]([O:36][CH3:37])=[O:35])[C:30]([O:32][CH3:33])=[O:31])(=[O:26])=[O:25])=[CH:20][CH:19]=1)[C:14]#[C:15][CH3:16]>ClCCl>[CH2:13]([O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:27][CH2:28][C:29]([N:38]2[CH2:39][CH2:40][N:41]([S:9]([CH3:8])(=[O:11])=[O:10])[CH2:42][CH2:43]2)([C:30]([O:32][CH3:33])=[O:31])[C:34]([O:36][CH3:37])=[O:35])(=[O:26])=[O:25])=[CH:20][CH:19]=1)[C:14]#[C:15][CH3:16]
Reactant: CS(=O)(=O)Cl
Reactant: CC#CCOc1ccc(S(=O)(=O)NCC(C(=O)OC)(C(=O)OC)N2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC#CCOc1ccc(S(=O)(=O)NCC(C(=O)OC)(C(=O)OC)N2CCN(S(C)(=O)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.7 %

Procedure:
0.6 ml (4 mmol) of triethylamine and then 0.3 ml (4 mmol) of methanesulfonyl chloride are added to a solution of 1.6 g (4 mmol) of dimethyl 2-[(4-but-2-ynyloxybenzenesulfonylamino)methyl]-2-piperazin-1-ylmalonate diluted in 30 ml of dichloromethane. The reaction medium is then stirred at ambient temperature for 3 h and then evaporated to dryness. The crude residue is purified by chromatography on silica gel, elution being carried out with a 99/1 dichloromethane/methanol mixture. 1.1 g (58%) of dimethyl 2-[(4-but-2-ynyloxybenzenesulfonylamino)methyl]-2-(4-methanesulfonylpiperazin-1-yl)malonate are obtained in the form of a white solid.
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])[CH:5]=1.CC(C)(C)C(=O)CN1C2C=CC=CC=2C(C2C=CC=CC=2)=NN(CC(O)=O)C1=O.[C:69]([O:73][C:74](=[O:84])[N:75](C1C=CC=C(N)C=1)[CH3:76])([CH3:72])([CH3:71])[CH3:70].C1(C2C3C=CC=CC=3N(CC(=O)C(C)(C)C)C(=O)N(CC(O)=O)N=2)CCCCC1.COC(=O)C1C=CC=C(N)C=1>>[C:69]([O:73][C:74](=[O:84])[N:75]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:17]3[CH2:16][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:35])[CH3:33])[C:14]2=[O:37])[CH:5]=1)[CH3:76])([CH3:72])([CH3:71])[CH3:70]
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(N)c1
Agent: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(C2CCCCC2)c2ccccc21
Agent: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(c2ccccc2)c2ccccc21
Agent: COC(=O)c1cccc(N)c1
Product: CN(C(=O)OC(C)(C)C)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1, step e) except that [1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-5-phenyl-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 4, step a) and (3-amino-phenyl)-methyl-carbamic acid tert-butyl ester (Example 3, step c) were used in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 1, step d) and 3-amino-benzoic acid methyl ester respectively, followed by reaction of the product obtained, in place of (3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-phenyl)-methyl-carbamic acid tert-butyl ester (Example 3, step d), according to the method of Example 3, step e. 1H NMR (CDCl3) 8.01 (1H, s), 7.63 (2H, m), 7.55 (1H, m), 7.42 (3H, m), 7.25 (2H, m), 7.14 (1H, d), 7.00 (1H, t), 6.90 (1H, t), 6.40 (1H, dd), 6.29 (1H, dd), 4.76 (2H, m), 4.52 (1H, d), 4.34 (1H, d), 3.25 (1H, br s), 2.77 (3H, s), 1.26 (9H, s). Found: C, 68.44; H, 6.46; N, 13.80%; C29H31N5O3.0.6H2O requires: C, 68.41; H, 6.39; N, 13.76%.
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3]([OH:5])=[O:4].[CH2:7](O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1CCCCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][CH:2]([CH3:6])[C:3]([O:5][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CC(Br)C(=O)O
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Solvent: O
Product: CC(Br)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 104.5 %

Procedure:
A mixture of 2-bromopropanoic acid (15.3 g; 100 mmol), benzyl alcohol (13.0 g; 120 mmol) and p-toluenesulphonic acid monohydrate (50 mg) in cyclohexane (200 mL) was refluxed in a Dean-Stark apparatus for 19 h. The reaction mixture was cooled to ambient temperature, washed with saturated NaHCO3 solution (1×30 mL), water (1×30 mL) and saturated NaCl solution (1×30 mL). After drying (MgSO4), filtration, and evaporation, the residue was vacuum-distilled. 25.4 g (87%) product was obtained (colourless liquid, by 111-113° C./1.1 mm Hg).
Reaction SMILES: [Na].[N:2]([C:4]1[C:5]([NH2:12])=[N:6][C:7]([NH2:11])=[N:8][C:9]=1[NH2:10])=O.[OH:13][CH:14]([CH2:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1)[CH2:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([CH2:21][C:22]#[N:23])=[CH:19][CH:18]=1>C(OCCO)C>[OH:13][CH:14]([CH2:26][N:27]1[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH2:32]1)[CH2:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]2[N:2]=[C:4]3[C:5](=[N:12][C:22]=2[NH2:23])[N:6]=[C:7]([NH2:11])[N:8]=[C:9]3[NH2:10])=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(O)COc2ccc(CC#N)cc2)CC1
Reactant: Nc1nc(N)c(N=O)c(N)n1
Agent: [Na]
Solvent: CCOCCO
Product: CC(C)(C)OC(=O)N1CCN(CC(O)COc2ccc(-c3nc4c(N)nc(N)nc4nc3N)cc2)CC1
Temperature: 25 °C

Procedure:
Sodium metall (0.22 g, 9.6 mg-atom) was dissolved in 2-ethoxyethanol (60 ml) at 40°-50° C., the solution was cooled to room temperature and 5-nitroso-2,4,6-triamino-pirimidine (1.46 g, 9.5 mmol) was added, followed by 4-[2-hydroxy-3-[4-(tert-butoxy-carbonyl)-1-piperazinyl]propoxy]benzylcyanide (3.92 g, 10.4 mmol) prepared as described in Example 45. The mixture was stirred under reflux in an atmosphere of nitrogen for one hour and the obtained dark brown solution was cooled to room temperature. After dilution with 200 ml of ethyl acetate the precipitate was collected, washed with ethyl acetate and dried to yield a yellow powder, mp. 244°-246° C. (dec.). The filtrate was concentrated and the residue was dissolved in 30 ml of methanol. After treatment with decolorizing carbon the solution was concentrated to a volume of 10 ml and the separated crystals were collected. Total yield of the two generations: 84.8%.
Reaction SMILES: N(OCCC(C)C)=O.[CH3:9][C:10]1[C:11]([N+:17]([O-:19])=[O:18])=[C:12]([CH:14]=[CH:15][CH:16]=1)N.[CH:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CCCCCCC>[CH3:9][C:10]1[C:11]([N+:17]([O-:19])=[O:18])=[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: Cc1cccc(N)c1[N+](=O)[O-]
Reactant: c1ccccc1
Agent: CC(C)CCON=O
Solvent: CCCCCCC
Product: Cc1cccc(-c2ccccc2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
During a two hour period isoamyl nitrite (92.43 g, 0.189 mole) was added to a stirred solution of 3-methyl-2-nitroaniline (60.0 g, 0.394 mole) in 352 ml of benzene. The reaction mixture was stirred at room temperature for approximately 18 hours, then heated at 65° for five hours. The reaction mixture was cooled and the solvent removed by distillation under reduced pressure to give an oil. The oil was diluted with n-heptane and the solvent removed by distillation under reduced pressure to give an oil. The oil was slurried with 100 g silica gel in 300 ml of n-heptane for 15 minutes, then allowed to stand for approximately 18 hours. The slurry was filtered and the filter cake rinsed with toluene. The filtrate was subjected to column chromatography on 500 g of silica gel, elution with toluene:n-heptane (15.85), to give an oil. The oil was rechromatographed on 480 g of silica gel, elution with toluene:n-heptane (15:85), to give 3-methyl-2-nitro-[1,1'-biphenyl].
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[C:7]([O:11][C:12]([N:14]1[CH2:21][CH2:20][C:19]2([CH3:25])[C:22]([CH3:24])([CH3:23])[CH:15]1[CH2:16][C:17]1[CH:29]=[C:28](OS(C(F)(F)F)(=O)=O)[CH:27]=[CH:26][C:18]=12)=[O:13])([CH3:10])([CH3:9])[CH3:8].[C:38]1(B(O)O)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C)C=O>[C:7]([O:11][C:12]([N:14]1[CH2:21][CH2:20][C:19]2([CH3:25])[C:22]([CH3:23])([CH3:24])[CH:15]1[CH2:16][C:17]1[CH:29]=[C:28]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:27]=[CH:26][C:18]=12)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CCC2(C)c3ccc(OS(=O)(=O)C(F)(F)F)cc3CC1C2(C)C
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(C)c3ccc(-c4ccccc4)cc3CC1C2(C)C
Temperature: 100 °C
Reaction time: 4 h

Procedure:
Aqueous 2 M Na2CO3 solution (5 mL) is added to a mixture of 6,11,11-trimethyl-9-trifluoromethanesulfonyloxy-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylic acid tert-butyl ester (1.00 g) and phenylboronic acid (0.34 g) in N,N-dimethylformamide (5 mL) in argon atmosphere. The resulting mixture is flushed with argon and then 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.18 g) is added. The mixture is heated to 100° C. and stirred at this temperature for 4 h. After cooling to room temperature, water is added and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are dried (MgSO4) and the solvent is removed under reduced pressure. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 9:1→1:1) to give the product as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([C@@H:19]([OH:22])[CH2:20][Br:21])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>CN(C1C=CN=CC=1)C.CN(C)C=O>[CH3:14][O:13][C:11](=[O:12])[C:10]1[CH:15]=[C:16]([C@@H:19]([O:22][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:20][Br:21])[CH:17]=[CH:18][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)c1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)c1cc([C@H](CBr)O[Si](C)(C)C(C)(C)C)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.3 %

Procedure:
A solution of methyl 2-(benzyloxy)-5-[(1R)-2-bromo-1-hydroxyethyl]benzoate (71.0 g, 195 mmol), imidazole (18.5 g, 272 mmol), tert-butyldimethylsilyl chloride (32.2 g, 214 mmol) and 4-(N,N-dimethylamino)pyridine (440 mg, 3.60 mmol) in N,N-dimethylformamide (270 ml) was left to stir at room temperature under a nitrogen atmosphere for a period of 24 hours. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (500 ml) and water (500 ml). The organic phase was separated and washed with 2N aqueous hydrochloric acid (2×500 ml), saturated aqueous sodium bicarbonate (2×500 ml), brine (500 ml), dried (magnesium sulfate) and the solvent removed in vacuo to give the title compound as a colourless oil (91.0 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[OH:11].[Br:12]Br>C(O)(=O)C.O>[Br:12][C:9]1[CH:10]=[C:2]([F:1])[C:3]([OH:11])=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6]
Reactant: BrBr
Reactant: O=C(O)c1cccc(F)c1O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cc(Br)cc(F)c1O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
5.00 g (32 mmol) of 3-fluorosalicylic acid was suspended in 50 ml of glacial acetic acid. 2.2 ml of bromine were added and the mixture was stirred at ambient temperature for 48 h. The resulting suspension was diluted with 500 ml of water and the precipitate filtered off and dried by suction to afford 9.394 g of 5-bromo-3-fluoro-2-hydroxybenzoic acid as an ivory solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[Br:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]=[C:36]=[O:37]>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([CH2:25][CH3:26])[C:36]([NH:35][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[Br:28])=[O:37])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Reactant: O=C=Nc1ccccc1Br
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(=O)Nc1ccccc1Br

Procedure:
Prepared according to the procedure described in Example 41, Step 5, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and 2-bromophenyl isocyanate.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]([CH3:13])([CH:10]([CH3:12])[CH3:11])[C:8]#[N:9].[OH-:14].[NH4+]>C1COCC1>[NH2:6][C:7]([CH3:13])([CH:10]([CH3:12])[CH3:11])[C:8]([NH2:9])=[O:14]
Reactant: [OH-]
Reactant: CC(C)C(C)(N)C#N
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)C(C)(N)C(N)=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To concentrated sulfuric acid (29.7 ml), cooled with stirring in an ice-acetone cooling bath, is added 11.8 g (-)-2-amino-2,3-dimethylbutyronitrile with [α]D25 =7.31° (c=0.0368 g/ml THF) at such a rate that the temperature does not go above 25° C. After the addition, the temperature of the reaction mixture is slowly raised to 100° C. and held at that temperature for one hour. After cooling the mixture in an ice-acetone bath, 85 ml concentrated ammonium hydroxide is added at such a rate that the temperature does not exceed 75° C. The mixture is extracted five times with methylene chloride, the combined extracts dried and concentrated. This gives 11.95 g of white solid, mp 79°-81° C. and [α]D25 =+57.43° (c=0.0213 g/ml THF). This solid is recrystallized from methylene chloride-hexane to give 11.2 g of (+)-2-amino-2,3-dimethylbutyramide, mp 81°-82° C. [ α]D25 =+59.38° (c=0.0162 g/ml THF).
Reaction SMILES: ClC(Cl)C.[NH2:5][N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.C([C@@H]1COC(=O)N1[C:25](=[O:47])[C@H:26]([CH2:30][C:31]1[C:36]([Cl:37])=[CH:35][C:34]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:33][C:32]=1[Cl:46])[CH2:27][CH:28]=O)C1C=CC=CC=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:39]([O:38][C:34]1[CH:33]=[C:32]([Cl:46])[C:31]([CH2:30][C@@H:26]2[CH2:27][CH2:28][N:5]([N:6]3[CH2:11][CH2:10][O:9][CH2:8][CH2:7]3)[C:25]2=[O:47])=[C:36]([Cl:37])[CH:35]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: NN1CCOCC1
Reactant: O=CC[C@@H](Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: O=C1[C@H](Cc2c(Cl)cc(OCc3ccccc3)cc2Cl)CCN1N1CCOCC1
Yield: 8 %

Procedure:
Stir a mixture of dichloroethane (25 mL), N-aminomorpholine (0.204 g, 2 mmol), (R)-4-((R)-4-benzyl-2-oxo-oxazolidin-3-yl)-3-(4-benzyloxy-2,6-dichloro-benzyl)-4-oxo-butyraldehyde (1.064 g, 2 mmol) and sodium triacetoxyborohydride (1.266 g, 6 mmol) at room temperature for 12 hours. Bring the reaction to 60° C. and stir for 3 hours. Cool the reaction, dilute with dichloromethane, and wash with water. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify on silica with a 50 to 75% ethyl acetate in hexanes gradient to afford 0.07 g (80%) of the titled product. MS (m/z): 435 (M+).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:19]([O:21]C)=[O:20])=[C:8]2[C:13]=1[O:12][CH2:11][CH:10]([CH2:14][O:15]C(=O)C)[O:9]2)=[O:4].[OH-].[K+].O>C(O)C>[OH:15][CH2:14][CH:10]1[O:9][C:8]2=[C:7]([C:19]([OH:21])=[O:20])[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:13]2[O:12][CH2:11]1
Reactant: COC(=O)c1sc(C(=O)OC)c2c1OCC(COC(C)=O)O2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1sc(C(=O)O)c2c1OCC(CO)O2
Reaction time: 0.5 h

Procedure:
2-Acetoxymethyl-2,3-dihydro-thieno[3,4-b][1,4]dioxine-5,7-dicarboxylic acid dimethyl ester (60 g, 0.18 mol) was dissolved in ethanol (680 mL). Potassium hydroxide (36 g) was added to this solution after which water (500 mL) was added upon continuous cooling. After addition of the water the reaction mixture was stirred for another 30 minutes after which the solvents were removed by distillation. To the remaining part of the reaction mixture, we dropwise added a mixture of ice (50 g) and concentrated hydrochloric acid (25 mL), and stirred. The mixture was then filtered and the residue was washed with water. Subsequent drying resulted in quantitative formation of pure 2-hydroxymethyl-2,3-dihydro-thieno[3,4-b][1,4]dioxine-5,7-dicarboxylic acid as demonstrated by NMR and mass spectroscopy.
Reaction SMILES: C1([O:7][C:8](=[O:34])NC2C=CC(OC3C=CC(NC(=O)C4C=CC(Cl)=C(Cl)C=4)=CN=3)=CC=2)C=CC=CC=1.[CH2:35]([N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)[C:36]1[CH:44]=[CH:43][C:42]2[O:41][CH2:40][O:39][C:38]=2[CH:37]=1>CN(C=O)C>[CH2:35]([N:45]1[CH2:50][CH2:49][N:48]([C:8]([OH:34])=[O:7])[CH2:47][CH2:46]1)[C:36]1[CH:44]=[CH:43][C:42]2[O:41][CH2:40][O:39][C:38]=2[CH:37]=1
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Reactant: O=C(Nc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cn2)cc1)Oc1ccccc1
Solvent: CN(C)C=O
Product: O=C(O)N1CCN(Cc2ccc3c(c2)OCO3)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of {4-[5-(3,4-dichlorobenzoyl-amino)pyridin-2-yloxy]phenyl}-carbamic acid phenyl ester (320 mg, 0.65 mmol) in DMF (4 mL) was added 1-piperonylpiperazine (285 mg, 1.29 mmol), and the resulting solution was stirred for 17 hours at room temperature. This reaction solution was concentrated under reduced pressure. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was then purified by silica gel column chromatography (dichloromethane:methanol=25:1). The obtained residue was dissolved in a mixed solvent of ethanol-ethyl acetate. To the resulting solution was added a solution of 4 N hydrogen chloride in ethyl acetate to bring the pH to 3. The precipitated white powder was then filtered off and washed with ethanol, to thereby yield 330 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]([Cl:15])=[CH:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9](O)=[C:8]([Cl:14])[CH:7]=1.[O:16]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[Cl:14][C:8]1[CH:7]=[C:6]([O:5][CH2:4][CH:3]=[C:2]([Cl:15])[Cl:1])[CH:11]=[C:10]([Cl:12])[C:9]=1[CH2:26][C:25]1[CH:28]=[CH:29][CH:30]=[C:23]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:24]=1
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: OCc1cccc(Oc2ccccc2)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: ClC(Cl)=CCOc1cc(Cl)c(Cc2cccc(Oc3ccccc3)c2)c(Cl)c1
Temperature: 25 °C
Yield: 59.6 %

Procedure:
To a solution of 0.33 g of 4-(3,3-dichloro-2-propenyloxy)-2,6-dichlorophenol, 0.23 g of m-phenoxybenzyl alcohol and 0.34 g of triphenylphosphine dissolved in 10 ml of tetrahydrofuran was added dropwise a solution of 0.26 g of diisopropylazodicarboxylate dissolved in 5 ml of tetrahydrofuran, while stirring at room temperature. After stirring at room temperature for 12 hours, the reaction mixture was concentrated, and then mixed with 20 ml of diethyl ether. The precipitate was filtered, and the filtrate was concentrated. The residue was subjected to silica gel chromatography, which afforded 0.31 g of 3,5-dichloro-4-(3-phenoxybenzyl)-1-(3,3-dichloro-2-propenyloxy)-benzene (57% yield), nD25.5 1.6066.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19](O)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([N:24]1[CH:28]=[C:27]([CH2:29][NH:30][C:31]2[CH:36]=[CH:35][C:34]([CH:37]([CH3:39])[CH3:38])=[CH:33][CH:32]=2)[CH:26]=[N:25]1)[CH3:23]>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:30]([CH2:29][C:27]1[CH:26]=[N:25][N:24]([CH2:22][CH3:23])[CH:28]=1)[C:31]1[CH:36]=[CH:35][C:34]([CH:37]([CH3:38])[CH3:39])=[CH:33][CH:32]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCn1cc(CNc2ccc(C(C)C)cc2)cn1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Product: CCn1cc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)cc2)cn1
Yield: 71.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.56 g) and [(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.49 g) as starting materials, 5-benzyloxy-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.72 g) was obtained.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[O:21][CH2:20][CH2:19][N:18]([CH2:22][C:23]#[C:24][CH2:25]Cl)[C@H:17]2[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N-:36]=[N+:37]=[N-:38].[Na+].[Cl-].[NH4+].C(OCC)(=O)C>CS(C)=O>[N:36]([CH2:25][C:24]#[C:23][CH2:22][N:18]1[CH2:19][CH2:20][O:21][C@H:16]([O:15][C@@H:13]([C:5]2[CH:4]=[C:3]([C:2]([F:35])([F:34])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=2)[CH3:14])[C@@H:17]1[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)=[N+:37]=[N-:38]
Reactant: C[C@@H](O[C@H]1OCCN(CC#CCCl)[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: C[C@@H](O[C@H]1OCCN(CC#CCN=[N+]=[N-])[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 20 h

Procedure:
To a solution of 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl) ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-chlorobut -2-ynyl)morpholine (4 g) in dimethyl sulphoxide (17 ml) was added sodium azide (0.562 g). The solution was stirred for 20 h and aqueous ammonium chloride and ethyl acetate were added. The organic phase was washed with water (2 times), saturated brine and dried (MgSO4). The solvent was removed in vacuo and the residue chromatographed on silica gel (eluting with 20% ethyl acetate in petroleum ether bp 60°-80° C.) to give the title compound. 1H NMR (360 MHz, CDCl3) δ 1.48 (3H, s, J=6.6 Hz), 2.87 (1H, app t, J=10.2 Hz), 2.98 (1H, td, J=3.6, 11.7 Hz), 3.35 (2H, t, J=1.9 Hz), 3.61 (1H, d, J=2.8 Hz), 3.72 (1H, dq, J=1.4 Hz, 10.0 Hz), 3.92 (2H, t, J=1.9 Hz), 4.30-4.40 (2H, m), 4.89(1H, q, J=6.6 Hz), 7.03 (2H, t, J=8.7 Hz), 7.17 (2H, s), 7.27 (2H, br s), 7.63 (1H, s).