Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1.[CH:36]1(O)[CH2:40][CH2:39][CH2:38][CH:37]1[OH:41]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:30][CH2:31][C:32]2([O:41][C@H:37]3[CH2:38][CH2:39][CH2:40][C@H:36]3[O:35]2)[CH2:33][CH2:34]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Reactant: OC1CCCC1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)O[C@H]2CCC[C@H]2O3)c2ncnn12
Temperature: 110 °C
Reaction time: 16 h
Yield: 135.5 %

Procedure:
A mixture of 4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.75 g), cyclopentane-1,2-diol (0.42 g), p-toluenesulfonic acid monohydrate (0.018 g) and toluene (30 mL) was subjected to an azeotropic dehydration reaction by stirring at 110° C. for 16 hr in a reaction vessel equipped with a Dean-stark trap. The reaction mixture was concentrated, and the obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.2 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.N[C@H](C([NH:19][CH:20]1[C:26](=[O:27])[N:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:24]2[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=2[N:22]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:21]1=[O:44])=O)C>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:19][C@H:20]([C:26]([C:20]2([NH2:19])[C:21](=[O:44])[N:22]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:23]3[CH:37]=[CH:36][CH:35]=[CH:34][C:24]=3[N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:26]2=[O:27])=[O:27])[CH3:21])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](N)C(=O)NC1C(=O)N(c2ccccc2)c2ccccc2N(c2ccccc2)C1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: Cl
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)C1(N)C(=O)N(c2ccccc2)c2ccccc2N(c2ccccc2)C1=O

Procedure:
Following General Procedure I above using 3,5-difluorophenylacetic acid (Lancaster) and 3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-W), the tide compound was prepared as a white solid (melting point=139-141° C.). Purification was by flash chromatography eluting with CH2Cl2/EtOAc (1:1). Rf=0.46 (CH2Cl2/EtOAc, 1:1).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:27]=[CH:28][C:29]([C:31](=[O:38])[CH2:32][CH2:33][C:34]([O:36]C)=[O:35])=[CH:30][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.C(O)(=O)C>C(O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:27]=[CH:28][C:29]([C:31](=[O:38])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:30][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc(C(=O)CCC(=O)OC)ccc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCCCc1nc2cc(C(=O)CCC(=O)O)ccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 200 mg (0.39 mMol) of methyl 4'-[[2-n-butyl-5-(3-methoxycarbonyl-propionyl)-benzimidazol-1-yl]-methyl]biphenyl-2-carboxylate and 0.75 ml of sodium hydroxide solution in 4 ml of ethanol is stirred for 2 hours at 75° C., then mixed with 40 ml of water and acidified with glacial acetic acid. The alcohol is then distilled off, the resulting mixture is stirred for one hour at ambient temperature, the product precipitated is suction filtered, washed with 10 ml of water and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[C:15]([Cl:16])=[CH:14][C:11]([CH2:12]Br)=[CH:10][C:9]=2[Cl:17])=[O:7])=[CH:4][CH:3]=1.[N-:20]=[N+:21]=[N-:22].[K+]>C(O)C>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[C:15]([Cl:16])=[CH:14][C:11]([CH2:12][N:20]=[N+:21]=[N-:22])=[CH:10][C:9]=2[Cl:17])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1c(Cl)cc(CBr)cc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [K+]
Solvent: CCO
Product: [N-]=[N+]=NCc1cc(Cl)c(C(=O)c2ccc(Cl)cc2)c(Cl)c1
Yield: 100.9 %

Procedure:
A suspension of 4-(4-chlorobenzoyl)-3,5-dichlorobenzyl bromide (3.2 g, 8.5 mmol) and potassium azide (1.3 g, 16 mmol) in ethanol (32 ml) was refluxed 5 hours, cooled, and filtered. The precipitate was washed once with ethanol and the combined filtrate and wash were evaporated under vacuum. The residue was triturated with diethyl ether (50 ml) and filtered. The filtrate was evaporated under vacuum to provide 2.92 g (100%) of 4-(4-chlorobenzoyl)-3,5-dichlorobenzyl azide, m.p. 50°-55° C.
Reaction SMILES: F.F.F.C(N(CC)CC)C.C(N(CC)CC)C.[Si]([O:35][CH2:36][C@H:37]1[O:41][C@@H:40]([N:42]2[CH:49]=[C:48]([CH3:50])[C:46](=[O:47])[NH:45][C:43]2=[O:44])[C@H:39]([O:51][CH2:52][CH2:53][O:54][N:55]([CH3:57])[CH3:56])[C@@H:38]1[OH:58])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CO>C1COCC1>[CH3:56][N:55]([CH3:57])[O:54][CH2:53][CH2:52][O:51][C@@H:39]1[C@H:38]([OH:58])[C@@H:37]([CH2:36][OH:35])[O:41][C@H:40]1[N:42]1[CH:49]=[C:48]([CH3:50])[C:46](=[O:47])[NH:45][C:43]1=[O:44]
Reactant: Cc1cn([C@@H]2O[C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@@H](O)[C@H]2OCCON(C)C)c(=O)[nH]c1=O
Agent: F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OCCON(C)C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.4 %

Procedure:
Triethylamine trihydrofluoride (3.91 mL, 24.0 mmol) was dissolved in dry THF and triethylamine (1.67 mL, 12 mmol, dry, kept over KOH). This mixture of triethylamine-2HF was then added to 5'-O-tert-butyldiphenylsilyl-2'-O-[N,N-dimethylaminooxyethyl]-5-methyluridine (1.40 g, 2.4 mmol) and stirred at room temperature for 24 hrs. Reaction was monitored by TLC (5% MeOH in CH2CO2) Solvent was removed under vacuum and the residue placed on a flash column and eluted with 10% MeOH in CH2Cl2 to get 2'-O-(dimethylaminooxyethyl)-5-methyluridine (766 mg, 92.5%).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[Cl:7][C:8]1[S:12][C:11]([S:13](Cl)(=[O:15])=[O:14])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18].C(N(CC)CC)C.O>O1CCOCC1>[OH:4][CH2:3][C:2]([NH:1][S:13]([C:11]1[S:12][C:8]([Cl:7])=[C:9]([N+:17]([O-:19])=[O:18])[CH:10]=1)(=[O:15])=[O:14])([CH3:6])[CH3:5]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)sc1Cl
Reactant: CC(C)(N)CO
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(CO)NS(=O)(=O)c1cc([N+](=O)[O-])c(Cl)s1
Temperature: 25 °C
Reaction time: 17 h
Yield: 30.4 %

Procedure:
To a stirred solution of 2-amino-2-methyl-1-propanol (0.75 g, 8.39 mmol) in dioxane (21 ml) was added at room temperature 5-chloro-4-nitrothiophene-2-sulfonyl chloride (2.0 g, 7.63 mmol) and triethylamine (1.17 ml, 8.39 mmol). The light yellow suspension was stirred at room temperature for 17 h, poured into water (100 ml) and extracted with dichloromethane (3×75 ml). The combined organic layers were washed with water (100 ml) and brine (70 ml), dried (MgSO4) and evaporated. The crude product was further purified by column chromatography on silica gel (heptane/ethyl acetate 1:1) and subsequent crystallization from ethyl acetate/hexane to yield 5-chloro-4-nitro-thiophene-2-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (0.73 g, 30%) as a light brown solid. MS (ISP) 313.1 [(M−H)−], mp 136° C.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:19]2[C:14]([CH:15]=[N:16][C:17]([NH:20][C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=3)=[N:18]2)=[C:13]([CH3:33])[N:12]=1)(=O)C.C1COCC1.O.[Li+].[OH-].Cl>O.CCOC(C)=O>[CH3:33][C:13]1[N:12]=[C:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[OH:4])[N:19]2[C:14]=1[CH:15]=[N:16][C:17]([NH:20][C:21]1[CH:22]=[C:23]([O:31][CH3:32])[C:24]([O:29][CH3:30])=[C:25]([O:27][CH3:28])[CH:26]=1)=[N:18]2
Reactant: COc1cc(Nc2ncc3c(C)nc(-c4ccccc4OC(C)=O)n3n2)cc(OC)c1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(Nc2ncc3c(C)nc(-c4ccccc4O)n3n2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
To a solution of 2-{5-methyl-2-[(3,4,5-trimethoxyphenyl)amino]imidazo[5,1-f][1,2,4]triazin-7-yl}phenyl acetate (Example 23 below) (26 mg, 0.058 mmol) in 5:1 THF/H2O (4 mL) was added LiOH (30 mg, 1.25 mmol). The reaction was stirred at room temperature for 3 hours then poured into EtOAc (100 mL) and water (20 mL) with aqueous 1 N HCl (2 mL). The aqueous layer was extracted with EtOAc and the combined organic layers then washed with brine, dried over MgSO4, concentrated and purified by silica gel chromatography, eluting with 1% MeOH/DCM to give 2-{5-methyl-2-[(3,4,5-trimethoxyphenyl)amino]-imidazo[5,1-f][1,2,4]triazin-7-yl}phenol (13 mg, (56%)) as a yellow solid. 1H NMR (CDCl3): δ12.73 (s, 1H), 8.94 (dd J=7.87, 1.46 Hz, 1H), 8.86 (s, 1H), 7.31 (m, 1H), 7.09 (d, J=8.06 Hz, 1H), 6.86-6.96 (m, 4H), 3.90 (s, 6H), 3.88 (s, 3H), 2.61 (s, 3H). MS m/z 407 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.NC(N)=[S:14].[OH-].[K+].[OH-].[Na+]>O.C(O)C>[SH:14][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1
Reactant: FC(F)(F)c1ccnc(Cl)c1
Reactant: NC(N)=S
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: FC(F)(F)c1ccnc(S)c1
Yield: 51 %

Procedure:
To 1.0 g of 2-chloro-4-trifluoromethylpyridine (Lancaster Chemical Co) is added 10 ml of absolute ethanol and 417 mg of thiourea. The reaction mixture is heated at reflux for 4 hours and 1.25 ml of a solution of 7.44 g KOH in 20 ml of water is added. The solution is heated at reflux for an additional 1 hour. The reaction solution is cooled and poured into 100 ml of a 0.1N NaOH solution. The resulting solution is extracted three times with 100 ml of methylene chloride and the resulting aqueous solution is acidified to pH 4 by addition of glacial acetic acid. The aqueous solution is extracted three times with 100 ml of methylene chloride and the organic solution is dried over anhydrous sodium sulfate. Filtration followed by evaporation to dryness gives 501 mg of a yellow crystalline solid.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20](O)(=[O:30])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH2:29]>C(OCC)(=O)C.CCCCCC>[C:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:30])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH2:29]
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Reactant: C=CCCCCCCCC(=O)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C=CCCCCCCCC(=O)OCCCCCCCCC=CCCCCCCCC
Yield: 96 %

Procedure:
Compound E was prepared from Oleyl alcohol and 9-decenoic acid following the general procedure previously discussed and shown in FIG. 10. Pure compound E was a colorless oil obtained by column chromatography with Ethyl acetate/Hexane=1:40.
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[CH:15][N:16]=2)[CH:13]=1)[C:5](=O)[CH3:6].[C:18]([CH2:20][C:21]([NH2:23])=[O:22])#[N:19].C[O-].[Na+]>CN(C)C=O>[CH3:6][C:5]1[NH:23][C:21](=[O:22])[C:20]([C:18]#[N:19])=[CH:3][C:4]=1[C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[CH:15][N:16]=2)[CH:13]=1
Reactant: N#CCC(N)=O
Reactant: CC(=O)C(=CN(C)C)c1ccc2nccn2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1[nH]c(=O)c(C#N)cc1-c1ccc2nccn2c1
Yield: 50.7 %

Procedure:
In 230 ml of N,N-dimethylformamide was dissolved 23.5 g of 4-dimethylamino-3-(imidazo[1,2-a]pyridin-6-yl)-3-buten-2-one. The solution was stirred at 80° to 90° C. for 12 hours, together with 9.48 g of α-cyanoacetamide and 12.2 g of sodium methoxide. After cooling, the solvent was removed by distillation under reduced pressure and 500 ml of water was added to the residue to dissolve it. The solution was washed with 600 ml of chloroform. Next, about 5 ml of acetic acid was added to the aqueous layer to adjust pH to 6.5. Crystals precipitated upon cooling were taken by filtration. After the crystals were washed with water, acetonitrile and then ether, they were dissolved in 200 ml of a 2.5% aqueous sodium hydroxide solution. The solution was treated with activated charcoal. The filtrate was again adjusted to pH of 6.5 with about 7 ml of acetic acid. Crystals precipitated upon cooling were taken by filtration. After the crystals were washed with water, acetonitrile and the ether, they were recrystallized from 100 ml of N,N-dimethylformamide to obtain 13 g of 1,2-dihydro-6-methyl-2-oxo-5-(imidazo[1,2-a]pyridin-6-yl)-3-pyridinecarbonitrile.
Reaction SMILES: ClC(OCC)=O.[O:7]1[C:11]([C:12](O)=O)=[CH:10][CH:9]=[N:8]1.C(N(CC)CC)C.[NH2:22][C:23]1[C:31]([NH2:32])=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([NH2:27])=[O:26]>O1CCCC1>[O:7]1[C:11]([C:12]2[NH:22][C:23]3[C:24]([C:25]([NH2:27])=[O:26])=[CH:28][CH:29]=[CH:30][C:31]=3[N:32]=2)=[CH:10][CH:9]=[N:8]1
Reactant: O=C(O)c1ccno1
Reactant: NC(=O)c1cccc(N)c1N
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NC(=O)c1cccc2nc(-c3ccno3)[nH]c12
Temperature: -10 °C
Reaction time: 1 h
Yield: 7 %

Procedure:
A solution of 0.81 g (7.5 mmol) of ethyl chloroformate in 5 ml of tetrahydrofuran was added dropwise to a solution of 0.85 g (7.5 mmol) of isoxazole-5-carboxylic acid and 3.79 g (37.5 mmol) of triethylamine in 50 ml of tetrahydrofuran at −10° C. After stirring at −10° C. for 1 hour, 1.68 g (7.5 mmol) of 2,3-diaminobenzamide were added. The reaction mixture was stirred at room temp. for 16 hours. The reaction mixture was then concentrated in vacuo. The residue was partitioned between methylene chloride and saturated sodium bicarbonate solution. The aqueous phase was extracted with methylene chloride. The combined organic phases were dried over magnesium sulfate. The residue obtained after concentration in vacuo was taken up in 10 ml of glacial acetic acid and stirred at 100° C. for 60 minutes. The reaction mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfate and concentrated in vacuo. The residue was taken up in isopropanol, and the precipitate produced with petroleum ether was filtered off, washed with petroleum ether and dried in vacuo at 35° C. 120 mg of yellow crystals were obtained.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([OH:10])=[CH:4][CH:3]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH2:11]([O:10][C:5]1[C:6]([C:8]#[N:9])=[N:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#Cc1nc(Br)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: N#Cc1nc(Br)ccc1OCc1ccccc1

Procedure:
6-Bromo-3-hydroxypyridine-2-carbonitrile (53.8 g) obtained in Reference Example 72(1) is dissolved in acetone (550 ml), and thereto are added benzyl bromide (35.6 ml) and potassium carbonate (43.1 g). The mixture is then heated under reflux for 4 hours. After allowing to cool, water (600 ml) is added to the reaction solution, and the mixture is extracted with ethyl acetate. The aqueous layer is extracted with ethyl acetate once, and combined with the previous organic layer. The solution is washed with saturated brine and dried over sodium sulfate. The solvent is removed by evaporation under reduced pressure and the residue is purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/1, followed by 3/1). The resulting residue is suspended in diethyl ether/n-hexane and the solid is collected by filtration to give the title compound (24.1 g).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH3:7][O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=2)[CH:10]=1>F>[C:4]([C:10]1[C:11]2[C:16](=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[O:8][CH3:7])(=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: C=C1CC(=O)O1
Reactant: COc1ccc2cc(OC)ccc2c1
Agent: F
Product: COc1ccc2c(C(=O)CC(C)=O)c(OC)ccc2c1
Reaction time: 8 h

Procedure:
33.6 g (0.4 mol) of diketene were added drop by drop, while stirring at -30°C, to 37.6 g (0.2 mol) of 2,6-dimethoxynaphthalene in 200 ml of anhydrous hydrofluoric acid and the mixture was stirred for another 8 hours at said temperature. The hydrogen fluoride was distilled off under reduced pressure at a temperature of the still of -30°C and the residue washed until it was free from acid. After sublimation of unreacted starting product (11 g = 71 % conversion) colorless crystals of 1-acetoacetyl-2,6-dimethoxynaphthalene melting at 88°C were obtained by column chromatography (silica gel, 0.065 - 0.2 mm, CH2Cl2) in an amount of 35 g (90 % calculated on 2,6-dimethoxynaphthalene).
Reaction SMILES: [F:1][C:2]([C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)=[N:6]O)([F:4])[F:3].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OC(C)C)(C)C>[F:15][C:14]([F:16])([F:17])[C:10]1[CH:9]=[C:8]([CH:5]([NH2:6])[C:2]([F:1])([F:3])[F:4])[CH:13]=[CH:12][CH:11]=1
Reactant: ON=C(c1cccc(C(F)(F)F)c1)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CC(C)OC(C)C
Product: NC(c1cccc(C(F)(F)F)c1)C(F)(F)F

Procedure:
2.5 g (3-trifluoromethyl phenyl) trifluoromethyl Ketoxime are suspended in 40 ml isopropyl ether and to this suspension 4 g lithium aluminum hydride are added. The mixture is heated to reflux for 3 hours then cooled. The excess of reagent is destroyed by cautious addition of an aqueous solution of tartaric acid. The mixture is made basic by adding sodium hydroxide and the ethereal phase is separated. The aqueous phase is further extracted with isopropyl ether; the organic solutions are united, washed with water, dried and evaporated off under reduced pressure.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].Cl.[NH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C>CO.C(=O)([O-])O.[Na+]>[N+:11]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])([O-:13])=[O:12]
Reactant: CCOC(=O)CCCN
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOC(=O)CCCNc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 120 h
Yield: 100 %

Procedure:
A mixture of 2-chloro-1,3-dinitrobenzene (30.0 g, 0.148 mol), ethyl 4-aminobutyrate hydrochloride (74.5 g, 0.444 mol), triethylamine (165 mL) in methanol (600 mL) was stirred at room temperature for 5 days. The mixture was diluted with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, washed with 1N hydrochloric acid, dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a brown oil (44.0 g, 0.148 mol, 100%).
Reaction SMILES: [Na].CO.Cl.[NH2:5][C:6]([NH2:8])=[NH:7].Cl.[Cl:10][C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH3:22])[CH:20]=2)[N:15]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][N:24]=2)[CH:14]=1)=[O:12]>COCCOC>[ClH:10].[NH:7]([C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH3:22])[CH:20]=2)[N:15]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][N:24]=2)[CH:14]=1)=[O:12])[C:6]([NH2:8])=[NH:5]
Reactant: N=C(N)N
Reactant: Cc1ccc2c(c1)c(C(=O)Cl)cn2-c1nccc2ccccc12
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: COCCOC
Product: Cc1ccc2c(c1)c(C(=O)NC(=N)N)cn2-c1nccc2ccccc12
Temperature: 20 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
0.457 g (19.8 mmol) of sodium is added at 20° C. under an argon atmosphere to 60 cm3 of methanol. After complete dissolution, 1.79 g (18.75 mmol) of guanidine hydrochloride are added. After stirring at 20° C. for 2 hours, the reaction mixture is filtered under an argon atmosphere. The filtrate is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is dissolved in 20 cm3 of 1,2-dimethoxyethane. 1.2 g of 3-chlorocarbonyl-1-(isoquinol-1-yl)-5-methyl-1H-indole hydrochloride, suspended in 40 cm3 of 1,2-dimethoxyethane, are subsequently added at 20° C. under an argon atmosphere. After stirring at 20° C. for 17.5 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is triturated in 20 cm3 of water. After stirring at 22° C. for 1 hour, the suspension is filtered and then dried to give a beige-coloured solid which is purified by flash chromatography [eluent: cyclohexane/ethyl acetate (7/3 by volume) and then dichloromethane/methanol/20% aqueous ammonia (18/3/0.5 by volume)]. After concentrating the fractions under reduced pressure, 1.2 g of a beige-coloured solid are obtained, which solid is triturated in 12 cm3 of N hydrochloric acid for 1 hour. After filtering off, the residue is recrystallised under hot conditions from 80 cm3 of methanol to give 0.885 g of 3-guanidinocarbonyl-1-(isoquinol-1-yl)-5-methyl-1H-indole hydrochloride in the form of beige-coloured crystals melting at 268° C. IR spectrum (KBr): 3350, 3092, 1693, 1625, 1524, 1462, 1406, 1216 and 832 cm−1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH:9]=[CH:10][CH2:11][NH2:12])([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH2:22][CH2:23][CH2:24][CH2:25][C:26](O)=[O:27])=[CH:17][CH:16]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH:9]=[CH:10][CH2:11][NH:12][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]([C:29]1[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=1)[C:18]1[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC=CCN
Reactant: O=C(O)CCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCC=CCNC(=O)CCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of (4-amino-but-2-enyl)-carbamic acid tert-butyl ester (1.0 g, 5.36 mmol) in dry CH2Cl2 (40 ml) was added 6,6-bis-(4-fluorophenyl)-hexanoic acid (1.62 g, 5.36 mmol) under nitrogen. To the reaction was added EDC (2.04 g, 10.72 mmol) and DMAP (cat) and the reaction mixture stirred under nitrogen at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue dissolved in ethyl acetate:water (10:1) (150 ml). The organic was washed with water (30 ml, 2×) and 10% NaOH (30 ml) and dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using CH2Cl2:CH3OH (15:1) to give the desired product in 70% yield.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[C:5]2[O:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[C:4]=2[N:3]=1.[Cl:22]C1C=C2C(C3OC4C=CC=CC=4C=3N=C2O)=CC=1>>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6]([C:5]3[O:13][C:14]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=4[C:4]=3[N:3]=[C:2]2[Cl:22])=[CH:7][CH:8]=1
Reactant: COc1ccc2oc3c4ccc(Cl)cc4c(O)nc3c2c1
Reactant: Oc1nc2c3ccccc3oc2c2ccc(Cl)cc12
Product: COc1ccc2oc3c4ccc(Cl)cc4c(Cl)nc3c2c1

Procedure:
The procedure was similar to step S19C, while the starting material was 26B in stead of 19B.