Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C@H]1[O:9][C:8](=[O:10])[C@@:7]([C@@H:17]2[CH2:21][CH2:20][C:19](=[O:22])[CH2:18]2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:6]1)(C)(C)C>CO.[OH-].[Na+]>[O:22]=[C:19]1[CH2:20][CH2:21][C@@H:17]([C@@:7]([OH:6])([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:8]([OH:10])=[O:9])[CH2:18]1
Reactant: CC(C)(C)[C@H]1OC(=O)[C@](c2ccccc2)([C@@H]2CCC(=O)C2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1CC[C@@H]([C@](O)(C(=O)O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.6 %

Procedure:
To a solution of 61 mg of (2R,5R)-2-(t-butyl)-5-[(1R)-3-oxocyclopentyl]-5-phenyl-1,3-dioxolan-4-one in 3 ml of methanol, 1 ml of 1N aqueous sodium hydroxide solution was added, followed by stirring for 3 hours at room temperature. Distilling the methanol off under reduced pressure, the residue was diluted with water and washed with diethyl ether. The aqueous layer was made acidic with 1N hydrochloric acid and extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate to provide 48 mg of the title compound.
Reaction SMILES: O[CH:2]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[CH2:11][OH:12].P(=O)(O)(O)O>C(OC(=O)C)C>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH:2]2[C:3]3[C:4](=[CH:5][C:6]([C:7]#[N:8])=[CH:9][CH:10]=3)[CH2:11][O:12]2)=[CH:14][CH:15]=1
Reactant: COc1ccc(C(O)c2ccc(C#N)cc2CO)cc1
Agent: O=P(O)(O)O
Solvent: CCOC(C)=O
Product: COc1ccc(C2OCc3cc(C#N)ccc32)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
33.82 g (125.6 mmol) of the 4-{hydroxy(4-methoxyphenyl)methyl}-3-(hydroxymethyl)benzonitrile prepared in step 2 was dissolved in 150 ml of ethylacetate, and 150 ml of a 85% aqueous solution of phosphoric acid was added at room temperature. The mixture was raised to 80° C. and stirred for 3 hrs. The reaction mixture was then cooled again to room temperature, and washed with water and saturated NaCl solution. An organic layer was dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was treated with 2-propanol to afford 18.0 g of a white solid (yield: 57%).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:22]([CH3:24])[CH3:23])[C:7]([N:9]1[C@H:17]([C:18]([O:20]C)=[O:19])[CH2:16][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:10]1)=[O:8])=[O:4].C(O)(C)(C)C.[Li+].[OH-].Cl>CCOC(C)=O>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:22]([CH3:24])[CH3:23])[C:7]([N:9]1[C@H:17]([C:18]([OH:20])=[O:19])[CH2:16][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:10]1)=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1C(=O)OC)OCCO2)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1C(=O)O)OCCO2)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 10 mL round-bottomed flask, (S)-methyl 7-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-1,4-dioxa-7-azaspiro[4.4]nonane-8-carboxylate (150 mg, 436 μmol) was combined with tert-butanol (250 μl) to give a colorless solution. LiOH (1M, 871 μl, Eq: 2) was added and stirred at room temperature for 2 hr. It was acidified with 1N HCl to pH 3 and diluted with 100 ml of EtOAc. It was washed with brine (5 ml), dried with MgSO4, filtered and concentrated in vacuo to afford (S)-7-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-1,4-dioxa-7-azaspiro[4.4]nonane-8-carboxylic acid as a white solid which was used for the next reaction without further purification. (75 mg, 52.1%).
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8](N)[CH:7]=1)(=[O:5])=[O:4].[OH-].[Na+].C(Cl)Cl.N([O-])=[O:19].[Na+]>O.C(Cl)Cl.O>[CH3:2][S:3]([C:6]1[CH:7]=[C:8]([OH:19])[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4]
Reactant: O=N[O-]
Reactant: CS(=O)(=O)c1cccc(N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)c1cccc(O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.3 %

Procedure:
The title compound was prepared by a slightly modified literature procedure.* 3-aminophenyl methyl sulfone hydrochloride (1.18 g, 5.70 mmol) was suspended in water/CH2Cl2. The mixture was neutralized with 25% aqueous NaOH. The CH2Cl2 layer was isolated and evaporated to dryness. Aqueous H2SO4 (60%; 10 mL) was added to the residue and the solution was cooled to 0° C. A solution of NaNO2 (0.345 g, 5.00 mmol) in water (5 mL) was added dropwise. The solution was stirred at 0° C. for 30 min. and at 90° C. for 30 min. The reaction mixture was allowed to come to room temperature. Extraction with CH2Cl2, drying (MgSO4), and concentration gave 0.39 g (40%) of the title compound as a solid. MS m/z 172 (M)+. HRMS m/z calcd for C7H8O3S (M)+ 172.0194, found 172.0198.
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([CH:33]=O)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C(O)(=O)C>CO>[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][NH:19][CH2:33][CH:30]2[CH2:31][CH2:32][N:27]([C:25]([O:24][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:26])[CH2:28][CH2:29]2)[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(CNCC2CCN(C(=O)OC(C)(C)C)CC2)CC1
Reaction time: 0.25 h
Yield: 63.5 %

Procedure:
Sodium cyanoborohydride (440 mg; 7.0 mmol) was added to a solution of [(1-tert-butoxycarbonyl-4-piperidinyl)-methyl]amine (1.5 g; 7.0 mmol) in methanol (30 ml) under ice cooling, and the mixture was stirred for 15 minutes. A solution of 1-tert-butoxycarbonyl-4-piperidine-carbaldehyde (1.4 g; 9.1 mmol) in methanol (5 ml) and acetic acid (0.40 ml; 7.0 mmol) were added to the resultant solution, and the mixture was stirred for 4 hours. After the ice bath was removed, the mixture was stirred at room temperature for 48 hours. The reaction mixture was concentrated under reduced pressure and the resultant concentrated residue was added to a saturated aqueous solution of sodium hydrogencarbonate to conduct extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant crude oil was purified by column chromatography on silica gel, thereby obtaining 1.83 g (yield: 63%) of N,N-bis[(1-tert-butoxycarbonyl-4-piperidinyl)methyl]amine as a colorless oil.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH2:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C(C)=CC=CC=1C.ClC(OCC(C)C)=O.C[Si](C)(C)[O:45][NH2:46]>ClCCl.CO>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH2:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[N:16]=2)[CH2:11][C:12]([NH:46][OH:45])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)ON
Reactant: CCCS(=O)(=O)Cc1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Agent: CC(C)COC(=O)Cl
Solvent: CO
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CCCS(=O)(=O)Cc1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.3 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-{3-[(propylsulfonyl)methyl]-1,2,4-oxadiazol-5-yl}hexanoic acid (Preparation 97) (298 mg, 0.77 mmol) and 2,6-lutidine (135 μl, 1.16 mmol) in dichloromethane (10 ml) was cooled to 0° C., treated with isobutyl chloroformate (100 μl, 0.77 mmol) and stirred under a nitrogen atmosphere for 1 hour. O-(Trimethylsilyl)hydroxylamine (310 μl, 2.31 mmol) was added and the mixture was stirred for 4 hours, being allowed to warm to room temperature over this time. The mixture was then treated with methanol (5 ml) and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with hydrochloric acid (1 M) and brine, dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The oil was purified by column chromatography on silica gel eluting with a gradient system of 100:0 (dichloromethane:methanol) gradually changing to 95:5 (dichloromethane:methanol) to afford the title compound as a white solid (140 mg).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][O:8][C:9]1[CH:18]=[C:17]2[C:12](C(C(O)=O)=[CH:14][C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:16]2)=[CH:11][CH:10]=1>ClCl>[CH3:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:1]([C:2]([Cl:4])=[O:3])=[CH:14][C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:16]2)=[CH:11][CH:10]=1
Reactant: COc1ccc2c(C(=O)O)cc(-c3ccccc3)nc2c1
Reactant: O=C(Cl)C(=O)Cl
Agent: ClCl
Product: COc1ccc2c(C(=O)Cl)cc(-c3ccccc3)nc2c1
Temperature: -10 °C
Reaction time: 8 h
Yield: 123.7 %

Procedure:
2.8 ml (32.3 mmol) of oxalyl chloride were dissolved in 60 ml of CH2 Cl2. The solution was cooled at -10° C. and 6 g (19.0 mmol) of 7-methoxy-2-phenylquinoline-4-carboxylic acid were added portionwise. The reaction mixture was left overnight at room temperature and then evaporated to dryness to yield 7 g of the title compound, used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=O)[C:16]3[C:11](=[CH:12][C:13]([OH:20])=[C:14]([Cl:19])[CH:15]=3)[O:10][C:9]=2[CH3:21])=[CH:4][CH:3]=1.O.[NH2:23][NH2:24]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([C:16]3[CH:15]=[C:14]([Cl:19])[C:13]([OH:20])=[CH:12][C:11]=3[OH:10])=[N:23][NH:24][C:9]=2[CH3:21])=[CH:4][CH:3]=1
Reactant: Cc1oc2cc(O)c(Cl)cc2c(=O)c1-c1ccc(Br)cc1
Reactant: NN
Solvent: O
Product: Cc1[nH]nc(-c2cc(Cl)c(O)cc2O)c1-c1ccc(Br)cc1

Procedure:
This compounds was synthesised in the same manner as described above. 3-(4-Bromo-phenyl)-6-chloro-7-hydroxy-2-methyl-chromen-4-one (0.5 g, 1.4 mmol), Hydrazine hydrate (5 ml). 4-[4-(4-Bromo-phenyl)-5-methyl-1H-pyrazol-3-yl]-6-chloro-benzene-1,3-diol precipitated out as a pale orange solid (0.08 g, 63.7%); Rf 0.48 cf SM 0.8 [ethyl acetate/petroleum ether 40–60° C. (80/20)].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][C:6]([C:7]#[N:8])=[C:5](O)[CH:4]=1.N[C@@H:15]([C:18]([OH:20])=[O:19])[CH2:16][SH:17].C(=O)(O)[O-].[Na+]>CO>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][C:6]([C@H:7]2[NH:8][C:15]([C:18]([OH:20])=[O:19])=[CH:16][S:17]2)=[CH:5][CH:4]=1
Reactant: N[C@H](CS)C(=O)O
Reactant: COc1cc(O)c(C#N)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1ccc([C@H]2NC(C(=O)O)=CS2)cc1OC

Procedure:
(S)-2-(4′,5′-dimethoxyphenyl)-4-thiazoline-4-carboxylic acid (1) and (S)-2-(4′,5′-dimethoxyphenyl)-4-methylthiazoline-4-carboxylic acid (2) (also referred to as (S)-4′,5′-dimethoxydesazadesmethyldesferrithiocin and (S)-4′,5′-dimethoxydesazadesferrithiocin, respectively) were prepared starting with 2-benzyloxy-4,5-dimethoxybenzaldehyde (6), which was converted to the corresponding oxime by reacting 6 with hydroxylamine hydrochloride and triethylamine in acetonitrile at about 50° C. for about 18 hours. The corresponding nitrile (7) was prepared from the oxime by refluxing the intermediate product with phthalic anhydride for 1 day to give nitrile 7 in 87% yield. Nitrile 7 was reacted with hydrogen on a Pd—C catalyst in an ethanol/ethyl acetate mixture for about 50 minutes to remove the O-benzyl group and form 4,5-dimethoxy-2-hydroxybenzonitrile (8) in 84% yield. The deprotected nitrile 8 was subsequently reacted with D-cysteine or D-alpha-methylcysteine in a pH 6 buffer containing sodium bicarbonate and methanol to form products 1 and 2, respectively.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[C:22]([CH2:23][CH2:24][CH3:25])=[C:21]([C:26](O)=[O:27])[N:20]=[N:19]3)=[CH:14][CH:13]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C[C:32]2N(O)N=[N:35][C:33]=2[CH:34]=1.C1(N)CC1.CCN=C=NCCCN(C)C.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.CN(C=O)C>[CH:33]1([NH:35][C:26]([C:21]2[N:20]=[N:19][N:18]([C:15]3[CH:14]=[CH:13][C:12]([C:10]([NH:9][CH2:8][CH2:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[O:11])=[CH:17][CH:16]=3)[C:22]=2[CH2:23][CH2:24][CH3:25])=[O:27])[CH2:34][CH2:32]1
Reactant: On1nnc2ccccc21
Reactant: CCCc1c(C(=O)O)nnn1-c1ccc(C(=O)NCCc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(C(=O)NCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 149.9 %

Procedure:
1-(4-{[(2-Phenylethyl)amino]carbonyl}phenyl)-5-propyl-1H-1,2,3-triazole-4-carboxylic acid (510 mg, 1.35 mmol) obtained in Example 59b), HOBt (92 mg, 0.674 mmol, 0.5 eq.) and cyclopropylamine (0.125 ml, 1.75 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (2:1, 9.0 ml), WSC (316 mg, 1.62 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 2 hr. 2% Aqueous sodium carbonate solution (10 ml) was added to the reaction mixture and the mixture was stirred at room temperature for 1 hr. The precipitate was collected by filtration, washed with ice-cold water and dried to give a grayish white powder. This was crystallized from methanol-diethyl ether to give the title compound as a white powder (421 mg, 1.01 mmol, 74.7%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]#[N:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:28]=[N+:29]=[N-:30].[Na+].[Cl-].[NH4+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]4[NH:30][N:29]=[N:28][N:27]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(COc2ccc(Nc3ncnc4ccc(-c5nnn[nH]5)cc34)cc2)cc1
Temperature: 180 °C
Reaction time: 18 h
Yield: 20.2 %

Procedure:
(4-Benzyloxy-phenyl)-(6-cyanoquinazolin-4-yl)-amine (0.106 g) in dimethylformamide was treated with sodium azide (0.06 g) and ammonium chloride (0.05 g) and the mixture stirred at 180° C. for 18 hours. The mixture was cooled, poured onto water and extracted with ethyl acetate/THF (3:1). The organic extracts were dried and concentrated in vacuo. The residue was purified using solid phase extraction to yield the title compound (0.024 g); δH [2H6]DMSO 10.18(1H,s), 9.25(1H,s), 8.55(1H,s), 8.40(1H,d), 7.88(1H,d), 7.74(2H,d), 7.45(6H,m), 7.07(2H,d), 5.17(1H,s), m/z (M+1)+396.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[C:13]([Cl:14])=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:9]=1[Cl:18])=S.C(=O)([O-])[O-].[Cs+].[Cs+]>C(O)CC>[Cl:18][C:9]1[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=[C:13]([Cl:14])[C:8]=1[N:7]=[C:5]1[NH:4][CH2:3][CH2:2][NH:1]1
Reactant: NCCNC(=S)Nc1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCO
Product: O=[N+]([O-])c1cc(Cl)c(N=C2NCCN2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The thiourea (7) (0.50 g, 1.6 mmole) was suspended in 10 mL of n-propanol and cesium carbonate (0.53 g, 1.6 mmole) was added. The yellow suspension was stirred at ambient temperature for approximately 30 minutes, when the color changed from yellow to orange. The mixture was heated at reflux for about 24 hours, and the solvent was then removed on a rotary evaporator. The residue was partitioned between 1M HCl and ethyl acetate and the aqueous phase was brought to a pH of 8-9 with 1N NaOH. The resulting yellow solid was collected by filtration, washed successively with water and hexane, and then air dried to provide 0.10 g (23%) of nitroclonidine (3).
Reaction SMILES: [F:1][CH:2]([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][Si](C)(C)C)=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CCOCC.CCCCCC.C(Cl)Cl>[F:1][CH:2]([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[CH:6][CH:5]=1
Reactant: C[Si](C)(C)C#Cc1ccc(OC(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: ClCCl
Product: C#Cc1ccc(OC(F)F)cc1
Reaction time: 1.5 h
Yield: 97 %

Procedure:
A solution of {[4-(difluoromethoxy)phenyl]ethynyl}(trimethyl)silane (10.0 g, 41.7 mmol) in MeOH/CH2Cl2 (1/1) was treated with cesium carbonate (16.3 g, 50 mmol) at room temperature, stirred for 1.5 h, diluted with CH2Cl2 and filtered through a pad of silica gel. The filtrate was concentrated to dryness to give the title compound (6.8 g, 97%) as an oil, identified by NMR and mass spectral analyses.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[CH:36][CH:35]=[CH:34][C:4]=1[CH2:5][C:6]1[C:7]([NH:22][S:23]([C:26]2[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=2)(=[O:25])=[O:24])=[N:8][CH:9]=[N:10][C:11]=1[O:12][CH2:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1.[BH4-].[Na+]>CO>[OH:31][CH2:30][C:29]1[CH:28]=[CH:27][C:26]([S:23]([NH:22][C:7]2[C:6]([CH2:5][C:4]3[CH:34]=[CH:35][CH:36]=[CH:37][C:3]=3[O:2][CH3:1])=[C:11]([O:12][CH2:13][CH2:14][O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[N:10]=[CH:9][N:8]=2)(=[O:24])=[O:25])=[CH:33][CH:32]=1
Reactant: COc1ccccc1Cc1c(NS(=O)(=O)c2ccc(C=O)cc2)ncnc1OCCOC1CCCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1Cc1c(NS(=O)(=O)c2ccc(CO)cc2)ncnc1OCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
53 mg of rac-p-[[5-(o-methoxybenzyl)-6-[2-[(tetrahydro-2H-pyran-2-yl]oxy]ethoxy]-4-pyrimidinyl]sulfamoyl]benzalde-hyde were dissolved in 3 ml of methyl alcohol and treated with 37 mg of sodium borohydride at room temperature. After stirring at room temperature for 1 hour, the methanol was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and NaCl solution (saturated), dried and distilled under reduced pressure. There were obtained 42 mg of rac-α-hydroxy-N-[5-(o-methoxybenzyl)-6-[2-[(tetra-hydro-2H-pyran-2-yl)oxy]ethoxy]-4-pyrimidinyl]-p-toluene-sulfonamide as a colorless oil. MS: 529 (M); 445 (tetrahydro-2H-pyran-2-yl); 434 (--OCH3 +SO2).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[CH3:29][NH:30][CH3:31]>>[CH3:29][N:30]([CH3:31])[C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)[CH:4]=2)[N:9]=[C:8]([N:12]2[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]2)[N:7]=1
Reactant: CNC
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(N4CCCCC4)cc3c(=O)[nH]2)c1
Product: CN(C)c1nc(-n2cc(C(=O)O)cn2)nc2cc(Cl)c(N3CCCCC3)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-chloro-4-oxo-6-(piperidin-1-yl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and dimethylamine in step E. MS (ESI): predicted mass calcd. for C19H21ClN6O2, 400.9
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]34[CH2:18][CH2:17][CH:14]([CH2:15][CH2:16]3)[NH:13][CH2:12]4)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[OH:19][CH2:20][CH2:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[CH3:31])[CH:26]=O>>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]34[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18]3)[N:13]([CH2:26][C:25]3[CH:28]=[CH:29][C:30]([CH3:31])=[C:23]([CH:24]=3)[O:22][CH2:21][CH2:20][OH:19])[CH2:12]4)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: c1cc2[nH]ncc2cc1NC12CCC(CC1)NC2
Reactant: Cc1ccc(C=O)cc1OCCO
Product: Cc1ccc(CN2CC3(Nc4ccc5[nH]ncc5c4)CCC2CC3)cc1OCCO

Procedure:
Reaction of Intermediate 26 with 3-(2-hydroxyethoxy)-4-methylbenzaldehyde affords the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH2:13][C:14]([OH:16])=[O:15])([O-:3])=[O:2].OS(O)(=O)=O.[CH3:22]O>>[CH3:22][O:15][C:14](=[O:16])[CH2:13][C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
To a solution of (2,4-dinitro-phenyl)-acetic acid (5 g) in MeOH (100 mL) was added concentrated H2SO4 (1 mL) and the resulting solution was heated at reflux for overnight. After removing solvent in vacuum, the residue was partitioned between EtOAc and aqueous NaHCO3 (sat.). The organic solution was concentrated in vacuum to give the desired compound which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:32]=[CH:31][C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][NH:26][C:25](=[O:29])[C:24]2=[O:30])=[CH:16][CH:15]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:36]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:37]([O:39][CH:40]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38].C(OCC)(=O)C>CN(C)C=O.O>[CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:32]=[CH:31][C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH:36]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[C:37]([O:39][CH:40]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[O:38])[C:25](=[O:29])[C:24]2=[O:30])=[CH:16][CH:15]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C(Br)c1ccccc1
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc(OCCCCN2CCNC(=O)C2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N=C(NC(=O)OCc1ccccc1)c1ccc(OCCCCN2CCN(C(C(=O)OC(c3ccccc3)c3ccccc3)c3ccccc3)C(=O)C2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
In 5 ml of N,N-dimethylformamide was dissolved 0.2 g of 1-[4-(4-benzyloxycarbonylamidinophenoxy)butyl]-2,3-dioxopiperazine, followed by adding thereto 20 mg of sodium hydride (60%, oil), and the resulting mixture was stirred at 50° C. for 30 minutes. The reaction mixture was cooled to room temperature and 0.17 g of diphenyl-methyl α-bromophenylacetate was added thereto. After stirring at the same temperature for 2 hours, the reaction mixture was added to a mixed solvent of 20 ml of ethyl acetate and 20 ml of water. The organic layer as separated, washed with water and then a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent; chloroform: methanol=20:1) to obtain 0.29 g of diphenylmethyl α-[4-[4-(4-benzyloxycarbonylamidino-phenoxy) butyl]-2,3-dioxopiperazin-1-yl]-α-phenylacetate as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[N:18]([C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([O:26][CH3:27])=[O:25])=[C:19]=[O:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:19]([NH:18][C:21]2[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=2)[C:24]([O:26][CH3:27])=[O:25])=[O:20])[CH2:7]1
Reactant: COC(=O)c1cccc(N=C=O)c1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: COC(=O)c1cccc(NC(=O)NCC2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)c1
Yield: 90 %

Procedure:
Example 15 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and methyl 3-isocyanatobenzoate (0.0241 g) to give the title compound (0.037 g). LC-MS (System A): Rt 2.32 mins, Mass Spectrum m/z 452 [MH+].