Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH2:11][OH:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[S:13](=O)(=[O:16])([OH:15])[OH:14]>O>[S:13]([OH:16])([O:12][CH2:11][CH2:10][N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)(=[O:15])=[O:14]
Reactant: CCN(CCO)c1ccccc1
Reactant: O=S(=O)(O)O
Solvent: O
Product: CCN(CCOS(=O)(=O)O)c1ccccc1
Reaction time: 2 h

Procedure:
In 1.1, 16.5 grams (g) (0.10 mol) of 2-(N-ethylanilino)ethanol were added to 25.0 milliliters (ml) of concentrated sulfuric acid at a temperature of 35 to 40 degrees Celsius (° C.). The reaction proceeded slightly exothermically and was held within the specified temperature range by cooling with iced water. The mixture was stirred for an additional 2 hours. On completion of the reaction, the mixture was poured onto ice and made up to 250 ml by adding water. The result was a transparent yellow solution, which was used in the next stage with no further processing.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]([F:29])([F:28])[C:11]1[CH:12]=[C:13]([C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[CH2:19][CH2:20][CH2:21][C:22]3=[O:27])[CH:14]=[CH:15][CH:16]=1.Br[CH2:31][C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=1>C1COCC1>[O:27]=[C:22]1[C:23]2[C:18](=[C:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([C:10]([F:28])([F:29])[F:9])[CH:12]=3)[CH:26]=[CH:25][CH:24]=2)[CH2:19][CH2:20][CH:21]1[CH2:31][C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=1
Reactant: O=C1CCCc2c1cccc2-c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC2CCc3c(cccc3-c3cccc(C(F)(F)F)c3)C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.4 %

Procedure:
A solution of lithium diisopropylamide (2.0 M in THF, 0.8 mL, 1.6 mmol) was added to a solution of 5-(3-(trifluoromethyl)phenyl)-3,4-dihydronaphthalen-1(2H)-one (435 mg, 1.5 mmol) in THF (5 mL) at −78° C. After 1 h at −78° C., a solution of methyl 4-(bromomethyl)benzoate (378 mg, 1.65 mmol) in THF (2.5 mL) was added via cannula. The reaction mixture was allowed to warm to room temperature naturally. After stirring at room temperature overnight, the reaction was quenched with saturated aqueous NH4Cl (25 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The resulting crude residue was purified by combiflash (40 g column, hexanes→40% EtOAc/hexanes, gradient) to afford 55 mg (8%) of methyl 4-((1-oxo-5-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydronaphthalen-2-yl)methyl)benzoate.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].[H-].[Na+].Br[C:19]1[C:20]([Cl:34])=[C:21]2[CH:27]=[N:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]2=[N:23][CH:24]=1.[Li]CCCC.[Na]>C1COCC1.[Cl-].[NH4+]>[Cl:34][C:20]1[C:19]([C:3]([C:5]2[C:13]3[C:8](=[N:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)([OH:4])[C:2]([F:1])([F:14])[F:15])=[CH:24][N:23]=[C:22]2[N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:26]=[CH:27][C:21]=12
Reactant: O=C(c1c[nH]c2ncccc12)C(F)(F)F
Reactant: Clc1c(Br)cnc2c1cnn2-c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1cnc2c(cnn2-c2ccccc2)c1Cl)(c1c[nH]c2ncccc12)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 46 %

Procedure:
To a chilled (ice-bath) solution of 369 mg (1.72 mmol) of 2,2,2-trifluoro-1-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethanone in 10 mL of THF was added 70 mg (1.75 mmol) of 60% sodium hydride in mineral oil and the mixture was then chilled to −78° C. In another flask, to a chilled (−78° C.) solution of 508 mg (1.65 mmol) of 5-bromo-4-chloro-1-phenyl-1H-pyrazolo[3,4-b]pyridine (prepared according to the procedures in Misra, Bioorg. Med. Chem. Lett. 2003, 13, 2405, and Nakai in Chem. Pharm. Bull. 2004, 52, 1098) in 10 mL of anhydrous THF was added 670 μL (1.68 mmol) of a 2.5 M solution of n-BuLi in hexanes. The mixture stirred for 5 minutes and was then added to the sodium salt of 2,2,2-trifluoro-1-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethanone. The reaction was monitored by TLC [ethyl acetate-hexanes (6:4)] indicating a new more polar product than both starting materials. After 1 hour, the mixture was diluted with 30 mL of saturated aqueous ammonium chloride and extracted with three 30 mL portions of ethyl acetate. The combined organic layers were washed with three 30 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was chromatographed on silica gel using dichloromethane to load the sample and then eluting with ethyl acetate-hexanes (10-50% gradient) to afford 337 mg (44%) of title compound. Trituration with ether afforded 85 mg of the title compound as a white solid. MS m/z 444.38 (MH+).
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([CH:9]=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11]([Mg]Br)#[CH:12]>>[N+:1]([C:4]1[O:8][C:7]([CH:9]([OH:10])[C:11]#[CH:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C#C[Mg]Br
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Product: C#CC(O)c1ccc([N+](=O)[O-])o1

Procedure:
Using the procedure of Stage B of Preparation 2, 2.82 g of 5-nitro-2-furaldehyde and 45 ml of ethynylmagnesium bromide were reacted to obtain 1.84 g of the expected product after chromatography on silica (eluent: 8/2 hexane/ethyl acetate).
Reaction SMILES: [NH:1]1[CH2:13][CH2:12][CH2:11][CH:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH2:2]1.F[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22].[F-].[Cs+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N+:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:1]1[CH2:13][CH2:12][CH2:11][CH:3]([C:4]([O:6][C:7]([CH3:9])([CH3:10])[CH3:8])=[O:5])[CH2:2]1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC(C)(C)OC(=O)C1CCCNC1
Agent: [Cs+]
Agent: [F-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C1CCCN(c2ccccc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.2 %

Procedure:
To a solution of Example 437C (10.4 g, 56.1 mmol) in toluene (112 mL) was added 2-fluoronitrobenzene (6.0 mL, 56 mmol) and CsF (852 mg, 5.6. mmol). The reaction mixture was stirred under reflux conditions for 18 h, and allowed to cool to ambient temperature. The mixture was diluted with ethyl acetate (100 mL), washed with 10% HCl (2×50 mL), followed by brine (3×100 mL), then dried (Na2SO4) and evaporated in vacuo to obtain the title compound (16.5 g, 94%). MS (ESI) m/e 307 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20].CS(C)=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C>ClCCl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[O:20]
Reactant: OCCCCCCCCOc1ccc2ccccc2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=CCCCCCCCOc1ccc2ccccc2n1

Procedure:
The above alcohol (723 mg) was oxidised under Swern conditions (dimethyl sulphoxide (450 mg), oxalyl chloride (248 μl), triethylamine (1.58 ml)) in dichloromethane (25 ml) to give 8-(2-quinolinyloxy)octan-1-al. This was used directly in the next stage.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:18]2[CH:17]=[C:16]3[C:8]([C:9]4[CH:10]=[C:11]5[C:22]([CH3:24])([CH3:23])[CH2:21][CH2:20][C:19]([CH3:26])([CH3:25])[C:12]5=[CH:13][C:14]=4[CH2:15]3)=[CH:7][C:6]=2[C:5]([CH3:28])([CH3:27])[CH2:4][CH2:3]1.CCCCCC.[Li]CCCC.[C:41]1([C:47]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[C:48]2[CH:52]=[CH:51][CH:50]=[CH:49]2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1COCC1>[CH:48]1([C:47]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:20]2[CH2:21][C:22]([CH3:24])([CH3:23])[C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][C:12]=3[C:19]2([CH3:26])[CH3:25])[CH2:15][C:16]2[CH:17]=[C:18]3[C:2]([CH3:29])([CH3:1])[CH2:3][CH2:4][C:5]([CH3:28])([CH3:27])[C:6]3=[CH:7][C:8]4=2)[CH:49]=[CH:50][CH:51]=[CH:52]1
Reactant: C1=CC(=C(c2ccccc2)c2ccccc2)C=C1
Reactant: CC1(C)CCC(C)(C)c2cc3c(cc21)Cc1cc2c(cc1-3)C(C)(C)CCC2(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1(C)CCC(C)(C)c2cc3c(cc21)Cc1cc2c(cc1-3)C(C)(C)CC(C(c1ccccc1)(c1ccccc1)C1C=CC=C1)C2(C)C
Temperature: 1 °C
Yield: 79 %

Procedure:
In a 200 ml three-necked flask purged with nitrogen, 2.64 g (6.83 mmol, 1 eq) of 1,1,4,4,7,7,10,10-octamethyl-1,2,3,4,7,8,9,10-octahydrodibenzo(b,h)-fluorene was placed at room temperature. Then, 40 ml of dehydrated THE was added, and the mixture was stirred by a magnetic stirrer to give a solution. The solution was cooled with an ice bath (light yellow solution). To the solution, 4.6 ml (7.50 mmol, 1.10 eq) of a hexane solution of n-BuLi was dropwise added over a period of 10 minutes. Then, the ice bath was removed, and the solution was stirred at room temperature for 23 hours (dark red solution). The solution was cooled to 1° C. with an ice bath, and to the solution, a solution of 2.06 (8.94 mmol, 1.31 eq) of 6,6-diphenylfulvene in 20 ml of dehydrated THF was dropwise added over a period of 20 minutes (dark red slurry). The ice bath was removed, and the solution was stirred at room temperature for 65 hours. The resulting dark reddish brown solution was poured into 100 ml of a diluted hydrochloric acid solution to perform quenching. From the aqueous layer, the soluble component was extracted with diethyl ether, and the organic phase was washed with 100 ml of a saturated saline solution. The dispensed organic phase was dried over MgSO4, then the MgSO4 was filtered off, and from the filtrate the solvent was vacuum distilled off by a rotary evaporator to obtain an orangy yellow amorphous product. The amorphous product was washed with methanol, then filtered and dried in a vacuum disiccator to obtain 3.31 g of a slightly yellow powder (yield: 79%).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][CH3:14])=[CH:9][CH:10]=2)[N:5]([CH2:15][CH3:16])[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:32])[NH:25][CH2:26][C:27]([O:29]CC)=O)=[CH:19][CH:18]=1)#[N:2].CC(C)([O-])C.[K+].C(O)(C)(C)C>C1COCC1>[O:32]=[C:24]1[NH:25][CH2:26][C:27](=[O:29])[N:23]1[C:20]1[CH:19]=[CH:18][C:17]([C:4]2[N:5]([CH2:15][CH3:16])[C:6]3[C:11]([C:3]=2[C:1]#[N:2])=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH3:14])[CH:7]=3)=[CH:22][CH:21]=1
Reactant: CCOC(=O)CNC(=O)Nc1ccc(-c2c(C#N)c3ccc(OCC)cc3n2CC)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CCOc1ccc2c(C#N)c(-c3ccc(N4C(=O)CNC4=O)cc3)n(CC)c2c1
Reaction time: 8 h

Procedure:
A solution of ethyl {3-[4-(3-cyano-6-ethoxy-1-ethyl-1H-indol-2-yl)-phenyl]-ureido}-acetate (compound 773, 101 mg, 0.232 mmol) in THF (10 mL) is treated with a solution of potassium tert-butoxide in tert-butanol (0.30 mL, 1.0 M, 0.30 mmol), and the resulting mixture is allowed to stir overnight. The reaction mixture is partitioned between water and ethyl acetate (50 mL each), and the organic phase is washed with saturated brine. The aqueous phases are extracted with more ethyl acetate, and the extracts are combined, dried over anhydrous magnesium sulfate, filtered and evaporated. The residual material is separated by column chromatography (eluting 2/1 ethyl acetate/hexane on silica gel 60) to afford 2-[4-(2,5-dioxo-imidazolidin-1-yl)-phenyl]-6-ethoxy-1-ethyl-1H-indole-3-carbonitrile, compound 779, which is purified further by trituration with ether, collection by filtration and drying under high vacuum (76 mg, 0.196 mmol, 84%).
Reaction SMILES: [ClH:1].O[C@@H:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[S:8][CH2:9][C:10]([OH:12])=[O:11].[Cl-].[Na+]>O>[Cl:1][C@@H:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[S:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: Cl
Reactant: O=C(O)CS[C@@H]1CCC[C@H]1O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CS[C@@H]1CCC[C@H]1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Concentrated hydrochloric acid (50 ml) was added to the product of Example 3 (8.4 g) and stirred for 20 hours at room temperature. The reaction mixture was poured into a solution of water (50 ml) containing sodium chloride and extracted three times with 75 ml of diethyl ether. The combined diethyl ether extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to an oil with a rotary evaporator. The product was purified by silica gel chromatography, and the structure was supported by NMR spectroscopy. The NMR spectrum showed a small amount of the cis- product as well.
Reaction SMILES: [OH:1][CH:2]([C:15]1[CH:19]([O:20][CH3:21])[O:18][C:17](=[O:22])[CH:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Br:23]Br.N1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.C(O)(=O)C>[Br:23][C:16]1[C:17](=[O:22])[O:18][CH:19]([O:20][CH3:21])[C:15]=1[CH:2]([OH:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCC(O)C1=CC(=O)OC1OC
Reactant: BrBr
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCC(O)C1=C(Br)C(=O)OC1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.3 g. of 4-(1-hydroxytridecyl)-5-methoxy-2(5H)-furanone and 0.5 ml of carbon tetrachloride is cooled to 0° and 0.55 ml of a 3.1M solution of bromine in carbon tetrachloride is added dropwise over 15 minutes. Two drops of glacial acetic acid are added and the mixture is allowed to warm to room temperature. The reaction is monitored by TLC. After one hour, the mixture is cooled to 0° and 25 ml of pyridine is added over 5 minutes. The mixture is stirred for one hour, filtered to remove pyridine hydrobromide and solvent removed to give a residue which is purified by flash chromatography to give 3-bromo-4-(1-hydroxytridecyl)-5-methoxy-2(5H)-furanone.
Reaction SMILES: C1CCCCC=1.[F:7][C:8]([F:29])([F:28])[CH2:9][CH2:10][CH2:11][CH:12]([NH:17]C(=O)OCC1C=CC=CC=1)[C:13]([OH:16])([CH3:15])[CH3:14].[ClH:30]>[Pd].C(O)C.C(OCC)C>[ClH:30].[NH2:17][CH:12]([CH2:11][CH2:10][CH2:9][C:8]([F:7])([F:28])[F:29])[C:13]([CH3:14])([OH:16])[CH3:15]
Reactant: CC(C)(O)C(CCCC(F)(F)F)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Solvent: C1=CCCCC1
Product: CC(C)(O)C(N)CCCC(F)(F)F

Procedure:
Under argon, 319 mg (0.30 mmol, 10% pure) of palladium on activated carbon and 9.1 ml (90.0 mmol) of cyclohexene were added to 1.0 g (3.0 mmol) of rac-benzyl (7,7,7-trifluoro-2-hydroxy-2-methylheptan-3-yl)carbamate Example 101A in ethanol (21 ml), and the reaction mixture was stirred at reflux overnight. The mixture was filtered through a Millipore® filter and the filter cake was washed with ethanol. 3 ml (6.0 mmol) of 2 N hydrochloric acid in diethyl ether were added to the filtrate and the mixture was concentrated and dried under high vacuum. This gave 785 mg (111% of theory) of the target compound. The product was used without further purification for the next reaction.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][C:13]([N+:21]([O-:23])=[O:22])=[C:12]2[CH:24](C#N)[C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mn]([O-])(=O)(=O)=[O:36].[K+].C(OCC)(=O)C>O.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][C:13]([N+:21]([O-:23])=[O:22])=[C:12]2[C:24]([C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=1)=[O:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COc1cc2ncc([N+](=O)[O-])c(C(C#N)c3ccc(C#N)cc3)c2cc1OCc1ccccc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2ncc([N+](=O)[O-])c(C(=O)c3ccc(C#N)cc3)c2cc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
4-[(6-Benzyloxy-7-methoxy-3-nitroquinolin-4-yl)cyanomethyl]benzonitrile (5.0 g, 11.1 mmol) is suspended in water (250 ml) and heated to the boil. Potassium permanganate (5.26 g, 33.3 mmol) is subsequently added in portions at such a rate that the subsequent addition is only made when the previous one has decoloured (time needed: about 2.5 h). The mixture is then heated under reflux for a further 2 h. After cooling to about 60° C., the mixture is filtered with suction. The aqueous filtrate is discarded, the filter cake is suspended four times in N,N-dimethylformamide (250 ml each time) and filtered off with suction (TLC (HPTLC) product monitoring). The combined DMF solutions are acidified to about pH 4 using 1.0 M hydrochloric acid (colour change) and evaporated to dryness in vacuo, giving an oil. The residue is taken up in tetrahydrofuran (5.0 ml), and ethyl acetate (100 ml) is subsequently added, the mixture is stirred for 30 min, and subsequently cooled in an ice bath. The precipitate obtained is filtered off with suction and dried in a high vacuum, giving 4-(6-benzyloxy-7-methoxy-3-nitroquinoline-4-carbonyl)benzonitrile (3.61 g, 8.22 mmol) as a solid having a melting point of 262° C. MS: 440.1 (M+H+), TLC (HPTLC) (HPTLC): Rf=0.44 (cyclohexane/ethyl acetate 1:1 parts by volume).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][NH2:23])[CH:18]=[CH:19][CH:20]=1.[BH4-].[Na+]>CO.Cl>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:23][CH2:22][CH2:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([F:13])([F:24])[F:25])[CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(CNCCc2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.4 %

Procedure:
A solution of 4-tert-butylbenzaldehyde (0.38 mL, 2.25 mmol) and 2-(3-trifluoromethyl-phenyl)-ethylamine (0.24 mL, 1.50 mmol) in methanol (4.5 mL) was stirred for 30 min at RT and subsequently refluxed for 4 h. After cooling, sodium borohydride (85 mg, 2.25 mmol) was added at RT, then after stirring for 5 min the reaction mixture was refluxed for 4 h. After cooling down to RT, the reaction mixture was treated with 1 M aq. hydrochloric acid solution (4 drops) and concentrated. The residue was dissolved in water/ethyl acetate. After separation of the organic phase, the aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with brine, dried with magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (SiO2; ethyl acetate/heptane 1:2) to afford the title compound (450 mg, 89%). Colorless viscous oil, MS (ISP) 336.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.[H-].[Na+].[CH3:9][O:10][C:11]1[CH:20]=[CH:19][C:14]([C:15](OC)=[O:16])=[C:13]([O:21][CH:22]([CH3:24])[CH3:23])[CH:12]=1.Cl>CS(C)=O.C(O)C>[CH3:9][O:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([NH:1][C:2]2[NH:6][N:5]=[N:4][N:3]=2)=[O:16])=[C:13]([O:21][CH:22]([CH3:24])[CH3:23])[CH:12]=1
Reactant: Nc1nnn[nH]1
Reactant: COC(=O)c1ccc(OC)cc1OC(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCO
Product: COc1ccc(C(=O)Nc2nnn[nH]2)c(OC(C)C)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 3.0 g (35.3 mmol) of anhydrous 5-aminotetrazole in 20 ml of dimethyl sulfoxide is added dropwise to a 15° to 20° C. slurry of 2.8 g (70.0 mmol) of 60% NaH (oil dispersion) in 75 ml of dimethyl sulfoxide under nitrogen atmosphere. The resulting mixture is stirred at 25° C. for 2.5 hours. A solution of 6.50 g (28.98 mmol) of methyl 4-methoxy-2-(1-methylethoxy)benzoate in 25 ml of dimethyl sulfoxide is added dropwise to the reaction and stirred at 25° C. for 18 hours. The reaction is poured onto 600 g of ice-water and the resulting aqueous solution is acidified with aqueous 10% HCl. The product is isolated by vacuum filtration and recrystallization from 95% ethanol gives 1.90 g (8.03 g theoretical, 24%) of the analytically pure 4-methoxy-2-(1-methylethoxy)-N-1H-tetrazol-5-ylbenzamide as fine, white needles having a melting point of 212° -213° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[NH:10][C:11]([NH:13][C:14]([NH:16][CH3:17])=[NH:15])=[NH:12].S(=O)(=O)(O)O.[N+:23]([O-])([OH:25])=[O:24].[OH-].[Na+]>O>[N+:23]([C:7]1[CH:8]=[C:3]([Cl:2])[C:4]([NH:10][C:11]([NH:13][C:14]([NH:16][CH3:17])=[NH:15])=[NH:12])=[C:5]([Cl:9])[CH:6]=1)([O-:25])=[O:24]
Reactant: CNC(=N)NC(=N)Nc1c(Cl)cccc1Cl
Reactant: O=[N+]([O-])O
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CNC(=N)NC(=N)Nc1c(Cl)cc([N+](=O)[O-])cc1Cl
Reaction time: 0.08 h

Procedure:
1-(2,6-Dichlorophenyl)-5-methylbiguanide hydrochloride (14 g) is added to concentrated sulfuric acid (18 ml) and stirred for 5 minutes. Concentrated nitric acid (Sp. G. 1.51) (2.5 ml) is added dropwise, maintaining the temperature between 30° and 40° by water cooling if necessary. After addition of the nitric acid is complete, the mixture is stirred for 10 minutes, then poured into water. The mixture is made alkaline with sodium hydroxide, then extracted with ether. The ether extract is washed, dried (Na2SO4), evaporated and the residue crystallized from aqueous methanol to give 1-(4-nitro-2,6-dichlorophenyl)-5-methylbiguanide.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[NH:4][N:3]=1.[C:14]1([CH2:20][C:21](O)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[NH:4][N:3]=[C:2]([NH:1][C:21](=[O:22])[CH2:20][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:6]=2)=[CH:8][CH:9]=1
Reactant: Nc1cc(-c2ccc(Cl)cc2)[nH]n1
Reactant: O=C(O)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(Cc1ccccc1)Nc1cc(-c2ccc(Cl)cc2)[nH]n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.2 %

Procedure:
3-Amino-5-(4-chlorophenyl)pyrazole (96.8 mg) and phenylacetic acid (74.9 mg) were dissolved in pyridine (2.5 ml) to which was subsequently added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (143.8 mg), and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate (30 ml), washed with 1 N aqueous potassium hydrogensulfate solution (15 ml×2) and saturated brine (15 ml) and then dried over anhydrous magnesium sulfate. The solvent was distilled away under a reduced pressure, and the resulting residue was crystallized from ethyl acetate and hexane to obtain the title compound (107.8 mg) as white crystals (melting point: 222-224° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:6][N:7]1[CH:16]=[C:15]([C:17](O)=[O:18])[C:14]2[N:13]=[C:12]3[C:20]([CH3:24])=[CH:21][CH:22]=[CH:23][C:11]3=[CH:10][C:9]=2[C:8]1=[O:25].[CH:31]1[N:35]=[CH:34][N:33]([C:36](N2C=NC=C2)=O)[CH:32]=1>C(#N)C>[CH3:34][N:33]([CH3:36])[CH2:32][CH2:31][NH:35][C:17]([C:15]1[C:14]2[N:13]=[C:12]3[C:20]([CH3:24])=[CH:21][CH:22]=[CH:23][C:11]3=[CH:10][C:9]=2[C:8](=[O:25])[N:7]([CH2:6][C:5]2[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:16]=1)=[O:18]
Reactant: COc1ccc(Cn2cc(C(=O)O)c3nc4c(C)cccc4cc3c2=O)cc1OC
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: COc1ccc(Cn2cc(C(=O)NCCN(C)C)c3nc4c(C)cccc4cc3c2=O)cc1OC
Yield: 85 %

Procedure:
From acid 18r with a reflux time of 48 h and a recharge with an equal amount of CDI after 24 h, and obtained as a yellow solid (85%), mp 213-214° C. (from acetonitrile). 1H NMR (CDCl3): δ 2.22 [s, 6H, N(CH3)21, 2.52 (t, J=6.4 Hz, 2H, CH2CH2NMe2), 2.63 (s, 3H, ArCH3), 3.62 (q, J=6.1 Hz, 2H, CH2CH2NMe2), 3.75 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 5.09 (s, 2H, CH2Ph), 6.74 (d, J=8.5 Hz, 1H, H-5′), 6.90-6.92 (m, 2H, H-2′, H-6′), 7.27 (t, J=7.6 Hz, 1H, H-8), 7.49 (d, J=6.8 Hz, 1H, H-7), 7.61 (d, J=8.1 Hz, 1H, H-9), 8.55 (s, 1H, H-3), 8.99 (s, 1H, H-10), 10.70 (br t, J=5.3 Hz, 1H, CONH). 13C NMR (CDCl3) δ 18.2 (ArCH3), 37.4 (CH2CH2NMe2), 45.2 (N(CH3)2], 51.9 (CH2Ph), 55.6 (OCH3), 55.7 (OCH3), 58.6 (CH2CH2NMe2), 109.6 (C-4), 111.1 (CH, C-5′), 111.5 (CH, C-6′), 119.1 (C-10a), 120.9 (CH, C-2′), 125.4 (C-9a), 126.2 (CH, C-8), 126.9 (CH, C-9), 128.2 (C-1′), 132.4 (CH, C-7), 135.5 (C-6), 139.5 (CH, C-10), 142.3 (CH, C-3), 147.6 (C-5a), 148.2 (C-4a), 148.9 (C-4′), 149.1 (C-3′), 162.1 (C-1), 164.1 (CONH).