Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]2[N:8]([CH2:28][C:29]3[C:30]([CH3:39])=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=3)[C:9](=[O:27])[C:10]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:6]2=[N:5][N:4]=1.[I-].[Na+].CC(C)=[O:44].O>[OH-].[Na+].CCOC(C)=O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]2[C:6]3[N:7]([C:3]([CH2:2][OH:44])=[N:4][N:5]=3)[N:8]([CH2:28][C:29]3[C:30]([CH3:39])=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=3)[C:9](=[O:27])[C:10]=2[C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)=[CH:13][CH:14]=1
Reactant: CC(C)=O
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1c(=O)c(-c2ccc(C#N)cc2)c(-c2ccc(Cl)cc2)c2nnc(CCl)n21
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(C(F)(F)F)ccc1Cn1c(=O)c(-c2ccc(C#N)cc2)c(-c2ccc(Cl)cc2)c2nnc(CO)n21
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
To a round bottom flask was added 4-(3-(chloromethyl)-8-(4-chlorophenyl)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-7-yl)benzonitrile (30 mg, 0.053 mmol), sodium iodide (40 mg, 0.264 mmol) and acetone (2 ml). The reaction was stirred at room temperature for 8 hr. After this time, water (0.3 ml) was added followed by 1 drop of 1N NaOH. The reaction was stirred at room temperature for an additional 14 hrs. The solution was then diluted with EtOAc (25 ml) and washed with water (2×15 ml) and saturated NaCl (15 ml). The organic layer was dried (MgSO4), filtered and concentrated. The crude material was purified using an ISCO automated chromatography system (4 g silica gel, 20%-50% EtOAC/CH2Cl2) to give the product 4-(8-(4-chlorophenyl)-3-(hydroxymethyl)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-7-yl)benzonitrile as a white solid (15 mg, 51% yield). HPLC retention time 2.990 min (Method A); LCMS (M+1)=551.0. 1HNMR (CDCl3, 500 Hz) 7.61(2H, d, J=8.25 Hz), 7.52(1H, d, J=7.7 Hz), 7.30-7.37(7H, m), 6.05(2H, s), 4.60(2H, s), 2.78(3H, s); 13CNMR (CDCl3, 500 Hz) 161.00, 158.90, 156.25, 146.20, 144.10, 137.10, 136.80, 132.80, 131.96, 131.74, 129.90, 129.09, 118.00, (m), 113.00, 100.00, 55.10, 49.10, 22.10.
Reaction SMILES: Cl[C:2]1[N:31]=[CH:30][C:5]2[N:6]=[C:7]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]4[CH2:24][CH2:23][N:22]([CH:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)[CH2:21][CH2:20]4)=[CH:14][CH:13]=3)[N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[CH:3]=1.C(N(CC)CC)C.[H][H]>C(OCC)(=O)C.[C].[Pd]>[CH:25]1([N:22]2[CH2:21][CH2:20][CH:19]([O:18][C:15]3[CH:14]=[CH:13][C:12]([C:7]4[N:8]([CH3:11])[C:9](=[O:10])[C:4]5[CH:3]=[CH:2][N:31]=[CH:30][C:5]=5[N:6]=4)=[CH:17][CH:16]=3)[CH2:24][CH2:23]2)[CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: Cn1c(-c2ccc(OC3CCN(C4CCCC4)CC3)cc2)nc2cnc(Cl)cc2c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cn1c(-c2ccc(OC3CCN(C4CCCC4)CC3)cc2)nc2cnccc2c1=O
Yield: 72.2 %

Procedure:
6-Chloro-2-{4-[(1-cyclopentylpiperidin-4-yl)oxy]phenyl}-3-methylpyrido[3,4-d]pyrimidin-4(3H)-one (11 mg, 0.025 mmol) produced in Example 30 and triethylamine (17 μL, 0.15 mmol) were dissolved in ethyl acetate (0.5 mL), and 10% palladium-carbon (3 mg) was added thereto and stirred in a hydrogen atmosphere at room temperature for 15 hours. The reaction solution was filtered through Celite, then the Celite was washed with ethyl acetate, and the mother liquid was concentrated. The residue was purified through silica gel thin-layer chromatography (chloroform/methanol=9/1) to obtain the entitled compound (7.3 mg, 71%) as a pale brown solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:33][CH3:34])[C:4](=[O:32])[CH:5]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)[C:6]([NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)(=[O:11])=[O:10])=[O:7])[CH3:2].C(N[C:38]1[CH:43]=CC=[CH:40][CH:39]=1)C>>[CH2:33]([N:3]([C:1]1[CH:40]=[CH:39][CH:38]=[CH:43][CH:2]=1)[C:4](=[O:32])[CH:5]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=1)[C:6]([NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)(=[O:10])=[O:11])=[O:7])[CH3:34]
Reactant: CCNc1ccccc1
Reactant: CCN(CC)C(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Product: CCN(C(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Yield: 44 %

Procedure:
In the same manner as in Example 1 (4), a crude product was obtained using the compound (500 mg) obtained in Example 6 (4) and N-ethylaniline (141 mg). This was purified by silica gel column chromatography to give the title compound (242 mg) as a white powder.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([NH:12][C:13]2([C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=3)[CH2:15][CH2:14]2)=[O:11])[CH2:3][CH2:2]1.[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:30]Cl.CCN(C(C)C)C(C)C>C(#N)C.CCCC[N+](CCCC)(CCCC)CCCC.[I-]>[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:30][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([NH:12][C:13]2([C:16]3[CH:17]=[CH:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][CH:25]=3)[CH2:14][CH2:15]2)=[O:11])[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(C2(NC(=O)c3cccc4c3NCC4)CC2)cc1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(C2(NC(=O)c3cccc4c3N(Cc3ccc(Cl)c(Cl)c3)CC4)CC2)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Methyl 4-{1-[(2,3-dihydro-1H-indol-7-ylcarbonyl)amino]cyclopropyl}benzoate (110 mg, 0.327 mmol) was dissolved in acetonitrile (1.3 ml). 3,4-dichlorobenzyl chloride (136 ul. 0.981 mmol), DIPEA (171 ul, 0.981 mmol) and a crystal of TBAI were added. The mixture stirred at 70° C. for 2 h. The solvent was removed. Purification on silica gel.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:10]([CH2:19][OH:20])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:10]([CH2:19][O:20][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 82.0 g (0.31 mol) of 1-benzyl-3-(R)-hydroxymethyl-4-(S)-phenyl pyrrolidine (from Step C) and 46.5 g (0.36 mol) of N,N-diisopropylethylamine in 1 L of CH2Cl2 was treated with 54.2 g (0.36 mol) of t-butyldimethylsilyl chloride and the resulting mixture was stirred at rt for 20 h. The reaction was quenched with 750 mL of sat'd NaHCO3 and the layers were separated. The organic layer was combined with 150 g of silica gel and aged for 45 min. The mixture was filtered and the filtrate was concentrated to afford the title compound.
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[CH3:19][N:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH2:21]>>[CH3:16][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[C:6]1=[CH:17][C:2]([NH:21][N:20]([CH3:19])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:3][C:4](=[O:18])[N:5]1[CH2:14][CH2:13]2
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Reactant: CN(N)c1ccccc1
Product: COc1ccc2c(c1)CCn1c-2cc(NN(C)c2ccccc2)nc1=O

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (4) and N-methyl-N-phenyl-hydrazine as in Example 1 d. 1H-NMR (400 MHz, d6-DMSO at 60° C.) δ 9.12 (br, 1H), 7.68 (d, 1H), 7.22 (t, 2H), 6.95-6.75 (5H), 6.24 (s, 1H), 3.96 (br, 2H), 3.82 (s, 3H), 3.16 (s, 3H) and 2.94 (t, 2H); MS (ESI) (M+H)+ 349.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10](=[O:38])[NH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][N:16]=[C:15]2[NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:37])[NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:25][CH:24]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[NH2:7][CH2:8][CH2:9][C:10]([NH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][N:16]=[C:15]2[NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([NH:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:37])=[CH:25][CH:24]=1)=[O:38]
Reactant: CC(C)(C)OC(=O)NCCC(=O)Nc1ccc2ncnc(Nc3ccc(C(=O)Nc4ccccc4)cc3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCC(=O)Nc1ccc2ncnc(Nc3ccc(C(=O)Nc4ccccc4)cc3)c2c1
Yield: 88.2 %

Procedure:
350 mg of the compound obtained in Example 80 dissolved in 7 ml of methylene chloride was reacted with 7 ml of trifluoroacetic acid at room temperature for 4 hours. The residue obtained from distillation of the reacted solution under a reduced pressure was stirred in 50 ml of saturated aqueous sodium bicarbonate for 30 mins, filtered under a reduced pressure, and dried to obtain the title compound (250 mg, 89%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:15])=[C:5](/[C:7](=[N:13]/[OH:14])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[C:16](Cl)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>CN(C)C=O>[OH:14]/[N:13]=[C:7](/[C:5]1[N:6]=[C:2]([NH:1][C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[S:3][C:4]=1[CH3:15])\[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)/C(=N\O)c1nc(N)sc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C(=N\O)c1nc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)sc1C
Yield: 89.9 %

Procedure:
A solution of ethyl 2-(2-amino-5-methylthiazol-4-yl)-2-(Z)-(hydroxyimino)acetate (8.73 g) in dimethylformamide (60 ml) was treated portionwise with trityl chloride (11.7 g) and dropwise with triethylamine (6.4 ml). The reaction mixture was quenched by water and extracted with ethyl acetate. The combined extracts were washed with water and brine, and were dried with magnesium sulfate. The solvent was removed under reduced pressure to afford ethyl 2-(Z)-hydroxyimino-2-(5-methyl-2-tritylaminothiazol-4-yl)acetate (16.15 g).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][Cl:14]>>[Cl:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCCCCBr
Reactant: Sc1ccccc1
Product: ClCCCCCSc1ccccc1

Procedure:
Prepared by Procedure R and Scheme Z using benzenethiol and 1-bromo-5-chloropentane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=S)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][NH2:30])=O)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]2[NH:18][C:16]([NH:15][C:5]3[CH:6]=[CH:7][C:8]([N:9]4[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]4)=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:30][N:29]=2)=[CH:22][CH:21]=1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: NNC(=O)Cc1ccc(Cl)cc1
Product: COc1cc(Nc2nnc(Cc3ccc(Cl)cc3)[nH]2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 71c) starting with [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (150 mg, 0.57 mmol) and (4-chloro-phenyl)-acetic acid hydrazide (116 mg, 0.57 mmol). Obtained as a brownish solid (36 mg, 16%) after chromatography of the crude reaction product on amino-modified silica gel (Merck HPTLC Silica Gel 60 NH2F254S) using ethyl acetate as eluent.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[C:4](N)[CH:3]=1.C(ON=O)CC(C)C.C[Si](C)(C)[Br:25]>BrCBr>[Br:25][C:4]1[CH:3]=[C:2]([Cl:1])[N:7]=[N:6][C:5]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: Nc1cc(Cl)nnc1OCC(F)(F)F
Reactant: C[Si](C)(C)Br
Agent: CC(C)CCON=O
Solvent: BrCBr
Product: FC(F)(F)COc1nnc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.8 %

Procedure:
To a suspension of 2.30 g 6-chloro-3-(2,2,2-trifluoro-ethoxy)-pyridazin-4-ylamine in 23 mL dibromomethane was added 5.11 g isoamylnitrite at once and drop wise 4.642 g trimethylbromosilane at ambient temperature (during ca 10 min). A moderate exotherm was observed and a dark brown solution was obtained. The mixture was stirred at ambient temperature for 18 h. The solvents were evaporated and the residue was purified (3×) by chromatography on silica gel using a gradient of heptane to dichloromethane to yield 0.70 g of the title compound as white crystalline solid, MS 292 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[C:5]([OH:8])(=[O:7])[CH3:6].[C:9]([OH:12])(=[O:11])[CH3:10].[N:13]1([C:20]2[C:25]([CH2:26][NH:27][C:28]3[N:32]([C:33]4[CH:38]=[CH:37][C:36]([F:39])=[C:35]([Cl:40])[C:34]=4[Cl:41])[N:31]=[N:30][N:29]=3)=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:5]([OH:8])(=[O:7])[CH3:6].[C:9]([OH:12])(=[O:11])[CH3:10].[Cl:41][C:34]1[C:35]([Cl:40])=[C:36]([F:39])[CH:37]=[CH:38][C:33]=1[N:32]1[C:28]([NH:27][CH2:26][C:25]2[C:20]([N:13]3[CH2:19][CH2:18][CH2:17][N:16]([CH:2]([CH3:4])[CH3:1])[CH2:15][CH2:14]3)=[N:21][CH:22]=[CH:23][CH:24]=2)=[N:29][N:30]=[N:31]1
Reactant: CC(C)=O
Reactant: Fc1ccc(-n2nnnc2NCc2cccnc2N2CCCNCC2)c(Cl)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)N1CCCN(c2ncccc2CNc2nnnn2-c2ccc(F)c(Cl)c2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetone (0.5 mL) was added to a mixture of the product of Example 289 (80 mg, 0.183 mmol) and sodium triacetoxyborohydride (77 mg, 0.366 mmol) in 1,2-dichloroethane (5 mL). The reaction mixture was stirred at room temperature overnight. The mixture was filtered and washed with dichloromethane. The filtrate was concentrated under reduced pressure and purified by preparative HPLC on a Thermoquest, hyperprep HS C18 column (250×21.2 mm., 8 μm particle size) using a gradient of 5% to 75% acetonitrile to ammonium acetate (10 mM) over 20 minutes at a flow rate of 21 mL/min to provide the title compound. MS (ESI+) m/z 479.3 (M+H)+; Rt=1.63 min. 1H-NMR (400 MHz, DMSO-d6) δ 0.96 (d, J=6.6 Hz, 1H), 1.80 (m, 2H), 1.90 (s, 2H), 2.65 (m, 2H), 2.70 (m, 2H), 2.86 (m, 1H), 3.38 (m, 4H), 4.44 (d, J=5.3 Hz, 1H), 5.75 (s, 1H), 6.84 (dd, J=4.8 Hz, J=7.5 Hz, 1H), 7.52 (dd, J=1.9 Hz, J=7.5 Hz, 1H), 7.58 (t, J=5.5 Hz, 1H), 7.73 (t, J=8.8 Hz, 1H), 7.86 (dd, J=5.3 Hz, J=9.0 Hz, 1H), 8.07 (dd, J=1.9 Hz, J=4.7 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[N:4][C:5](Br)=[CH:6][CH:7]=1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Br:1][C:2]1[N:3]=[N:4][C:5]([O:16][C:13]2[CH:14]=[CH:15][C:10]([NH2:9])=[CH:11][C:12]=2[N+:17]([O-:19])=[O:18])=[CH:6][CH:7]=1
Reactant: Nc1ccc(O)c([N+](=O)[O-])c1
Reactant: Brc1ccc(Br)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(Oc2ccc(Br)nn2)c([N+](=O)[O-])c1
Yield: 61.2 %

Procedure:
3.0 g of 3,6-dibromopyridazine was dissolved in 15 ml of dimethyl sulfoxide. To this solution, a mixture of 2.0 g of 4-amino-2-nitrophenol, 3.6 g of potassium carbonate and 10 ml of water was added and, after flushing with nitrogen, the mixture was reacted at a temperature of from 100° to 110° C. for 2 hours. After the completion of the reaction, the reaction product was cooled and poured into water, and then extracted with methylene chloride. The extract layer was washed with an aqueous sodium hydroxide solution and then with water, and dried over anhydrous sodium sulfate. Then, the solvent was distilled off, whereby 2.4 g of 4-(6-bromo-3-pyridazinyloxy)-3-nitroaniline was obtained. (2) 1.0 g of 4-(6-bromo-3-pyridazinyloxy)-3-nitroaniline obtained in the above step (1) was dissolved in 20 ml of dioxane. To this solution, 8 ml of a dioxane solution containing 0.62 g of 2-nitrobenzoyl isocyanate was added, and the mixture was reacted at room temperature for 15 hours. After the completion of the reaction, the reaction product was poured into water and collected by filtration. The obtained solid was dried and, after the addition of methylene chloride, again subjected to filtration, whereby 1.0 g of the desired product having a melting point of from 222° to 225° C. was obtained.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[C:12]2[N:11]=[C:10]([CH3:13])[NH:9][C:8]=2[C:7](=[O:14])[NH:6][C:5]1=[O:15].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O.CO>[CH2:16]([N:9]1[C:8]2[C:7](=[O:14])[NH:6][C:5](=[O:15])[N:4]([CH3:3])[C:12]=2[N:11]=[C:10]1[CH3:13])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1nc2c([nH]1)c(=O)[nH]c(=O)n2C
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nc2c(c(=O)[nH]c(=O)n2C)n1Cc1ccccc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A solution of sodium hydroxide (400 mg) in water (5 ml) was added to a suspension of 3,8-dimethylxanthine (1.80 g) in methanol (10 ml). After stirring for 1 hour at 70° C., benzyl bromide (1.2 ml) was added. After stirring for 5 hours at 70-80° C., the solvent was evaporated under reduced pressure. The residue was treated with saturated aqueous ammonium chloride solution (50 ml) and extracted with ethyl acetate (3×75 ml). The combined extracts were washed with saturated aqueous sodium chloride solution (30 ml), dried over magnesium sulfate and concentrated under reduced pressure. The solid was purified by recrystallization from ethanol to provide 7-benzyl-3,8-dimethylxanthine (1.06 g).
Reaction SMILES: [O:1]([CH:8]([CH2:12][CH2:13][CH3:14])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:15]([O:22][C@H:23]1[CH2:32][C@H:31](O)[C@H:30]2[C:25]([CH:26]=[CH:27][C@H:28]([CH3:51])[C@@H:29]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@@H:38]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[CH2:37]2)=[CH:24]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>>[Si:15]([O:22][C@H:23]1[CH2:32][C@H:31]([O:10][C:9](=[O:11])[CH:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][CH2:13][CH3:14])[C@H:30]2[C:25]([CH:26]=[CH:27][C@H:28]([CH3:51])[C@@H:29]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:45])[CH3:46])[CH2:37]2)=[CH:24]1)([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:17])[CH3:16]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: CCCC(Oc1ccccc1)C(=O)O
Product: CCCC(Oc1ccccc1)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 101.5 %

Procedure:
A procedure similar to that described in Example 10, above, was followed, but using 0.70 g of (2RS)-2-phenoxyvaleric acid and 1.0 g of (4S,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 1.34 g of the title compound as a colorless foam.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([NH2:19])[CH:16]([CH3:18])[CH3:17].[C:20]([O:24][C:25]([N:27]1[CH2:33][CH2:32][CH2:31][C@H:28]1[CH:29]=O)=[O:26])([CH3:23])([CH3:22])[CH3:21].[OH-].[Na+]>ClCCCl.O>[CH2:15]([NH:19][CH2:29][C@@H:28]1[CH2:31][CH2:32][CH2:33][N:27]1[C:25]([O:24][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:26])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Reactant: CC(C)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: O
Product: CC(C)CNC[C@@H]1CCCN1C(=O)OC(C)(C)C
Yield: 76.1 %

Procedure:
Sodium triacetoxyborohydride (2.9 g, 14 mmol, 1.4 eq) is added to a solution of isobutylamine (0.77 g, 10 mmol, 1.05 eq) and N-(tert-butoxycarbonyl)-L-prolinal (2 g, 10 mmol, 1 eq) in 1,2-dichloroethane (35 ml). After 1 hr water (25 ml) followed by 2N aqueous sodium hydroxide (25 ml) is added. The aqueous layer is separated and extracted with dichloromethane (3×50 ml). The organic layers are combined and dried over magnesium sulphate, filtered, and concentrated in vacuo giving a residue. The residue is purified by flash chromatography, eluting with 20-70% methanol in ethyl acetate to give the tert-butyl (2S)-2-[(isobutylamino)methyl]pyrrolidine-1-carboxylate (1.95 g, 76%): 1H NMR (300 MHz, CDCl3) δH: 3.69-4.07 (1H, m), 3.19-3.50 (2H, m), 2.67-2.87 (1H, m), 2.48-2.65 (1H, m), 2.35-2.47 (2H, m), 1.62-2.01 (5H, m), 1.34-1.53 (9H, m) and 0.88 (6H, d); LCMS: Rt=2.74 (6 min method) [M+H]=257.5.
Reaction SMILES: S=[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]#[N:12])[CH:9]=[CH:10][C:4]=2[O:3]1.S(Cl)([Cl:15])=O>CN(C=O)C.C(Cl)Cl>[Cl:15][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:5]=2[N:6]=1
Reactant: N#Cc1ccc2oc(=S)[nH]c2c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1ccc2oc(Cl)nc2c1
Temperature: 67.5 °C
Yield: 65 %

Procedure:
To a mixture of 2-thioxo-2,3-dihydrobenzooxazole-5-carbonitrile (2.56 g, 14.5 mmol) and thionylchloride (14.1 mL) was added two drops of DMF. The mixture was heated at 65-70° C. for 1 h. Then the mixture was cooled to rt and diluted with CH2Cl2. The solvent and excess thionylchloride were removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: 20% EtOAc in Petroleum ether) to give 2-chlorobenzo-oxazole-5-carbonitrile 1.69 g (65%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].[O:15]([C:22](OC1C=CC=CC=1)(OC1C=CC=CC=1)[CH2:23][N+:24]([O-:26])=[O:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:22]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:23][N+:24]([O-:26])=[O:25])=[CH:7][CH:6]=1)[CH3:1]
Reactant: O=[N+]([O-])CC(Oc1ccccc1)(Oc1ccccc1)Oc1ccccc1
Reactant: CN(C)Cc1ccc(CSCCN)o1
Solvent: CC#N
Product: CN(C)Cc1ccc(CSCCNC(=C[N+](=O)[O-])Oc2ccccc2)o1
Temperature: 40 °C
Yield: 1.9 %

Procedure:
21·4 g (0·1 mol) of 2-[[[5-[(dimethylamino)methyl]-2-furanyl]methyl]thio]ethylamine and 35·1 g (0·1 mol) of 1,1,1-triphenoxy-2-nitroethane are boiled for 3 hours in 250 ml of acetonitrile under a nitrogen atmosphere. The solvent is evaporated off under vacuum after cooling to 40° C. and the yellow oil left behind is chromatographed on 560 g of silica gel with dichloromethane/methanol (95:5). After concentration by evaporation under vacuum, the main fraction yields 28·7 g (76%) of the title compound in the form of a yellowish, viscous oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)([O-:3])=[O:2].C(N(CC)CC)C.[CH3:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[CH3:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([O:14][CH:11]2[CH2:10][CH2:9][N:8]([CH2:7][C:6]3[CH:15]=[CH:16][CH:17]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[CH2:13][CH2:12]2)=[O:31])=[CH:28][CH:27]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: O=[N+]([O-])c1cccc(CN2CCC(O)CC2)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)OC2CCN(Cc3cccc([N+](=O)[O-])c3)CC2)cc1
Yield: 73.4 %

Procedure:
0.65 g (0.00275 mol) of 1-(3-nitro-benzyl)-piperidin-4-ol and 1.9 ml (0.0136 mol) of triethylamine were dissolved in 27.5 ml of toluene, treated with 1.09 ml (0.00825 mol) of 4-methyl-benzoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:3). 0.715 g (73%) of 1-(3-nitro-benzyl)-piperidin-4-yl 4-methyl-benzoate was obtained as yellow crystals; m.p. 90°-93°.