Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([O:17]C)=O.[NH2:19][C:20]1[CH:25]=[N:24][CH:23]=[C:22]([Cl:26])[N:21]=1.C1(C)C(C)=CC=CC=1>CO>[Cl:26][C:22]1[N:21]=[C:20]([NH:19][C:15]([C:3]2[N:4]([CH3:14])[S:5](=[O:12])(=[O:13])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:2]=2[OH:1])=[O:17])[CH:25]=[N:24][CH:23]=1
Reactant: Nc1cncc(Cl)n1
Reactant: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Solvent: CO
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2cncc(Cl)n2)=C(O)c2ccccc2S1(=O)=O
Reaction time: 8 h
Yield: 65.4 %

Procedure:
A mixture of 9.0 g (33 mmols) of methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide, 4.36 g (33 mmols) of 2-amino-6-chloro-pyrazine and 1200 ml of xylene was refluxed for 24 hours in a nitrogen atmosphere. The methanol formed by the reaction was removed with the aid of a 4 Å molecular sieve arranged in a Soxhlet attachment. After cooling and standing overnight, the crystals were filtered off and recrystallized from dioxane. 7.91 g (64% of theory) of N-(6-chloro-pyrazin-2-yl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][CH2:12][OH:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([NH:31][C:32]2[C:37]([Cl:38])=[CH:36][N:35]=[C:34](Cl)[N:33]=2)=[C:23]([S:25]([N:28]([CH3:30])[CH3:29])(=[O:27])=[O:26])[CH:24]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([NH:31][C:32]2[C:37]([Cl:38])=[CH:36][N:35]=[C:34]([NH:1][C:2]3[C:15]([O:16][CH3:17])=[CH:14][C:5]4[CH2:6][CH2:7][N:8]([CH2:11][CH2:12][OH:13])[CH2:9][CH2:10][C:4]=4[CH:3]=3)[N:33]=2)=[C:23]([S:25]([N:28]([CH3:30])[CH3:29])(=[O:26])=[O:27])[CH:24]=1
Reactant: CN(C)S(=O)(=O)c1cc(Cl)ccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(CCO)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccc(Cl)cc3S(=O)(=O)N(C)C)n1)CCN(CCO)CC2

Procedure:
The title compound was prepared from 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-ethanol and 5-Chloro-2-(2,5-dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide in an analogous manner to Example 61e. Product isolated as a tan foam (0.058 g, 48%). MP: 194-199° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 9.22 (s, 1H), 8.47 (d, 1H, J=8.8 Hz), 8.15 (s, 1H), 7.95 (s, 1H), 7.87-7.85 (m, 1H), 7.53-7.47 (m, 2H), 6.66 (s, 1H), 3.88 (s, 3H), 3.67-3.62 (m, 2H), 2.91-2.86 (m, 2H), 2.77 (s, 6H), 2.75-2.65 (m, 8H). MS: 581.14 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13](O)[CH3:14])[CH:5]=[C:6]([Br:12])[C:7]=1[O:8]C(=O)C>C1(C)C=CC=CC=1.S([O-])([O-])(=O)=O.[Cu+2]>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Br:12])[C:7]=1[OH:8])[CH:13]=[CH2:14]
Reactant: CC(=O)Oc1c(Br)cc(C(C)O)cc1Br
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: Cc1ccccc1
Product: C=Cc1cc(Br)c(O)c(Br)c1
Yield: 70.5 %

Procedure:
5 g 1-(3',5'-dibromo-4-acetoxyphenyl)ethanol are dissolved in 50 g of toluene, to which mixture are added 0.25 g of anhydrous copper(II)sulfate. The mixture is refluxed for 2 hours and the toluene then removed on a rotary evaporator. A yellow oil remains which after recrystallization from petrol ether yields 2.9 g of 3,5-dibromo-4-hydroxystyrene as white crystals, mp. 75° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[CH:8][O-].[Na+].[C:11]([CH2:13][C:14]([NH2:16])=[O:15])#[N:12].N1CCCCC1>O>[OH:1][C:2]12[NH:16][C:14](=[O:15])[CH:13]([C:11]#[N:12])[CH:8]=[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7]2
Reactant: N#CCC(N)=O
Reactant: O=C1CCCCC1=C[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCNCC1
Product: N#CC1C=C2CCCCC2(O)NC1=O
Temperature: 40 °C
Reaction time: 96 h
Yield: 217.7 %

Procedure:
Sodium 2-oxocyclohexylidenemethanolate (15 g), 2-cyanoacetamide (4.3 g) and piperidine (1.0 ml) were suspended in water (35 ml), and the mixture was stirred at 40° C. for 4 days. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was suspended in methanol, and insoluble material was filtered off. The filtrate was concentrated under reduced pressure to give the object compound (21.4 g).
Reaction SMILES: C(NCC)C.[C:6]([O:10][C:11]([NH:13][CH:14]1[CH2:19][CH2:18][CH2:17][N:16](C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)[CH2:15]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>C(O)C>[NH:16]1[CH2:17][CH2:18][CH2:19][CH:14]([NH:13][C:11](=[O:12])[O:10][C:6]([CH3:8])([CH3:7])[CH3:9])[CH2:15]1
Reactant: CC(C)(C)OC(=O)NC1CCCN(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Solvent: CCO
Solvent: CCNCC
Product: CC(C)(C)OC(=O)NC1CCCNC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.7 %

Procedure:
25 ml of diethylamine was added to 250 ml of an ethanol solution of 1.88 g of 9H-fluoren-9-ylmethyl 3-t-butoxycarbonylaminopiperidine-1-carboxylate, and the mixture was stirred at room temperature for 18 hours. After the solution had been concentrated under reduced pressure, the residue was dissolved in a mixture consisting of 150 ml of toluene and 100 ml of 10% aqueous citric acid solution. The aqueous layer was made alkaline with a 5N aqueous sodium hydroxide solution, and then extracted twice with 100 ml of dichloromethane. The organic layers were combined together, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 0.79 g of the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[Br:8][C:9]1[C:10]([OH:20])=[C:11]([NH2:19])[C:12](=[C:16]([Br:18])[CH:17]=1)[C:13]([OH:15])=[O:14].[O-]S([O-])(=O)=O.[Na+].[Na+].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[Br:8][C:9]1[C:10]([OH:20])=[C:11]([NH:19][CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[C:12](=[C:16]([Br:18])[CH:17]=1)[C:13]([OH:15])=[O:14]
Reactant: O=Cc1cccs1
Reactant: Nc1c(O)c(Br)cc(Br)c1C(=O)O
Agent: O=S(=O)([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)c1c(Br)cc(Br)c(O)c1NCc1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.3 %

Procedure:
A solution of 2-thiophenecarboxaldehyde (38 mg, 0.34 mmol) in dry methanol (0.8 mL) was added to a mixture of 4,6-dibromo-3-hydroxyanthranilic acid (105 mg, 0.34 mmol) and Na2SO4 (240 mg, 1.7 mmol) in methanol (2 mL). The reaction mixture was stirred overnight at room temperature. Sodium cyanoborohydride (32 mg, 0.51 mmol) was added, and the mixture was stirred for 2 days at room temperature. Conc. acetic acid (1 mL) was added, and the solvent was removed in vacuo. The residue was partitioned between brine and EtOAc (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The obtained material was purified by column chromatography (SiO2, CH2Cl2 -hexane-EtOAc-conc. HOAc 30:30:20:3). Preparative HPLC (H2O-acetonitrile-conc. HOAc 50:50:1) yielded the title compound as a yellowish solid (17 mg): 1H NMR (CD 3 OD-d4) 7.26 (dd, J=5 Hz, 1 Hz), 7.20 (s, 1H), 6.99 (m, 1H), 6.92 (dd, J=5 Hz, J=5 Hz, 1H), 4.54 (s, 2H); MS (TSP): m/z (rel. int.) 410/408/406 (M+1, 5/12/7), 234/232 (31/28), 154 (100).
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=1)=[O:6])[CH:2]=[CH2:3].[CH3:16][C:17]1([CH3:31])[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[C:23]2[CH:22]=[C:21]([CH2:29][OH:30])[CH:20]=[CH:19][C:18]1=2>>[CH3:16][C:17]1([CH3:31])[CH2:26][CH2:25][C:24]([CH3:27])([CH3:28])[C:23]2[CH:22]=[C:21]([CH2:29][O:30][C:11]([C:10]3[CH:14]=[CH:15][C:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])=[CH:8][CH:9]=3)=[O:12])[CH:20]=[CH:19][C:18]1=2
Reactant: C=CCOC(=O)c1ccc(C(=O)O)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(CO)ccc21
Product: C=CCOC(=O)c1ccc(C(=O)OCc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
In a manner similar to Example 4(c), by reaction of 2.06 g (10 mmol) of 4-(allyloxycarbonyl)benzoic acid with 2.18 g (10 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylmethanol, 2.8 g (70%) of allyl ester are obtained in the form of a translucent oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:20])=[C:4]([C:13]([NH:15][CH2:16][CH:17]([OH:19])[CH3:18])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([OH:9])=[O:8].[C:21](Cl)(=[O:29])[CH2:22][CH2:23][CH2:24][CH2:25][C:26](Cl)=[O:27]>CC(N(C)C)=O>[C:21]([NH:1][C:2]1[C:3]([I:20])=[C:4]([C:13]([NH:15][CH2:16][CH:17]([OH:19])[CH3:18])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([OH:9])=[O:8])(=[O:29])[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([NH:1][C:2]1[C:3]([I:20])=[C:4]([C:13]([NH:15][CH2:16][CH:17]([OH:19])[CH3:18])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([OH:9])=[O:8])=[O:27]
Reactant: CC(O)CNC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Reactant: O=C(Cl)CCCCC(=O)Cl
Solvent: CC(=O)N(C)C
Product: CC(O)CNC(=O)c1c(I)c(NC(=O)CCCCC(=O)Nc2c(I)c(C(=O)O)c(I)c(C(=O)NCC(C)O)c2I)c(I)c(C(=O)O)c1I

Procedure:
Analogously to Example 10, 5-amino-N-(2-hydroxypropyl)2,4,6-triiodoisophthalamic acid is reacted with hexanedioic acid dichloride in dimethylacetamide and then worked up. The thus-obtained product melts at 284°-285° C., with decomposition.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([F:8])[C:5]([F:9])=[C:4](F)[C:3]=1[F:11].[NH3:12]>>[NH2:12][C:4]1[C:3]([F:11])=[C:2]([F:1])[N:7]=[C:6]([F:8])[C:5]=1[F:9]
Reactant: Fc1nc(F)c(F)c(F)c1F
Reactant: N
Product: Nc1c(F)c(F)nc(F)c1F
Temperature: 25 °C

Procedure:
A mixture of 20.0 g (118 mmol) of pentafluoropyridine (Aldrich Chemical Company, Milwaukee, Wis., USA) and 40 ml of concentrated aqueous ammonia was heated on a steam bath for two hours in a sealed stainles steel reaction vessel. The vessel and contents were cooled to room temperature and the resulting suspension suspension was partitioned between water and diethyl ether.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH2:12][C:13](=[O:15])[CH3:14])[C:4](=[O:16])[C:3]=1[NH:17][C:18]([C:20]12[CH2:27][CH:26]3[CH2:28][CH:22]([CH2:23][CH:24]1[CH2:25]3)[CH2:21]2)=O.[OH-].[Ca+2].[OH-].C(O)C.Cl>O>[O:15]=[C:13]([CH3:14])[CH2:12][N:5]1[C:4](=[O:16])[C:3]2[NH:17][C:18]([C:20]34[CH2:27][CH:26]5[CH2:28][CH:22]([CH2:23][CH:24]3[CH2:25]5)[CH2:21]4)=[N:1][C:2]=2[N:7]([CH2:8][CH2:9][CH3:10])[C:6]1=[O:11]
Reactant: CCCn1c(N)c(NC(=O)C23CC4CC(CC2C4)C3)c(=O)n(CC(C)=O)c1=O
Agent: Cl
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCn1c(=O)n(CC(C)=O)c(=O)c2[nH]c(C34CC5CC(CC3C5)C4)nc21
Yield: 53.9 %

Procedure:
A suspension of Compound B (1.70 g, 4.38 mmol) and calcium hydroxide (2.27 g, 30.7 mmol) in water (30 ml) -ethanol (22 ml) was refluxed under heating for 30 minutes. After cooling, the reaction solution was adjusted to pH 2 with concentrated hydrochloric acid, and then extracted three times with chloroform. The extract was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was recrystallized from acetone/water to give 874 mg (yield 54%) of Compound C as white plates.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([O:21][CH2:22][CH3:23])=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][CH:8]=1)[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:22]([O:21][CH:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:24])[CH3:23]
Reactant: CCOC(=O)C(=Cc1ccc(OCc2ccccc2)cc1)OCC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Yield: 100.7 %

Procedure:
Compound (a) (62 g; 0.19 mole) was hydrogenated in ethyl acetate (400 ml) at atmospheric pressure using Pd/C (10%) as catalyst. The mixture was filtered through celite and evaporated in vacuo to give 45.6 g (yield 100%) of the desired product
Reaction SMILES: [C:1]([N:8]1[CH2:11][C:10](=[O:12])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F:13][C:14]1[CH:15]=[C:16]([Mg]Br)[CH:17]=[CH:18][CH:19]=1>O1CCCC1.[NH4+].[Cl-]>[F:13][C:14]1[CH:19]=[C:18]([C:10]2([OH:12])[CH2:11][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]2)[CH:17]=[CH:16][CH:15]=1
Reactant: Fc1cccc([Mg]Br)c1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(O)(c2cccc(F)c2)C1
Temperature: 0 °C
Yield: 105.8 %

Procedure:
1-Boc-3-azetidinone (500 mg, 2.77 mmol, available from Aldrich #696315) was dissolved in dry tetrahydrofuran (20 ml) under N2 atmosphere. The solution obtained was cooled at 0° C. and 3-Fluorophenylmagnesiumbromide (1M in THF) (3.33 ml, 3.33 mmol) was added dropwise under stirring. The reaction was warmed to room temperature and stirred overnight. The reaction mixture was diluted with NH4Cl sat. sol. (50 ml) and the organics were extracted with ethylacetate (3×50 ml). Collected organics after solvent evaporation afforded the title compound (D28) (783 mg)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:34]=[CH:33][C:15]3[N:16]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:18][C:14]=3[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:37][O:38][C:39](=[O:46])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]Br>O>[CH3:37][O:38][C:39](=[O:46])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][N:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[C:12]1[CH:34]=[CH:33][C:15]2[N:16]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:18][C:14]=2[CH:13]=1
Reactant: COC(=O)CCCCCBr
Reactant: COc1ccc(-n2c(-c3ccccc3)nc3cc(NS(=O)(=O)c4ccc(Cl)cc4)ccc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COC(=O)CCCCCN(c1ccc2c(c1)nc(-c1ccccc1)n2-c1ccc(OC)cc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
75 mg of 4-chloro-N-[1-(4-methoxyphenyl)-2-phenyl-1H-benzimidazol-5-yl]benzenesulfonamide was suspended in 0.5 ml of N,N-dimethylfonmamide, mixed with 6 mg of sodium hydride and stirred for 30 minutes at 20° C. 44 mg of 6-bromohexanoic acid methyl ester was added, allowed to stir for 15 hours, mixed with water, extracted three times with ethyl acetate, the extracts were dried on sodium sulfate, concentrated by evaporation in a vacuum, and the residue was chromatographed on silica gel.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([N:18]1[CH2:22][CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]([CH2:29][N:30]2[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]2)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[CH2:11]([N:18]1[CH2:22][CH:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]([CH2:29][N:30]2[CH2:35][CH2:34][C:33](=[O:36])[CH2:32][CH2:31]2)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OC1CCN(CC2CN(Cc3ccccc3)CC2c2ccccc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C1CCN(CC2CN(Cc3ccccc3)CC2c2ccccc2)CC1
Reaction time: 0.17 h
Yield: 95.4 %

Procedure:
To a solution of 0.14 mL of oxalylchloride in 3 mL of CH2CI2 at -70° C. was added 0.16 mL of DMSO. After 5 min 270 mg of 1-Benzyl-3-(SR)-(4-hydroxypiperidin- 1-ylmethyl)-4-(SR)-phenylpyrrolidine (from Example 14) in 3 mL of CH2Cl2 was added. After stirring for 10 min, the reaction was warmed to 0 OC for 45 min. The reaction was quenched with H20 and partitioned between 100 mL H20 and 100 mL CH2C-2. After separating phases, the aqueous layer was extracted with 100 mL CH2C-2. The combined organic layers were washed with 100 mL brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography eluting with 2% MeOH in CH2C12 to provide 256 mg of the title compound as a light yellow oil. RF : 0.40 (5% MeOH in CH2Cl2). 1H NMR (300 MHz, CDCl3): δ2.2-2.4 (m, 4H), 2.4-2.7 (m, 9H), 2.9-3.1 (m, 3H), 3.7 (ABq, 2H), 7.1-7.4 (m, 10H). Mass Spectrum (ESI): 349.3 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[CH:15]=[O:16])=[CH:9][CH:8]=1.CO.[BH4-].[Na+]>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[CH2:15][OH:16])=[CH:9][CH:8]=1
Reactant: O=C/C=C/c1ccc(-c2ccccn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: OC/C=C/c1ccc(-c2ccccn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(2E)-3-[4-(2-pyridinyl)phenyl]-2-propenal (500 mg, 2.4 mmol, prepared as described in Reference Example 32) was dissolved in THF (10 mL) and methanol (10 mL) at 0° C. Sodium borohydride (109 mg, 2.9 mmol) was added and the mixture was stirred at 0° C. for 30 min. The reaction mixture was concentrated. Water (10 mL) was added and the mixture was extracted with ethyl acetate (3×15 mL). The organic layer was collected, dried and concentrated. MS 212 (M+H)+.
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7][OH:8].[N+:9]([C:12]1[O:16][C:15]([C:17]2[C:21]([CH:22]=O)=[CH:20][N:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:18]=2)=[CH:14][CH:13]=1)([O-:11])=[O:10]>CN(C)C=O>[N+:9]([C:12]1[O:16][C:15]([C:17]2[C:21]([CH:22]=[N:7][OH:8])=[CH:20][N:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:18]=2)=[CH:14][CH:13]=1)([O-:11])=[O:10]
Reactant: O=Cc1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-c2nn(-c3ccccc3)cc2C=NO)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
Add (while stirring) 7.61 g of sodium acetate and 6.58 g of hydroxylamine hydrochloride to 25.0 g of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxaldehyde in 75 ml of dimethylformamide, the temperature rising slightly. Stir for a further 45 minutes at from 30° to 35° C and for one hour at room temperature. Clafify with degased active charcoal and then pour the solution onto 1 kg of ice and water. Vacuum filter and wash with water to obtain 98% yield of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxaldehydeoxime [m.p. 199° to 201° C with decomposition (from toluene)].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].[Br:13]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[Cl:1]
Reactant: COC(=O)c1ccc(C)c(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)c(Cl)c1
Temperature: 25 °C
Yield: 15.2 %

Procedure:
To a solution of methyl 3-chloro-4-methylbenzoate (920 mg, 5.0 mmol) in carbon tetrachloride (10 mL) were added N-bromosuccinimide (1.067 g, 6.0 mmol) and 2,2′-Azobis(2-methylpropionitrile) (81 mg, 0.50 mmol). The mixture was stirred at reflux overnight. The mixture was cooled to room temperature and concentrated. The residue was purified by column chromatography (Hexanes:ethyl acetate=10:1) to give the desired product (200 mg, 19%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CN(C)P(N(C)C)(N(C)C)=O.Br[CH:26]([C:31]1[CH:36]=[CH:35][C:34]([O:37][C:38]2[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=2)=[CH:33][CH:32]=1)[C:27]([O:29][CH3:30])=[O:28]>O1CCCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH:26]([C:31]2[CH:32]=[CH:33][C:34]([O:37][C:38]3[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=3)=[CH:35][CH:36]=2)[C:27]([O:29][CH3:30])=[O:28])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C(Oc1ccc(C(C)(C)C)cc1)c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
To a solution of 3.75 g of 4-t-butylphenol in 40 ml of tetrahydrofuran was added 0.88 g of sodium hydride (oil dispersion). After stirring 30 minutes, 1 ml of hexamethylphosphoramide was added and a solution of 7.36 g of methyl α-bromo-α-[p-(p-nitrophenoxy)phenyl]acetate in 25 ml of tetrahydrofuran was added over a period of 30 minutes. The mixture was stirred at room temperature for 30 minutes and refluxed for 30 minutes. The mixture was poured into 130 ml of ice-water and extracted with dichloromethane. The extracts were washed with saturated sodium chloride solution and chilled. Filtration gave 2.1 g of product. The filtrate was concentrated to an oil under vacuum and chromatographed over silica gel (eluent-CCl4). From the first fractions there was obtained 4.3 g of solid which was dissolved in hot methanol and the volume reduced. Chilling gave 3.7 g of product as pale yellow crystals, mp 101°-103° C.
Reaction SMILES: Br[CH2:2][C:3](=[O:18])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH2:16])(=[O:15])=[O:14])=[C:9]([Cl:17])[CH:8]=1)([CH3:6])[CH3:5].[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C=O)C.O>[N:19]([CH2:2][C:3](=[O:18])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH2:16])(=[O:15])=[O:14])=[C:9]([Cl:17])[CH:8]=1)([CH3:6])[CH3:5])=[N+:20]=[N-:21]
Reactant: CC(C)(C(=O)CBr)c1ccc(S(N)(=O)=O)c(Cl)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C(=O)CN=[N+]=[N-])c1ccc(S(N)(=O)=O)c(Cl)c1
Reaction time: 2 h
Yield: 79.4 %

Procedure:
To a solution of 4-(4-bromo-2-methyl-3-oxobutan-2-yl)-2-chlorobenzenesulfonamide (11.3 g, 31.8 mmol) in DMF (50 mL) was added NaN3 (3.1 g, 47.8 mmol, 1.5 eq) at 0° C. After stirring 2 h, the residue was diluted with water and extracted with EtOAc. The combined extracts were washed with 1M HCl and water successively, dried over MgSO4, filtered and evaporated. The residue was purified by chromatography (Hex/EtOAc=4:1 to 2:1) to give 4-(4-azido-2-methyl-3-oxobutan-2-yl)-2-chlorobenzenesulfonamide (8.0 g, 79% yield) as yellow sticky oil. 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.29 (d, J=2.2 Hz, 1H), 5.12 (s, 2H), 4.11 (s, 2H), 1.58 (s, 6H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:5]=[N+:6]([O-:20])[C:7]2[CH:16]=[C:15]3[C:11]([CH2:12][CH:13]([N:17]([CH3:19])[CH3:18])[CH2:14]3)=[CH:10][C:8]=2[N:9]=1)[CH3:2].ClC1N=[N+]([O-:35])C2C3CCCC=3C=CC=2N=1>>[CH2:1]([NH:3][C:4]1[N:5]=[N+:6]([O-:20])[C:7]2[CH:16]=[C:15]3[C:11]([CH2:12][CH:13]([N:17]([CH3:19])[CH3:18])[CH2:14]3)=[CH:10][C:8]=2[N+:9]=1[O-:35])[CH3:2]
Reactant: [O-][n+]1nc(Cl)nc2ccc3c(c21)CCC3
Reactant: CCNc1nc2cc3c(cc2[n+]([O-])n1)CC(N(C)C)C3
Product: CCNc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CC(N(C)C)C3

Procedure:
H2O2 (70%, 0.35 mL, ca. 6.9 mmol) was added dropwise to a stirred solution of TFAA (1.0 mL, 6.9 mmol) in DCM (10 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 113 (188 mg, 0.7 mmol) and TFA (0.26 mL, 3.4 mmol) in DCM (10 mL) at 0° C. The solution was stirred at 20° C. for 6 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×30 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give (i) starting material 113 (175 mg, 93%) and (ii) 1,4-dioxide 114 (8 mg, 4%) as a red gum: 1H NMR δ 8.11 (s, 1H, H-9), 8.08 (s, 1H, H-5), 6.98 (br s, 1H, NH), 3.63 (dq, J=7.2, 1.0 Hz, 2H, CH2N), 3.15-3.30 (m, 3H, CH, CH2), 2.95-3.07 (m, 2H, CH2), 2.33 [s, 6H, N(CH3)2], 1.36 (t, J=7.2 Hz, 3H, CH3); MS (FAB+) m/z 290 (MH+, 20%), 274 (5); HRMS (FAB+) calcd for C14H20N5O2 (MH+) m/z 290.1617, found 290.1607.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@H:3]([O:6][C:7]2[C:12]([NH2:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1.[CH3:14][O:15][C:16]([C:18]1[S:27][C:21]2[N:22]=[CH:23][N:24]=[C:25](Cl)[C:20]=2[C:19]=1[CH3:28])=[O:17]>>[CH3:14][O:15][C:16]([C:18]1[S:27][C:21]2[N:22]=[CH:23][N:24]=[C:25]([NH:13][C:12]3[C:7]([O:6][C@H:3]4[CH2:4][CH2:5][O:1][CH2:2]4)=[N:8][CH:9]=[CH:10][CH:11]=3)[C:20]=2[C:19]=1[CH3:28])=[O:17]
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Reactant: Nc1cccnc1O[C@H]1CCOC1
Product: COC(=O)c1sc2ncnc(Nc3cccnc3O[C@H]3CCOC3)c2c1C

Procedure:
Prepared analogously from 2-[(S)-(tetrahydro-furan-3-yl)oxy]-pyridin-3-ylamine and 4-chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester.