Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Sn](CCCC)(CCCC)C1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[N:12]=2)[CH:10]=1)CCC.BrC1C=C([CH2:46][S:47](CC2C=CC=C(Br)C=2)(=[O:49])=[O:48])C=CC=1.CCCCCCC.[C:65]1([CH3:71])[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>>[CH3:46][S:47]([C:67]1[CH:66]=[C:65]([C:71]2[N:7]=[CH:8][N:9]([C:11]3[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=4)[N:12]=3)[CH:10]=2)[CH:70]=[CH:69][CH:68]=1)(=[O:49])=[O:48]
Reactant: O=S(=O)(Cc1cccc(Br)c1)Cc1cccc(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)n2)cn1
Reactant: Cc1ccccc1
Solvent: CCCCCCC
Product: CS(=O)(=O)c1cccc(-c2cn(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)cn2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
A stirred mixture of 2-(4-tributylstannanyl-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (Example G.11) (0.718 g, 1.0 mmol), commercially available 3-bromophenylmethyl sulfone (259 mg, 1.1 mmol), tetrakis(triphenyl-phosphine)palladium (0.058 g, 0.050 mmol) in toluene (5 mL) was heated under reflux conditions for 18 h. Cooled to rt, some precipitate occurred, diluted with toluene (˜5 mL), placed in freezer for 30 min, added heptane (total volume: 25 mL), filtered the precipitate off, washed with toluene/heptane (ca. 1:1, 3×10 mL), purified by silica gel column chromatography with heptane/ethyl acetate followed by trituration with diethyl ether/heptane to give the title compound as a white solid (0.150 g, 29%). MS (ISP) 512.3 [(M+H)+].
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH:3]1[C:15]([NH2:17])=O.B.CSC.CO>C1COCC1>[NH2:17][CH2:15][CH:3]1[CH:2]([OH:1])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4]1
Reactant: NC(=O)C1CN(Cc2ccccc2)CCC1O
Agent: B
Solvent: CO
Solvent: CSC
Solvent: C1CCOC1
Product: NCC1CN(Cc2ccccc2)CCC1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
A suspension of 4-hydroxy-1-(phenylmethyl)-3-piperidinecarboxamide (5.62 g, 23.9 mmol) in THF (65 mL) was treated dropwise with borane-methyl sulphide complex (2M solution in THF, 26.4 mL, 52.8 mmol). After stirring for 0.5 h at room temperature, the reaction mixture was heated at 80° C. for 1.5 h. Methanol (16 mL) was added and heating continued for 0.5 h. The mixture was evaporated and the residue was chromatographed on silica gel, eluting with 10-30% (2M ammonia/methanol)/dichloromethane to give the product (2.67 g, 51%).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[C:13]([C:17]([F:20])([F:19])[F:18])=[N:14][NH:15][CH:16]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:21]([SH:24])[CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:21]([S:24][C:2]1[CH:11]=[C:10]([C:12]2[C:13]([C:17]([F:20])([F:19])[F:18])=[N:14][NH:15][CH:16]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[CH2:22][CH3:23]
Reactant: COC(=O)c1ccc(-c2c[nH]nc2C(F)(F)F)cc1Cl
Reactant: CCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCSc1cc(-c2c[nH]nc2C(F)(F)F)ccc1C(=O)OC
Yield: 18 %

Procedure:
1.52 g (5.0 mmol) of methyl 2-chloro-4-(3-trifluoromethylpyrazolyl)benzoate, 0.66 g (8.6 mmol) of 1-propanethiol and 0.83 g (6.0 mmol) of potassium carbonate were stirred in 5 ml of N,N-dimethylformamide at 60° C. for 24 hours. The resulting reaction mixture was poured into 50 ml of water, and the organic matters were extracted with 20 ml of ethyl acetate twice. The ethyl acetate layers were combined, washed with 30 ml of water twice and dried over anhydrous magnesium sulfate, and the ethyl acetate was distilled off under reduced pressure. Purification of the residue by thin layer chromatography afforded 0.31 g of methyl 2-propylthio-4-(3-trifluoromethylpyrazolyl)benzoate as a white powder (m.p. 114-116° C.).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](=O)[CH3:22])=[CH:16][CH:15]=1.[OH:24][CH:25]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=1)[CH2:26][NH2:27]>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([NH:27][CH2:26][CH:25]([OH:24])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:36])([F:37])[F:35])[CH:29]=2)[CH3:22])=[CH:16][CH:15]=1
Reactant: NCC(O)c1cccc(C(F)(F)F)c1
Reactant: CC(=O)Cc1ccc(OCCCCCCCCCCCO)cc1
Product: CC(Cc1ccc(OCCCCCCCCCCCO)cc1)NCC(O)c1cccc(C(F)(F)F)c1

Procedure:
The compound was prepared as in Example 4, from 1-[4-(11-hydroxyundecyloxy)phenyl]propan-2-one (7.3 g) and 2-hydroxy-2-(3-trifluoromethylphenyl)-ethanamine (4.7 g) and purified by chromatography on silica gel in 5% methanol dichloromethane, mp 45°-50° C. as a 50:50 mixture of diastereoisomers.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][C:21]1[C:25]([Br:26])=[C:24]([Br:27])[S:23][C:22]=1[CH2:28][Cl:29]>C1(C)C=CC=CC=1>[Cl-:29].[Br:20][C:21]1[C:25]([Br:26])=[C:24]([Br:27])[S:23][C:22]=1[CH2:28][P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: ClCc1sc(Br)c(Br)c1Br
Solvent: Cc1ccccc1
Product: Brc1sc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(Br)c1Br
Product: [Cl-]
Temperature: 25 °C

Procedure:
Triphenylphosphine (9.0 g.) and 10.4 g. of 3,4,5-tribromo-2-chloromethylthiophene were dissolved in 200 ml. of toluene. The mixture was refluxed overnight under argon, cooled to room temperature and the precipitated phosphonium salt was collected by filtration, washed several times with cold benzene and dried at 80° C. under high vacuum. The resulting (3,4,5-tribromo-2-thenyl)triphenylphosphonium chloride has a m.p. 248°-249° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reaction time: 3 h
Yield: 920 %

Procedure:
To the solution of 1-tert-butoxycarbonyl-4-hydroxypiperidine (20.13 g, 10 mmol) and triethylamine (16.7 mL, 120 mmol) in THF (200 mL) was added dropwise methanesulfonyl chloride (9.3 mL, 120 mmol) under ice cooling, and the mixture was stirred at the same temperature for 3 hours. To the mixture was added water (200 mL), and the mixture was extracted with ethyl acetate (200 mL, 100 mL×2). The organic layer was washed with 1N-hydrochloric acid (50 mL×2), a saturated aqueous solution of sodium hydrogencarbonate (50 mL×2), saturated sodium chloride solution (50 mL), successively, dried over magnesium sulfate and concentrated under reduced pressure. To the concentrate were added diisopropyl ether (100 ml) and hexane (100 mL), and the resulting precipitates were collected by filtration. The precipitates were washed with diisopropyl ether/hexane (1/1) mixed solvent (100 mL), and dried under reduced pressure to give the titled compound (25.65 g, 92 mmol, Yield 92%) as white crystals.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][N:6]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Br:19])[C:10]2[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:9]=2[CH:8]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:7]1=[O:29])C.[OH-].[Na+].Cl>C1COCC1.CO.O>[Br:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:11]1[CH2:12][N:6]([CH2:5][C:4]([OH:30])=[O:3])[C:7](=[O:29])[CH:8]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:9]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:10]1=2
Reactant: CCOC(=O)CN1CC(c2ccccc2Br)c2cc(Cl)ccc2C(CC(C)C)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)CC1C(=O)N(CC(=O)O)CC(c2ccccc2Br)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
185 mg of the compound from Example 14A (0.38 mol) are dissolved in 6 ml of THF/methanol (1:1) and 1 ml of 1 N sodium hydroxide solution is added. The reaction mixture is stirred at room temperature for 16 h. It is diluted with water and acidified with 2 N hydrochloric acid, and the mixture is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulphate and concentrated in a rotary evaporator. 172 mg (99% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:22])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[OH:21])=[CH:4][CH:3]=1.Br[CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:22])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH2:10][CH:9]2[O:21][CH2:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)=[CH:6][CH:7]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)C(O)C1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to the procedure described under (c), by alkylating tert-butyl (3RS,4RS)-4-(4-chlorophenyl)-3,4-dihydroxy-piperidine-1-carboxylate with 2-bromomethylnaphthalene there was obtained tert-butyl (3RS,4RS)-4-(4-chlorophenyl)-4-hydroxy-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a light yellow oil; MS: 411, 41 3 [M-(C4H8)]+.
Reaction SMILES: [CH3:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[N:4][C:3]2[CH:5]=[CH:6][CH:7]=[C:8]([Cl:9])[C:2]=2[CH3:1])=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Cc1c(N)cccc1Cl
Product: Cc1c(Cl)cccc1N=Cc1ccc(Cl)cc1
Reaction time: 1.5 h

Procedure:
2-methyl-3-chloroaniline (0.25 mole) and 4-chlorobenzaldehyde (0.25 mole) were ground in a mortar. The mixture was heated, with stirring in a water bath for 1.5 hours. Distillation at reduced pressure gave N-(p-chlorobenzylidene)-2-methyl-3-chloroaniline as a second fraction; B.p. 139° C./0.020 mm.; m.p. 79°-81° C.
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].[OH-].[Na+].[CH:8]([S:16](Cl)(=[O:18])=[O:17])=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CC(C)=O>[CH:8]([S:16]([NH:4][C:2](=[NH:5])[CH3:3])(=[O:18])=[O:17])=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=S(=O)(Cl)C=Cc1ccccc1
Reactant: CC(=N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(=N)NS(=O)(=O)C=Cc1ccccc1
Yield: 76 %

Procedure:
A mixture of acetamidine hydrochloride (28.8 g., 0.15 mole) and 50% sodium hydroxide (12.0 g., 0.15 mole) in 150 ml. of acetone is stirred for a period of 10 min. to liberate the free base. A solution of styrylsulfonyl chloride (10.1 g., 0.05 mole) in 50 ml. of acetone is added dropwise to the mixture at a temperature of 20°-25° C. with stirring. After further stirring for 10 min., the mixture is concentrated under reduced pressure to remove acetone, the concentrate diluted with 200 ml. of water and acidified with 3 N hydrochloric acid to provide a precipitate. The precipitate is collected, dissolved in chloroform and the chloroform extract dried. Evaporation of the chloroform solvent under reduced pressure provides a white solid, m.p. 130°-134° C. which is crystallized from isopropyl acetate affording 8.5 g. (76% yield) of N-(STYRYLSULFONYL)ACETAMIDINE, m.p. 134.5°-137.0° C. (corr.).
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[N:16]1([C:24]([O:26][CH2:27][CH:28]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]3[C:29]2=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:25])[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([OH:20])=O.Cl.[NH2:42][C@@H:43]([C:45]([NH2:47])=[O:46])[CH3:44].C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[N:16]1([C:24]([O:26][CH2:27][CH:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:35]3[C:40]2=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:25])[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([NH:42][C@@H:43]([C:45]([NH2:47])=[O:46])[CH3:44])=[O:20]
Reactant: C[C@@H](N)C(N)=O
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)[C@@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21)C(N)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3.36 g of DCC are added to a stirred solution of 5.4 g (16 mmol) of Fmoc-Pro-OH, 2 g of HCl.H-D-Ala-NH2 and 2.24 g of HOBt in 30 ml of dimethylformamide at 0° C. The mixture is left to stir at 0° C. for 1 hour and to stand at room temperature overnight. The precipitate is filtered off with suction and the filtrate is concentrated. The residue is dissolved in ethyl acetate and extracted by shaking successively with water, twice with saturated NaHCO3 solution, water, KHSO4 buffer and water. Fmoc-Pro-D-Ala-NH2 precipitates in the ethyl acetate phase during this and is filtered off with suction. The ethyl acetate mother liquor is concentrated and triturated with diethyl ether and filtered with suction.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH:32]1[CH2:36][CH2:35][CH2:34][NH:33]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:33]1[CH2:34][CH2:35][CH2:36][CH:32]1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=1)=[O:6])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: c1ccc(C2CCCN2)nc1
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1ccc(C(=O)N2CCCC2c2ccccn2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, rac.-2-(pyridin-2-yl)pyrrolidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.98 minutes; C26H23Cl2N5O2 (508.41); mass spectrum: (M−H)−=507/509/511 (chlorine isotope).
Reaction SMILES: O=C1NC2[C:14]3[CH:6]([CH2:7][N:8]([CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])[C:9]=3[CH:10]=[CH:11][CH:12]=2)[CH2:5][CH2:4][CH2:3]1.[H-].[Na+].IC.[CH3:28][N:29]([CH:31]=[O:32])[CH3:30]>>[C:6]([CH:16]([N:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:28]3[N:29]([CH3:30])[C:31](=[O:32])[CH2:3][CH2:4][CH2:5][CH:6]([C:14]=23)[CH2:7]1)[C:17]([OH:19])=[O:18])([CH3:14])([CH3:7])[CH3:5]
Reactant: CC(C)(C)OC(=O)CN1CC2CCCC(=O)Nc3cccc1c32
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CN1C(=O)CCCC2CN(C(C(=O)O)C(C)(C)C)c3cccc1c32
Reaction time: 0.08 h

Procedure:
To a solution of tert-butyl (6-oxo-2a,3,4,5,6,7-hexahydroazocino[4,3,2-cd]indol-1(2H)-yl)acetate, enantiomer A, from Step F (20 mg, 0.063 mmol) in DMF (0.5 mL) at ambient temperature was added sodium hydride (3 mg of a 60% dispersion in mineral oil, 0.075 mmol). The reaction mixture was stirred for 5 min, then iodomethane (10 mg, 0.070 mmol) was added and stirring was continued for 10 min. The reaction was quenched with saturated aqueous NaHCO3 (1 mL) and extracted with EtOAc (2×3 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=331 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10](O)=O)=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[C:20](Cl)(=[O:24])C(Cl)=O.C1C[O:29]CC1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][C:20]([OH:24])=[O:29])=[C:7]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:6]=2[CH:19]=1
Reactant: C1CCOC1
Reactant: O=C(O)c1oc2ccc(Cl)cc2c1-c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(O)Cc1oc2ccc(Cl)cc2c1-c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of 5-chloro-3-phenylbenzofuran-2-carboxylic acid (0.66 g) in anhydrous THF (15 ml) were added oxalyl chloride (0.30 ml) and DMF (one drop) at room temperature. The mixture was stirred for 0.5 hour. The solvent was distilled off, and the residue (containing the acid chloride) was dissolved in anhydrous THF (10 ml). To this solution was added an ethyl ether solution of diazomethane (prepared from 1.5 g of N-nitrosomethyl urea). The mixture was stirred for 0.5 hour at room temperature. The solvent was distilled off, and the residue (containing the diazoketone compound) was dissolved in methanol (20 ml). To the solution was added portionwise silver oxide (Ag2O) (0.20 g), while stirring at 50° C. This mixture was stirred with heating under reflux for 3 hours, which was then subjected to filtration with celite. From the filtrate was distilled off the solvent. The residue was purified by means of a silica gel (30 g) column chromatography (hexane-ethyl acetate=5:1) to afford methyl ester of 5-chloro-3-phenylbenzofuran-2-acetic acid as a pale yellow oily product (0.44 g)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.Br[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:12]([O:11][C:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:7][CH:6]=1)=[O:10])[CH3:13]
Reactant: CCOC(=O)CCCBr
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCNc1ccc(CC(=O)OCC)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 74.4 %

Procedure:
A mixture of ethyl 4-aminophenylacetate (2.0 g, 11 mmols), ethyl 4-bromobutanoate (8.7 g, 45 mmols), potassium carbonate (2.3 g, 17 mmols) and N,N-dimethylformamide (50 ml) was stirred at 60° C. for 24 hours. The reaction mixture was cooled, then poured into water, and extracted with ethyl acetate. The extract was washed with water and brine, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography to give an oil of ethyl 4-[4-(ethoxycarbonylmethyl)phenyl]aminobutanoate (2.4 g, 74%).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][C:18](=[O:21])[N:19]([CH3:20])[C:12]2=[N:11][C:10]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23])C1C=CC=CC=1.FC(F)(F)C(O)=O>C(OCC)(=O)C.CCCCCC>[OH:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][C:18](=[O:21])[N:19]([CH3:20])[C:12]2=[N:11][C:10]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCC(=O)N2C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1nc2n(c(=O)c1O)CCC(=O)N2C
Yield: 85.2 %

Procedure:
Reaction of intermediate 16, ethyl 3-benzyloxy-9-methyl-4,8-dioxo-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidine-2-carboxylate, (0.413 g, 1.16 mmol) with trifluoroacetic acid (20 ml) as described in the preparation of intermediate 5 gave 0.264 g (85% yield) of the title ester as white crystals, mp 182° C. (ethyl acetate/hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.44 (3H, t, J=7.1 Hz, CH3), 2.80 (2H, t, J=6.8 Hz, CH2), 3.43 (3H, s, NCH3), 4.28 (2H, t, J=6.8 Hz, CH2), 4.46 (2H, q, J=7.1 Hz, OCH2), 10.48 (1H, s, OH). Anal. Calcd for C11H13N3O5: C, 49.43; H, 4.90; N, 15.72. Found: C, 49.39; H, 4.89; N, 15.75.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:18][CH2:19][CH3:20])=[C:7](B(O)O)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:21](=[O:24])([O-])[O-].[Na+].[Na+].O.[CH2:28]([OH:30])[CH3:29]>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>[C:28]([C:21]1[O:24][C:10]2[C:9]([C:7]3[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=3[O:18][CH2:19][CH3:20])=[CH:8][CH:7]=[CH:6][C:5]=2[CH:1]=1)(=[O:30])[CH3:29]
Reactant: CCOc1c(B(O)O)cc(C(C)(C)C)cc1C(C)(C)C
Reactant: CCO
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOc1c(-c2cccc3cc(C(C)=O)oc23)cc(C(C)(C)C)cc1C(C)(C)C
Yield: 93 %

Procedure:
A mixture of 300 mg (1.08 mmol) of 3,5-di-tert-butyl-2-ethoxy phenylboronic acid, 498 mg (1.62 mmol) of 2-acetyl-7-trifluoromethanesulfonate benzo[b]furan and 62 mg (0.05 mmol) of Pd(PPh3)4, 1 mL of 2N aqueous sodium carbonate in 9 mL of toluene and 4 mL ethanol was heated to reflux. After complexion (TLC), water was added and the solution was extracted with ethyl acetate. The organic layer is dried over MgSO4 and after evaporation of the solvents, the crude oil was purified over a short silica plug (eluent: 10/90=ethyl acetate/hexane) to afford 395 mg (1.00 mmol, yield: 93%/boronic acid) of 2-acetyl-7-(3,5-di-tert-butyl-2-ethoxyphenyl)-benzo[b]furan as a clear yellow pasty solid. 1H NMR (CDCl3), δ: 7.72 (d, J=7.4 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.56 (s, 1H), 7.42 (s, 2H), 7.38 (d, J=7.6 Hz, 1H), 3.35 (dd, J=13.9, 7.0 Hz, 2H), 2.58 (s, 3H), 1.48 (s, 9H), 1.36 (s, 9H), 0.86 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:7]=[O:8].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].[C-:28]#[N:29].[K+]>COCCOCCOC.O.C(O)C>[OH:8][CH:7]([CH:6]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[O:5][C:4]1[CH:15]=[CH:16][CH:17]=[CH:18][C:3]=1[O:2][CH3:1])[C:28]#[N:29]
Reactant: COc1ccccc1OC(C=O)c1ccccc1
Reactant: [C-]#N
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOCCOC
Solvent: O
Product: COc1ccccc1OC(c1ccccc1)C(O)C#N
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.9 %

Procedure:
150 g of α-(2-methoxy-phenoxy)-phenyl acetaldehyde dissolved in approximately 1800 ml of diglyme was stirred with 176.5 g of sodium metabisulphite in 550 ml of water and 200 ml of ethanol at 50° C. for 16 hours. The whole was cooled to room temperature and addition was made of 44.4 g of potassium cyanide in 200 ml of water. The whole was stirred at 90° C. (external temperature) for 5 hours, concentrated to approximately 800 ml and poured into water: extraction was performed with 4×750 ml of ethyl ether and the whole washed with water, dried over Na2SO4 and evaporated to dryness to obtain 156.5 g of 2-hydroxy-3-phenyl-3-(2-methoxy-phenoxy)-propionitrile as a viscous oil. Yield=94%. Analogously, all the 2-hydrox-propionitrile derivatives useful for the preparation of the 2-hydroxy-propylamines mentioned in Examples 3 and 4 were prepared.