Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C@@H:18]([C:26]1[CH:31]=[CH:30][C:29]([O:32]CC2C=CC=CC=2)=[CH:28][CH:27]=1)[CH2:19][N:20]1[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21]1)[C:3](=[O:17])[CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][N:2]([C@@H:18]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[CH2:19][N:20]1[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21]1)[C:3](=[O:17])[CH:4]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: [H][H]
Reactant: CN(C(=O)C(c1ccccc1)c1ccccc1)[C@H](CN1CC[C@H](O)C1)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN(C(=O)C(c1ccccc1)c1ccccc1)[C@H](CN1CC[C@H](O)C1)c1ccc(O)cc1

Procedure:
A solution of 1 g of N-methyl-N-[(1S)-1-(p-benzyloxyphenyl)-2-((3S)-3-hydroxypyrrolidino)ethyl]-2,2-diphenylacetamide in 25 ml of ethyl acetate is hydrogenated on 0.5 g of 5% Pd-C at 20° and under 1 bar until hydrogen uptake ceases, the mixture is filtered, the filtrate is evaporated, and N-methyl-N-[(1S)-1-(p-hydroxyphenyl)-2-((3S)-3-hydroxypyrrolidino)ethyl]-2,2-diphenylacetamide is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C@H:6]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Br)=[CH:20][CH:19]=3)[C@H:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:8][O:9]2)=[CH:4][CH:3]=1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[CH2:6]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C@H:6]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[CH:20][CH:19]=3)[C@H:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:8][O:9]2)=[CH:4][CH:3]=1)[C:5]1[CH:10]=[CH:11][CH:2]=[CH:3][CH:4]=1
Reactant: C1COCCN1
Reactant: Oc1ccc2c(c1)OC[C@@H](c1ccccc1)[C@H]2c1ccc(OCCCCCCCCCCBr)cc1
Product: c1ccc(COc2ccc3c(c2)OC[C@@H](c2ccccc2)[C@H]3c2ccc(OCCCCCCCCCCN3CCOCC3)cc2)cc1

Procedure:
From (+,-) cis 7-Hydroxy-4-[4-(10-Bromodecyloxy)-phenyl]-3-phenyl-chroman (300 mg, 0.48 mmol) and morpholine (208 mg, 2.4 mmol).
Reaction SMILES: [CH:1]([CH:3]([CH:6]([CH3:8])[CH3:7])[C:4]#[N:5])=O.O.[NH2:10][NH2:11].C(O)(=O)C>CCO>[CH:6]([C:3]1[CH:1]=[N:10][NH:11][C:4]=1[NH2:5])([CH3:8])[CH3:7]
Reactant: CC(C)C(C#N)C=O
Reactant: NN
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CC(C)c1cn[nH]c1N

Procedure:
Next, 2-formyl-3-methylbutanenitrile (9.97 g, 90 mmol), hydrazine hydrate (5.68 mL, 117 mmol) and glacial acetic acid (9.02 mL, 158 mmol) were dissolved in EtOH (250 mL) and the mixture was heated under reflux for 16 h. The reaction was then concentrated to approximately one third of the original volume. The residue was diluted with sat. NaHCO3 (100 mL) and the product extracted with CH2Cl2 (3×100 mL). The combined organic fractions were washed with brine, dried over MgSO4 and the solvent was removed in vacuum. Crude 4-isopropyl-1H-pyrazol-5-amine was obtained as a yellow oil (7.17 g, 64%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl:5][C:6]1[C:11]([O:12][CH2:13][C@@H:14]2[CH2:16][O:15]2)=[CH:10][CH:9]=[CH:8][N:7]=1.O.[N-]=[N+]=[N-].[Na+]>O.O1CCOCC1>[N:1]([CH2:16][C@H:14]([OH:15])[CH2:13][O:12][C:11]1[C:6]([Cl:5])=[N:7][CH:8]=[CH:9][CH:10]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: Clc1ncccc1OC[C@@H]1CO1
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: [N-]=[N+]=NC[C@H](O)COc1cccnc1Cl
Temperature: 90 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
Dissolve sodium azide (22.84 g, 351.3 mmol) in water (195 mL). Separately, dissolve 2-chloro-3-[[(2S)-oxiran-2-yl]methoxy]pyridine (32.6 g, 175.6 mmol) in 1,4-dioxane (800 mL). Slowly add the water/sodium azide solution to the dioxane solution; heat to 90° C.; and stir for 1 hour. Cool the mixture and concentrate it under reduced pressure. Add water; extract with EtOAc (2×); combine the extracts; dry the combined extracts over Na2SO4; filter; and collect the filtrate. Remove the solvents under reduced pressure to provide the title compound (40.28 g, 92.8%) as a reddish white solid. MS (m/z): 229 (M+1).
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][N:7]=[C:8]([C:35]1([O:40][CH2:39][CH2:38][O:37]1)[CH3:36])[C:9]([NH:11][CH:12]1[C:33](=[O:34])[N:14]2[C:15]([C:30]([OH:32])=[O:31])=[C:16]([CH2:19]SC3SC4C=CC=CC=4N=3)[CH2:17][S:18][C@H:13]12)=[O:10].CON=C(C1(OCCO1)C)C(NC1C(=O)N2C(C(O)=O)=C(C)CS[C@H]12)=O>O1CCCC1.O.[Zn]>[CH3:5][O:6][N:7]=[C:8]([C:35]1([O:40][CH2:39][CH2:38][O:37]1)[CH3:36])[C:9]([NH:11][CH:12]1[C:33](=[O:34])[N:14]2[CH:15]([C:30]([OH:32])=[O:31])[C:16](=[CH2:19])[CH2:17][S:18][C@H:13]12)=[O:10]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nc4ccccc4s3)CS[C@H]12)C1(C)OCCO1
Agent: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C)CS[C@H]12)C1(C)OCCO1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: C=C1CS[C@@H]2C(NC(=O)C(=NOC)C3(C)OCCO3)C(=O)N2C1C(=O)O
Reaction time: 2 h
Yield: 34.3 %

Procedure:
Acetic acid (1 ml.) was added to a solution of 7-(2-methoxyimino-3,3-ethylenedioxybutyramido)-3-(benzothiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 500 mg.) in tetrahydrofuran (6 ml.) and water (2 ml.). Zinc powder (500 mg.) and copper sulfate 5-hydrate (50 mg.) were added to the solution at room temperature, and stirred at the same temperature for 2 hours. The resultant mixture was treated in a similar manner to that of Example 10-(3) Method A to give a mixture (120 mg.) of 7-(2-methoxyimino-3,3-ethylenedioxybutyramido)-3-methylenecepham-4-carboxylic acid (syn isomer) and 7-(2-methoxyimino-3,3-ethylenedioxybutyramido)-3-methyl-3-cephem-4-carboxylic acid (syn isomer) (5:1).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](Cl)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[O:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][OH:17].CC(N(C)C)=O.[H-].[Na+]>CCOC(C)=O>[NH2:1][C:2]1[CH:9]=[C:8]([O:17][CH2:16][CH:12]2[CH2:13][CH2:14][CH2:15][O:11]2)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: OCC1CCCO1
Reactant: N#Cc1cnc(N)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: N#Cc1cnc(N)cc1OCC1CCCO1
Temperature: 70 °C

Procedure:
6-amino-4-chloronicotinonitrile (intermediate 16, 70 mg, 0.456 mmol) and (tetrahydrofuran-2-yl)methanol (233 mg, 2.28 mmol) were charged into a vial. DMA (1 ml) was added to the mixture at room temperature followed by NaH (60% in mineral oil dispersion, 109 mg, 2.73 mmol). The mixture was then heated at 70° C. for 16 h. The reaction mixture was cooled to room temperature, diluted in EtOAc and washed with aq. pH7 buffer (2×) and brine. The organic layer was dried over
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.I[CH:13]([CH3:15])[CH3:14]>>[Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][N:8]([CH:13]([CH3:15])[CH3:14])[C:6]=2[N:7]=1
Reactant: CC(C)I
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Product: CC(C)n1ccc2c(Cl)nc(Cl)nc21

Procedure:
Following the procedure of Example 15b, 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (0.5 g, 2.67 mmol) was reacted with 2-iodopropane. The crude residue was purified by silica gel chromatography (15 to 25% ethyl acetate in hexane eluant) to afford the title compound as a solid. MS m/z 230.2 (M+1).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31](Br)[N:30]=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[F:27])=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.[NH2:36][C@H:37]1[CH2:42][CH2:41][C@H:40]([OH:43])[CH2:39][CH2:38]1.CO>CN1C(=O)CCC1>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([NH:36][C@H:37]4[CH2:42][CH2:41][C@H:40]([OH:43])[CH2:39][CH2:38]4)[N:30]=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[F:27])=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: N[C@H]1CC[C@H](Nc2cc(Nc3cccc(Br)n3)c3ncc(C(=O)Nc4ccncc4F)n3n2)CC1
Solvent: CN1CCCC1=O
Solvent: CO
Product: N[C@H]1CC[C@H](Nc2cc(Nc3cccc(N[C@H]4CC[C@H](O)CC4)n3)c3ncc(C(=O)Nc4ccncc4F)n3n2)CC1
Temperature: 160 °C

Procedure:
A mixture of 46A (25 mg, 0.046 mmol) and (trans)-4-aminocyclohexanol (100 mg, 0.868 mmol) in NMP (0.4 mL) was heated at 160° C. in a microwave for 1.5 h (300 W), and then cooled to room temperature. The mixture was diluted by MeOH, and purified by preparative reversed-phase HPLC to give 6-((trans-4-aminocyclohexyl)amino)-N-(3-fluoro-4-pyridinyl)-8-((6-((trans-4-hydroxycyclohexyl)amino)-2-pyridinyl)amino)imidazo[1,2-b]pyridazine-3-carboxamide (12 mg, 28%) as a yellow solid. HPLC Rt=2.517 min (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA, 4 min gradient, monitored at 220 nm), [M+H]=575.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([OH:31])[CH:22]=1.O[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42].N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:41]([O:40][C:39]([NH:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][O:31][C:23]1[CH:22]=[C:21]([F:20])[CH:30]=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26])=[O:45])([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)NCCCCCO
Reactant: COC(=O)c1ccc(F)cc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(F)cc1OCCCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The reaction was carried out under N2 atmosphere. Triphenyl phosphine (0.52 mol) was added to a solution of methyl 4-fluoro-2-hydroxybenzoate (0.47 mol), tert-butyl 5-hydroxypentylcarbamate (0.47 mol) and diisopropyl azodicarboxylate (DIAD; 0.94 mol) in THF (1 l) dropwise at −20° C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 2 h. The resulting mixture was used directly in the next step without further purification.
Reaction SMILES: [C@H:1]12[CH2:9][O:8][C:7](=[O:10])[C@H:6]1[CH2:5][CH2:4][CH2:3][CH2:2]2.[NH3:11].ClCCl.CO>C(O)C>[OH:8][CH2:9][C@@H:1]1[CH2:2][CH2:3][CH2:4][CH2:5][C@@H:6]1[C:7]([NH2:11])=[O:10]
Reactant: N
Reactant: O=C1OC[C@@H]2CCCC[C@H]12
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: NC(=O)[C@H]1CCCC[C@H]1CO
Yield: 62.4 %

Procedure:
(1R,6S)-(+)-8-oxabicyclo[4.3.0]nonan-7-one (1 gram) was dissolved in 5 ml of absolute ethanol, followed by the addition of 0.5 gram of gaseous ammonia. The solution was kept in a stoppered flask, and the progress of the reaction was followed by thin layer chromatography (eluent dichloromethane/methanol 20:1). After the reaction was judged complete, the ethanol was evaporated and the resulting residue redissolved in ethyl acetate. Ammonia was removed by extraction with 1% HCl, and the ethyl acetate solution was dried over MgSO4, filtered, and rotary evaporated to leave 0.7 grams of (1S,2R)-2-hydroxymethyl-1-cyclohexanecarboxamide.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([S:17]([CH3:19])=[O:18])=[CH:11][CH:10]=3)[CH3:2].[CH:20]1([CH2:26][NH2:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:27][CH2:26][CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([S:17]([CH3:19])=[O:18])=[CH:11][CH:10]=3)[CH3:2]
Reactant: NCC1CCCCC1
Reactant: CCn1ncc2c(Cl)c3cc(S(C)=O)ccc3nc21
Solvent: CS(C)=O
Product: CCn1ncc2c(NCC3CCCCC3)c3cc(S(C)=O)ccc3nc21
Temperature: 110 °C
Yield: 11.1 %

Procedure:
A mixture of 1-ethyl-4-chloro-6-(methylsulfinyl)-1H-pyrazolo[3,4-b]quinoline (0.4 g, 2.8 mmol), DMSO (1.5 ml) and cyclohexylmethylamine (0.73 ml, 5.6 mmol) is heated at 110° C. over night. The reaction mixture is cooled to room temperature, then is partitioned between CHCl3 (20 ml) and water (20 ml) containing NH4OH (3 ml). The layers are separated, the aqueous layer is extracted with CH2Cl2 (10 ml), and the organic layers are combined dried over MgSO4 and evaporated. The residue is purified by column chromatography on silica gel eluting with ethyl acetate, followed by recrystallization from ethyl acetate (2×) to afford 0.115 g of 1-ethyl-6-(methylsulfinyl)-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, m.p. 186°-187° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]2)#[N:2].Cl.[NH2:20][OH:21].CCN(C(C)C)C(C)C>CCO>[OH:21][NH:20][C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]2)=[NH:2]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(C#N)cc2C1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1Cc2ccc(C(=N)NO)cc2C1
Yield: 99.7 %

Procedure:
A product of Step C (0.22 g; 0.904 mmol), HCl×NH2OH (0.16 g; 2.3 mmol) and DIPEA (0.48 ml; 5 mmol) in anhydrous EtOH (3.5 ml) was refluxed for 2 h under N2. The solvents were removed under reduced pressure and the residue was diluted to 30 ml with EtOAc, washed with H2O (2×5 ml), brine, dried over anhydrous MgSO4, filtered and the filtrate evaporated to dryness to give the title compound (0.25 g; 100%) as colourless foam, which was used in next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)=O.[CH3:24][CH2:25][O:26][C:27]([CH2:29][C:30]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=O)=[O:28].S(=O)(=O)(O)O>C(O)(=O)C>[CH2:25]([O:26][C:27](=[O:28])[CH2:29][C:30]1[C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:4]([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=2)[C:3]2[C:2](=[CH:19][C:18]([O:20][CH3:21])=[C:17]([O:22][CH3:23])[CH:16]=2)[N:1]=1)[CH3:24]
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCOC(=O)Cc1nc2cc(OC)c(OC)cc2c(-c2ccc(OC)c(OC)c2)c1C(=O)OCC
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 73 %

Procedure:
To a mixture of 2-amino-4,5,3',4'-tetramethoxybenzophenone (50.0 g), acetonedicarboxylic acid diethyl ester (35.0 g) and acetic acid (400 ml), concentrated sulfuric acid (1.5 ml) was added, followed by stirring at 100° C. for 2.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was poured over water, neutralized with a saturated aqueous sodium hydrogen carbonate solution and then extracted with chloroform. The chloroform layer was washed with water and dried (MgSO4), after which the solvent was distilled off under reduced pressure. The residual crystal was recrystallized from ethanol to yield 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-3-ethoxycarbonylquinoline-2-acetic acid ethyl ester (55.6 g, 73%) as a colorless prismatic crystal having a melting point of 146 to 147° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([O:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:26])=[CH:12][CH:13]=[N:14]2)=[CH:9][C:8]=1[O:33][CH3:34].[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:34][O:33][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:7]=1[O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:39]1[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]1)[N:14]=[CH:13][CH:12]=[C:11]2[O:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:26]
Reactant: CN1CCNCC1
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCCN1CCN(C)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 60.3 %

Procedure:
(2-{[7-(4-Chlorobutoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (60 mg), 4-methylpiperazine (39 mg), and potassium carbonate (90 mg) were suspended in N,N-dimethylformamide (2 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (41 mg, yield 60%).
Reaction SMILES: [CH2:1]1CCC(N=C=NC2CCCCC2)C[CH2:2]1.[C:16]([OH:21])(=O)[CH2:17][CH2:18][CH3:19].[C:22]([O:26][C:27]([NH:29][C@H:30]([C:34]([O:36][CH2:37][CH2:38][C@@H:39]([CH2:52][OH:53])[CH2:40][N:41]1[CH:49]=[N:48][C:47]2[C:46](=[O:50])[NH:45][C:44]([NH2:51])=[N:43][C:42]1=2)=[O:35])[CH:31]([CH3:33])[CH3:32])=[O:28])(C)([CH3:24])C>ClCCl>[CH2:22]([O:26][C:27]([NH:29][C@H:30]([C:34]([O:36][CH2:37][CH2:38][C@@H:39]([CH2:52][O:53][C:16](=[O:21])[CH2:17][CH2:18][CH3:19])[CH2:40][N:41]1[CH:49]=[N:48][C:47]2[C:46](=[O:50])[NH:45][C:44]([NH2:51])=[N:43][C:42]1=2)=[O:35])[CH:31]([CH3:32])[CH3:33])=[O:28])[CH2:24][CH2:1][CH3:2]
Reactant: CCCC(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC[C@@H](CO)Cn1cnc2c(=O)[nH]c(N)nc21
Solvent: ClCCl
Product: CCCCOC(=O)N[C@H](C(=O)OCC[C@@H](COC(=O)CCC)Cn1cnc2c(=O)[nH]c(N)nc21)C(C)C
Temperature: 25 °C
Reaction time: 120 h
Yield: 34.4 %

Procedure:
DCC (110 mg, 0.53 mmol) was dissolved in dichloromethane (10 ml) and butyric acid (82 mg, 0.93 mmol) was added. After 4 hours at room temperature the mixture was filtered and the filtrate was evaporated. The residue was dissolved in pyridine (5 ml) and (R)-9-[4-(N-tert-Butoxycarbonyl-L-valyloxy)-2-hydroxymethylbutyl]guanine (200 mg, 0.44 mmol) (Example 1, step a) was added. The mixture was stirred for 120 hours at room temperature. According to TLC the reaction was incomplete and more anhydride was made using the procedure above. This anhydride was added and the mixture was stirred for an additional 20 hours. The reaction mixture was evaporated and chromatographed first on silica gel and then on aluminum oxide, in both cases eluted with dichloromethane/methanol to give 79 mg of the intermediate product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)[C:14]1=[O:32].Cl.O1CCOCC1>C(Cl)Cl.CO>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([CH:19]2[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]2)[C:14]1=[O:32]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCCC(Nc3ccc(S(C)(=O)=O)cc3F)C2=O)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(NC2CCCN(C3CCNCC3)C2=O)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
Tert-butyl 3-(2-fluoro-4-(methylsulfonyl)phenylamino)-2-oxo-1,4′-bipiperidine-1′-carboxylate (7.9 g, 17 mmol) was dissolved in CH2Cl2 (100 mL) and MeOH (10 mL). 4N HCl in dioxane (29 mL, 118 mmol) was added and the reaction stirred at ambient temperature for 3 hours. The reaction was concentrated and purified over silica gel (50-100% EtOAc in hexanes followed by 5% ammoniated methanol in CH2Cl2) to afford 3-(2-fluoro-4-(methylsulfonyl)phenylamino)-1,4′-bipiperidin-2-one (6.2 g, 17 mmol, 100% yield) as yellow solid.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:16]([F:17])=[C:15]([F:18])[CH:14]=[CH:13][C:5]=1[NH:6][C@@H:7]([CH3:12])[C:8](OC)=[O:9].CO.O>ClC1C=CC=CC=1>[F:3][C:4]1[C:16]([F:17])=[C:15]([F:18])[CH:14]=[CH:13][C:5]=1[NH:6][C@@H:7]([CH3:12])[CH2:8][OH:9]
Reactant: COC(=O)[C@H](C)Nc1ccc(F)c(F)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: Clc1ccccc1
Solvent: CO
Solvent: O
Product: C[C@@H](CO)Nc1ccc(F)c(F)c1F
Reaction time: 6 h

Procedure:
At room temperature, sodium borohydride (35.7 mg) was suspended in chlorobenzene (0.2 ml). Then a solution (0.8 ml) of methyl (2S)-2-(2,3,4-trifluoroanilino)propionate (200 mg, 99.8% ee) in chlorobenzene was added to the solution. After adding methanol (137.4 mg), the liquid reaction mixture was stirred for 6 hours. Then water was added to the liquid reaction mixture followed by extraction with ethylacetate. The organic layer was washed with water and a saturated aqueous solution of ammonium chloride and dried over anhydrous magnesium sulfate. After evaporating the solvent, the obtained residue was subjected to silica gel column chromatography to thereby give 162.9 mg (99.8% ee) of the title compound as an oily substance. The 1H-NMR and IR spectral data of this product was identical with those of the compound obtained in Example 51.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]3[C:14]([O:15][CH:16]([F:18])[F:17])=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][C:9](=[O:10])[C:4]=2[C:3]=1[Br:21].Cl[C:23](Cl)([O:25][C:26](=[O:32])OC(Cl)(Cl)Cl)Cl.C(O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1>[CH2:23]([O:25][C:26]([NH:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]3[C:14]([O:15][CH:16]([F:18])[F:17])=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][C:9](=[O:10])[C:4]=2[C:3]=1[Br:21])=[O:32])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Nc1ccc2c(c1Br)c(=O)oc1cccc(OC(F)F)c12
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCc1ccccc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc2c(c1Br)c(=O)oc1cccc(OC(F)F)c12)OCc1ccccc1
Temperature: 25 °C

Procedure:
A solution of Example 27C (1.13 g, 3.19 mmol) in THF (100 mL) was treated with triphosgene (0.95 g, 3.19 mmol), heated at reflux for 4 hours, treated with benzyl alcohol, (3.44 g. 31.9 mmol), heated at reflux for 16 hours, cooled to room temperature, and concentrated to a fraction of its original volume. The solution was cooled to 0° C. and filtered to provide the desired product. MS (ESI(−)Q1MS) m/z 488 (M−H)−.
Reaction SMILES: [CH2:1]1[CH2:29][O:28][C:3]2([C:20]3[C:19](=[O:21])[C:18]4[C:9](=[C:10]([OH:24])[C:11]5[CH2:12][CH2:13][CH:14]([OH:23])[CH2:15][C:16]=5[C:17]=4[OH:22])[C:8](=[O:25])[C:7]=3[CH:6]=[CH:5][CH:4]2[CH2:26][CH3:27])[O:2]1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:42]Br>C(Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl.O>[Br:42][CH:12]1[CH2:13][CH:14]([OH:23])[CH2:15][C:16]2[C:17]([OH:22])=[C:18]3[C:9]([C:8](=[O:25])[C:7]4[CH:6]=[CH:5][CH:4]([CH2:26][CH3:27])[C:3]5([O:2][CH2:1][CH2:29][O:28]5)[C:20]=4[C:19]3=[O:21])=[C:10]([OH:24])[C:11]1=2
Reactant: BrBr
Reactant: CCC1C=CC2=C(C(=O)c3c(O)c4c(c(O)c3C2=O)CCC(O)C4)C12OCCO2
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCC1C=CC2=C(C(=O)c3c(O)c4c(c(O)c3C2=O)C(Br)CC(O)C4)C12OCCO2
Reaction time: 1 h

Procedure:
9-(1,1-Ethylenedioxy)ethyl-6,9,11-trihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione (10.0 g) was dissolved in a mixture of chloroform (395 ml), carbon tetrachloride (980 ml) and water (890 ml) while heating, azobisisobutyronitrile (2.0 g) and bromine (8.0 g) were added thereto in order, and the resultant mixture was stirred under reflux for 1.5 hours. The reaction mixture was stirred in an ice bath for 1 hour, and the precipitated red orange crystals were collected by filtration, washed with water and dried under reduced pressure to give the crude product of 7-bromo-9-(1,1-ethylenedioxy)ethyl-6,9,11-trihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione. M.P., 196°-235° C.; IR (Nujol) ν cm-1 : 3550, 1625, 1590. This product was used as such in the following step without purification.