Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5](I)=[CH:4][N:3]=1.[C:10]([Si:12]([CH3:15])([CH3:14])[CH3:13])#[CH:11]>C1COCC1.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.[Cu]I>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:11]#[C:10][Si:12]([CH3:15])([CH3:14])[CH3:13])=[CH:4][N:3]=1
Reactant: Clc1ncc(I)c(Cl)n1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cnc(Cl)nc1Cl
Temperature: 35 °C
Reaction time: 4 h
Yield: 55.9 %

Procedure:
Under nitrogen atmosphere, a mixture of 2,4-dichloro-5-iodopyrimidine (2.0 g, 7.3 mmol, 1.0 eq), Pd(PPh3)2Cl2 (256 mg, 0.37 mmol, 0.05 eq), CuI (139 mg, 0.73 mmol, 0.1 eq) Et3N (2.2 g, 21.9 mmol, 3.0 eq) and ethynyltrimethylsilane (1.4 g, 14.6 mmol, 1.2 eq) in THF (20 ml) was stirred at 35° C. for 4 h. The mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (PE/EtOAc=200:1) to give compound 2,4-dichloro-5-((trimethylsilyl)ethynyl)pyrimidine (1.0 g, 56%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N+:14]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)([O-])=O.C(N(CC)CC)C>CN(C=O)C>[NH2:14][C:17]1[CH:25]=[CH:24][C:20]([C:21]([N:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]2)=[O:22])=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N)cc2)CC1

Procedure:
1-Boc-piperazine and 4-nitrobenzoyl chloride were allowed to undergo the reaction in DMF in the presence of triethylamine, and then the nitro group was reduced in the sama manner as the catalytic hydrogenation shown in Reference Example 3 to obtain tert-butyl 4-(4-aminobenzoyl)piperazine-1-carboxylate. ESI: 307.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][O:12][CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:13][O:12][CH2:11][CH2:10][O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: COCCBr
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1ccc(I)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 100.8 %

Procedure:
A mixture of 4-iodophenol (20 g), 2-bromoethylmethyl ether (11.4 g), potassium carbonate (12.5 g) and dimethylformamide (100 ml) was stirred at 80° C. for 4 hours. A further portion of 2-bromoethylmethyl ether (2.24 g) and potassium carbonate (2.5 g) was then added and the mixture stirred at 80° C. for a further 1 hour. The dimethylformamide was removed by evaporation. The residue was treated with a 2M aqueous sodium hydroxide solution (50 ml) and the mixture extracted with diethyl ether (3×50 ml). The ethereal extracts were combined, washed with 2M aqueous sodium hydroxide solution (2×20 ml), brine (20 ml), dried (MgSO4) and evaporated to give 4-(2-methoxyethoxy)iodobenzene (23 g) as a white solid, m.p. 36-37° C. NMR ([CD3 ]2SO): 3.3 (3H, s), 3.6-3.7 (2H, m), 4.0-4.1 (2H, m), 6.72-6.82 (2H, d) and 7.52-7.62 (2H, d).
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.O>CS(C)=O>[CH2:9]([O:8][C:6](=[O:7])[C:5]1[CH:11]=[CH:12][C:2]([NH:22][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:3]([N+:13]([O-:15])=[O:14])[CH:4]=1)[CH3:10]
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(NC2CCCCC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100.9 %

Procedure:
Ethyl 4-chloro-3-nitrobenzoate (20.00 g, 87 mmol) was dissolved in DMSO (50 mL) and cyclohexylamine (2.1 equiv. 21 mL, 183 mmol) was added and the mixture stirred at 600C for 5 h. After cooling to ambient temperature, the reaction mixture was added drop-wise with vigorous stirring to water (500 mL). After stirring for an additional 15 min, the precipitated solid was collected by filtration, washed with water and dried. The title compound (25.67 g, 100% yield) was obtained as a bright yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18]C(=O)C)=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[C:4]([CH3:22])[N:3]=1.Cl>[OH-].[Na+]>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([NH:8][C:6]2[CH:5]=[C:4]([CH3:22])[N:3]=[C:2]([Br:1])[CH:7]=2)(=[O:11])=[O:10])=[CH:13][CH:14]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2cc(C)nc(Br)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(NS(=O)(=O)c2ccc(N)cc2)cc(Br)n1
Yield: 92.5 %

Procedure:
1.15 g (0.003 mol) of N-[4-(2-bromo-6-methyl-pyridin-4-ylsulfamoyl)-phenyl]-acetamide were dissolved in 15 ml of 2N NaOH and boiled at reflux for 1 hour. After cooling the mixture was acidified to pH 5 with 2N HCl and the colourless precipitate which separated was filtered off. The material on the suction filter was washed with copious water and dried. There was obtained 0.95 g (93%) of 4-amino-N-(2-bromo-6-methyl-pyridin-4-yl)-benzenesulfonamide as colorless crystals; m.p.: >110° C. (dec.).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]([OH:19])[CH2:17][OH:18])=[N:14][CH:15]=1)[CH3:9].[S:20](Cl)(Cl)=[O:21]>ClCCl>[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[CH2:17][O:18][S:20](=[O:21])[O:19]2)=[N:14][CH:15]=1)[CH3:9]
Reactant: O=S(Cl)Cl
Reactant: CCc1ccc(C(O)CO)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccc(C2COS(=O)O2)nc1
Reaction time: 1 h

Procedure:
4.98 mL (0.387 mol) triethylamine was added to a solution of 3 g (0.017 mol) 1-(5-ethyl-pyridin-2-yl)-ethan-1,2-diol dissolved in 60 mL dichloromethane at 0-5° C. To this 1.43 mL (0.019 mol) thionyl chloride was added drop wise in 15 min. and stirring was continued for 1 hr. Reaction mixture was quenched with 10% sodium bicarbonate solution. Product was extracted with dichloromethane, which was concentrated in vacuo to obtain titled product. Yield of the product was 3.44 g (90%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]([CH3:30])[C:20]3[C:25]([NH:26][CH:27]([CH3:29])[CH3:28])=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:15][CH2:14]1)=[O:12])=[CH:5]2.[CH3:31][N:32]([CH3:37])[S:33](Cl)(=[O:35])=[O:34]>N1C=CC=CC=1.C(Cl)Cl.Cl>[CH3:31][N:32]([CH3:37])[S:33]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]([CH3:30])[C:20]3[C:25]([NH:26][CH:27]([CH3:28])[CH3:29])=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:15][CH2:14]1)=[O:12])=[CH:5]2)(=[O:35])=[O:34]
Reactant: CC(C)Nc1cccnc1N(C)C1CCN(C(=O)c2cc3cc(N)ccc3[nH]2)CC1
Reactant: CN(C)S(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)Nc1cccnc1N(C)C1CCN(C(=O)c2cc3cc(NS(=O)(=O)N(C)C)ccc3[nH]2)CC1
Reaction time: 16 h

Procedure:
To a solution of 1-[5-aminoindole-2-carbonyl]-4-[N-methyl-N-(3-(1-methylethylamino)-2-pyridinyl)amino]piperidine (PREPARATION 56, 91 mg) in pyridine (0.5 ml) under nitrogen is added N,N-dimethylsulfamoyl chloride. The mixture is stirred at 20°-25° for 16 hr and then diluted with methylene chloride (35 ml) and 1M hydrochloric acid (20 ml). The layers are separated and the organic layer is washed with 1M hydrochloric acid (20 ml) and saline, dried over sodium sulfate, and concentrated to give a solid film which is then chromatographed on two 2000 μ preparative silica gel plates, eluting with methanol/chloroform (5/95). The desired band is extracted and concentrated to give the title compound, NMR (CDCl3) 10.34, 7.72, 7.64, 7.56, 7.37, 7.16, 6.95, 6.84, 6.70, 4.65, 4.50, 3.56, 3.46, 3.40-3.00, 2.80, 2.63, 1.93, 1.64 and 1.22 δ.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[C:4](C(Cl)(Cl)Cl)[N:3]=1.[CH3:15][O-:16].[Na+].O>CO>[NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[C:4]([O:16][CH3:15])[N:3]=1
Reactant: Nc1nc(C2CC2)nc(C(Cl)(Cl)Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nc(N)nc(C2CC2)n1
Temperature: 60 °C
Reaction time: 1.33 h

Procedure:
25.3 g of 2-amino-4-cyclopropyl-6-trichloromethyl-1,3,5-triazine are added to a solution of 10.8 g of sodium methylate in 50 ml of methanol, and the mixture is stirred at 60° C. for 80 minutes. There are added 300 ml of water, and the formed suspension is filtered. The filter residue is suspended twice in 100 ml of acetyl acetate each time, and again filtered. The organic phases are collected, dried over magnesium sulfate and concentrated by evaporation to thus obtain an oil, which crystallises when stirred up in ether. The yield is 6.7 g of the title compound, m.p. 158°-159° C.
Reaction SMILES: C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[OH:16][C@@H:17]([C@H:19]1[C:40](=[O:41])[N:21]2[CH:22]([C:27]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=3)=[O:28])[C:23](=O)[C@H:24]([CH3:25])[C@H:20]12)[CH3:18].FC(F)(F)S(O)(=O)=O.[SH:50][C@@H:51]1[CH2:55][N:54]([CH3:56])[C@H:53]([C:57]([N:59]2[CH2:65][CH2:64][CH2:63][N:62]([C:66]([O:68][CH2:69][C:70]3[CH:75]=[CH:74][C:73]([N+:76]([O-:78])=[O:77])=[CH:72][CH:71]=3)=[O:67])[CH2:61][CH2:60]2)=[O:58])[CH2:52]1>C(#N)C.C(N(C(C)C)CC)(C)C>[N+:76]([C:73]1[CH:74]=[CH:75][C:70]([CH2:69][O:68][C:66]([N:62]2[CH2:63][CH2:64][CH2:65][N:59]([C:57]([C@@H:53]3[CH2:52][C@H:51]([S:50][C:23]4[C@H:24]([CH3:25])[C@@H:20]5[C@@H:19]([C@H:17]([OH:16])[CH3:18])[C:40](=[O:41])[N:21]5[C:22]=4[C:27]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=4)=[O:28])[CH2:55][N:54]3[CH3:56])=[O:58])[CH2:60][CH2:61]2)=[O:67])=[CH:71][CH:72]=1)([O-:78])=[O:77]
Reactant: CN1C[C@@H](S)C[C@H]1C(=O)N1CCCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCCN(C(=O)OCc5ccc([N+](=O)[O-])cc5)CC4)N(C)C3)[C@H](C)[C@H]12
Reaction time: 0.67 h
Yield: 57.4 %

Procedure:
0.89 ml of diphenylphosphoryl chloride and 0.75 ml of diisopropylethylamine were simultaneously added dropwise, whilst ice-cooling, to a solution of 1.4 g of 4-nitrobenzyl (1R, 5R, 6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate in 14 ml of dry acetonitrile, and the resulting mixture was stirred at the same temperature for 40 minutes. A solution of 2.68 g of (2S, 4S)-4-mercapto-1-methyl-2-[4-(4-nitrobenzyloxycarbonyl)-1-homopiperazinylcarbonyl]pyrrolidine trifluoromethanesulfonate (prepared as described in Preparation 49) in 14 ml of dry acetonitrile and 1.64 ml of diisopropylethylamine were then simultaneously added dropwise to the mixture, whilst ice-cooling, and the resulting mixture was stirred at the same temperature for 5 hours, after which it was allowed to stand overnight at room temperature. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was diluted with ethyl acetate. The dilute solution was then washed with an aqueous solution of sodium hydrogencarbonate, with a phosphate buffer solution (pH 6.86), with water and with an aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel (Merck Art No. 7734), using a gradient elution method with mixtures of ethyl acetate and methanol ranging from 85:15 to 80:20 by volume as the eluent, to give 1.7 g of the title compound, as a powder.
Reaction SMILES: [C:1]([C:3](=[N:9]O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].CCCCCCC.II>C(O)(=O)C.CCOC(C)=O.[Pt]>[CH2:7]([O:6][C:4](=[O:5])[CH:3]([NH2:9])[C:1]#[N:2])[CH3:8]
Reactant: CCOC(=O)C(C#N)=NO
Agent: [Pt]
Agent: II
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCOC(=O)C(N)C#N
Yield: 141.1 %

Procedure:
Combine ethyl cyanoglyoxylate-2-oxime (20.0 g, 141 mmol) and 5% Pt/C (2.0 g, 10% wt. load) in acetic acid (120 mL) and EtOAc (60 mL) and hydrogenate under 40 psi H2 overnight until the reaction is complete by TLC (5:1/heptane:EtOAc, I2 stain). Carefully filtered the spent catalyst using partial vacuum through glass fiber paper, and rinse with HOAc/EtOAc without allowing the cake to dry out. Concentrate the filtrate in vacuo on a rotovapor to an oil, leaving 25.5 g (96%) of crude amino-cyano-acetic acid ethyl ester as the HOAc salt. Partition a portion (13.0 g) of the HOAc salt between EtOAc (70 mL) and water (35 mL). Stir the biphasic solution and add dropwise aqueous 5N NaOH (16.5 mL) to adjust the pH to 8.0-8.2. Separate the layers, and extract the aqueous layer with more EtOAc (3×25 mL). Combine the organic layer, dry (MgSO4), filter, and concentrate the filtrate to dryness in vacuo on a rotovapor at low bath temperature (30-35° C.) to afford 5.68 g (65%) crude amino-cyano-acetic acid ethyl ester which was used immediately in the next reaction.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11](=[O:29])[C@H:12]([CH2:25][CH:26]([CH3:28])[CH3:27])[NH:13][C:14](=[O:24])[C@H:15]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH2:16])[CH3:9].C(N(CC)CC)C.[CH2:37]([O:44][C:45]([NH:47][CH2:48][CH2:49][CH2:50][CH2:51][C@@H:52]([C:61](O)=[O:62])[NH:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])=[O:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[CH2:8]([O:10][C:11](=[O:29])[C@H:12]([CH2:25][CH:26]([CH3:28])[CH3:27])[NH:13][C:14](=[O:24])[C@H:15]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[NH:16][C:61](=[O:62])[C@H:52]([CH2:51][CH2:50][CH2:49][CH2:48][NH:47][C:45]([O:44][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:46])[NH:53][C:54]([O:56][C:57]([CH3:60])([CH3:58])[CH3:59])=[O:55])[CH3:9]
Reactant: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
To a mixture of 1.68 g (4 mmol) of L-phenylalanyl-L-leucine ethyl ester trifluoroacetate, 0.56 mL (4 mmol) of triethylamine and 32 mL of chloroform were added at 0° C., first 1.52 g (4 mmol) of Nε -benzyloxycarbonyl-Nα -(tert-butoxycarbonyl)-L-lysine, and then 0.83 g (4 mmol) of dicyclohexylcarbodiimide, each being added in a single portion. The reaction mixture was warmed gradually to room temperature and then stirred overnight at that temperature. The precipitate which formed was removed by filtration. The filtrate was evaporated in vacuo and the residue was chromatographed on silica gel using 3:1 methylene chloride/ethyl acetate as eluent to give 2.48 g (92.7%) of the title compound as a white solid melting at 135°-136° C. after crystallization from a mixture of ethyl acetate and isopropyl ether. The product has the structural formula: ##STR93## as further confirmed by NMR, IR and elemental analyses.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH:9]=[CH:10][CH:11]=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:17]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH:28]1[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]1)#[N:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.Cl>ClC(Cl)C.CCOC(C)=O>[CH2:33]1[CH:28]([C:22]2[C:21]3[CH:20]=[C:19]([C:17]#[N:18])[CH:27]=[CH:26][C:25]=3[NH:24][CH:23]=2)[CH2:29][CH2:30][CH:31]([N:4]2[CH2:3][CH2:2][N:1]([C:7]3[C:8]4[CH:9]=[CH:10][CH:11]=[N:12][C:13]=4[CH:14]=[CH:15][CH:16]=3)[CH2:6][CH2:5]2)[CH2:32]1
Reactant: c1cc(N2CCNCC2)c2cccnc2c1
Reactant: N#Cc1ccc2[nH]cc(C3CCC(=O)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: N#Cc1ccc2[nH]cc(C3CCC(N4CCN(c5cccc6ncccc56)CC4)CC3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(1-piperazinyl)-quinoline (500 mg, 2.35 mmol), 4-(5-cyano-1H-3-indolyl)-cyclohexanone (540 mg, 2.35 mmol), and sodium triacetoxyborohydride (740 mg, 3.5 mmol) in dichloroethane (20 mL) was added acetic acid (0.27 mL, 4.7 mmol) and stirred overnight at room temperature. The reaction was quenched with 1 M NaOH (50 mL) and extracted in CH2Cl (3×100 mL). The organic fractions were combined, dried over Na2SO4, concentrated, filtered and chromatographed (5% MeOH/EtOAc) yielding 410 mg (41%) of the cis isomer as a white solid. The HCl salt was generated from EtOAc yielding a white solid: mp 220-223° C. Elemental Analysis for C28H29N5.HCl.1H2O; Calc'd C, 68.62; H, 6.58; N, 14.29; Found C, 68.99; H, 6.54; N, 14.06.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[C:3]1[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>[O-2].[O-2].[O-2].[Cr+6].N1C=CC=CC=1>[O:1]=[C:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[C:3]1[CH:18]=[CH:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)CCCCCCC1=C(C=Cc2ccccc2)C(O)CC1=O
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Product: COC(=O)CCCCCCC1=C(C=Cc2ccccc2)C(=O)CC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 1.3 parts of chromium trioxide with 15 parts of pyridine is added a solution of 1.5 parts of methyl 3-hydroxy-5-oxo-2-styrylcyclopent-1-eneheptanoate in 8 parts of pyridine and the resulting reaction mixture is stirred at room temperature for about 1 hour, then is allowed to stand at that temperature for about 16 hours. To the reaction mixture ice water is then added carefully and the resulting aqueous mixture is extracted with methylene chloride. The organic extract is washed successively with dilute hydrochloric acid and dilute aqueous sodium chloride, then dried over anhydrous sodium sulfate and stripped of solvent under reduced pressure. The resulting residue is purified by dry column chromatography on silica gel containing 8% of water followed by extraction of the column with 18% ethyl acetate in benzene. The resulting crystalline product is purified further by recrystallization from benzenecyclohexane to afford methyl 3,5-dioxo-2-styrylcyclopent-1-eneheptanoate, obtained as yellow needle-like crystals melting at about 62.5°. This compound displays ultraviolet absorption maxima at about 340.5 and 250.5 millimicrons with molecular extinction coefficients of 24,000 and 10,500, respectively. It is further characterized by the following structural formula ##SPC8##
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][C:10]1[N:15]=[C:14]([C:16]([C:18]2[C:19]3[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=3[S:21][C:22]=2[CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])=[CH2:17])[CH:13]=[CH:12][CH:11]=1>CO.[Pd]>[CH3:8][O:9][C:10]1[N:15]=[C:14]([CH:16]([C:18]2[C:19]3[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=3[S:21][C:22]=2[CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH3:17])[CH:13]=[CH:12][CH:11]=1
Reactant: C=C(c1cccc(OC)n1)c1c(CCN(C)C)sc2ccccc12
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(C(C)c2c(CCN(C)C)sc3ccccc23)n1
Reaction time: 2.5 h

Procedure:
The TFA salt of (2-{3-[1-(6-methoxy-pyridin-2-yl)-vinyl]-benzo[b]thiophen-2-yl}-ethyl)-dimethyl-amine (190 mg, mmol) was dissolved in MeOH (12 mL) and a catalytic amount of 10% Pd/C was added. The reaction was stirred under 1 Atm of H2 for 2.5 hours, filtered over celite, washed with dichloromethane, concentrated in vacuo and purified by mass triggered preparative HPLC to give (2-{3-[1-(6-methoxy-pyridin-2-yl)-ethyl]-benzo[b]thiophen-2-yl}-ethyl)-dimethyl-amine (Compound 15-2). MH+=341.0, tR=5.2 min.
Reaction SMILES: [CH:1]1([CH:7]=[C:8]2[CH2:13][CH2:12][O:11][C:9]2=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>[Ni](Cl)Cl.CO>[CH:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][O:11][C:9]2=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1OCCC1=CC1CCCCC1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C1OCCC1CC1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
2-(Cyclohexyl-methylene)-γ-butyrolactone (8.90 g) was added fast to a mixture of nickel(II) chloride (1.76 g) and methanol (30 mL) at room temperature. The obtained reaction mixture was cooled to 0° C., stirred at this temperature for 30 min and then treated portionwise with sodium borohydride (5.60 g). Upon completion of the addition, the mixture was stirred for 1 h at room temperature and then quenched by pouring onto a mixture of ice and 10% aqueous hydrochloric acid. The formed organic phase was separated and the aqueous phase was extracted with ether. The combined organic phases were dried over magnesium sulfate, filtered and concentrated on a rotary evaporator to give 6.96 g (77%) of the title compound.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:16]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][CH2:17]1.O>ClCCl>[F:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:20]([CH:16]2[CH2:19][CH2:18][CH2:17]2)=[O:21])=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)nc1
Reactant: O=C(Cl)C1CCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1ccc(F)nc1)C1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
[step 1] 6-Fluoropyridin-3-amine (600 mg, 5.35 mmol) was dissolved in dichloromethane (20 mL), triethylamine (1.49 mL, 10.7 mmol) and cyclobutanecarbonyl chloride (0.67 mL, 5.89 mmol) were added, and the mixture was stirred at room temperature overnight. Water was added to the mixture, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the obtained residue was added diisopropyl ether and the precipitated crystals were collected by suction filtration to give N-(6-fluoropyridin-3-yl)cyclobutanecarboxamide (899 mg, 86%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:33])[CH2:11][C:12]2[NH:16][N:15]=[C:14]([NH:17][C:18]3[CH:27]=[CH:26][N:25]=[C:24]4[C:19]=3[C:20]3[CH:32]=[CH:31][CH:30]=[CH:29][C:21]=3[C:22](=[O:28])[NH:23]4)[CH:13]=2)[CH:5]=[CH:6][C:7]=1F.NC1C=CC=CC=1>>[O:28]=[C:22]1[C:21]2[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=2[C:19]2[C:24](=[N:25][CH:26]=[CH:27][C:18]=2[NH:17][C:14]2[CH:13]=[C:12]([CH2:11][C:10]([NH:9][C:4]3[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=3)=[O:33])[NH:16][N:15]=2)[NH:23]1
Reactant: O=C(Cc1cc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)n[nH]1)Nc1ccc(F)c(F)c1
Solvent: Nc1ccccc1
Product: O=C(Cc1cc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)n[nH]1)Nc1ccccc1

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 300 using the carboxylic acid intermediate from example 313 and aniline to provide 315. LC-MS (M+H=411, obsd.=411).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[CH2:15]([CH:22]([O:26][C:27](=[O:29])[CH3:28])[C:23](=O)[CH3:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([CH:22]([O:26][C:27](=[O:29])[CH3:28])[CH:23]([NH:14][C:9]1[C:10]([CH3:13])=[N:11][O:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH3:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)OC(Cc1ccccc1)C(C)=O
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Product: CC(=O)OC(Cc1ccccc1)C(C)Nc1c(C)noc1-c1ccc(Br)cc1

Procedure:
Prepared according to the procedure described in Example 8, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and acetic acid 1-benzyl-2-oxo-propyl ester.