Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:32][CH2:31][C:14]2([C:18](=[O:19])[N:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:10])=[O:9].[CH3:33][O-:34].[Na+]>>[CH3:33][O:34][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:32][CH2:31][C:14]2([C:18](=[O:19])[N:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:10])=[O:9]
Reactant: C[O-]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1cnccc1Cl)CC2
Agent: [Na+]
Product: COc1ccncc1S(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1

Procedure:
The title compound was prepared in analogy to example 194 from 8-(4-chloro-pyridine-3-sulfonyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in 199) and sodium methoxide. Off-white solid. MS (ESI): 486.3 (MH+).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:8][CH:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][N:5]1[C:17](=[O:28])[CH:18]([NH2:27])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH:2]=[CH2:3].[C:29]([N:36]1[CH:45]([C:46](O)=[O:47])[CH2:44][CH:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH2:42]2)[CH2:37]1)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.CN(C)CCCN=C=NCC>CN(C=O)C>[C:32]([O:31][C:29]([N:36]1[CH:45]([C:46](=[O:47])[NH:27][CH:18]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[C:17]([N:5]2[CH2:6][CH:7]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:8][CH:4]2[CH2:1][CH:2]=[CH2:3])=[O:28])[CH2:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37]1)=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: C=CCC1CC(OCc2ccccc2)CN1C(=O)C(N)Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CC2=CC=CCC2CC1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C=CCC1CC(OCc2ccccc2)CN1C(=O)C(Cc1ccc(F)cc1)NC(=O)C1Cc2ccccc2CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To solution of 1-(2-allyl-4-benzyloxy-pyrrolidin-1-yl)-2-amino-3-(4-fluorophenyl)-propan-1-one, 54, (1.4 mmol) is dissolved in DMF (10 mL) are added N-Boc-tetrahydroisoquinoline-3-carboxylic acid (0.47 g, 1.5 mmol), 1-hydroxybenzotriazole (0.43 g, 2.8 mmol), N-methylmorpholine (0.84 g, 8.3 mmol) and 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide (0.32 g, 1.7 mmol) at 0° C. The reaction mixture is stirred at 0° C. for 1 hour and then warmed to room temperature and stirred an additional 1.5 hour. The reaction is quenched with saturated NH4Cl solution and then extracted 3 times with EtOAc (70 mL). The organic layers are combined, washed with saturated NaCl solution, dried over Na2SO4, and the solvent is removed in vacuo. The crude product is purified over silica to afford 0.69 g (77% yield) of the desired product as a white solid. 1H NMR (300 MHz, MeOD, Rotamers) δ 6.90–7.41 (m, 13H), 5.55–5.81 (m, 1H), 4.32–5.12 (m, 8H), 3.94–4.18 (m, 2H), 2.75–3.89 (m, 6H), 2.39–2.64 (m, 1H), 1.78–2.29 (m, 2H), 1.20–1.64 (m, 10H); MS (ESMS) m/z 642.2 (M+H)+.
Reaction SMILES: [CH:1]1([CH:6]=[C:7]([C:18]2[NH:29][C:21]3=[N:22][CH:23]=[C:24]([C:26]([OH:28])=[O:27])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>[Pd].CO>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:29][C:21]3=[N:22][CH:23]=[C:24]([C:26]([OH:28])=[O:27])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(C(=O)O)cnc3[nH]2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(C(=O)O)cnc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 117.3 %

Procedure:
A mixture of 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid (680 mg, 1.24 mmol) and 10% palladium on activated carbon (204 mg) in methanol (300 mL) was heated at 50° C. under 50 bar of hydrogen in a steel bomb and kept for 5 h. The mixture was cooled to 25° C., the solids were filtered off, washed with ethyl acetate and the filtrate concentrated in vacuo to afford 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid (600 mg, 87%) which was used without further purification.
Reaction SMILES: O=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[NH:12]1[CH2:18][C:16](=[O:17])[NH:15][C:13]1=[O:14].C(CN)O.Cl>O>[CH3:7][O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:8]=1[OH:9])[CH:2]=[C:18]1[NH:12][C:13](=[O:14])[NH:15][C:16]1=[O:17]
Reactant: COc1cc(C=O)ccc1O
Reactant: O=C1CNC(=O)N1
Agent: Cl
Solvent: O
Solvent: NCCO
Product: COc1cc(C=C2NC(=O)NC2=O)ccc1O
Reaction time: 0.5 h

Procedure:
Vanillin (3.04 g.) and hydantoin (2.0 g.) in water (20 ml) were heated on the steam-bath for a few minutes until dissolution occurred. Ethanolamine (0174 g.) was then added and the solution heated at 85°-90° (bath temperature) for 4.5 hours. The solution deposited crystals and solidified within 0.5 hours. Concentrated HCl (5 ml) was added, the mixture was refrigerated overnight (18 hours), filtered, water washed and dried. The title compound was obtained as a yellow solid (4.18 g; 93%), m.p. 266°-271° decomp.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[O:6][CH:7]=[CH:8][CH:9]=1)[OH:4].CC1(C)[NH:16][C:15](=[O:17])[C:14]2[CH:18]=[C:19]([O:22][CH2:23][CH2:24]Br)[CH:20]=[CH:21][C:13]=2[O:12]1.N>C(O)(C)C>[C:15]([C:14]1[CH:18]=[C:19]([CH:20]=[CH:21][C:13]=1[OH:12])[O:22][CH2:23][CH2:24][NH:1][CH2:2][CH:3]([C:5]1[O:6][CH:7]=[CH:8][CH:9]=1)[OH:4])(=[O:17])[NH2:16]
Reactant: CC1(C)NC(=O)c2cc(OCCBr)ccc2O1
Reactant: NCC(O)c1ccco1
Agent: N
Solvent: CC(C)O
Product: NC(=O)c1cc(OCCNCC(O)c2ccco2)ccc1O
Reaction time: 1 h

Procedure:
A mixture of 7.0 g of α-(aminomethyl)-2-furan-methanol and 7.5 g of 2,3-dihydro-2,2-dimethyl-6-(2-bromoethoxy)-4H-1,3-benzoxazin-4-one is melted and the melt is stirred for 1 hour in a bath at about 110°. 50 ml of isopropanol and 2 ml of concentrated ammonia solution are added to the reaction mixture whilst this is still warm, the mixture is boiled for 5 minutes and filtered and the filtrate is allowed to cool. After working up, α-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethyl]-aminomethyl]-2-furanmethanol with a melting point of 169°-171° is obtained.
Reaction SMILES: Cl.O1CCOCC1.C(OC([NH:15][C@@H:16]1[C@H:21]([NH:22][C:23]([C:25]2[NH:26][C:27]([CH2:31][CH3:32])=[C:28]([Cl:30])[N:29]=2)=[O:24])[CH2:20][CH2:19][N:18]([C:33]2[S:34][C:35]3[C:41]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:40][CH:39]=[CH:38][C:36]=3[N:37]=2)[CH2:17]1)=O)(C)(C)C>>[NH2:15][C@@H:16]1[C@H:21]([NH:22][C:23]([C:25]2[NH:26][C:27]([CH2:31][CH3:32])=[C:28]([Cl:30])[N:29]=2)=[O:24])[CH2:20][CH2:19][N:18]([C:33]2[S:34][C:35]3[C:41]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:40][CH:39]=[CH:38][C:36]=3[N:37]=2)[CH2:17]1
Reactant: CCOC(=O)c1cccc2nc(N3CC[C@@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@@H](NC(=O)OC(C)(C)C)C3)sc12
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1cccc2nc(N3CC[C@@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@@H](N)C3)sc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
A 4 N hydrochloric acid/1,4-dioxane solution (3 mL) was added to ethyl 2-[(3S,4R)-3-[(tert-butoxycarbonyl)amino]-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}piperidin-1-yl]-1,3-benzothiazole-7-carboxylate obtained in Example (202d) (121 mg, 0.210 mmol), and the mixture was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the resulting residue, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (eluent: chloroform:methanol=10:1 v/v) to obtain 100 mg of the title compound (100%) as a colorless solid.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:9][PH:10](=[O:14])[O:11][CH2:12][CH3:13])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:15]I.O>O1CCCC1>[CH:3]1([CH2:9][P:10]([CH3:15])(=[O:14])[O:11][CH2:12][CH3:13])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CCO[PH](=O)CC1CCCCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOP(C)(=O)CC1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 2.25 g of sodium hydride (55% dispersion in oil) in 10 ml of anhydrous tetrahydrofuran is cooled to 0° under an inert atmosphere. A solution of 8.9 g of ethyl (cyclohexylmethyl)phosphinate in 10 ml of anhydrous tetrahydrofuran is added dropwise maintaining the temperature at between 0°-5°. After the addition is complete the suspension is warmed to room temperature and stirred for 30 minutes before re-cooling to 0° C. A solution of 19.87 g of methyl iodide in 10 ml of anhydrous tetrahydrofuran is added slowly--very exothermic! After warming to room temperature, the reaction mixture is stirred for 45 minutes, re-cooled to 0° and carefully treated with water. Removal of the organic phase, drying and concentration affords a yellow oil. Chromatography on silica gel gives ethyl P-cyclohexylmethyl-P-methylphosphinate as a colourless oil; 1H-NMR (CDCl3): δ (ppm)=4.04 (2H, m, CH2OP), 1.94-1.57 (7H, m, 3×CH2 +CH), 1.45 (3H, d, J=15 Hz, P--CH3), 1.36-0.95 (9H, m, 3×CH2 +CH3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][CH:7]2[C:12]([OH:14])=O.[CH2:15]([N:17]1[CH:21]=[C:20]([CH2:22][NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[CH:19]=[N:18]1)[CH3:16]>>[CH2:15]([N:17]1[CH:21]=[C:20]([CH2:22][N:23]([C:24]2[CH:25]=[CH:26][C:27]([CH:30]([CH3:31])[CH3:32])=[CH:28][CH:29]=2)[C:12]([CH:7]2[C:8]3[C:4](=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][CH:9]=3)[CH2:5][CH2:6]2)=[O:14])[CH:19]=[N:18]1)[CH3:16]
Reactant: CCn1cc(CNc2ccc(C(C)C)cc2)cn1
Reactant: COc1cccc2c1CCC2C(=O)O
Product: CCn1cc(CN(C(=O)C2CCc3c(OC)cccc32)c2ccc(C(C)C)cc2)cn1
Yield: 61.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 4-methoxyindan-1-carboxylic acid (0.29 g) and [(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.37 g) as starting materials, N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-4-methoxyindan-1-carboxamide (0.39 g) was obtained.
Reaction SMILES: [C:1]1([C:7]2([CH3:14])[O:13][CH:8]2[C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH2:20]([OH:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([O:27][C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([CH3:14])[CH:8]([OH:13])[C:9]([O:11][CH3:12])=[O:10])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)C1OC1(C)c1ccccc1
Reactant: OCc1ccccc1
Agent: O=S(=O)(O)O
Product: COC(=O)C(O)C(C)(OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
9.6 g (50 mmol) of methyl 3-phenyl-2,3-epoxybutyrate are dissolved in 150 ml of benzyl alcohol, and 0.5 ml of concentrated sulfuric acid is added. Stirring is carried for 6 hours at 50° C. and the mixture is allowed to cool to room temperature. After neutralization with sodium bicarbonate solution, the excess benzyl alcohol is distilled off under greatly reduced pressure 0 and the residue is purified by flash chromatography over silica gel using 9:1 n-hexane/ethyl acetate. After the solvent has been distilled off, 6.5 g of a colorless oil remain.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:11].O>C1COCC1>[CH2:1]([NH:8][C:9]([NH2:11])=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: S=C=NCc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: NC(=S)NCc1ccccc1
Reaction time: 0.5 h
Yield: 108.1 %

Procedure:
96.3 g (366 mmoles) of benzylisothiocyanate were dissolved in 100 ml o THF and treated with 44.2 ml (732 mmoles) of 32% ammonia solution. After 0.5 hour at 40-45° C., 300 ml of water were added and the THF removed in vacuo. The gummy suspension is treated with 200 ml of ether, the crystals collected and washed with water and ether. Suspension in 30 ml of methylenechloride and collection gave 65.77 g (64.2%) of benzyl-2-thiourea with mp 144-5° C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]2[C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH2:3]1.Cl.[CH3:23][O:24][C:25]12[CH2:32][CH2:31][C:28]([NH2:33])([CH2:29][CH2:30]1)[CH2:27][CH2:26]2.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]2[C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=[C:11]([NH:33][C:28]34[CH2:31][CH2:32][C:25]([O:24][CH3:23])([CH2:26][CH2:27]3)[CH2:30][CH2:29]4)[N:10]=2)[CH2:3]1
Reactant: CS(=O)(=O)c1ncc(C(N)=O)c(N[C@@H]2CCC[C@H](O)C2)n1
Reactant: COC12CCC(N)(CC1)CC2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COC12CCC(Nc3ncc(C(N)=O)c(N[C@@H]4CCC[C@H](O)C4)n3)(CC1)CC2
Temperature: 130 °C
Reaction time: 3 h
Yield: 15.5 %

Procedure:
To a solution of 4-((1R,3S)-3-hydroxycyclohexylamino)-2-(methylsulfonyl)pyrimidine-5-carboxamide (1.2 g, 3.8 mmol; synthesis described herein) and 4-methoxybicyclo[2.2.2]octan-1-amine hydrochloride (600 mg, 3.1 mmol) in NMP (12 mL) was added DIEA (1.03 g, 8 mmol). The resulting mixture was stirred at 130° C. under microwave irradiation for 3 h. The resulting mixture was purified by reverse phase column chromatography to give the desired product (230 mg, 0.6 mmol, 15.5% yield). 1H-NMR (400 MHz, CDCl3) δ ppm 8.70 (brs, 1H), 8.08 (s, 1H), 5.40 (brs, 2H), 5.01 (br. s, 1H), 3.99-3.96 (m, 1H), 3.75-3.70 (m, 1H), 3.19 (s, 3H), 2.37-2.34 (m, 1H), 2.15-2.11 (m, 6H), 1.99-1.97 (m, 2H), 1.90-1.86 (m, 1H), 1.80-1.76 (m, 6H), 1.38-1.22 (m, 4H). MS (ESI) m/z=390.2[M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[C:7]([OH:9])[CH:8]=1.F[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[C:7]([CH:8]=1)[O:9][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COc1ccc(Cc2ccc(OC)cc2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(Cc2ccc(OC)cc2Oc2ccc(C=O)cc2)cc1
Yield: 74.2 %

Procedure:
The title compound was synthesized by referring to Synthesis, 1991, (1), 63. To a solution of 5-methoxy-2-(4-methoxybenzyl)phenol (1.9 g) in N,N-dimethylacetamide (6 ml) was added 4-fluorobenzaldehyde (960 mg) and potassium carbonate (1.3 g), and the solution was refluxed for 1 hour and 10 minutes. The solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (2.0 g).
Reaction SMILES: Cl.[CH3:2][C:3]1[O:7][C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:5][N:4]=1.Br[C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:2][C:3]1[O:7][C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:15]3[N:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:10][CH2:9]2)=[N:5][N:4]=1
Reactant: Brc1ncccn1
Reactant: Cc1nnc(C2CCNCC2)o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nnc(C2CCN(c3ncccn3)CC2)o1
Temperature: 60 °C
Reaction time: 18 h
Yield: 30.6 %

Procedure:
4-(5-Methyl-[1,3,4]oxadiazole-2-yl)-piperidine hydrochloride (203 mg, 1 mmol) (see reference WO 0039125, preparation 43) was added to a solution of 2-bromopyrimidine (207 mg, 1.3 mmol) and potassium carbonate (207 mg, 1.5 mmol) in N,N-dimethylformamide (0.5 mL). The solution was heated to 60° C. for 4 hours, before cooling and stirring at room temperature for 18 hours. The solvent was evaporated under reduced pressure, and the residue partitioned between water and dichloromethane. The aqueous layer was extracted with dichloromethane, and the combined organic layers were washed with brine, before being dried over magnesium sulphate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (25 g) eluting with dichloromethane and methanol (97.5:2.5) to give the title compound as a crystalline solid (75 mg).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH3:10])[CH:4]=1.O>Br.C(O)(=O)C>[CH3:10][S:9][C:5]1[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=1
Reactant: COc1cccc(SC)c1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CSc1cccc(O)c1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 64.6 %

Procedure:
1-Methoxy-3-methylsulfanyl-benzene (32.87 g, 0.213 mol) was dissolved in a mixture of 30% hydrogen bromide in acetic acid (96 ml) and 48% aqueous hydrobromic acid (24 ml). The reaction was heated to reflux, and stirred at this temperature under nitrogen for 5.5 h. After cooling to room temperature the reaction mixture was poured into water (600 ml) and extracted with diethylether (3×300 ml). The combined organic extracts were washed with water (2×150 ml), brine (100 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of ethyl acetate:pentane (1:19 changing to 3:37 then 1:9, by volume) and the product was azeotroped with toluene (2×100 ml) to give 3-Methylsulfanyl-phenol (19.3 g) as a crimson oil.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=2)=[CH:8][C:7]=1[CH3:20].[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([OH:37])=[C:27]([C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:30])[CH:28]=1>>[C:29]([C:27]1[CH:28]=[C:23]([Cl:22])[CH:24]=[CH:25][C:26]=1[O:37][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:21])=[C:7]([CH3:20])[CH:8]=1)(=[O:30])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: COC(=O)CCc1ccc(Oc2cccc(Br)c2)cc1C
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1O
Product: Cc1cc(Oc2cccc(Oc3ccc(Cl)cc3C(=O)c3ccccc3)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepared by reacting the compound of 3-[4-(3-bromo-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester with (5-chloro-2-hydroxy-phenyl)-phenyl-methanone as in Example 18 to afford 0.080 g. 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C29H23O5Cl 486, found 487 and 489 (M+1 and M+3, 100%).
Reaction SMILES: C1C=CC=CC=1.[OH:7][CH:8]1[CH:12]([CH2:13][CH:14]=[CH2:15])[C:11](=[O:16])[CH:10]=[CH:9]1.[Al]>CC(C)=O>[O:7]=[C:8]1[CH:12]([CH2:13][CH:14]=[CH2:15])[C:11](=[O:16])[CH:10]=[CH:9]1
Reactant: C=CCC1C(=O)C=CC1O
Agent: [Al]
Solvent: c1ccccc1
Solvent: CC(C)=O
Product: C=CCC1C(=O)C=CC1=O
Temperature: 25 °C
Yield: 81.2 %

Procedure:
Into a mixture of 150 ml of dried benzene and 100 ml of acetone, was dissolved 1.5 g of 4-hydroxy-5-allyl-2-cyclopentenone. After adding 3 g of freshly distilled aluminum isoproproxide, the mixture was heated under reflux for 12 hours. The reaction mixture was cooled to room temperature, washed twice with 30% sulfuric acid, then with water until the washings had become neutral. After drying over anhydrous sodium sulfate, the mixture was stripped of the solvent by distillation and the residue was distilled in vacuo to obtain 1.2 g (81% yield) of 4-keto-5-allyl-2-cyclopentenone boiling at 53° C./4 mmHg.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1I)[C:5]([O:7][CH3:8])=[O:6].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[C:21]#[CH:22].C(NCC)C>C(#N)C.C(#N)C.C(#N)C.[Pd](Cl)Cl.[Cu]I>[NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:22]#[C:21][C:15]1[C:14]([Cl:13])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:20])[C:5]([O:7][CH3:8])=[O:6]
Reactant: C#Cc1c(Cl)cccc1Cl
Reactant: COC(=O)c1ccc(I)c(N)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Solvent: CC#N
Solvent: CCNCC
Product: COC(=O)c1ccc(C#Cc2c(Cl)cccc2Cl)c(N)c1
Temperature: 120 °C

Procedure:
A mixture of methyl 3-amino-4-iodobenzoate (604 mg, 2.18 mmol) (from Example 3-4), 2,6-dichlorophenylacetylene (447 mg, 2.61 mmol), palladium (II) chloride bis(acetonitrile) (23 mg, 89 μmol), diethylamine (449 μL, 318 mg, 4.35 mmol), and copper (I) iodide (21 mg, 110 μmol) in acetonitrile (10 mL) was heated for 35 min at 120° C. in a microwave apparatus. The mixture was filtered, and the filtrate concentrated, then chromatographed using a gradient of 0-30% heptane/ethyl acetate to give methyl 3-amino-4-(2,6-dichlorophenylethynyl)-benzoate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:11]([N:16]=1)=[N:12][CH:13]=[CH:14][CH:15]=2.[CH3:17][N:18]1CCCC1=O>>[C:17]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:11]([N:16]=1)=[N:12][CH:13]=[CH:14][CH:15]=2)#[N:18]
Reactant: CN1CCCC1=O
Reactant: Brc1ccccc1-c1nc2ncccc2o1
Product: N#Cc1ccccc1-c1nc2ncccc2o1
Temperature: 175 °C
Reaction time: 5 h

Procedure:
A mixture of 2.8 g. of 2-(2-bromophenyl)oxazolo[4,5-b]pyridine, 1.6 g. of cuprous cyanide and 15 ml. of N-methylpyrrolidinone was deairated by bubbling nitrogen through the mixture for 5 minutes. It was then heated to 175° C. in an oil-bath and held at that temperature for 5 hours under a nitrogen atmosphere and then allowed to cool to room temperature. The reaction mixture was treated with 75 ml. of 10% ammonium hydroxide and the resulting precipitate was collected. The precipitate was extracted with 100 ml. of boiling methylene chloride and the methylene chloride was evaporated. The residue was recrystallized from methylene chloride to give 2-(2-cyanophenyl)oxazolo]4,5-b]pyridine, m.p. 166-167° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[N:4][C:3]=1[CH3:10].C1C(=O)N([Br:18])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:10][C:3]1[C:2]([CH3:1])=[N:7][C:6]([CH3:8])=[C:5]([CH3:9])[N:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc(C)c(C)nc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1nc(C)c(CBr)nc1C
Yield: 70 %

Procedure:
Dehydrated tetramethylpyrazine 10 g was dissolved into CCl4 60 ml and then NBS 9.17 g was added at a mole ratio of tetramethylpyrazine to NBS=1:0.7 (a minute amount of benzoylperoxide can be added as radical initiator). Reaction was carried out under reflux under the illumination of an incandescent lamp for 10-12 h. The reaction sample was cooled and condensed, and the excess tetramethylpyrazine was sucked away at a reduced pressure in 60-70° C. water bath. The residue was kept in a fridge for standing and a pale red half-oily substance 7.75 g was obtained with a yield of 70%.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Br:6][C:7]1[C:8](Cl)=[N:9][C:10]([Cl:13])=[N:11][CH:12]=1.C(N(CC)CC)C>C(#N)C>[Br:6][C:7]1[C:8]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[N:9][C:10]([Cl:13])=[N:11][CH:12]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(C)(C)N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)Nc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
tert-Butylamine (5.28 g, 72 mmol) was added to 5-bromo-2,4-dichloropyrimidine (15 g, 66 mmol) and triethylamine (19.9 g, 197 mmol) in acetonitrile (450 mL) at room temperature and the mixture was stirred at room temperature for 16 hours. Then the mixture was evaporated in vacuo and the crude residue was partitioned between EtOAc (450 mL) and water (400 mL). The organic layer was separated, washed with brine (400 mL) then dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:EtOAc 88:12) to afford the title compound as a yellow oil in 52% yield, 8.8 g.