Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]3[CH:12]=[N:13][N:14]([CH3:15])[C:6]3=[C:5](Cl)[C:4]=2[CH:3]=1.C([Sn]([CH2:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[C:34]#[N:35])(CCCC)CCCC)CCC.[OH2:39]>CN(C)P(N(C)C)(N(C)C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:15][N:14]1[C:6]2[C:5](=[O:39])[C:4]3[CH:3]=[C:2]([CH2:30][C:31]4[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=4)[C:34]#[N:35])[CH:11]=[CH:10][C:9]=3[NH:8][C:7]=2[CH:12]=[N:13]1
Reactant: Cn1ncc2nc3ccc(Br)cc3c(Cl)c21
Reactant: CCCC[Sn](CCCC)(CCCC)Cc1cccc(C#N)c1
Reactant: O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cn1ncc2[nH]c3ccc(Cc4cccc(C#N)c4)cc3c(=O)c21
Temperature: 70 °C
Reaction time: 14 h
Yield: 64 %

Procedure:
A mixture of 7-bromo-9-chloro-1-methyl-1H-pyrazolo[4,3-b]quinoline (EXAMPLE 19, step 2, 800 mg, 2.70 mmol), 3-[(tributylstannyl)methyl]benzonitrile ((H. Azizian et al., J. Organomet. Chem., 1981, 215, 49), 1.21 g, 2.97 mmol), dichlorobis(triphenylphosphine)palladium (II) (189 mg, 0.27 mmol) in hexamethylphosphoramide (15 ml) was stirred at 70° C. for 14 h. After cooling to room temperature, water (150 ml) was added, and extracted with ethyl acetate (300 ml×3). The combined organic layer was washed with water (100 ml), dried over magnesium sulfate, and concentrated in vacuo. The residue was chromatographed on a column of silica gel eluting with ethyl acetate/hexane (1:1.5 to 1:1) to give 572 mg (64%) of the title compound as a yellow solid.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][C@@H:12]3[CH2:14][C@H:9]2[CH2:10][N:11]3[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:4][CH:3]=1.[C:22]1([C:28]#[CH:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(C(C)C)CC)(C)C.[OH-].[Na+]>[Cu]I.O1CCOCC1>[NH3:6].[C:18]([O:17][C:15]([N:11]1[CH2:10][C@@H:9]2[CH2:14][C@H:12]1[CH2:13][N:8]2[C:5]1[N:6]=[N:7][C:2]([C:29]#[C:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:3][CH:4]=1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: C#Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1ccc(Br)nn1
Agent: [Cu]I
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1ccc(C#Cc2ccccc2)nn1
Product: N
Temperature: 100 °C
Reaction time: 40 h

Procedure:
A mixture of 2-[6-bromo-3-pyridazinyl]-(1S,4S)-5-tert-butoxycarbonyl-2,5-diazabicyclo-[2.2.1]-heptane (2.0 g; 5.6 mmol), phenylacetylene (2.4 ml; 22.6 mmol), palladacycle (105 mg; 0.11 mmol), CuI (106 mg; 0.56 mmol), diisopropylethylamine (0.97 ml; 5.6 mmol) and dioxane (20 ml) was stirred at 100° C. for 40 hours. Aqueous sodium hydroxide (50 ml; 1 M) was added. The mixture was extracted with dichloromethane (3×50 ml). Chromatography on silica gel with dichloromethane, methanol and conc. ammonia (89:10:1) gave the title compound as free base. Yield 1.0 g (48%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH:3]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4][C:5]([O:7]CC)=[O:6].[OH-].[Na+]>C1COCC1.CCO>[F:1][C:2]([F:17])([F:18])[CH:3]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4][C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)CC(Cc1ccccc1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CC(Cc1ccccc1)C(F)(F)F
Yield: 100.7 %

Procedure:
Ethyl ester (176) (1.08 g, 4.15 mmol) was saponified with 1 N NaOH in THF and EtOH to give 0.97 g (˜100%) of the title compound (177) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 2.41 (dd, J1=16.9 Hz, J2=5.8 Hz, 1H), 2.50-2.70 (m, 2H), 3.00-3.15 (m, 2H), 7.15-7.25 (m, 3H), 7.27-7.33 (m, 2H). LCMS (ESI): m/z 231 (M−H)−.
Reaction SMILES: [CH2:1]=CC1C=CC=CC=1.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH:10]=[CH2:11]>>[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH:10]=[CH2:11].[C:9]([OH:13])(=[O:12])[C:10]([CH3:1])=[CH2:11]
Reactant: C=Cc1ccccc1
Agent: C=CC(=O)OCC
Product: C=C(C)C(=O)O

Procedure:
styrene -- ethyl acrylate copolymer
Reaction SMILES: [F:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([C@H:8]([CH3:18])[CH2:9][C@:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH:24]=[CH:25][C:26](=[O:32])[NH:27]2>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[F:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([C@H:8]([CH3:18])[CH2:9][C@:10]([OH:17])([C:13]([F:14])([F:15])[F:16])[CH:11]=[N:21][C:22]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:23]=2[CH:24]=[CH:25][C:26](=[O:32])[NH:27]3)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(F)cccc1[C@H](C)C[C@@](O)(C=O)C(F)(F)F
Reactant: Nc1cccc2[nH]c(=O)ccc12
Agent: [Ti+4]
Agent: CC[O-]
Product: COc1c(F)cccc1[C@H](C)C[C@@](O)(C=Nc1cccc2[nH]c(=O)ccc12)C(F)(F)F

Procedure:
In the same way as in Example 1, 250 mg (0.46 mmol) of (2R*,4R*)-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanal, 132 mg (0.63 mmol) of 5-aminoquinolone and 0.4 ml of titanium tetraethoxide are reacted to give 5-{[(2R*,4R*)-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentylidene]amino}quinolin-2(1H)-one. 64 mg of imine purified by column chromatography (silica gel, hexane/ethyl acetate 0-75%) are cyclized in the same way as in Example 1 at −30° C. using 1.5 ml (1.5 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 0-75%) yields 52 mg of product.
Reaction SMILES: [Cl:1][CH2:2][C:3]#[N:4].[Na].Cl.[C:7]([O:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)(=[O:9])[NH2:8]>CO>[ClH:1].[C:7]([O:10][CH:11]1[CH2:16][CH2:15][N:14]([C:3](=[NH:4])[CH2:2][Cl:1])[CH2:13][CH2:12]1)(=[O:9])[NH2:8]
Reactant: NC(=O)OC1CCNCC1
Reactant: N#CCCl
Agent: Cl
Agent: [Na]
Solvent: CO
Product: N=C(CCl)N1CCC(OC(N)=O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.29 ml of chloroacetonitrile were added to a solution of 192 mg of metallic sodium in 80 ml of anhydrous methanol, and the mixture was stirred at room temperature for one hour. 15.10 g of 4-carbamoyloxypiperidine hydrochloride were than added, and the mixture was stirred for a further 2 hours. The reaction mixture was worked up in the same manner as in Example 1(1), giving 21.00 g of 2-(4-carbamoyloxypiperidin-1-yl)-2-iminoethylchloride hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:10]=[C:6]2[N:5]=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O>ClCCl>[Br:17][C:10]1[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][N:7]2[C:2]([Cl:1])=[CH:3][CH:4]=[N:5][C:6]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1ccnc2cc(-c3ccccc3)nn12
Solvent: ClCCl
Product: Clc1ccnc2c(Br)c(-c3ccccc3)nn12
Reaction time: 0.5 h
Yield: 81 %

Procedure:
7-Chloro-2-phenylpyrazolo[1,5-α]pyrimidine (0.1 g, 0.44 mmol, prepared as described in J. Med. Chem. 1981, 24, 610) was dissolved in dichloromethane (5 mL) and to this solution was added N-bromosuccinimide (108 mg, 0.61 mmol). The resulting reaction mixture was stirred for 30 minutes. Additional dichloromethane was added and the mixture was extracted with sodium hydroxide (1N), water and a saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered and concentrated. The resulting solid was purified by silica gel chromatography (ethyl acetate:hexane 1:2) to give 110 mg (82%) of 3-bromo-7-chloro-2-phenylpyrazolo[1,5-α]pyrimidine as a yellow solid.
Reaction SMILES: CO.C(=O)([O-])[O-].[K+].[K+].C([O:12][CH2:13][C:14](=[O:35])[C@@H:15]1[C@:32]2([CH3:33])[C@H:18]([C@H:19]3[C@H:29]([CH2:30][CH2:31]2)[C@:27]2([CH3:28])[C:22](=[CH:23][C:24](=[O:34])[CH2:25][CH2:26]2)[CH:21]=[CH:20]3)[CH2:17][CH2:16]1)(=O)C.[CH3:36][C:37]([SH:39])=[O:38]>C(Cl)Cl>[C:37]([S:39][C@@H:20]1[CH2:21][C:22]2[C@:27]([CH3:28])([CH2:26][CH2:25][C:24](=[O:34])[CH:23]=2)[C@@H:29]2[C@@H:19]1[C@H:18]1[C@:32]([CH3:33])([CH2:31][CH2:30]2)[C@@H:15]([C:14](=[O:35])[CH2:13][OH:12])[CH2:16][CH2:17]1)(=[O:38])[CH3:36]
Reactant: CC(=O)S
Reactant: CC(=O)OCC(=O)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: CC(=O)S[C@@H]1CC2=CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(=O)CO)CC[C@H]3[C@H]12

Procedure:
The product of Example 3 was hydrolyzed by treating 0.5 g of the 21-acetoxy derivative in 8 ml methylene chloride with 10 ml methanol and 4 ml 0.2M aqueous potassium carbonate at room temperature under nitrogen for 30 minutes. The hydrolyzed product was extracted with methylene chloride, washed with water, dried and evaporated. A sample obtained by preparative high performance liquid chromatography showed M+ =404 daltons. An identical product was obtained by a different synthetic route involving alkaline hydrolysis of 21-acetoxy-4,6-pregnadiene-3,20-dione to the C-21-alcohol, followed by reaction with ethanethiolic acid.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[Br:7][C:8]1[CH:9]=[C:10]([C:29]#[C:30][Si](C)(C)C)[C:11]([N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N:12][CH:13]=1>CN(C=O)C.CCOC(C)=O.O>[Br:7][C:8]1[CH:9]=[C:10]([C:29]#[CH:30])[C:11]([N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[N:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)cc1C#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C#Cc1cc(Br)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.2 %

Procedure:
2M aqueous Na2CO3 (639.0 μL, 1.278 mmol) was added to a stirred solution of tert-butyl N-[5-bromo-3-(2-trimethylsilylethynyl)-2-pyridyl]-N-tert-butoxycarbonyl-carbamate (500 mg, 1.065 mmol) in DMF (1.5 mL) and the resulting suspension stirred at ambient temperature for 18 hours. The reaction mixture was diluted with EtOAc and water and the layers separated. The aqueous layer was extracted with EtOAc (×2) and the combined organic extracts washed with water (×3), brine (×2), dried (MgSO4), filtered and concentrated in vacuo to give the sub-title compound as an off-white solid (424 mg, 100% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.34 (s, 18H), 4.78 (s, 1H), 8.38 (d, J=2.4 Hz, 1H) and 8.66 (d, J=2.4 Hz, 1H) ppm; MS (ES+) 399.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH2:13][CH3:14])=[C:10]([CH:15]3[C:19](=[O:20])[CH:18]=[CH:17][C:16]3=[O:21])[CH:9]=2)=[CH:4][CH:3]=1.[I-].[Mg+2].[I-].[O:25]1[CH:29]=[CH:28][CH:27]=[CH:26]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([CH2:13][CH3:14])=[C:10]([CH:15]3[C:16](=[O:21])[CH:17]4[CH:18]([CH:26]5[O:25][CH:29]4[CH:28]=[CH:27]5)[C:19]3=[O:20])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: c1ccoc1
Reactant: CCc1sc(-c2ccc(Cl)cc2)cc1C1C(=O)C=CC1=O
Agent: [I-]
Agent: [Mg+2]
Product: CCc1sc(-c2ccc(Cl)cc2)cc1C1C(=O)C2C3C=CC(O3)C2C1=O
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a stirred solution of 2-[5-(4-chloro-phenyl)-2-ethyl-thiophen-3-yl]-cyclopent-4-ene-1,3-dione (248 mg, 0.78 mmol) in furan (3 ml) is added magnesium iodide (44 mg, 0.15 mmol) and the reaction allowed to stir at room temperature for 4 days. The crude reaction mixture is purified by flash chromatography to give 4-[5-(4-chloro-phenyl)-2-ethyl-thiophen-3-yl]-10-oxa-tricyclo[5.2.1.0*2,6*]dec-8-ene-3,5-dione as a white solid (180 mg).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([O:11][CH3:12])=[O:10])[CH:4]=1.Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15].[Cl-].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([Zn+])=[C:27]([F:32])[C:26]=1[O:33][CH3:34]>C1COCC1>[C:17]1([O:16][C:14]([N:6]2[CH:7]([C:28]3[CH:29]=[CH:30][C:25]([Cl:24])=[C:26]([O:33][CH3:34])[C:27]=3[F:32])[CH2:8][C:3](=[O:2])[CH:4]=[C:5]2[C:9]([O:11][CH3:12])=[O:10])=[O:15])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1c(Cl)ccc([Zn+])c1F
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COC(=O)c1cc(OC)ccn1
Agent: [Cl-]
Solvent: C1CCOC1
Product: COC(=O)C1=CC(=O)CC(c2ccc(Cl)c(OC)c2F)N1C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 57.1 %

Procedure:
Methyl 4-methoxypicolinate (11.92 g, 0.0713 mol) was dissolved in anhydrous THF (300 mL) under N2. The solution was cooled in an ice bath. Neat phenyl chloroformate (10.5 mL, 0.0837 mol) was added. After 45 min the stock solution of (4-chloro-2-fluoro-3-methoxyphenyl)zinc(II) chloride (1.19 M in THF, 76.0 mL, 0.0904 mol) was added dropwise over 1 h. The solution was stirred at room temperature for 3 days (d) and then quenched by addition of a saturated aqueous ammonium chloride (NH4Cl) solution (200 mL). The organic layer was separated, and the aqueous layer was extracted with ether (2×100 mL). The combined organic extracts were washed with H2O and then brine. The solution was dried (MgSO4) and evaporated to a bright yellow liquid which was dissolved in THF (250 mL) and 1 M HCl (250 mL). The reaction mixture was stirred at room temperature for 2 d and then neutralized with saturated NaHCO3 solution. The reaction mixture was extracted with ether. The ether extracts were washed with H2O followed by brine, then dried (MgSO4) and evaporated to a yellow oil. The crude product was purified by silica gel chromatography (hexane-EtOAc gradient) to give a yellow oil. The oil was crystallized from MeOH to give 6-(4-chloro-2-fluoro-3-methoxyphenyl)-4-oxo-5,6-dihydro-4H-pyridine-1,2-dicarboxylic acid 2-methyl ester 1-phenyl ester (15; 17.67 g, 57%) as a white solid: mp 112-114° C.; 1H NMR (300 MHz, CDCl3) δ 7.40 (m, 2H), 7.27 (m, 1H), 7.14 (m, 4H), 6.22 (d, J=6.6 Hz, 1H, H6), 5.90 (d, J=1.2 Hz, 1H, H3), 3.97 (d, JF-H=0.9 Hz, 3H, OMe), 3.87 (s, 3H, CO2Me), 3.30 (dd, J=6.6, 17.4 Hz, 1H, H5a), 3.05 (d, J=18 Hz, 1H, H5b); 13C{1H} NMR (75.4 MHz, CDCl3) δ 191.7 (C4), 163.8 (CO2Me), 153.9 (d, JF-C=250 Hz, C2′), 151.0, 150.3, 145.0, 144.8, 129.6 (meta Ph), 128.8 (d, JF-C=3 Hz, C4′), 126.5 (para Ph), 125.2 (d, JF-C=3 Hz, C5′), 124.5 (d, JF-C=12 Hz, C1′), 121.0 (d, JF-C=4 Hz, C6′), 120.9 (ortho Ph), 114.5 (C3), 61.6 (d, JF-C=5 Hz, OMe), 53.8, 53.4, 41.6; Anal. Calcd for C21H17ClFNO6: C, 58.14; H, 3.95; N, 3.23. Found: C, 57.82; H, 3.90; N, 3.18.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:13]=[C:12]2[C:7]([C:8](=O)CC(CC)=N2)=[CH:6][CH:5]=1.[Cl:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[C:20](=[O:30])[CH2:21][C:22]([CH2:28][CH3:29])=[N:23]2.[H][H].C(Br)C1C=CC=CC=1>CN(C=O)C>[CH2:8]([O:30][C:20]1[C:19]2[C:24](=[CH:25][CH:26]=[CH:27][C:18]=2[Cl:17])[N:23]=[C:22]([CH2:28][CH3:29])[CH:21]=1)[C:7]1[CH:12]=[CH:13][CH:4]=[CH:5][CH:6]=1
Reactant: CCC1=Nc2cccc(Cl)c2C(=O)C1
Reactant: [H][H]
Reactant: CCC1=Nc2cc(Cl)ccc2C(=O)C1
Agent: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cc(OCc2ccccc2)c2c(Cl)cccc2n1
Reaction time: 18 h

Procedure:
Sodium hydride (60% dispersion in mineral oil; 1.95 g) was added to a stirred solution of a mixture of 7-chloro-2-ethyl-4-quinolone and 5-chloro-2-ethyl-4-quinolone (43.5:56.5, 10 g) in DMF (100 ml). The mixture was stirred until evolution of hydrogen had ceased and benzylbromide (8.25 g) was added. The mixture was stirred for 18 hours. The solvent was removed by evaporation and the residue partitioned between water (80 ml) and dichloromethane (2×100 ml). The organic layer was washed with saturated sodium chloride solution (50 ml) and dried (MgSO4). The solvent was removed by evaporation and the resultant yellow oil was purified by flash chromatography, eluting with increasing concentration of ethyl acetate in dichloromethane. The product was eluted with ethyl acetate/dichloromethane (10:90 v/v) to give 4-benzyloxy-5-chloro-2-ethylquinoline as a white solid (2.6 g), m.p. 78°-80° C.; NMR: 1.39(t,3H), 2.94(q,2H), 5.38(s,2H), 6.72(s,1 H), 7.30-7.55(m,6H), 8.0(d,1H), 8.13(d,1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([CH3:19])=[CH:5][C:6]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[N:7][C:8]=1[O:9][CH3:10].[Br:20][C:21]1[CH:22]=[C:23]([C:34](O)=[O:35])[C:24]2[C:25]([CH3:33])=[CH:26][N:27]([CH:30]([CH3:32])[CH3:31])[C:28]=2[CH:29]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[Br:20][C:21]1[CH:22]=[C:23]([C:34]([NH:1][CH2:2][C:3]2[C:4]([CH3:19])=[CH:5][C:6]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[N:7][C:8]=2[O:9][CH3:10])=[O:35])[C:24]2[C:25]([CH3:33])=[CH:26][N:27]([CH:30]([CH3:31])[CH3:32])[C:28]=2[CH:29]=1
Reactant: Cc1cn(C(C)C)c2cc(Br)cc(C(=O)O)c12
Reactant: COc1nc(NC(=O)OC(C)(C)C)cc(C)c1CN
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1nc(NC(=O)OC(C)(C)C)cc(C)c1CNC(=O)c1cc(Br)cc2c1c(C)cn2C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a stirred solution of tert-butyl (5-(aminomethyl)-6-methoxy-4-methylpyridin-2-yl)carbamate (0.40 g, 1.496 mmol), 6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxylic acid (0.44 g, 1.486 mmol), and HOAt (0.21 g, 1.543 mmol) in DMF (25 mL) was added EDC free base (0.25 g, 1.610 mmol). The reaction was stirred at RT overnight then evaporated to dryness under vacuum. The remaining was purified by silica gel chromatography (Analogix, SF25-60 g, 0 to 30% EtOAc in hexanes) to give the product tert-butyl (5-((6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxamido)methyl)-6-methoxy-4-methylpyridin-2-yl)carbamate (0.81 g, 1.485 mmol, 99% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=9.42 (s, 1 H), 8.41 (t, J=4.8 Hz, 1 H), 7.77 (d, J=1.5 Hz, 1 H), 7.33 (s, 1 H), 7.21 (s, 1 H), 6.99 (d, J=1.8 Hz, 1 H), 4.40 (d, J=5.1 Hz, 2 H), 3.81 (s, 3 H), 2.35 (s, 3 H), 2.10 (d, J=1.0 Hz, 3 H), 1.47 (s, 9 H), 1.38 (d, J=6.6 Hz, 6 H). MS(ES)+m/e 545.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9]O)[CH2:4][CH2:3]1.[Na].[CH3:12][O:13][C:14]1[CH:31]=[CH:30][C:17]([CH:18]=[CH:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][N:21]=2)=[CH:16][CH:15]=1>>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([CH:18]=[CH:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][N:21]=2)=[CH:30][CH:31]=1.[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH3:9])[CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc(C=Cc2ccc(OC)cc2)nc1
Reactant: CN1CCN(CCO)CC1
Agent: [Na]
Product: CCN1CCN(C)CC1
Product: COc1ccc(C=Cc2ccc(C(=O)O)cn2)cc1
Reaction time: 8 h

Procedure:
The apparatus and procedures of Example 3 were used, employing 2-(N-methyl-N'-piperazinyl)ethan-1-ol (42.7 g.), sodium (0.2 g.), methyl 6-p-methoxystyrylnicotinate (13.46 g.), and a temperature of 70° C. for 8 hours. The crude ester was treated to give the dimaleate of N-methyl-N'-ethylpiperazine 6-p-methoxystyrylnicotinate, m.p. 214°-215° C.
Reaction SMILES: O1CCOCC1.[OH:7][CH:8]1[CH:12]([CH2:13][CH:14]=[CH2:15])[C:11](=[O:16])[CH:10]=[CH:9]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C(OCC)(=O)C.CCCCCC>[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: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C=CCC1C(=O)C=CC1=O
Reaction time: 16 h
Yield: 91.3 %

Procedure:
Into 6 ml of dioxane, were dissolved 500 mg of 4-hydroxy-5-allyl-2-cyclopentenone and 450mg of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. The solution was left standing at room temperature for 16 hours and the precipitated 2,3-dichloro-5,6-dicyanohydroquinone was collected by filtration and washed with methylene chloride. The filtrate together with the washings was concentrated. The concentration residue was dissolved in 50 ml of methylene chloride, washed with a 10% aqueous sodium hydroxide solution, then with water until the washings had become neutral. The residue thus treated was dried over anhydrous sodium sulfate, stripped of the solvent by distillation, and purified by column chromatography using 20 g of a silica gel (Wako Gel C-200) and an ethyl acetate-n-hexane (2:3 by volume) mixture as eluent, to obtain 450 mg (91% yield) of 4-keto-5-allyl-2-cyclopentenone.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=2[N+:25]([O-])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO>[NH2:25][C:18]1[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:17]=1[CH2:16][CH2:15][NH:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1
Reactant: [H][H]
Reactant: COc1ccc([N+](=O)[O-])c(CCNC2CCN(Cc3ccccc3)CC2)c1
Solvent: CO
Product: COc1ccc(N)c(CCNC2CCN(Cc3ccccc3)CC2)c1
Yield: 100.1 %

Procedure:
26.0 g (70.3 mmol) (1-benzylpiperidin-4-yl)-[2-(5-methoxy-2-nitrophenyl)-ethyl]-amine were hydrogenated with 5.00 g (2.45 mmol) rhodium charcoal (5%, moistened with water) in 350 mL methanol in a 3 bar hydrogen atmosphere for 3 h at RT. The catalyst was removed by suction filtering and the solution was concentrated by rotary evaporation. 23.9 g of residue was obtained, which was immediately reacted further without any further purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]2[C:5]([CH:6]3[CH2:16][CH:7]3[CH2:8][O:9]2)=[CH:4][CH:3]=1.[CH2:17]([N:19]1[CH2:23][CH2:22][C@H:21]([CH2:24][C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[S:32](Cl)(=[O:34])=[O:33])[CH2:20]1)[CH3:18]>C(Cl)Cl.N1C=CC=CC=1>[CH2:17]([N:19]1[CH2:23][CH2:22][C@H:21]([CH2:24][C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[S:32]([NH:1][C:2]2[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]3[C:5]([C@@H:6]4[CH2:16][C@@H:7]4[CH2:8][O:9]3)=[CH:4][CH:3]=2)(=[O:33])=[O:34])[CH2:20]1)[CH3:18]
Reactant: COC(=O)c1c(N)ccc2c1OCC1CC21
Reactant: CCN1CC[C@H](Cc2cc(F)ccc2S(=O)(=O)Cl)C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCN1CC[C@H](Cc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)OC)OC[C@H]2C[C@@H]32)C1
Temperature: 40 °C
Yield: 25.8 %

Procedure:
A solution of methyl 5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 42, 0.19 g) in DCM (10 mL) and pyridine (3.5 mL) was treated with a solution of 2-((S)-1-ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonyl chloride (Intermediate 114, 0.26 g) in DCM (5 mL) and the mixture was stirred and heated at 40° C. for 1 hour. The resultant mixture was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of DCM and methanol with a gradient of 0-25%, then flushed with 100% methanol to give methyl (1aS,7bR)-5-[2-((S)-1-ethylpyrrolidin-3-ylmethyl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.107 g) as a gum.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)[CH3:2].[CH:12]([NH:15][OH:16])([CH3:14])[CH3:13]>>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[N+:15]([CH:12]([CH3:14])[CH3:13])[O-:16])[CH3:2]
Reactant: CCOc1ccccc1C=O
Reactant: CC(C)NO
Product: CCOc1ccccc1C=[N+]([O-])C(C)C

Procedure:
The title compound was prepared according to the procedure described in Example 11 using 2-ethoxybenzaldehyde and N-isopropylhydroxylamine. The title compound was isolated in 48.8% yield as a solid, m.p. 59.4° C. (Rf =0.48 on a silica gel plate using ethyl acetate as the eluant).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH:14]([CH3:16])[CH3:15])[C:6]([O:8][CH3:9])=[O:7])=[O:2].[BH4-].[Li+]>O1CCCC1>[OH:2][CH2:1][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH:14]([CH3:16])[CH3:15])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(OC(C)C)c(C=O)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC(C)C)c(CO)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
Methyl 3-formyl-4-isopropoxy-benzoate (180 mg, 0.8 mmol) was dissolved in tetrahydrofuran (5 mL) and lithium borohydride (35 mg, 1.6 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes, then quenched with methanol (3 mL). The reaction mixture was neutralized by the addition of a saturated aqueous solution of sodium bicarbonate (3 mL) and extracted with ethyl acetate (3×10 mL). The organic layers were washed with brine solution (1×10 mL), dried over sodium sulfate, filtered and concentrated in vacuo to yield methyl 3-(hydroxymethyl)-4-isopropoxy-benzoate (180 mg, 99%) as a viscous liquid. ESI-MS m/z calc. 224.3. found 225.3 (M+1)+; Retention time: 1.26 minutes (3 min run); 1H NMR (400 MHz, DMSO) δ 8.09 (s, 1H), 7.89 (d, J=8.6 Hz, 1H), 7.13 (d, J=8.6 Hz, 1H), 5.25 (t, J=5.6 Hz, 1H), 4.86-4.68 (m, 1H), 4.54 (d, J=5.6 Hz, 2H), 3.87 (s, 3H), 1.35 (d, J=6.0 Hz, 6H).