Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH:15]1[CH2:20][O:19][C:17](=[O:18])[CH2:16]1.N1C=CC=CC=1>C(OCC)(=O)C.O>[Cl:1][CH2:2][C:3]([N:14]([CH:15]1[CH2:20][O:19][C:17](=[O:18])[CH2:16]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[O:7][CH3:6])=[O:4]
Reactant: COc1ccccc1NC1COC(=O)C1
Reactant: O=C(Cl)CCl
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccccc1N(C(=O)CCl)C1COC(=O)C1
Temperature: 46 °C
Reaction time: 0.25 h

Procedure:
A 5.4 g (0.044 mol) sample of chloroacetyl chloride was added dropwise to a solution of 9 g (0.044 mol) 3-(N-2-methoxyphenylamino)-gamma-butyrolactone and 3.8 g (0.048 mol) pyridine in 150 ml ethyl acetate at 37°-46° C. After stirring at 46° C for 15 minutes, the reaction mixture was cooled and diluted with water. The organic layer was separated, washed with 10% aqueous sodium bicarbonate, washed with water, dried over magnesium sulfate and evaporated under reduced pressure to give the product, as a colorless solid. The melting point and elemental analysis for the product is tabulated in Table I, as compound No. 3.
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:43])[C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH2:37][C:38]3[NH:39][CH:40]=[CH:41][N:42]=3)[CH2:25][C:26]3[N:27]([CH2:31][CH2:32][O:33]COC)[CH:28]=[CH:29][N:30]=3)=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].Cl>CO>[CH2:1]([N:4]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:43])[C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH2:25][C:26]3[N:27]([CH2:31][CH2:32][OH:33])[CH:28]=[CH:29][N:30]=3)[CH2:37][C:38]3[NH:39][CH:40]=[CH:41][N:42]=3)=[CH:19][CH:18]=2)=[CH:13][CH:14]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3nccn3CCOCOC)cc2)cc1
Agent: Cl
Solvent: CO
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3nccn3CCO)cc2)cc1

Procedure:
The compound (60.0 mg) obtained in Example 92-3 was dissolved in methanol (5.0 ml) and then added with 1 mol/l hydrochloric acid (1.5 ml). The solution was concentrated and dried under reduced pressure, thereby obtaining hydrochloride (80.0 mg) of the subject compound as a white solid.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+](N[C:23]1[NH:28][C:27](=[O:29])[C:26]([O:30][CH3:31])=[CH:25][N:24]=1)([O-])=O.N1C=CC=CC=1>C(O)C>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:23]2[NH:28][C:27](=[O:29])[C:26]([O:30][CH3:31])=[CH:25][N:24]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cnc(N[N+](=O)[O-])[nH]c1=O
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Solvent: c1ccncc1
Solvent: CCO
Product: COc1cnc(NCCCOc2cccc(CN3CCCCC3)c2)[nH]c1=O

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (1.64 g) and 2-nitroamino-5-methoxypyrimidin-4-one (1.12 g) were stirred under reflux, for 40 hours, in ethanol (15 ml). The ethanol was replaced by pyridine (15 ml) and the solution stirred under reflux for a further 10 hours to complete the reaction. The reaction mixture was cooled and evaporated under reduced pressure to give a residue. This was partitioned between water (25 ml) and chloroform (25 ml), the aqueous layer being further extracted with chloroform (2×25 ml). The combined chloroform extracts were dried (MgSO4), evaporated under reduced pressure and subjected to medium pressure chromatography using chloroform: methanol (95 : 5) to give the title compound. The fractions containing the title compound were dissolved in isopropanol and treated with maleic acid (0.6 g) in isopropanol to give 2-[3-[3-(piperidinomethyl)phenoxy]propylamino]-5-methoxypyrimidin-4-one maleate (0.96 g), m.p. 148°-149.5° C (recrystallisation from ethanol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=2)[CH:13]=[C:14]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][N:35]=2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CC1(C)OB(c2ccccn2)OC1(C)C
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccccn2)c1
Temperature: 80 °C
Yield: 33 %

Procedure:
To a solution of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester, compound 1g (105 mg, 0.205 mmol) in dimethoxyethane (1.4 mL), was added 2-pyridine boronic acid pinacol ester adduct (169 mg, 0.41 mmol), and 2M Na2CO3 (0.31 ml, 0.614 mmol). The mixture was degassed, tetrakis(triphenylphosphine)palladium (0) (24.0 mg, 0.02 mmol) was added and the mixture was degassed again, and then heated to 80° C. overnight. The reaction was cooled to room temperature, diluted with EtOAc and washed with NaHCO3 and brine. Purification by column chromatography gave the title compound (30 mg, 33%). Calcd for C26H26F3NO2 (M+H) 441.49, Found 442.2.
Reaction SMILES: [OH:1][C:2]([CH:5]1[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1)([CH3:4])[CH3:3].[ClH:17].O1CCOCC1>C(Cl)Cl.CCOC(C)=O>[ClH:17].[NH:7]1[CH2:8][CH2:9][CH:5]([C:2]([OH:1])([CH3:4])[CH3:3])[CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(C)(C)O)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(O)C1CCNC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102 %

Procedure:
To a solution of tert-butyl 3-(2-hydroxypropan-2-yl)pyrrolidine-1-carboxylate (0.69 g, 3.01 mmol) in DCM (15 mL) and EtOAc (5 mL) was added 4 M HCl in dioxane (3.01 mL, 12.04 mmol). The reaction was stirred overnight at RT and then concentrated to generate 2-(pyrrolidin-3-yl)propan-2-ol hydrochloride as a yellow oil (0.51 g, 102% yield).
Reaction SMILES: [CH2:1]([S:9]([NH:12][C:13]1[C:26]2[C:25](=[O:27])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[NH2:28])[C:18](=[O:29])[C:17]=2[CH:16]=[CH:15][CH:14]=1)(=[O:11])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:30]([C:32](=[O:39])[CH:33](Cl)[CH2:34][CH2:35][CH2:36][CH3:37])[CH3:31].[N+](C1C=CC=CC=1)([O-])=O>CO>[CH2:1]([S:9]([NH:12][C:13]1[C:26]2[C:25](=[O:27])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[NH:28][CH:33]([CH2:34][CH2:35][CH2:36][CH3:37])[C:32]([CH2:30][CH3:31])=[O:39])[C:18](=[O:29])[C:17]=2[CH:16]=[CH:15][CH:14]=1)(=[O:10])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCC(Cl)C(=O)CC
Reactant: CCCCCCCCS(=O)(=O)Nc1cccc2c1C(=O)c1c(N)cccc1C2=O
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CO
Product: CCCCCCCCS(=O)(=O)Nc1cccc2c1C(=O)c1c(NC(CCCC)C(=O)CC)cccc1C2=O

Procedure:
1-(n-octylsulfonylamino)-8-aminoanthraquinone (0.25g), 1-ethylhexanoyl chloride (0.5g) and nitrobenzene (5ml) were heated at reflux for 10 mins. After addition of methanol (10ml), the mixture was heated on a steam bath for a further 10 mins to destroy excess acid chloride. 0n evaporation of low-boiling material, the remaining liquid was diluted with toluene (100ml) and separated by chromatography on a silica gel column. Nitrobenzene eluted first, and the material eluted with a 50:50 mixture of toluene:ethyl acetate was collected. The solvent was evaporated and ethanol was added to the residue, which upon trituration afforded the product as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13](O)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:13][OH:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Br)cc2)CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1(c2ccc(Br)cc2)CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
To a solution of 1-(4-bromophenyl)cyclopentanecarboxylic acid (Enamine, 1 g, 3.72 mmol) in tetrahydrofuran (10 mL), at 0° C. was added slowly LiAlH4 1M/THF (7.43 mL, 7.43 mmol). The reaction mixture was stirred at room temperature for 1 h and quenched by water. The product was extracted with DCM and the organic layer was evaporated under reduced pressure. The product was purified on silica gel column chromatography using a cyclohexane to cyclohexane/EtOAc 70:30 as eluant. The appropriate fractions were combined and concentrated in vacuo to give the title product (1-(4-bromophenyl)cyclopentyl)methanol (832 mg, 3.26 mmol, 88% yield) as a colourless oil. 1H NMR: (DMSO-d6, 300 MHz) δ 7.40 (m, 2H), 7.25 (m, 2H), 4.65 (m, 1H), 3.38 (m, 2H), 1.95 (m, 2H), 1.65 (m, 6H).
Reaction SMILES: O1CCCC1.C[Si](C)(C)[C:8]([F:11])([F:10])[F:9].[O:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1.Cl>CCOC(C)=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[F:9][C:8]([F:11])([F:10])[C:17]1([OH:20])[CH2:18][CH2:19][O:14][CH2:15][CH2:16]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=C1CCOCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC1(C(F)(F)F)CCOCC1
Temperature: 0 °C
Yield: 42.6 %

Procedure:
Tetrahydrofuran (110 mL) was added to a round bottom flask and placed under N2. trimethyl(trifluoromethyl)silane (4.13 mL, 28.0 mmol) was then added and stirred under N2 and then cooled to 0° C. Dihydro-2H-pyran-4(3H)-one (1.845 mL, 19.98 mmol) was then added via syringe and stirred for 5 minutes at 0° C. to ensure complete mixing. TBAF (0.200 mL, 0.200 mmol) was added dropwise slowly via syringe. The reaction was then allowed to warm up to RT for 30 min. The reaction was then cooled back down to 0° C. and added 1M HCl (50 mL) and then stirred at RT for overnight. The reaction was diluted with EtOAc and separated with brine. The organic layer was dried over MgSO4, filtered and evaporated to give the crude material which was crystallized from hexane to give the product 4-(trifluoromethyl)tetrahydro-2H-pyran-4-ol (1.45 g, 8.52 mmol, 42.7% yield) as white crystals. 1H NMR (400 MHz, CHLOROFORM-d) d 3.96-3.84 (m, 2H), 3.76 (td, J=12.1, 2.1 Hz, 2H), 2.08-1.90 (m, 3H), 1.65-1.48 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][N:11]2[N:10]=[C:9]1[CH:18]([NH:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][N:11]2[N:10]=[C:9]1[CH:18]([N:21]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:19][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(NC1CCCCC1)c1nn2cccc2c(=O)n1Cc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCC(c1nn2cccc2c(=O)n1Cc1ccccc1)N(C(=O)c1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.7 %

Procedure:
3-Benzyl-2-(1-cyclohexylamino-propyl)-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (Example 28, 26.3 mg, 0.072 mmol) in CHCl3 (1.5 mL) at 25° C. was treated with benzoylchloride (34.9 mg, 0.248 mmol) and triethylamine (16.8 mg, 0.166 mmol). The resulting mixture was stirred at 25° C. for 18 h, then concentrated under vacuum and purified by preparative HPLC using a YMC S10 ODS 20×100 mm column affording the desired compound (8.0 mg, 23.7%) as a colorless film: LC/MS 94% at 4.42 min (ESI+) 469 (M++H).
Reaction SMILES: [F:1][CH:2]=[CH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C1C(C(OO)=[O:18])=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[F:1][CH:2]=[CH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]2[O:18][CH:7]2[CH:6]=1
Reactant: FC=CCc1ccccc1
Reactant: O=C(OO)c1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: FC=CCC1=CC2OC2C=C1
Reaction time: 120 h
Yield: 52 %

Procedure:
7 g of p-fluoroallylbenzene was added to 800 ml of chloroform solution containing perbenzoic acid prepared from 46 g of benzoyl peroxide and the mixture was allowed to stand at about 5° C for 5 days. The resulting mixture was washed with sodium hydroxide solution, water, Mohr's salt solution, then water, and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was distilled under reduced pressure to give 4.1 g (yield 52%) of p-fluoroallylbenzene oxide as colorless liquid.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH3:6].[C:9](Cl)(=O)C(Cl)=O.CN(C)C=O.CO>O1CCCC1>[C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH3:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCC/C=C/C(=O)O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CO
Product: CCC/C=C/C(=O)OC
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution (100 mL) of (2E)-hex-2-enoic acid (5.0 g) in tetrahydrofuran were added dropwise under ice-cooling oxalyl chloride (3.76 mL) and N,N-dimethylformamide (1 mL). The mixture was stirred at the same temperature for 30 min, methanol (10 mL) was gradually added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, and the residue was treated with 6% aqueous sodium hydrogencarbonate solution, and extracted with diethyl ether. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure (50 Torr, water bath 10° C.) to give the title compound as a colorless oil (yield 5.67 g, about 100%).
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[CH2:12][N:11]2[C@H:6]([CH2:7][O:8][CH2:9][CH2:10]2)[CH2:5][N:4]1CC1C=CC=CC=1>CC(O)=O.[Pd]>[F:1][CH2:2][C@@H:3]1[CH2:12][N:11]2[C@H:6]([CH2:7][O:8][CH2:9][CH2:10]2)[CH2:5][NH:4]1
Reactant: FC[C@@H]1CN2CCOC[C@@H]2CN1Cc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: FC[C@@H]1CN2CCOC[C@@H]2CN1
Reaction time: 1.5 h
Yield: 77.8 %

Procedure:
To a solution of (7S,9aS)-7-(fluoromethyl)-8-(phenylmethyl) octahydropyrazino[2,1-c][1,4]oxazine (D128, 30 mg, 0.11 mmol) in AcOH (30 ml) was added Pd-black (12 mg, 0.11 mmol) and the reaction mixture was stirred under a H2 atmosphere (5 atm.) for 1.5 hrs. The reaction mixture was filtered on a SCX cartridge washing with methanol and then with 2M methanolic ammonia. The fractions eluted with ammonia were combined and evaporated to dryness. The crude was purified by chromatography (silica, CH2Cl2:MeOH 1:0 to 8:2) to give the title compound (14.9 mg, y=78%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:11]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13][CH:12]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:17]([C:4]1[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[Cl:1])[NH:6][CH:5]=1)[C:14]1[CH:15]=[CH:16][C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:12][CH:13]=1)=[CH:5][NH:6]2
Reactant: Clc1cccc2[nH]ccc12
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Product: Clc1cccc2[nH]cc(C(c3ccc(-c4ccccc4)cc3)c3c[nH]c4cccc(Cl)c34)c12

Procedure:
The compound Bis(4-chloroindol-3-yl)-(1,1′-biphenyl-4-yl)methane was prepared following general procedure A, starting from 4-chloro indole and 4-biphenyl carboxaldehyde. LC: Tr 2.79 min, MS: 467 (M+H)+
Reaction SMILES: [BrH:1].C1(O[CH2:9][C:10]2[CH:17]=[C:16]([C@:18]3([O:36][C@H:35]([CH2:37][O:38][C:39](=[O:41])[CH3:40])[C@@H:30]([O:31][C:32](=[O:34])[CH3:33])[C@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@H:20]3[O:21][C:22](=[O:24])[CH3:23])[OH:19])[CH:15]=[CH:14][C:11]=2[C:12]#[N:13])C=CC=CC=1.C(OC(=O)C)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[Br:1][CH2:9][C:10]1[CH:17]=[C:16]([C@:18]2([O:36][C@H:35]([CH2:37][O:38][C:39](=[O:41])[CH3:40])[C@@H:30]([O:31][C:32](=[O:34])[CH3:33])[C@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@H:20]2[O:21][C:22](=[O:24])[CH3:23])[OH:19])[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: CC(=O)OC[C@H]1O[C@](O)(c2ccc(C#N)c(COc3ccccc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1O[C@](O)(c2ccc(C#N)c(CBr)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 55 °C
Reaction time: 6 h

Procedure:
A 33% solution of hydrobromic acid in acetic acid (15 mL) is added to a solution of 2-phenyloxymethyl-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-benzonitrile (0.71 g) and acetic anhydride (0.12 mL) in acetic acid (10 ml). The resulting solution is stirred at 55° C. for 6 h and then cooled in an ice-bath. The reaction mixture is neutralized with chilled aqueous potassium carbonate solution, and the resultant mixture is extracted with ethyl acetate. The combined organic extracts are dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is taken up in ethyl acetate/cyclohexane (1:5), and the precipitate is separated by filtration and dried at 50° C. to give the product.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:17][CH2:18][Cl:19])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O.ON1C(=O)CCC1=O.[CH2:28]([O:30][P:31]([CH:36]([P:41]([O:46][CH2:47][CH3:48])(=[O:45])[O:42][CH2:43][CH3:44])[CH2:37][CH2:38][CH2:39][NH2:40])(=[O:35])[O:32][CH2:33][CH3:34])[CH3:29]>>[CH2:43]([O:42][P:41]([CH:36]([P:31]([O:30][CH2:28][CH3:29])(=[O:35])[O:32][CH2:33][CH3:34])[CH2:37][CH2:38][CH2:39][NH:40][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[N:4]([CH2:3][CH2:2][Cl:1])[CH2:17][CH2:18][Cl:19])(=[O:45])[O:46][CH2:47][CH3:48])[CH3:44]
Reactant: O=C(O)CCCc1ccccc1N(CCCl)CCCl
Reactant: CCOP(=O)(OCC)C(CCCN)P(=O)(OCC)OCC
Agent: O=C1CCC(=O)N1O
Product: CCOP(=O)(OCC)C(CCCNC(=O)CCCc1ccccc1N(CCCl)CCCl)P(=O)(OCC)OCC

Procedure:
Following the procedure described in Example 1b), by reacting 4-[2-[bis(2-chloroethyl)amino]phenyl]butyric acid (J. Org. Chem. 26, 1554, (1961)) with N-hydroxysuccinimide and N-morpholinoethylisonitrile, 4-[2-[bis(2-chloroethyl)amino]phenyl]butyric acid N-hydroxysuccinimido ester is prepared. Said N-hydroxysuccinimido ester is reacted with 4-aminobutane-1,1-diphosphonic acid tetraethyl ester, according to the procedure described in Example 10, to give N-{4-[2-[bis(2-chloroethyl)amino]phenyl]butyroyl}-4-aminobutane-1,1-diphosphonic acid tetraethyl ester, which is reacted with iodotrimethylsilane, following the procedure described in Example 11, to obtain N-{4-[2-[bis(2-chloroethyl)amino]phenyl]butyroyl}-4-aminobutane-1,1-diphosphonic acid disodium salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:18]2[CH:25]([C:26]3[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[C:28]([F:34])[CH:27]=3)[C:24]3[C:20](=[N:21][N:22]([C:38]4[C:39]([O:47][CH3:48])=[N:40][C:41]([N:44]([CH3:46])[CH3:45])=[N:42][CH:43]=4)[C:23]=3[CH:35]([CH3:37])[CH3:36])[C:19]2=[O:49])[C:5](=[O:17])[N:6](CC2C=CC(OC)=CC=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([N:18]2[CH:25]([C:26]3[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[C:28]([F:34])[CH:27]=3)[C:24]3[C:20](=[N:21][N:22]([C:38]4[C:39]([O:47][CH3:48])=[N:40][C:41]([N:44]([CH3:45])[CH3:46])=[N:42][CH:43]=4)[C:23]=3[CH:35]([CH3:37])[CH3:36])[C:19]2=[O:49])[C:5](=[O:17])[NH:6][CH:7]=1
Reactant: COc1ccc(Cn2cc(Cl)cc(N3C(=O)c4nn(-c5cnc(N(C)C)nc5OC)c(C(C)C)c4C3c3ccc(C#N)c(F)c3)c2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc(N(C)C)ncc1-n1nc2c(c1C(C)C)C(c1ccc(C#N)c(F)c1)N(c1cc(Cl)c[nH]c1=O)C2=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 37.9 %

Procedure:
A mixture of 4-(5-(5-chloro-1-(4-methoxybenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-(2-(dimethylamino)-4-methoxypyrimidin-5-yl)-3-isopropyl-6-oxo-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-4-yl)-2-fluorobenzonitrile (388 mg, 0.568 mmol, product from step 193.1) and TFA (2.188 ml, 28.4 mmol) was stirred at 100° C. for 1 hour. Then the reaction mixture was quenched with a saturated NaHCO3 solution and extracted twice with CH2Cl2. The organic layers were combined and washed with saturated NaHCO3 solution, dried (Na2SO4) and evaporated. The reaction mixture was purified by chromatography (Silicagel, EtOAc). After evaporation of the fractions, the residue was triturated in diisopropylether to afford 121 mg (0.215 mmol, 37.8% yield) of the title compound as a white solid. LCMS: (M+H)=563/565; tR=1.04 min (LC−MS 4). TLC: Rf=0.34 (EtOAc). 1H−NMR (DMSO−d6, 600 MHz) δ ppm 12.36 (s, 1H) 8.28 (s, 1H) 7.91 (t, 1H) 7.65−7.53 (m, 3H) 7.40 (d, 1H) 6.84 (bs, 1H) 3.87 (s, 3H) 3.18 (s, 6H) 2.60 (m, 1H) 1.08 (d, 3H) 0.47 (d, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH2:11][F:12])[CH:10]=1)[CH2:6][OH:7].N1C=CN=C1.[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20]>CN(C=O)C>[Si:22]([O:7][CH2:6][C:5]1[CH:4]=[C:3]([CH:10]=[C:9]([CH2:11][F:12])[CH:8]=1)[CH2:2][NH2:1])([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23]
Reactant: NCc1cc(CO)cc(CF)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cc(CN)cc(CF)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
3-Aminomethyl-5-fluoromethylbenzylalcohol (38) (520 mg, 3.07 mmol) and imidazole (923 mg, 13.6 mmol) were dissolved in DMF (15.5 mL). The air was evacuated from the reaction system, and then Ar was charged therein. To the solution was added TBDMSCl (1.03 g, 6.83 mmol), and dissolved. Again the air was evacuated from the reaction system, and then Ar was charged therein. The mixture was stirred for 18 hours at a room temperature. TLC was used to confirm the progress of the reaction. The reaction mixture was extracted with EtOAc. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to remove the solvent. The residue was purified by neutral silica gel column chromatography (hexane:EtOAc=1:1) to isolate 3-(t-butyldimethylsilyloxy)methyl-5-fluoromethylbenzylamine (41) (661 mg, 76%) as a colorless oil.
Reaction SMILES: [H-].[Na+:2].O=C1CCCC1C(OCC)=O.F[N+:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[S:23]([O-:26])(=[O:25])=[O:24]>O1CCCC1>[CH3:22][C:18]1[CH:19]=[C:20]([CH3:21])[N:15]=[C:16]([S:23]([O-:26])(=[O:24])=[O:25])[CH:17]=1.[Na+:2]
Reactant: Cc1cc(C)[n+](F)c(S(=O)(=O)[O-])c1
Agent: CCOC(=O)C1CCCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)nc(S(=O)(=O)[O-])c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.3 %

Procedure:
In an inert gas atmosphere, to a mixture of sodium hydride (120 mg, 3 mmol) and tetrahydrofuran (6 ml), ethyl 2-oxocyclopentanecarboxylate (445 μl, 3 mmol) was added and then N-fluoro-4,6-dimethylpyridinium-2-sulfonate (615 mg) was added while cooling with ice, followed by stirring at room temperature for 1.5 hours. The reaction mixture was filtrated and the obtained crystal was washed with tetrahydrofuran and ethyl ether successively to obtain sodium 4,6-dimethylpyridine-2-sulfonate (535 mg). Yield, 85%.