Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].O=[C:12]1[CH2:29][CH2:28][C:15]2([CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH2:14][CH2:13]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH:12]2[CH2:29][CH2:28][C:15]3([CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:19][CH2:20]3)[CH2:14][CH2:13]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)CC1
Reactant: CC(C)(C)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CCC(N3CCN(C(C)(C)C)CC3)CC2)CC1
Reaction time: 0.08 h

Procedure:
1-tert-Butylpiperazine (0.21 g, 1.49 mmol) was added to tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (see product of step (v) of the synthesis of amine AMN-06) (0.4 g, 1.49 mmol) and triethylamine (0.52 ml, 3.74 mmol) in methylene chloride (9.6 ml). The mixture was stirred for 5 min and sodium triacetoxyborohydride (0.44 g, 2.09 mmol) was then added and the mixture was stirred at room temperature overnight. Sat. NaHCO3 solution was added and, after separation of the phases, the organic phase was washed with sat. NaCl solution (2×), dried over sodium sulfate and concentrated in vacuo. Yield: 0.27 g (45%)
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.O.N.[CH2:29](O)[CH3:30]>>[C:1]1([C:7]2[N:8]=[C:9]([CH2:17][CH2:18][C:19]([O:21][CH2:29][CH3:30])=[O:20])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCO
Reactant: O=C(O)CCc1nc(-c2ccccc2)cc2ccccc12
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)CCc1nc(-c2ccccc2)cc2ccccc12

Procedure:
3-Phenyl-1-isoquinolinepropanoic acid (6.7 g) and concentrated sulphuric acid (7 cc) in ethanol (70 cc) are stirred for 20 hours at 20° C. The solution is poured into water (400 cc) and the aqueous phase alkalinised with concentrated ammonia solution. The mixture is extracted with methylene chloride (3×100 cc), and the organic phase dried and evaporated to dryness under reduced pressure. Ethyl 3-phenyl-1-isoquinolinepropionate (6.3 g), m.p. 60° C., is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:35][C:36]1[C:41]([Cl:42])=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:40]5[CH:39]=[CH:38][CH:37]=[C:36]([Cl:35])[C:41]=5[Cl:42])[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Reactant: OB(O)c1cccc(Cl)c1Cl
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cccc(Cl)c5Cl)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2,3-dichlorophenylboronic acid.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10](OCC)=[O:11])[C:5]=12.[K+].[Br-]>>[OH:11][CH2:10][C:6]1[C:5]2[N:4]([CH:3]=[CH:2][N:1]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1cccn2ccnc12
Agent: [Br-]
Agent: [K+]
Product: OCc1cccn2ccnc12

Procedure:
From 2a (yield: 82%); mp 177-479° C.; IR (KBr) 1505, 1300, 1140, 1015, 780, 735 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.99 (s, 2H), 5.65 (s, 1H), 6.78 (t, 1H, J=6.5 Hz), 7.17 (d, 1H, J=6.5 Hz), 7.27 (s, 1H), 7.59 (s, 1H), 8.08 (d, 1H, J=6.5 Hz); 13C NMR (100 MHz, CDCl3) δ 58.5, 112.5, 112.7, 121.6, 125.0, 130.0, 132.7, 144.4.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:18][NH2:19].O>CS(C)=O>[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:18][NH:19][C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1
Reactant: Cc1cc(Cl)c2cccc(O)c2n1
Reactant: NCc1ccc(Cl)c(Cl)c1
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(O)c2n1
Yield: 40.7 %

Procedure:
4-Chloro-8-hydroxy-2-methylquinoline (500 mg, 2.58 mmole) and 3,4-dichlorobenzylamine (910 mg, 5.16 mmole) in dimethylsulfoxide (5 mL) were stirred at 140° C. for 90 min in a microwave oven. Water was added and the mixture was decanted to obtain an oily residue. The residue was washed with ethyl acetate to give a brownish solid (350 mg, 41%). ESI-MS [M+H]+=333.1/337.0 calculated for C17H14Cl2N2O=333 g/mole
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=O)[CH2:2]1.Cl.[CH3:12][O:13][NH2:14].C([O-])(=O)C.[Na+]>CO>[CH3:12][O:13][N:14]=[C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][CH2:2]1
Reactant: O=C1COc2ccccc21
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CON=C1COc2ccccc21
Yield: 89.1 %

Procedure:
6.7 g (0.05 mol) of benzofuran-3-one together with 4.2 g (0.05 mol) of O-methylhydroxylamine hydrochloride and 4.1 g (0.05 mol) of sodium acetate in 50 ml of methanol are heated under reflux for 3 hours. The solvent is distilled off under reduced pressure and the reaction mixture is poured into water and extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium carbonate solution. The organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure. 7.27 g (89.2% of theory) of crude benzofuran-3-one O-methyl-oxime are obtained. For analysis, the crude product is distilled at 2 torr and 70° C. using a Kugelrohr. An oil is obtained which, both according to NMR analysis and according to HPLC analysis, comprises two stereoisomers (79% of isomer B and 21% of isomer A).
Reaction SMILES: [Cl:1][C:2]([S:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25])=[C:3]=[C:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C:18](=[CH:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.C1C[O:35][CH2:34]C1.C[O-].[Na+]>CO>[Cl:1][CH:2]([S:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25])[C:3]([O:35][CH3:34])=[C:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C:18](=[CH:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1
Reactant: C1CCOC1
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@]2(C)C(=C=C(Cl)S(=O)c3ccccc3)CC[C@@H]12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=C1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@]12C)C(Cl)S(=O)c1ccccc1

Procedure:
21-Chloro-21-(phenylsulfinyl)pregna-4,9(11),17(20),20-tetraen-3-one, (V, Example 2, 100 mg) and THF (1 ml) are slurried and cooled to 0°-5° under nitrogen. Sodium methoxide in methanol (25%, 0.05 ml) is added with stirring. The mixture is stirred 1 hr and then quenched with water (10 ml). The mixture is extracted with ethyl acetate (2×15 ml). The organic extracts are combined, backwashed with water (10 ml), dried over sodium sulfate and concentrated under reduced pressure to give the title compound.
Reaction SMILES: C(OP([C:9]([Cl:12])([Cl:11])Cl)(=O)OCC)C.[CH2:13]([O:15][C:16]([CH:18]1[CH:20]([CH:21]=O)[C:19]1([CH3:24])[CH3:23])=[O:17])[CH3:14].[Mg]>CN(C)C=O>[CH2:13]([O:15][C:16]([CH:18]1[CH:20]([CH:21]=[C:9]([Cl:11])[Cl:12])[C:19]1([CH3:23])[CH3:24])=[O:17])[CH3:14]
Reactant: CCOP(=O)(OCC)C(Cl)(Cl)Cl
Reactant: CCOC(=O)C1C(C=O)C1(C)C
Agent: [Mg]
Solvent: CN(C)C=O
Product: CCOC(=O)C1C(C=C(Cl)Cl)C1(C)C
Temperature: 25 °C
Yield: 60 %

Procedure:
A mixture of 25.5 g (0.1 mole) of trichloromethanephosphonic acid diethyl ester and 17.2 g (0.1 mole) of 3-formyl-2,2-dimethyl-cyclopropane-1-carboxylic acid ethyl ester was added dropwise to 9.6 g of activated magnesium filings in 100 ml of dimethylformamide in a manner such that the reaction temperature did not exceed 60° C. When the exothermic reaction had ended, the reaction mixture was allowed to cool to room temperature. It was then filtered. 200 ml of water were added to the filtrate; this solution was extracted twice with 100 ml of methylene chloride each time. The combined methylene chloride extracts were dried over sodium sulphate and filtered. The filtrate was distilled. 3-(2,2-Dichloro-vinyl)-2,2-dimethyl-cyclopropane-1-carboxylic acid ethyl ester was obtained in a yield of 60% of theory.
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[C:7]([CH:9]=[O:10])[CH:6]=[CH:5][CH:4]=1.[CH3:11][CH2:12][O:13][C:14]([CH:16](P(OCC)(OCC)=O)[CH3:17])=[O:15].C[O-].[Na+]>CN(C=O)C.CO>[OH:10][CH2:9][C:7]1[N:8]=[C:3](/[CH:2]=[C:16](\[CH3:17])/[C:14]([O:13][CH2:12][CH3:11])=[O:15])[CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1cccc(CO)n1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCOC(=O)/C(C)=C/c1cccc(CO)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 50.9 %

Procedure:
6-hydroxymethylpyridine-2-carbaldehyde (2.95 g) and triethyl 2-phosphonopropionate (5.12 g) were dissolved in 20 mL of dry DMF, and to the solution was added a solution of 1.30 g of sodium methoxide in 10 mL of methanol dropwise, and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was thrown into ice-water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (hexane-ethyl acetate=1:1) to give 2.42 g of ethyl (E)-3-(6-hydroxymethylpyridin-2-yl)-2-methylacrylate as a colorless oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([NH2:11])[CH:9]=[CH:10][C:2]1=2.[CH2:12]([N:19]1[CH2:28][CH2:27][C:26]2[C:25](Cl)=[N:24][CH:23]=[N:22][C:21]=2[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(#N)C>[CH2:12]([N:19]1[CH2:28][CH2:27][C:26]2[C:25]([NH:11][C:8]3[CH:9]=[CH:10][C:2]4[O:1][CH2:6][CH2:5][O:4][C:3]=4[CH:7]=3)=[N:24][CH:23]=[N:22][C:21]=2[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: Clc1ncnc2c1CCN(Cc1ccccc1)C2
Solvent: CC#N
Product: c1ccc(CN2CCc3c(ncnc3Nc3ccc4c(c3)OCCO4)C2)cc1

Procedure:
The title compound was prepared using the general procedure set forth in Example 2, above, using 2,3-dihydrobenzo[b][1,4]dioxin-6-amine (0.32 mL, 2.63 mmol) and 7-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine, prepared as described in Example 1.B. (0.621 g, 2.39 mmol) in acetonitile (3 mL). The title compound was obtained as a brown solid (0.756 g, 84%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:16][C:17](=[O:19])[CH3:18])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[F:15])[CH:7]=1.[Br:20][C:21]1[CH:26]=[CH:25][C:24](F)=[C:23]([N+:28]([O-:30])=[O:29])[CH:22]=1.[F-].[K+]>CN(C=O)C>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([NH:1][C:2]2[CH:3]=[C:4]([NH:16][C:17](=[O:19])[CH3:18])[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=3[F:15])[CH:7]=2)=[C:23]([N+:28]([O-:30])=[O:29])[CH:22]=1
Reactant: CC(=O)Nc1cc(N)cc(-c2ccc(F)cc2F)c1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(Nc2ccc(Br)cc2[N+](=O)[O-])cc(-c2ccc(F)cc2F)c1
Yield: 45 %

Procedure:
A solution of N-(5-amino-2′,4′-difluorobiphenyl-3-yl)acetamide (3.0 g, 11.44 mmol), 4-bromo-1-fluoro-2-nitrobenzene (2.52 g, 11.44 mmol, 1.0 eq.) and potassium fluoride (0.663 g, 11.44 mmol, 1.0 eq.) in DMF was heated at 130° C. for 5 h. The mixture was quenched and extracted as in Example 1(d). The solvent was distilled off under reduced pressure and the crude residue was purified by column chromatography (60-120 silica gel, 40% ethyl acetate in hexane) to afford the product in 45% yield (2.4 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][C:5]2[C:10]=1[C:9](=[O:11])[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[N:6]=2.[O:18]1[CH:22]=[CH:21][CH2:20][CH2:19]1.B(F)(F)F.CCOCC>CN(C=O)C>[O:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[N:4]1[C:5]2=[N:6][C:7]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[N:8][C:9](=[O:11])[C:10]2=[C:2]([CH3:1])[NH:3]1
Reactant: CC1=C2C(=O)N=C(c3ccncc3)N=C2N=N1
Reactant: C1=COCC1
Agent: FB(F)F
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1[nH]n(C2CCCO2)c2nc(-c3ccncc3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 108 h
Yield: 37 %

Procedure:
A solution of 3-methyl-6-(4-pyridyl)-pyrazolo[3,4-d]-pyrimidin-4-one (2.3 g, 0.01 mol), DMF (50 ml) and 2,3-dihydrofuran (14.0 g, 0.20 mol) was stirred at 0° C. for 10 minutes and BF3. Et2O (1.5 ml, 0.012 mol) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 108 hours. The reaction was quenched with concentrated ammonium hydroxide until pH of 7.5 and the resulting precipitate was collected by filtration. The solid residue was taken up in isopropanol (200 ml), heated to reflux and filtered to remove insoluble material. Concentration of the filtrate to 75 ml and cooling caused precipitation of the product. The product was collected by filtration and washed with ether to afford 1.1 g (37%) of 1-(2-tetrahydrofuranyl)-3-methyl-6-(4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-one as a white powder, m.p. 268°-9° C. when dried at 70° C. in high vacuum.
Reaction SMILES: C[O:2][C:3](=[O:46])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28]CC3C=CC=CC=3)[C:25]([C:36]3[N:37]=[CH:38][O:39][CH:40]=3)=[CH:24][C:23]=2[CH2:41][CH3:42])[C:12]=1[CH2:43][CH2:44][CH3:45].B(F)(F)F.CCOCC.CCOCC>C(S)C>[CH2:41]([C:23]1[CH:24]=[C:25]([C:36]2[N:37]=[CH:38][O:39][CH:40]=2)[C:26]([OH:28])=[CH:27][C:22]=1[O:21][CH2:20][CH2:19][CH2:18][O:17][C:13]1[C:12]([CH2:43][CH2:44][CH3:45])=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([OH:46])=[O:2])[CH3:42]
Reactant: CCCc1c(OCCCOc2cc(OCc3ccccc3)c(-c3cocn3)cc2CC)cccc1Oc1ccccc1C(=O)OC
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCS
Product: CCCc1c(OCCCOc2cc(O)c(-c3cocn3)cc2CC)cccc1Oc1ccccc1C(=O)O
Yield: 46.9 %

Procedure:
To a solution of 2-{3-[3-(5-benzyloxy-2-ethyl-4-oxazol-4-yl-phenoxy)propoxy]-2-propylphenoxy}benzoic acid methyl ester (89 mg, 0.14 mmol) in ethanethiol (2 mL) was treated with boron trifluoride etherate (0.27 mL, 2.2 mmol) at room temperature for 4 h. The solution was poured into ether and washed once with water, once with saturated sodium bicarbonate solution, once with saturated sodium chloride solution, dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 15% ethyl acetate/85% hexane) of the residue provided 34 mg (45%) of the title product as a light brown oil. 1H NMR (CDCl3) δ 7.99 (d, J=1 Hz, 1H), 7.90 (d, J=1 Hz, 1H), 7.88 (dd, J=8, 2 Hz, 1H), 7.38 (t, J=7 Hz, 1H), 7.15 (s, 1H), 7.10 (d, J=9 Hz, 1H), 7.06 (d, J=9 Hz, 1H), 6.81 (d, J=9 Hz, 1H), 6.70 (d, J=9 Hz, 1H), 6.52 (s, 1H), 6.44 (d, J=9 Hz, 1H), 4.20 (m, 4H), 3.83 (s, 3H), 2.65 (t, J=8 Hz, 2H), 2.58 (q, J=8 Hz, 2H), 2.33 (quintet, J=6 Hz, 2H), 1.55 (hextet, J=7 Hz, 2H), 1.17 (t, J=8 Hz, 3H), 0.91 (t, J=8 Hz, 3H); MS ES+m/e=532 (p+1).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([S:13]([CH2:16][CH:17]2[CH2:19][CH2:18]2)(=[O:15])=[O:14])[CH2:10][C@H:9]1[C:20](=[O:27])[NH:21][C:22]1([C:25]#[N:26])[CH2:24][CH2:23]1)=O)(C)(C)C.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>ClCCl>[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[C:25]([C:22]1([NH:21][C:20]([C@@H:9]2[CH2:10][C@@H:11]([S:13]([CH2:16][CH:17]3[CH2:18][CH2:19]3)(=[O:15])=[O:14])[CH2:12][NH:8]2)=[O:27])[CH2:24][CH2:23]1)#[N:26]
Reactant: CC(C)(C)OC(=O)N1C[C@H](S(=O)(=O)CC2CC2)C[C@H]1C(=O)NC1(C#N)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)CC3CC3)CN2)CC1

Procedure:
In analogy to the procedure described in example 409f, (2S,4R)-2-(1-cyano-cyclopropylcarbamoyl)-4-cyclopropylmethanesulfonyl-pyrrolidine-1-carboxylic acid tert-butyl ester was treated with trifluoroacetic acid in dichloromethane to give the title compound which was used in next step without further purification. MS: m/z=299.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][S:10]([CH3:13])(=[O:12])=[O:11].[Cl:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>>[Cl:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:5]=1)=[O:20]
Reactant: O=C(Cl)CCCCCl
Reactant: COc1ccccc1NS(C)(=O)=O
Product: COc1ccc(C(=O)CCCCCl)cc1NS(C)(=O)=O

Procedure:
Using N-(2-methoxyphenyl)methanesulfonamide (10.0 g) and 5-chlorovaleryl chloride (7.06 ml) according to the same method as that of Reference Example 1, the title compound (9.15 g) was obtained as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[O:12]C.[CH3:14][Li].Cl>O1CCCC1.C(OCC)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([CH3:14])[CH2:6][C:5]2=[O:12]
Reactant: COc1ccnc2ccc(F)cc12
Reactant: [Li]C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1CC(=O)c2cc(F)ccc2N1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
A stirred solution of 25.8 g (0.146 mole) of 6-fluoro-4-methoxyquinoline from example 3 in 300 ml of tetrahydrofuran was heated under a nitrogen atmosphere to its reflux temperature and then cooled to -20° C. To the cold solution was added 90 ml of 182 M methyl lithium in diethyl ether over a period of 0.5 hour. After adding 40 ml of the solution, the reaction temperature was allowed to rise to 0° C. After the addition of methyl lithium was completed, the reaction temperature was allowed to rise to 15° C. The solution was then poured into 1200 ml of a mixture of ice water and hydrochloric acid. After stirring for 0.5 hour the mixture was extracted with about 1200 ml of diethyl ether. The organic layer was dried, filtered and evaporated in vacuo to provide a yellow solid. The product was recrystallized from carbon tetrachloride to give 9.5 g. (37% yield) of 6-fluoro-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.[NH2:19][CH2:20][CH2:21][NH:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:19][CH2:20][CH2:21][NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: NCCNS(=O)(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(NCCNS(=O)(=O)c2ccc(Cl)cc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, N-(2-aminoethyl)-p-chlorobenzenesulfonamide hydrochloride and DBU in DME. ES-MS m/e (%): 419 (M+H+, 100).
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[N:10]=[N:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[CH:15]1([CH2:20][CH2:21][CH2:22]I)[CH2:19][CH2:18][CH2:17][CH2:16]1>CN(C)C=O>[CH:15]1([CH2:20][CH2:21][CH2:22][N:10]2[C:11](=[O:12])[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[N:9]2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=c1nn[nH]n1-c1ccccc1
Reactant: ICCCC1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=c1n(CCCC2CCCC2)nnn1-c1ccccc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 83.4 %

Procedure:
To a solution of 600 mg of 1-phenyl-5-tetrazolone (for the synthesis of this compound see: Horwitz, J. P.; Fisher, B. E.; Tomasewski, A. J. J Amer Chem Soc 1959, 81, 3076) in 2 mL of N,N-dimethylformamide (DMF) was added 280 mg of powdered 85% potassium hydroxide followed by 870 mg of 3-cyclopentyl-1-iodopropane from Step A. The mixture was stirred at 80° C. for 18 h and then quenched by addition of water. The product was extracted with dichloromethane and purification by flash chromatography on silica gel (9:1 hexane:ethyl acetate) afforded 830 mg of the title compound: 1H NMR (CDCl3) δ7.96 (d, 2H, J=8.5 Hz), 7.50 (t, 2H, J=7.5 Hz), 7.37 (t, 1H, J=7.5 Hz), 4.02 (t, 2H, J=7.1 Hz), 1.90 (m, 3H), 1.79 (m, 2H), 1.61 (m, 2H), 1.53 (m, 2H), 1.41 (m, 2H), 1.10 (m, 2H).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)[CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:31]1[C:43]2[CH:42]([CH2:44][O:45][C:46]([NH:48][C@H:49]([C:51](O)=[O:52])[CH3:50])=[O:47])[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35]=2[CH:34]=[CH:33][CH:32]=1>>[Si:1]([O:8][CH2:9][CH2:10][N:11]([CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=2)[CH:14]=1)[C:51](=[O:52])[C@H:49]([CH3:50])[NH:48][C:46]([O:45][CH2:44][CH:42]1[C:41]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:35]2[C:43]1=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:47])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COc1cc(-c2cc(CNCCO[Si](C)(C)C(C)(C)C)ccn2)cc(OC)c1OC
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Product: COc1cc(-c2cc(CN(CCO[Si](C)(C)C(C)(C)C)C(=O)[C@H](C)NC(=O)OCC3c4ccccc4-c4ccccc43)ccn2)cc(OC)c1OC

Procedure:
N-[2-(tert-Butyldimethylsilyloxy)ethyl]-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amine (756 mg) and N-(9-fluorenylmethoxycarbonyl)-L-alanine (544 mg) were treated in the same manner as in Preparation Example 9 to obtain the title compound. Since this compound was unable to be isolated from impurities, it was used in the next reaction without purifying it as it is.
Reaction SMILES: O[CH:2]([C:4]1[CH:21]=[CH:20][C:7]2/[C:8](=[CH:17]/[C:18]#[N:19])/[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[CH2:11][CH2:12][C:6]=2[CH:5]=1)[CH3:3].[CH2:22]([C:24]1[NH:34][C:27]2=[N:28][C:29]([CH3:33])=[CH:30][C:31]([CH3:32])=[C:26]2[N:25]=1)[CH3:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH2:22]([C:24]1[N:34]([CH:2]([C:4]2[CH:21]=[CH:20][C:7]3/[C:8](=[CH:17]/[C:18]#[N:19])/[C:9]4[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=4[CH2:11][CH2:12][C:6]=3[CH:5]=2)[CH3:3])[C:27]2=[N:28][C:29]([CH3:33])=[CH:30][C:31]([CH3:32])=[C:26]2[N:25]=1)[CH3:23]
Reactant: CC(O)c1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Reactant: CCc1nc2c(C)cc(C)nc2[nH]1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1nc2c(C)cc(C)nc2n1C(C)c1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.6 %

Procedure:
[step 3] (E)-[2-(1-Hydroxyethyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (100 mg, 0.36 mmol) obtained in step 2 and 2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (193 mg, 1.10 mmol) were dissolved in THF (1.5 mL), polymer-supported triphenylphosphine (734 mg, 15 mmol) and di-tert-butyl azodicarboxylate (70 mg, 0.305 mmol) were added, and the mixture was stirred at room temperature for 1 hr. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=40/60 to 30/70) to give (E)-{2-[1-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)ethyl]-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile (71 mg, 45%).