Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([BH3-])#N.[Na+].[CH:5]1([NH:11][C:12]2[CH:21]=[C:20]3[C:15]([C:16](=[O:30])[C:17]([CH:27]=[N:28][OH:29])=[CH:18][N:19]3[CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:14][C:13]=2[F:31])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.O1CCOCC1.Cl.[OH-].[Na+]>C1COCC1.CO>[CH:5]1([NH:11][C:12]2[CH:21]=[C:20]3[C:15]([C:16](=[O:30])[C:17]([CH2:27][NH:28][OH:29])=[CH:18][N:19]3[CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:14][C:13]=2[F:31])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: O=c1c(C=NO)cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc12
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Solvent: C1CCOC1
Product: O=c1c(CNO)cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.1 %

Procedure:
15 ml of methanol, 15 ml of THF and 250 mg of sodium cyanoborohydride were added to 300 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbaldehyde oxime. 2 ml of a 4 M hydrogen chloride dioxane solution was added thereto under ice-cooling, followed by stirring at room temperature for 3 hours. Under ice-cooling, aqueous 1 M sodium hydroxide solution was added thereto, followed by extraction with chloroform and subsequent washing with aqueous saturated sodium chloride. After drying over anhydrous sodium sulfate, the solvent was evaporated under a reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 130 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-[(hydroxyamino)methyl]quinolin-4(1H)-one.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][N:12]=[C:13]([C:20](=[O:22])[CH3:21])[CH2:14][C:15](OCC)=[O:16])[C:5]([OH:7])=[O:6].C(O)C.C(=O)([O-])[O-].[Na+].[Na+].Cl>O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[C:15](=[O:16])[CH2:14][C:13]([C:20](=[O:22])[CH3:21])=[N:12]1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)CC(=NNc1ccc(C(=O)O)cc1C)C(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=O)C1=NN(c2ccc(C(=O)O)cc2C)C(=O)C1

Procedure:
To a solution of a 5 g. (34 mmoles) of 3-methyl-4-[N'-(2-ethoxycarbonyl-1-acetylethylidene)hydrazino]benzoic acid in 25 ml. of ethanol and 25 ml. of water was added with stirring 34.3 ml. of a 1 M sodium carbonate solution. The mixture was stirred at room temperature for 24 hours. The resulting mixture was acidified to pH 3 with 6 M hydrochloric acid and the resulting solid was collected by filtration, washed with water and dried. The 3-methyl-4-(3-acetyl-5-oxo-2-pyrazolin-1-yl)benzoic acid has a melting point of>2500C.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH2:17]O)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=2)[N:5]=[N:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:38]N1C(=O)CCC1=O>C(Cl)Cl.C(OCC)(=O)C>[Br:38][CH2:17][C:9]1[CH:8]=[C:7]([N:6]2[C:2]([CH3:1])=[N:3][N:4]=[N:5]2)[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=1
Reactant: Cc1nnnn1-c1cc(CO)cc(C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1nnnn1-c1cc(CBr)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
(3-(5-Methyl-1H-tetrazol-1-yl)-5-(trifluoromethyl)phenyl)methanol (110 mg, 0.46 mmol) and triphenylphosphine (240 mg, 0.93 mmol) were combined in methylene chloride (4 mL) and cooled to 0° C. N-Bromosuccinimide (171 mg, 0.96 mmol) was introduced in portions and the reaction allowed to warm to room temperature. After 16 h, the reaction mixture was diluted with ethyl acetate, washed with concentrated sodium bicarbonate (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (20% ethyl acetate/hexanes) gave 120 mg (82%). LC/MS (HPLC method 3): tR=2.30 min, 323.01 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1I.C([Mg]Cl)(C)C.CN(C)[CH:17]=[O:18]>O1CCCC1.[Cl-].[NH4+]>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[CH:17]=[O:18]
Reactant: CN(C)C=O
Reactant: Fc1cc(I)ccc1I
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=Cc1ccc(I)cc1F
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
A solution of 2-fluoro-1,4-diiodo-benzene (804 mg, 2.31 mmol) in tetrahydrofuran (8 mL) was cooled to −78° C. (external) and a 2.0 M solution of isopropylmagnesium chloride in tetrahydrofuran (1.44 mL, 2.89 mmol) added via syringe. The resulting mixture was stirred for 30 minutes while allowing the temperature of the cooling bath to rise to −50° C. The reaction mixture was then immersed in an ice/water bath and anhydrous N,N-dimethylformamide (425 μL, 5.78 mmol) was added by syringe to the reaction mixture. The reaction was stirred at 0° C. for 10 minutes, then at room temperature for 5 minutes. Thin layer chromatography (TLC) indicated the reaction to be complete. The mixture was diluted with saturated aqueous ammonium chloride solution (8 mL) and extracted with diethylether (2×20 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by chromatography over silica gel gradient eluted with 0 to 15% v/v ethyl acetate/hexanes to give 2-fluoro-4-iodo-benzaldehyde as a fluffy-white solid (389 mg, 67%).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([OH:17])[CH:11]=[CH:10]2>O.C(O)(=O)C>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([N:1]=[O:3])=[C:12]([OH:17])[CH:11]=[CH:10]2
Reactant: O=N[O-]
Reactant: COc1ccc2cc(O)ccc2c1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2c(N=O)c(O)ccc2c1

Procedure:
A solution of sodium nitrite (3.19 g) in water (23.6 ml) is slowly added to a stirring solution of 6-methoxy-2-naphthol [8.0 g, prepared as described in Organic Synthesis 49, 90 (1969)] in acetic acid (46 ml) and water (4.6 ml) at 0° C. The resulting slurry is allowed to stand at room temperature for several hours and diluted with water. The solid is collected, washed, dried and crystallized from methanol to give 6-methoxy-1nitroso-2-naphthol, mp 147°-148° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][N:12]1[CH2:17][CH:16]=[C:15]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[CH2:14][CH2:13]1.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[CH3:11][N:12]1[CH2:13][CH:14]=[C:15]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[N:20]([S:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:35])=[O:34])[CH:19]=2)[CH2:16][CH2:17]1
Reactant: CN1CC=C(c2c[nH]c3ncccc23)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)CC1
Reaction time: 1 h
Yield: 50.2 %

Procedure:
Sodium bis(trimethylsilyl)amide (0.2 mL, 1M in THF, 0.23 mmol) was added to a solution of 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-7-azaindole (24.9 mg, 0.12 mmol) in THF (2.5 mL) at −78° C. and the mixture stirred for 1 h. Benzenesulfonyl chloride (30 μL, 0.24 mmol) was added and the mixture stirred at room temperature for 2 h, prior to quenching with water (4 drops) and silica gel (˜1 g). Purification using solid phase extraction tubes (1000 mg silica, eluting with 0-10% 2M methanolic ammonia in dichloromethane) yielded 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1-benzenesulfonyl-7-azaindole (21.3 mg, 51%, HRMS-FAB+ for C19H19N3O2S: calculated MH+:354.12762; found:354.12896).
Reaction SMILES: FC1C=CC=CC=1NC(=S)NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42][C:43](=[S:69])[NH:44][C:45]2[CH:50]=[CH:49][C:48]([C:51]3[CH:59]=[C:58]4[C:54]([CH2:55][N:56]([C@@H:61]([CH:66]([CH3:68])[CH3:67])[C:62]([O:64]C)=[O:63])[C:57]4=[O:60])=[CH:53][CH:52]=3)=[CH:47][CH:46]=2)=[CH:38][CH:37]=1>>[Cl:35][C:36]1[CH:37]=[CH:38][C:39]([NH:42][C:43](=[S:69])[NH:44][C:45]2[CH:50]=[CH:49][C:48]([C:51]3[CH:59]=[C:58]4[C:54]([CH2:55][N:56]([C@@H:61]([CH:66]([CH3:67])[CH3:68])[C:62]([OH:64])=[O:63])[C:57]4=[O:60])=[CH:53][CH:52]=3)=[CH:47][CH:46]=2)=[CH:40][CH:41]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccc(Cl)cc4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccc(Cl)cc4)cc3)cc2C1=O
Yield: 84 %

Procedure:
The compound of example 62 was prepared analogous to compound of example 52 by hydrolysis of compound of example 61.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]#[C:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[S:17][C:10]=12.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:40][CH2:39][CH:38]([C:41](O)=[O:42])[C:37]2=[O:44])=[CH:32][CH:31]=1>>[F:1][C:2]1[CH:3]=[C:4]([NH:28][C:41]([CH:38]2[CH2:39][CH2:40][N:36]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)[C:37]2=[O:44])=[O:42])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]#[C:19][CH2:20][N:21]3[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]3)[S:17][C:10]=12
Reactant: O=C(O)C1CCN(c2ccc(F)cc2)C1=O
Reactant: CN1CCN(CC#Cc2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Product: CN1CCN(CC#Cc2cc3nccc(Oc4ccc(NC(=O)C5CCN(c6ccc(F)cc6)C5=O)cc4F)c3s2)CC1
Yield: 31 %

Procedure:
The title compound was prepared from 3-fluoro-4-(2-(3-(4-methylpiperazin-1-yl)prop-1-ynyl)thieno[3,2-b]pyridin-7-yloxy)aniline (Example 17, Step B) and 1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxylic acid according to the procedure described for Example 89. The crude was purified by silica gel flash column chromatography (5% MeOH in CH2Cl2) to afford 4.7 mg (31%) of the desired product. 1H NMR (400 MHz, CD3OD) δ 8.49 (d, 1H), 7.89 (dd, 1H), 7.63 (m, 2H), 7.60 (s, 1H), 7.45 (m, 1H), 7.37 (t, 1H), 7.14 (t, 2H), 6.69 (d, 1H), 3.97 (m, 2H), 3.68 (s, 2H), 2.75 (m, 4H), 2.58 (m, 3H), 2.47 (m, 3H), 2.30 (s, 3H); 19F NMR (376 MHz, CD3OD) δ −119.2, −129.9. LRMS (ESI pos) m/e 602.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([OH:9])[C:3]=1[CH2:10][CH2:11][CH:12]1[O:17][C:16](=[O:18])[CH2:15][CH:14]([OH:19])[CH2:13]1.[C:20]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30]Br)=[CH:26][CH:25]=1)(=[O:22])[CH3:21].ClC1C=C(O)C(=C(Cl)C=1)C=O.C(Br)C1C=CC=CC=1>>[C:20]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][O:9][C:4]2[C:3]([CH2:10][CH2:11][CH:12]3[O:17][C:16](=[O:18])[CH2:15][CH:14]([OH:19])[CH2:13]3)=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[CH:26][CH:25]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)Oc1ccc(CBr)cc1
Reactant: O=C1CC(O)CC(CCc2c(O)cc(Cl)cc2Cl)O1
Agent: BrCc1ccccc1
Agent: O=Cc1c(O)cc(Cl)cc1Cl
Product: CC(=O)Oc1ccc(COc2cc(Cl)cc(Cl)c2CCC2CC(O)CC(=O)O2)cc1

Procedure:
By following the procedure of Example 1, Step A, but substituting equimolar amounts of 6-[2-(2,4-dichloro-6-hydroxyphenyl)ethyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one and 4-(bromomethyl)phenol acetate for the 4,6-dichlorosalicylaldehyde and benzyl bromide used therein, the title compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:16]=[C:15]([C:24]([N:26]3[CH2:30][CH2:29][S:28][CH2:27]3)=[O:25])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=NC=CC=3)N=C(C(N3CCS(=O)C3)=[O:51])C=2)C=C(F)C=1.ClC1C=CC=C(C(OO)=O)C=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:16]=[C:15]([C:24]([N:26]3[CH2:30][CH2:29][S:28](=[O:51])[CH2:27]3)=[O:25])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:10])([F:11])[F:12])[CH:7]=1
Reactant: O=C(c1cc(-c2cc(F)cc(Cl)c2)n(-c2cccnc2)n1)N1CCS(=O)C1
Reactant: O=C(c1cc(-c2cc(Cl)cc(OC(F)(F)F)c2)n(-c2cccnc2)n1)N1CCSC1
Agent: O=C(OO)c1cccc(Cl)c1
Product: O=C(c1cc(-c2cc(Cl)cc(OC(F)(F)F)c2)n(-c2cccnc2)n1)N1CCS(=O)C1

Procedure:
38 mg (0.08 mmol) of the compound of Example 77 is reacted analogously to the synthesis of the compound of Example 6 with 21 mg (0.08 mmol, 70%) of meta-chloroperbenzoic acid for 4 hours at room temperature. 39 mg (99% of theory) of the title compound is obtained.
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH:7](S(C)(=O)=O)[OH:8])[O:5][C@@H:4]([N:13]2[CH:21]=[C:19]([CH3:20])[C:17](=[O:18])[NH:16][C:14]2=[O:15])[CH2:3]1.C([O-])(=O)C.[K+]>CN(C)C=O>[F:1][C@@H:2]1[C@@H:6]([CH2:7][OH:8])[O:5][C@@H:4]([N:13]2[CH:21]=[C:19]([CH3:20])[C:17](=[O:18])[NH:16][C:14]2=[O:15])[CH2:3]1
Reactant: Cc1cn([C@H]2C[C@H](F)[C@@H](C(O)S(C)(=O)=O)O2)c(=O)[nH]c1=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]c1=O
Yield: 73.8 %

Procedure:
To a solution of 3.22 g (10 millimoles) 3'-deoxy-3'-fluoro-5'-mesylthymidine in 10 ml N,N-dimethylformamide, was added 1.96 g (20 millimoles) potassium acetate, and the mixture was heated at 110°±5° C. for 60 minutes with stirring. The solvent was distilled off from the reaction mixture under reduced pressure, 30 ml water was added to the residue, and the mixture was extracted twice with 50 ml ethyl acetate. The extract was washed twice with 30 ml water and dried over anhydrous sodium sulfate, the solvent was distilled off from the dried extract under reduced pressure, and the residue was dissolved in methanol. This solution was decolorized by treatment with 1.4 g of activated charcoal, the decolorized solution obtained by filtering off the charcoal was concentrated, and the residue was treated with ammonia-saturated methanol and subjected to purification in the same way as in Example 1, giving 1.8 g (7.38 millimoles) of 3'-deoxy-3'-fluorothymidine as white, granular crystals. The yield was 73.8%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[CH2:4][N:5]([C:11]1[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:14]=[C:13]([OH:37])[CH:12]=1)[CH2:6][C:7]([O:9][CH3:10])=[O:8].[CH2:39]([O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49]Br)[CH3:40].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].COC(=O)CN(C1C=CC(OCCCCCCCCCCCCOC2C=CC=CC=2)=C(OCCOCCOCCOCC)C=1)CC(OC)=O>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:38])[CH2:4][N:5]([C:11]1[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:14]=[C:13]([O:37][CH2:49][CH2:48][O:47][CH2:46][CH2:45][O:44][CH2:43][CH2:42][O:41][CH2:39][CH3:40])[CH:12]=1)[CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)CN(CC(=O)OC)c1cc(O)cc(OCCCCCCCCCCCCOc2ccccc2)c1
Reactant: CCOCCOCCOCCBr
Agent: CCOCCOCCOCCOc1cc(N(CC(=O)OC)CC(=O)OC)ccc1OCCCCCCCCCCCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCOCCOCCOCCOc1cc(OCCCCCCCCCCCCOc2ccccc2)cc(N(CC(=O)OC)CC(=O)OC)c1
Yield: 74 %

Procedure:
A mixture of 1.2 g (2.27 mmol) of N-[3-hydroxy-5[(12-phenoxydodecyl)oxy]phenyl]-N-(2-methoxy-2-oxoethyl)glycine methyl ester, 2.73 g (11.37 mmol) of 2-[2-(2-ethoxyethoxy)ethoxy]ethyl bromide, 0.94 g (6.8 mmol) of potassium carbonate and 1.0 g (6.8 mmol) of sodium iodide in 40 ml of acetone and 20 ml of DMF was stirred at reflux under argon for 64 hours. After the usual workup the product was purified by HPLC using 40% ethyl acetate-hexane to give 1.16 g (74% yield), mp<24°, of N-[3-[2-[2-(2-ethoxyethoxy)ethoxy]ethoxy]-4-[(12-phenoxydodecyl)oxy]phenyl]-N-(2-methoxy-2-oxoethyl)glycine methyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13]Cl)[CH:10]([CH2:15]Cl)[CH2:9][N+:8]([O-:17])=[C:7]([C:18]3[O:19][CH:20]=[CH:21][CH:22]=3)[C:6]=2[CH:23]=1>C(N)CCC>[CH2:7]([N:8]1[CH2:13][CH2:12][N:11]2[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:23][C:6]=3[C:7]([C:18]3[O:19][CH:20]=[CH:21][CH:22]=3)=[N+:8]([O-:17])[CH2:9][CH:10]2[CH2:15]1)[CH2:6][CH2:5][CH3:4]
Reactant: Cc1ccc2c(c1)C(c1ccco1)=[N+]([O-])CC(CCl)N2CCCl
Solvent: CCCCN
Product: CCCCN1CCN2c3ccc(C)cc3C(c3ccco3)=[N+]([O-])CC2C1
Temperature: 90 °C
Yield: 104.9 %

Procedure:
4 g of 7-methyl-1-(β-chloroethyl)-2-chloromethyl-5-(2-furyl)-2,3-dihydro-1H-1,4-benzodiazepine 4-oxide (prepared analogously to Example 5A-C) are dissolved in 10 ml of n-butylamine and the solution is heated to 90° C. in an autoclave for 14 hours. After the reaction mixture has been worked up, the resulting crude product is purified by chromatography on aluminium oxide of activity level II, using methylene chloride/chloroform, and is crystallised from ether. 2.1 g of 1,2,3,4,4a,5-hexahydro-3-(n-butyl)-9-methyl-7-(2-furyl)-pyrazino[1,2-a][1,4]benzodiazepine 6-oxide are obtained. Melting point: 104° to 106° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=O)CCC.Cl>>[CH3:6][N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:13][CH:14]=2)[CH2:9]1
Reactant: CCCCOC(=O)N1CCc2cccc(C(=O)OC)c2C1
Agent: Cl
Product: COC(=O)c1cccc2c1CN(C)CC2

Procedure:
2-butoxycarbonyl-1,2,3,4-tetrahydro-8-methoxycarbonyl-isoquinoline is deprotected with methanolic HCl and then methylated according to Example 11b.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8](O)=[O:9])=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:4][NH:3]1.C([N:19](CC)CC)C.S(Cl)(Cl)=O>O1CCCC1>[O:1]=[C:2]1[C:7]([C:8]([NH2:19])=[O:9])=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:4][NH:3]1
Reactant: O=C(O)c1cc(-c2ccccc2)n[nH]c1=O
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: NC(=O)c1cc(-c2ccccc2)n[nH]c1=O
Reaction time: 6 h

Procedure:
In an alternate procedure, a mixture of 2,3-dihydro-3-oxo-6-phenyl-4-pyridazinecarboxylic acid (1.92 g), triethylamine (3.0 ml), and thionyl chloride (5.0 ml) in tetrahydrofuran is allowed to stir at 20°-25° C. for 6 hours. The mixture is concentrated on the rotary evaporator and the residue is treated with 50 ml of cold ammonium hydroxide solution. The solid product is collected and recrystallized from acetic acid to give 2,3-dihydro-3-oxo-6-phenyl-4-pyridazinecarboxamide.
Reaction SMILES: C([O:4][CH:5]1[O:25][C@H:24]([C:26](=S)[O:27][C:28](=[O:30])[CH3:29])[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:11](OC2C=CC=CC=2)[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[C:8]([O:7][C@@H:6]1[CH2:11][C@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@@H:24]([CH2:26][O:27][C:28](=[O:30])[CH3:29])[O:25][CH:5]1[OH:4])(=[O:10])[CH3:9]
Reactant: CC(=O)OC(=S)[C@H]1OC(OC(C)=O)[C@H](OC(C)=O)[C@@H](Oc2ccccc2)[C@@H]1OC(C)=O
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(=O)OC[C@H]1OC(O)[C@H](OC(C)=O)C[C@@H]1OC(C)=O
Temperature: 80 °C
Yield: 135.5 %

Procedure:
1,2,4,6-tetra-O-acetyl-3-O-phenylthiono-glucopyranose (5.2 g) was dissolved in toluene (50 mL) and added to tributyl tin hydride (6.7 mL) and azobisisobutryonitrile (2.8 g). The reaction mixture was heated for 1 to 3 hours at 80° C. to provide for 3-deoxy-2,4,6-tri-O-acetyl-glucopyranose (4.5 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[O:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[N+:26]([O-])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[C].[Pd].C(OCC)(=O)C>[NH2:26][C:20]1[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=1[O:18][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[CH2:16][CH2:17][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9]2
Reactant: CC(C)(C)OC(=O)N1CCc2c(cccc2Oc2cc(Cl)ccc2[N+](=O)[O-])C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2c(cccc2Oc2cc(Cl)ccc2N)C1
Yield: 74.9 %

Procedure:
5% carbon-palladium (1.3 g) was added to an ethyl acetate (100 ml) solution of 2-tert-butoxycarbonyl-5-(5-chloro-2-nitrophenoxy)-1,2,3,4-tetrahydroisoquinoline (4.25 g, 10.5 mmols). The resulting mixture was hydrogenated at room temperature under atmospheric pressure. The catalyst was removed through filtration, and the filtrate was concentrated under reduced pressure. The residue was purified through silica gel column chromatography to give an oil of 5-(2-amino-5-chlorophenoxy)-2-tert-butoxycarbonyl-1,2,3,4-tetrahydroisoquinoline (2.95 g, 75%).
Reaction SMILES: [CH:1](=[N:8]/[OH:9])\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S([N-]Cl)(=O)=O)=CC=1.O.O.O.[Na+].[CH2:26]([Sn:30]([CH2:37][CH2:38][CH2:39][CH3:40])([CH2:33][CH2:34][CH2:35][CH3:36])[C:31]#[CH:32])[CH2:27][CH2:28][CH3:29].[OH-].[Na+].[OH-].[NH4+]>O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2].[Cu].O.C(O)CCC>[C:2]1([C:1]2[CH:32]=[C:31]([Sn:30]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])[O:9][N:8]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O/N=C/c1ccccc1
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Agent: [Cu+2]
Agent: [Cu]
Agent: Cc1ccc(S(=O)(=O)[N-]Cl)cc1
Solvent: CCCCO
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1cc(-c2ccccc2)no1
Reaction time: 6 h

Procedure:
(E)-benzaldehyde oxime (Sigma Aldrich; 3.3 g, 20 mmol) in tent butanol and water (1:1) 80 ml, is treated with chloramine T trihydrate (Sigma Aldrich; 5.9 g, 21 mmol) in small, portions over 5 min. The reaction is then treated with copper sulfate pentahydrate (0.15 g, 0.6 mmol) and copper turnings ˜50 mg and tributylethynylstannane (6.3 g, 20 mmol). The reaction is then adjusted to pH 6 with sodium hydroxide solution and stirred for 6 h. The reaction mixture is treated with dilute ammonium hydroxide solution to remove all copper salts. The product is collected by filtration, redissolved in ethyl acetate and filtered through a short plug of silica gel. The filtrate is concentrated in vacuum to give 3-phenyl-5-(tributylstannyl) isoxazole.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:17][CH3:18]>CN(C=O)C.CC(=O)OCC>[Cl:1][C:2]1[N:7]([CH2:17][CH3:18])[C:6](=[O:8])[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: CCI
Reactant: Oc1cc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1c(Cl)nc(Cl)cc1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
A solution of 2,6-dichloro-pyrimidin-4-ol (1.0 g, 6.1 mmol) and K2CO3 (1.1 g, 7.9 mmol) in DMF (10 mL) was stirred at RT for 15 min. The reaction mixture was cooled to 0° C., and iodoethane (1.1 mL, 6.7 mmol) was added dropwise. After stirring overnight at RT, the reaction mixture was diluted with EA, washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica chromatography (20:1, EA:PE) to give 330 mg (28%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 1.37 (t, J=7.6 Hz, 3H), 4.76 (q, J=6.8 Hz, 2H), 6.67 (s, 1H). [M+H] Calc'd for C6H6Cl2N2O, 193, 195, 197. Found, 193, 195, 197.
Reaction SMILES: [C:1]1([CH3:10])[C:2]([N:7]=[C:8]=[O:9])=[CH:3][CH:4]=[CH:5][CH:6]=1.Cl.[NH2:12][CH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[C:16](=[O:32])[N:17]([CH:24]1[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]1=[O:31])[C:18]2=[O:23].C(N(CC)CC)C>C1COCC1>[O:31]=[C:25]1[CH:24]([N:17]2[C:16](=[O:32])[C:15]3[C:19](=[CH:20][CH:21]=[CH:22][C:14]=3[CH2:13][NH:12][C:8]([NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:10])=[O:9])[C:18]2=[O:23])[CH2:29][CH2:28][C:27](=[O:30])[NH:26]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: Cc1ccccc1N=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccccc1NC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 72.4 %

Procedure:
o-Tolyl isocyanate (0.4 g, 3.0 mmol) was added to a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.8 g, 2.3 mmol) and triethylamine (0.3 g, 3.2 mmol) in THF (40 mL) at 5° C. After stirring for 10 minutes at 5° C., the mixture was warmed to room temperature and stirred overnight. The mixture was concentrated, and the residue was stirred with 1N HCl (30 mL) for 30 minutes. The solid was collected and slurried with hot acetone (15 mL) to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-o-tolyl-urea (0.7 g, 72%) as a white solid: mp>260° C.; 1H NMR (DMSO-d6) δ 2.05-2.09 (m, 1H), 2.19 (s, 3H), 2.49-2.65 (m, 2H), 2.84-2.98 (m, 1H), 4.73 (d, J=5.9 Hz, 2H), 5.13-5.20 (dd, J=5.4 and 12.7 Hz, 1H), 6.85-7.19 (m, 4H), 7.77-7.92 (m, 5H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 13.90, 17.99, 26.93, 34.68, 44.86, 116.73, 117.88, 118.14, 122.03, 123.05, 123.18, 126.06, 127.61, 129.69, 130.75, 133.93, '36.25, 151.47, 163.00, 163.56, 165.83, 168.76; Anal. calcd. for C22H20N4O5: C, 62.85; H, 4.79; N, 13.33. Found: C, 62.76; H, 4.75; N, 13.12.