Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:15]=1[CH2:14][N:13](CC1C=CC(OC)=CC=1OC)[C:12](=[O:27])[C:11]1[CH:28]=[C:29]([CH:32]([CH3:34])[CH3:33])[CH:30]=[CH:31][C:10]2=1)=[O:5])[CH3:2].FC(F)(F)S(O)(=O)=O>C(Cl)Cl.FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:15]=1[CH2:14][NH:13][C:12](=[O:27])[C:11]1[CH:28]=[C:29]([CH:32]([CH3:33])[CH3:34])[CH:30]=[CH:31][C:10]2=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncn2c1CN(Cc1ccc(OC)cc1OC)C(=O)c1cc(C(C)C)ccc1-2
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ncn2c1CNC(=O)c1cc(C(C)C)ccc1-2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-(2,4-Dimethoxy-benzyl)-8-isopropyl-6-oxo-5,6-dihydro-4H-2,5,10b-triaza-benzo[e]azulene-3-carboxylic acid ethyl ester (410 mg, 0.9 mmol) was suspended in CH2Cl2 (3.0 mL), cooled in ice, and diluted slowly with trifluoroacetic acid (2.0 mL). The resulting solution was treated at 5° C. with trifluoromethanesulfonic acid (1.0 mL, 1.3 mmol). The red solution was stirred at room temperature for 2 h. The mixture was then evaporated and dissolved in CH2Cl2 (20 mL), washed with sodium hydrogen carbonate (10%, 2×5 mL) and the organic layer was dried (Na2SO4) and evaporated. Trituration with EtOAc. Yield: 250 mg (90%). m/z 313 (MH).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][C:6]1[CH:7]=[C:8]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:9][N:10]([CH2:21][CH:22](OC)OC)S(C1C=CC(C)=CC=1)(=O)=O>ClCCl>[Cl:5][C:6]1[CH:7]=[C:8]2[C:27]([CH:22]=[CH:21][N:10]=[CH:9]2)=[CH:28][C:29]=1[F:30]
Reactant: COC(CN(Cc1ccc(F)c(Cl)c1)S(=O)(=O)c1ccc(C)cc1)OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Fc1cc2ccncc2cc1Cl
Reaction time: 0.5 h

Procedure:
343.6 (2.54 mol) of AlCl3 were suspended in 1.1 l of dichloromethane and were stirred for 30 min with a mechanical stirrer. To this suspension, a solution of 204 g (0.51 mol) (N-(3-Chloro-4-fluoro-benzyl)-N-(2,2-dimethoxy-ethyl)-4-methyl-benzene-sulfonamide (2) was added and the mixture was stirred at room temperature for 5 h. After standing overnight, the reaction suspension was poured on ice, the organic layer was separated and the aqueous phase was extracted twice with dichloromethane. The combined organic layers were washed twice with 1 N NaOH and saturated NaHCO3-solution, dried with MgSO4 and evaporated. The obtained crude product was purified by silicagel chromatography (heptane/ethyl acetate 1:1), which gave 61.3 g of the title compound. Rt=0.73 min (Method B). Detected mass: 182.1 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH2:30][C:31]([OH:33])=[O:32])[C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH2:11][C:12]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH3:21])[CH:15]=2)=O)=[CH:6][CH:5]=1.Cl.[NH2:35][OH:36].C([O-])(O)=O.[Na+]>>[OH:36]/[N:35]=[C:12](/[C:14]1[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH3:21])[CH:15]=1)\[CH2:11][CH:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([N:2]([CH2:30][C:31]([OH:33])=[O:32])[CH3:1])=[O:29])=[CH:5][CH:6]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28]
Reactant: NO
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)N(C)CC(=O)O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C(=O)N(C)CC(=O)O)cc1

Procedure:
In analogy to example 151, step 3, (methyl-{4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoyl}-amino)-acetic acid was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless solid, MS (ESI−): m/z=460.3 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[OH-].[Na+].Cl.[CH3:13][C:14]([CH3:16])=[O:15]>O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH:13][C:14](=[O:15])[CH3:16]
Reactant: O=Cc1ccccc1Cl
Reactant: CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60 %

Procedure:
A solution of 200 g (1.4 mole) of 2-chlorobenzaldehyde in 500 ml of acetone is treated with 200 ml of water, cooled in an ice bath, then treated with 40 ml of 10% NaOH by drops. The mixture is kept below 40° C. After the addition is complete the mixture is stirred at 25° C. for 1.5 hours, then acidified with 10% HCl. The mixture is diluted with water and extracted with benzene. 0.5 g of toluene-sulfonic acid is added to the benzene solution and the mixture refluxed under a water separator. A total of 6 ml of water is collected. The mixture is cooled, shaken with bicarbonate, dried (Na2SO4), and evaporated. Distillation gives 150 g (60%) of 4-(2-chlorophenyl)-but-3-ene-2-one, b.p. 106°-120° C. @ 1 mm Hg.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH2:9][C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C=O.[CH3:18]C1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[S:12]1[C:11]2[CH2:18][N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:15])[CH2:8][CH2:9][C:10]=2[CH:14]=[CH:13]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(C)OC(=O)NCCc1ccsc1
Agent: C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2ccsc2C1

Procedure:
To a solution of tert-butyl[2-(3-thienyl)ethyl]carbamate in toluene was added paraformaldehyde (2 equi.) and catalytic amount of PTSA and reaction mixture was then refluxed in dean stark apparatus for 4 hrs. Reaction mass wan then concentrated and extracted with dichloromethane dried over sodium sulphate and evaporated to yield tert-butyl 4,7-dihydrothieno[2,3-c]pyridine-6(5H)— carboxylate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl.O>[C:17]1([C:16]([NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)=[O:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1cccc(OCc2ccccc2)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1cccc(OCc2ccccc2)c1)c1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 3-benzyloxyaniline 23 (1.0 g, 5.0 mmol) and TEA (0.74 mL, 5.3 mmol) in CH2Cl2 was added benzoyl chloride (0.61 mL, 5.26 mmol) dropwise and the mixture was allowed to stir overnight. The reaction mixture was diluted with water and the resulting solid was collected by vacuum filtration. The solid was allowed to air dry, to yield compound 25 as a white solid. Synthesis of phenyl{[(3-phenylmethoxy)phenyl]amino}methane-1-thione (26):
Reaction SMILES: [CH:1]1([C:6]([OH:32])([CH2:17][CH2:18][C:19]2[CH:24]=[C:23]([CH2:25][CH3:26])[C:22]([OH:27])=[CH:21][C:20]=2[O:28][CH2:29][CH2:30][CH3:31])[CH2:7][C:8]2[O:13]C(C)(C)O[C:10](=[O:16])[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH:1]1([C:6]2([CH2:17][CH2:18][C:19]3[CH:24]=[C:23]([CH2:25][CH3:26])[C:22]([OH:27])=[CH:21][C:20]=3[O:28][CH2:29][CH2:30][CH3:31])[O:32][C:10](=[O:16])[CH2:9][C:8](=[O:13])[CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCCOc1cc(O)c(CC)cc1CCC(O)(CC1=CC(=O)OC(C)(C)O1)C1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCCOc1cc(O)c(CC)cc1CCC1(C2CCCC2)CC(=O)CC(=O)O1
Temperature: 45 °C
Yield: 71.5 %

Procedure:
6-[2-Cyclopentyl-4-(5-ethyl-4-hydroxy-2-propoxy-phenyl)-2-hydroxy-butyl]-2,2-dimethyl-[1,3]dioxin-4-one (0.8 g, 1.8 mmol,) was dissolved in methanol (15 mL), treated with potassium carbonate (0.74 g, 5.4 mmol) and heated at 45° C. under N2 for 90 mins. The reaction mixture was partitioned between H2O and IPE. The aqueous layer was made acidic with 1N HCl and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4 and concentrated to give the product as a yellow foam (0.5 g, 72% yield). 1H NMR (400 MHz, CDCl3): δ 1.02 (t, J=7.3 Hz, 3 H), 1.19 (t, J=7.6 Hz, 3 H), 1.41-1.87 (br m, 11 H), 1.95 (m, 1 H), 2.32 (m, 1 H), 2.49-2.80 (m, 6H), 3.41 (m, 2 H), 3.85 (m, 2 H), 4.62 (s, 1 H), 6.33 (s, 1 H), 6.80 (s, 1 H).
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([O:14][C:15]1[N:16]=[N:17][CH:18]=[C:19]2[C:23]([CH3:24])=[C:22]([CH3:25])[NH:21][C:20]=12)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1OCCOCCOCCOCCOCCOC1.[Cl:44][C:45]([Cl:49])=[CH:46][CH2:47]Br>O1CCCC1>[CH2:7]([O:14][C:15]1[N:16]=[N:17][CH:18]=[C:19]2[C:23]([CH3:24])=[C:22]([CH3:25])[N:21]([CH2:47][CH:46]=[C:45]([Cl:49])[Cl:44])[C:20]=12)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: ClC(Cl)=CCBr
Reactant: Cc1[nH]c2c(OCc3ccccc3)nncc2c1C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1c(C)n(CC=C(Cl)Cl)c2c(OCc3ccccc3)nncc12
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 22.6 %

Procedure:
0.13 g (0.0011 mole) of potassium tert-butoxide was added to a suspension of 0.29 g (0.0011 mole) of 7-benzyloxy-2,3-dimethylpyrrolo[2,3-d]pyridazine and 0.03 g (0.0001 mole) of 18-crown-6 in 8 ml of tetrahydrofuran and the resulting mixture was stirred at room temperature for 40 minutes. 0.22 g (0.0011 mole) of 3,3-dichloro-2-propenyl bromide was then added to the mixture and stirred at room temperature for 5 minutes. The reaction mixture was poured into ice-water and the aqueous mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography through silica gel using a 20:1 mixture of chloroform and methanol as an eluent to give 0.090 g of 7-benzyloxy-1-(3,3-dichloro-2-propenyl)-2,3-dimethylpyrrolo[2,3-d]pyridazine as a yellow powder.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1([C:9]1[O:10][C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:13]=1)[OH:8].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:8]1[CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]12[C:9]1[O:10][C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:13]=1
Reactant: OC1(c2nc(-c3ccccc3)c(-c3ccccc3)o2)CCCCC1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(-c2nc(C34CCCCC3O4)oc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.3 %

Procedure:
A mixture of 2-bromo-1-(4,5-diphenyl-2-oxazolyl)-cyclohexanol (120 mg) and potassium carbonate (83 mg) in N,N-dimethylformamide (0.3 ml) was stirred at room temperature for 6 hours and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo to afford 2-(1,2-epoxycyclohexyl)-4,5-diphenyloxazole (94 mg) as a pale yellow powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH2:6][NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].I[CH2:25][CH2:26][CH3:27]>O1CCCC1>[CH2:1]([O:3][C:4](=[O:13])[CH:5]([CH2:6][NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH2:25][CH2:26][CH3:27])[CH3:2]
Reactant: CCOC(=O)CCNC1CCCC1
Reactant: CCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC(CNC1CCCC1)C(=O)OCC
Reaction time: 1 h
Yield: 48.9 %

Procedure:
To a mixture of 2.0 g (0.0108 mole) of 3-cyclopentylamino-propanoic acid ethyl ester and 10 mL of anhydrous tetrahydrofuran, at −78 degrees, was added 24.0 mL (0.0236 mole) of lithium bis(trimethylsilyl)amide. The mixture was stirred for 1 hour and then a solution of 2.0 g (0.0119 mole) of iodopropane in 2.0 mL of tetrahydrofuran was added slowly. The mixture was stirred at room temperature for 24 hours and then quenched by the addition of water. The mixture was concentrated under reduced pressure and then extracted three times with 50 mL of ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 1.2 g of (rac)-2-cyclopentylaminomethyl-pentanoic acid ethyl ester, which was used without further purification in subsequent steps.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:42]([C:44]1[CH:53]=[CH:52][C:47]([C:48]([O:50][CH3:51])=[O:49])=[CH:46][CH:45]=1)=[O:43].C(=O)([O-])O.[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:7]([CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:42]([C:44]2[CH:53]=[CH:52][C:47]([C:48]([O:50][CH3:51])=[O:49])=[CH:46][CH:45]=2)=[O:43])[CH2:11][CH:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1ccccc1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
To a solution of 100 mg of tert-butyl[(1R)-1-(1-naphthyl)ethyl][(3-phenylpiperidin-4-yl)methyl]carbamate and 0.038 mL of triethylamine in 3 mL of THF was added 46.9 mg of methyl 4-(chlorocarbonyl)benzoate, followed by stirring at room temperature overnight. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 56.0 mg of methyl 4-{[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]carbonyl}benzoate as a colorless foamy substance. FAB+: 607
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Br:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[OH:19])[C:14]#[N:15].[CH3:20][O:21][CH2:22][CH2:23][O:24][CH2:25]Cl>ClCCl>[Br:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[C:14]#[N:15]
Reactant: COCCOCCl
Reactant: N#Cc1ccc(O)c(Br)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOCOc1ccc(C#N)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
Diisopropylethylamine (21.8 mL, 151.5 mmol) was added slowly to a magnetically stirred solution of 3-bromo-4-hydroxybenzonitrile (10 g, 50.5 mmol) and 2-methoxyethoxymethyl chloride (6.9 mL, 60.6 mmol) in dichloromethane (100 mL) and the mixture was stirred at room temperature for 30 minutes. The mixture was washed with 5% citric acid solution until the washings were acidic, dried and concentrated. Product was purified from the residue by chromatography (silica gel, 30% ethyl acetate/hexanes) gave 3-bromo-4-(2-methoxyethoxymethoxy)-benzonitrile (11.5 g).
Reaction SMILES: [CH3:1][NH2:2].CS[C:5]([NH:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[C:20]([O:21][CH2:22][CH3:23])=[CH:19][CH:18]=[CH:17][N:16]=1)=[CH:6][N+:7]([O-:9])=[O:8]>C(O)C>[CH3:1][NH:2][C:5]([NH:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[C:20]([O:21][CH2:22][CH3:23])=[CH:19][CH:18]=[CH:17][N:16]=1)=[CH:6][N+:7]([O-:9])=[O:8]
Reactant: CCOc1cccnc1CSCCNC(=C[N+](=O)[O-])SC
Reactant: CN
Solvent: CCO
Product: CCOc1cccnc1CSCCNC(=C[N+](=O)[O-])NC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methylamine in ethanol (33%, 25 cc) was added to 1-methylthio-1-[2-(3-ethoxy-2-pyridylmethylthio)ethylamino]-2-nitro ethylene (1.32 g) and the mixture was stirred at 40° for 1 hour and 1 hour at room temperature. Nitrogen was bubbled through the mixture for 1 hour and the precipitate was recrystallised from ethanol/ether to give the title product (0.52 g) m.p. 130°-131°.
Reaction SMILES: [N:1]1([C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=O)=[CH:12][N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Cl.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[O:30])=[CH:25][CH:24]=1>>[N:1]1([C:10]2[N:11]=[CH:12][C:13]([C:14]([N:34]3[CH2:35][CH2:36][CH:31]([C:29](=[O:30])[C:26]4[CH:25]=[CH:24][C:23]([CH3:22])=[CH:28][CH:27]=4)[CH2:32][CH2:33]3)=[O:16])=[CH:19][CH:20]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Cc1ccc(C(=O)C2CCNCC2)cc1
Reactant: CCOC(=O)c1ccc(-n2cnc3ccccc32)nc1
Agent: Cl
Product: Cc1ccc(C(=O)C2CCN(C(=O)c3ccc(-n4cnc5ccccc54)nc3)CC2)cc1
Yield: 45.6 %

Procedure:
Using ethyl 6-(benzimidazol-1-yl)nicotinate (300 mg) described in Preparation Example 78, (4-methylphenyl)(piperidin-4-yl)methanone hydrochloride (269 mg) and by the reaction and treatment in the same manner as in Example 170, the title compound (217 mg) was obtained.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][O:17][C:18](=[O:36])[C@H:19]([CH2:28][C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1)[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].N1C=CC=CC=1>ClCCl>[CH3:16][O:17][C:18](=[O:36])[C@@H:19]([NH:20][C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[CH:31][CH:30]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.1 %

Procedure:
Trifluoromethanesulfonic anhydride (3.27 ml, 19.47 mmol) was slowly added to a solution of Boc-L-tyrosine methyl ester (5.0 g, 16.93 mmol) and pyridine (4.11 ml, 50.79 mmol) in dichloromethane (145 ml) at 0° C. and the resulting orange solution was stirred at room temperature for 4 h. The reaction was quenched by addition of NaHCO3 solution (150 ml) and the organic layer was separated, washed with saturated aqueous NaHCO3 (2×100 ml) and brine (1×100 ml), and dried (MgSO4). The solvent was concentrated under reduced pressure to yield (S)-2-tert-butoxycarbonylamino-3-(4-trifluoromethanesulfonyloxyphenyl) propionic acid methyl ester (6.52 g, 90%) that was used in the next step without further purification.
Reaction SMILES: II.C(O[C@@H:7]1[O:19][C@H:18]([CH2:20][O:21]C(=O)C)[C@@H:13]([O:14]C(=O)C)[C@H:8]1[O:9]C(=O)C)(=O)C.[NH:25]([C:32]1[CH:37]=[C:36]([Cl:38])[N:35]=[C:34]2[NH:39][CH:40]=[N:41][C:33]=12)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO>[NH:25]([C:32]1[CH:37]=[C:36]([Cl:38])[N:35]=[C:34]2[N:39]([C@@H:7]3[O:19][C@H:18]([CH2:20][OH:21])[C@@H:13]([OH:14])[C@H:8]3[OH:9])[CH:40]=[N:41][C:33]=12)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Clc1cc(Nc2ccccc2)c2nc[nH]c2n1
Agent: II
Solvent: CO
Product: OC[C@H]1O[C@@H](n2cnc3c(Nc4ccccc4)cc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 155 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
After a crystal of iodine was added to an intimate mixture of 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose (5.2 g, 16 mMol) and 7-anilino-5-chloro-3H-imidazo[4,5-b]pyridine (4.0 g, 16 mMol), the mixture was heated in vacuo at 155° C. After 2 hours, the cooled reaction mixture was suspended in methanol and filtered to remove the unreacted heterocycle (2.29 g). The filtrate was taken to dryness in vacuo and treated with an excess of methanol previously saturated with ammonia. Purification by flash chromatography on silica gel (the residue was adsorbed onto silica gel and placed on the top of the column), elution with chloroform/methanol (20:1 v/v), and removal of the solvent gave 1.22 g (3.2 mMol) of 7-anilino-5-chloro-3-β-D-ribofuranosyl-3H-imidazo[4,5-b]pyridine; yield 46.8%; m.p. 157°-160° C. UV max (nm) at pH 1, 307 (ε15,700); pH 13, 250 sh (ε9,900), 300 ε19,400); NMR (DMSO-d6): 9.42 d (s, 1H, NH); 8.50 (s, 1H, H2); 7.43-7.12 (m, 5H, Phenyl); 6.71 (s, 1H, H5); 5.93 (d, 1H, J=5.97 Hz, H1').
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].C[O:12][CH2:13][C:14](=O)[CH2:15][C:16]([O:18][CH3:19])=O>>[OH:12][C:13]1[N:1]([C:3]2[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=2)[N:2]=[C:15]([CH2:16][O:18][CH3:19])[CH:14]=1
Reactant: N#Cc1ccnc(NN)c1
Reactant: COCC(=O)CC(=O)OC
Product: COCc1cc(O)n(-c2cc(C#N)ccn2)n1
Yield: 39 %

Procedure:
The title compound was prepared in 39% yield from 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and methyl 4-methoxy-3-oxobutanoate according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C11H10N4O2, 231. Found, 231.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1.[H-].[Na+].Cl[CH2:21][C:22]1[C:23]([CH3:39])=[N:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:29]=2[F:38])=[CH:26][CH:27]=1.O>CN(C)C=O>[F:38][C:29]1[CH:30]=[C:31]([C:34]([F:36])([F:37])[F:35])[CH:32]=[CH:33][C:28]=1[C:25]1[N:24]=[C:23]([CH3:39])[C:22]([CH2:21][O:17][C:4]2[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]3[CH:16]=[CH:15][N:14]=[N:13]3)=[C:2]([CH3:1])[CH:3]=2)=[CH:27][CH:26]=1
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2F)ccc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccc(-c3ccc(C(F)(F)F)cc3F)nc2C)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
A solution of 153 mg (0.66 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 8.0 ml N,N-dimethylformamide was treated at 0° C. with 26 mg (0.66 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 200 mg (0.66 mmol) 3-Chloromethyl-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl-pyridine were added and stirred continued at r. t. over night. After addition of 16 ml water, the precipitate was isolated, washed thoroughly with water and diisopropylether. The residue was dried at 40° C. to give 250 mg (76%) of the title compound as light brown powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:25](OCC)=[O:26])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=2)[CH2:25][OH:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(c1cccc(C(F)(F)F)c1)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(CO)c2cccc(C(F)(F)F)c2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
A solution of 4-[Ethoxycarbonyl-(3-trifluoromethyl-phenyl)-methyl]-piperazine-1-carboxylic acid tert-butyl ester (2.10 g, 5.05 mmol) in tetrahydrofuran (30 mL) at 0° C. was added lithium aluminum hydride (1M in tetrahydrofuran, 7.57 mL, 7.57 mmol) dropwise. The mixture was stirred at 0° C. for two hours. The excess LAH was quenched with ethyl acetate and the mixture was stirred with sodium sulfate decahydrate for 10 minutes. The slurry was filtered and the filtrate partitioned between ethyl acetate and water. The organic layer was dried with magnesium sulfate. Filtration, concentration gave a crude which was loaded onto a column of silica gel. Elution with 40% ethyl acetate/hexanes gave 4-[2-Hydroxy-1-(3-trifluoromethyl-phenyl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (1.4 g, 74% yield) as a colorless oil. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].C([Li:14])CCC.O1CCCC1>>[CH2:1]([N:5]([Li:14])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNCCCC
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: [Li]N(CCCC)CCCC

Procedure:
As a polymerization initiator, dibutylamine (13.0 mmol) and n-butyllithium (13.0 mmol) were previously reacted in the presence of tetrahydrofuran (26.0 mmol) to obtain dibutylamino lithium. A cyclohexane solution of dibutylamino lithium (13.0 mmol) was supplied to the reactor.