Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C=C([C:10]2=[C:11]([CH:37]=[CH:38][C:39]3[C:47]([CH3:49])([CH3:48])[C:46]4[C:41](=[CH:42][CH:43]=[C:44]([S:50]([O-:53])(=[O:52])=[O:51])[CH:45]=4)[N+:40]=3[CH2:54][CH2:55][CH2:56][CH2:57][S:58]([O-:61])(=[O:60])=[O:59])[CH2:12][CH2:13]/[C:14]/2=[CH:15]\[CH:16]=[C:17]2/[C:18]([CH3:36])([CH3:35])[C:19]3[C:20](=[N:34]/2)[N:21]([CH2:26][CH2:27][CH2:28][CH2:29][S:30]([O-:33])(=[O:32])=[O:31])[CH:22]=[C:23]([Cl:25])[CH:24]=3)C=CC=1)(O)=O.[Na+:62].[Na+].B([C:67]1[CH:68]=[C:69]([CH2:73][CH2:74][CH2:75][C:76]([OH:78])=[O:77])[CH:70]=[CH:71][CH:72]=1)(O)O>>[C:76]([CH2:75][CH2:74][CH2:73][C:69]1[CH:68]=[C:67]([C:10]2=[C:11]([CH:37]=[CH:38][C:39]3[C:47]([CH3:49])([CH3:48])[C:46]4[C:41](=[CH:42][CH:43]=[C:44]([S:50]([O-:53])(=[O:52])=[O:51])[CH:45]=4)[N+:40]=3[CH2:54][CH2:55][CH2:56][CH2:57][S:58]([O-:61])(=[O:60])=[O:59])[CH2:12][CH2:13]/[C:14]/2=[CH:15]\[CH:16]=[C:17]2/[C:18]([CH3:35])([CH3:36])[C:19]3[C:20](=[N:34]/2)[N:21]([CH2:26][CH2:27][CH2:28][CH2:29][S:30]([O-:33])(=[O:32])=[O:31])[CH:22]=[C:23]([Cl:25])[CH:24]=3)[CH:72]=[CH:71][CH:70]=1)([OH:78])=[O:77].[Na+:62].[Na+:62]
Reactant: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C1\CCC(C=CC2=[N+](CCCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)=C1c1cccc(C(=O)O)c1
Reactant: O=C(O)CCCc1cccc(B(O)O)c1
Agent: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C1\CCC(/C=C/C2=[N+](CCCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)=C1c1cccc(C(=O)O)c1
Agent: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C1\CCC(/C=C/C2=[N+](CCCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)=C1c1cccc(CCCC(=O)O)c1
Agent: [Na+]
Product: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C1\CCC(C=CC2=[N+](CCCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)=C1c1cccc(CCCC(=O)O)c1

Procedure:
Compound 41 is prepared analogously to compound 40 (Example 51), except with 4-(3-boronophenyl)butanoic acid as a starting material.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[CH:10]=[O:11].O>CO>[F:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[CH2:10][OH:11]
Reactant: O=Cc1ccncc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1ccncc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of sodium borohydride (454 mg, 12.0 mmol) in anhydrous methanol (15 mL) was added a solution of 3-fluoropyridine-4-carbaldehyde (1.0 g, 8.0 mmol) in anhydrous methanol (5 mL) at 0° C. The mixture was stirred overnight at room temperature. Water was added and extracted 3 times with ethyl acetate. The combined organic phase was washed with brine and dried over sodium sulfate. After evaporation of the solvent, (3-fluoropyridin-4-yl)methanol was obtained and used in the next step without purification; 1H NMR (400 MHz, CDCl3): δ 2.25 (bs, 1H), 4.85 (d, J=5.7 Hz, 2H), 7.50 (t, J=5.2 Hz, 1H) 8.38-8.43 (m, 2H).
Reaction SMILES: [F-].[K+].[F:3][C:4]([P:10](=[O:25])(C(F)(F)C(F)(F)F)[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])([F:9])[C:5]([F:8])([F:7])[F:6].[CH2:26]([OH:29])[C:27]#[CH:28]>>[P:10]([O:29][CH2:26][C:27]#[CH:28])([C:4]([C:5]([F:6])([F:7])[F:8])([F:3])[F:9])([C:11]([C:12]([F:15])([F:14])[F:13])([F:17])[F:16])=[O:25]
Reactant: C#CCO
Reactant: O=P(C(F)(F)C(F)(F)F)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Agent: [F-]
Agent: [K+]
Product: C#CCOP(=O)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 19.5 h

Procedure:
Potassium fluoride (0.262 g; 4.5 mmol) is suspended in cooled (0° C.) tris(pentafluoroethyl)phosphine oxide (14.930 g; 37.0 mmol) in a 100 ml glass flask, and propargyl alcohol (2.055 g; 36.7 mmol) is added. The yellow reaction solution is slowly warmed (about 6 h) and stirred at room temperature for 19.5 h. Volatile components are removed in vacuo (10−3 mbar) at 0° C. After recondensation in vacuo (10−3 mbar) at room temperature, propargyl bis(pentafluoroethyl)phosphinate, (C2F5)2P(O)OCH2C≡CH, is isolated as clear and colourless liquid (7.831 g; 23.0 mmol) in a yield of 63% and a purity of 95%. The ester becomes a brown colour after a few minutes at room temperature and is therefore stored at 3° C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[CH3:11][O:12][N:13]=[C:14]([C:20]1[N:21]=[C:22]([NH2:25])[S:23][CH:24]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>O>[CH3:11][O:12][N:13]=[C:14]([C:20]1[N:21]=[C:22]([NH:25][CH:1]=[O:3])[S:23][CH:24]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C(=NOC)c1csc(N)n1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: O=CO
Product: CCOC(=O)C(=NOC)c1csc(NC=O)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
A mixture of acetic anhydride (6.1 g) and formic acid (2.8 g) was stirred for 2 hours at 50° C. The resulting mixture was cooled and ethyl 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate (syn isomer) (4.6 g) was added thereto at 15° C. After the mixture was stirred for 3.5 hours at ambient temperature, cooled water (100 ml) was added thereto. The resulting mixture was extracted with ethyl acetate (200 ml). The extract was washed with water and then with a saturated aqueous solution of sodium bicarbonate until the washing was changed to weakly alkaline solution. The extract was further washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off and the residue was washed with diisopropyl ether, collected by filtration and dried to give ethyl 2-methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetate (syn isomer) (4.22 g), mp 122° to 124° C. (dec.).
Reaction SMILES: Cl.[F:2][C:3]1[CH:24]=[CH:23][C:6]([O:7][C:8]2[CH:9]=[C:10]([NH:14][C:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[O:16])[CH:11]=[CH:12][CH:13]=2)=[CH:5][CH:4]=1.Cl[C:26]1[C:27]2[C:34]([CH3:35])=[CH:33][NH:32][C:28]=2[N:29]=[CH:30][N:31]=1.C(N(CC)CC)C>C(O)(C)C>[F:2][C:3]1[CH:24]=[CH:23][C:6]([O:7][C:8]2[CH:9]=[C:10]([NH:14][C:15]([CH:17]3[CH2:18][CH2:19][N:20]([C:26]4[C:27]5[C:34]([CH3:35])=[CH:33][NH:32][C:28]=5[N:29]=[CH:30][N:31]=4)[CH2:21][CH2:22]3)=[O:16])[CH:11]=[CH:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: O=C(Nc1cccc(Oc2ccc(F)cc2)c1)C1CCNCC1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cc1c[nH]c2ncnc(N3CCC(C(=O)Nc4cccc(Oc5ccc(F)cc5)c4)CC3)c12
Temperature: 190 °C
Yield: 68.8 %

Procedure:
A mixture of piperidine-4-carboxylic acid [3-(4-fluoro-phenoxy)-phenyl]-amide hydrochloride (2.51 g, 7.16 mmol) and 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (1.00 g, 5.97 mmol) in iso-propanol (15 mL) was placed in a microwave vessel, followed by addition of triethylamine (2.5 mL, 18 mmol). The microwave vessel was sealed then heated in the microwave at normal absorbance at 190° C. for 60 min. The mixture was concentrated to remove most of the iso-propanol and triethylamine. The residue was washed with methanol (2×15 mL) to afford a brown solid. The solid was washed with water (3×30 mL) and dried overnight to afford 1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidine-4-carboxylic acid [3-(4-fluoro-phenoxy)-phenyl]-amide (1.83 g, 69%) as a light-brown solid ((M+H)+: 446.3).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[NH:12][C:13]([C:15]1[C:16](=[O:27])[NH:17][N:18]=[C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH:20]=1)=O.O1CCCC1.[OH-].[Li+].Cl>O.CO>[O:27]=[C:16]1[C:15]([C:13]2[NH:1][C:2]3[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=3[N:12]=2)=[CH:20][C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[N:18][NH:17]1
Reactant: COC(=O)c1ccc(N)c(NC(=O)c2cc(-c3ccncc3)n[nH]c2=O)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2[nH]c(-c3cc(-c4ccncc4)n[nH]c3=O)nc2c1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A mixture consisting of 500 mg of methyl 4-amino-3-[(3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carbonyl)amino]benzoate, 6 ml of tetrahydrofuran (THF), 6 ml of methanol, 6 ml of water and 173 mg of lithium hydroxide is stirred at 50° C. for 5 hours. After cooling to room temperature, the pH is adjusted to 4-5 with 1N HCl, whereupon a precipitate separates out and is filtered off with suction and then washed with water and dried in vacuo.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][CH:7]([N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][CH2:5]1.[Si:19]([O:26][CH2:27][CH2:28][C@H:29]1[CH2:40][CH2:39][C:38]2[S:37][C:36]3[N:35]=[CH:34][N:33]=[C:32](Cl)[C:31]=3[C:30]1=2)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>C1COCC1>[Si:19]([O:26][CH2:27][CH2:28][C@H:29]1[CH2:40][CH2:39][C:38]2[S:37][C:36]3[N:35]=[CH:34][N:33]=[C:32]([O:3][CH:4]4[CH2:9][CH2:8][CH:7]([N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16])[CH2:6][CH2:5]4)[C:31]=3[C:30]1=2)([C:22]([CH3:25])([CH3:23])[CH3:24])([CH3:21])[CH3:20]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(O)CC1
Reactant: CC(C)(C)[Si](C)(C)OCC[C@H]1CCc2sc3ncnc(Cl)c3c21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CCO[Si](C)(C)C(C)(C)C)CC4)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 58.4 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.9 g, 22.5 mmol, 4.60 equiv) was treated with tert-butyl N-(4-hydroxycyclohexyl)-N-methylcarbamate (1.8 g, 7.85 mmol, 1.6 equiv) in distilled THF (50 mL) at 0° C. for 1 h under nitrogen. Then a solution of 25.1 (1.8 g, 4.88 mmol, 1.00 equiv) in 15 mL of THF was added to the reaction mixture and the latter was stirred for 2 h at 60° C. The reaction was then quenched by the addition of 20 mL of water at 0° C. and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column with ethyl acetate/petroleum ether (1:5) and purified to afford tert-butyl N-(4-[[(3R)-3-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2 (6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (34.1, 1.6 g, 58%) as a yellow oil.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][CH2:7][C:8]([OH:10])=O.[CH3:11][NH:12][C:13](=[O:31])[CH2:14][NH:15][C:16](=[O:30])[C:17]1[C:22]([I:23])=[C:21]([NH2:24])[C:20]([I:25])=[C:19]([C:26]([OH:28])=[O:27])[C:18]=1[I:29].CNC(=O)[C@H](CC1C=CC=CC=1)NC(=O)C1C(I)=C(N)C(I)=C(C(O)=O)C=1I>CC(N(C)C)=O>[CH3:11][NH:12][C:13](=[O:31])[CH2:14][NH:15][C:16](=[O:30])[C:17]1[C:22]([I:23])=[C:21]([NH:24][C:8](=[O:10])[CH2:7][O:6][CH3:5])[C:20]([I:25])=[C:19]([C:26]([OH:28])=[O:27])[C:18]=1[I:29]
Reactant: COCC(=O)O
Reactant: CNC(=O)CNC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Agent: CNC(=O)[C@H](Cc1ccccc1)NC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: CNC(=O)CNC(=O)c1c(I)c(NC(=O)COC)c(I)c(C(=O)O)c1I
Temperature: 0 °C
Reaction time: 2 h

Procedure:
At maximally 10° C., 29.0 ml. of thionyl chloride is added dropwise under agitation to 28.2 ml. of methoxyacetic acid in 100 ml. of dimethylacetamide within 40 minutes. After, at 0° C., the reaction mixture has been agitated for another 2 hours, 63.0 g. (0.1 mole) of N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-glycine methylamide (IV a), m.p. 252°-253° C. (decomposition), in 100 ml. of dimethylacetamide is added dropwise under agitation to the reaction mixture at maximally 8° C. during the course of one hour. Then, the solution is agitated overnight. After the addition of 5 ml. of water, the mixture is concentrated under vacuum, the residue is stirred with 700 ml. of water, the precipitate is vacuum-filtered, carefully washed with water, and, while still moist, reprecipitated from dilute ammonia with concentrated hydrochloric acid. After allowing the mixture to stand for some time, the acid is vacuum-filtered, washed well with water, stirred with fresh water, and, after another filtering step, dried under vacuum at 70° C.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([N:8]([CH2:10][CH2:11]CC)[CH3:9])=[O:7])=[C:4]([S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])[CH:3]=1.BrC1C=CC([C:27](O)=[O:28])=C(S(C(C)C)(=O)=O)C=1.N1CCOCC1>>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([N:8]2[CH2:9][CH2:27][O:28][CH2:11][CH2:10]2)=[O:7])=[C:4]([S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])[CH:3]=1
Reactant: CCCCN(C)C(=O)c1ccc(Br)cc1S(=O)(=O)C(C)C
Reactant: CC(C)S(=O)(=O)c1cc(Br)ccc1C(=O)O
Solvent: C1COCCN1
Product: CC(C)S(=O)(=O)c1cc(Br)ccc1C(=O)N1CCOCC1

Procedure:
Following the general method as outlined in Intermediate 253, starting from 4-bromo-2-(isopropylsulfonyl)benzoic acid (Intermediate 242) and morpholine, the title compound was obtained as a pink solid.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([OH:22])[CH:16]=1.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][O-:27].[Na+]>O1CCCC1.O>[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][O:27][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([OH:22])[CH:16]=1
Reactant: Cc1ccc(Nc2c(C#N)cnc3cnc(F)cc23)cc1O
Reactant: CN(C)CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(Nc2c(C#N)cnc3cnc(OCCN(C)C)cc23)cc1O

Procedure:
To 160 mg of 6-fluoro-4-(3-hydroxy-4-methyl-phenylamino)-[1.7]naphthyridine-3-carbonitrile under an inert atmosphere was added 3 mL of 1 M sodium (2-dimethylamino-ethoxide) in tetrahydrofuran. After refluxing for 3 hours, the reaction was diluted with water and the product extracted five times with chloroform. The crude product was purified by flash chromatography with 1% triethyl amine and 10% methanol/chloroform followed by recrystallized from chloroform/ether to give 106 mg of 6-(2-dimethylamino-ethoxy)-4-(3-hydroxy-4-methyl-phenylamino)-[1.7]naphthyridine-3-carbonitrile as a yellowish solid: melting point 100-180° C. (decomposed, effervescence); mass spectrum (m/e): M+H 419.9.
Reaction SMILES: [O:1]([CH2:9][CH2:10][C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Cl)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].CC(C)=O.[I-:23].[Na+]>>[O:1]([CH2:9][CH2:10][C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][I:23])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: [I-]
Reactant: CC(C)(C)[Si](C)(C)OCCC#CCCCCCCl
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCC#CCCCCCI
Yield: 96 %

Procedure:
To 7.9 g (27 mmol) of 17 was added 100 mL of acetone containing 8.2 g (55 mmol) of sodium iodide. The resultant solution was refluxed for 65 hr and then concentrated in vacuo, diluted with water (150 mL) and extracted with ether (3×75 mL). The ether extract was washed with aqueous sodium thiosulfate (2×75 mL) and brine (2×75 mL). Distillation (Vigreux) gave 10.0 g (96% yield) of 18.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=S)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1.[CH3:20][O:21][CH:22]([O:26][CH3:27])[CH:23]([NH2:25])[CH3:24]>C(O)CCC>[CH3:20][O:21][CH:22]([O:26][CH3:27])[CH:23]([NH:25][C:10]1[CH2:9][N:8]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:6]2[CH:19]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:11]=1)[CH3:24]
Reactant: S=C1CN=C(c2ccccn2)c2cc(Cl)ccc2N1
Reactant: COC(OC)C(C)N
Solvent: CCCCO
Product: COC(OC)C(C)NC1=Nc2ccc(Cl)cc2C(c2ccccn2)=NC1

Procedure:
A solution of 7-chloro-1,3-dihydro-5-(2-pyridyl)-1,4-benzodiazepin-2-thione in butanol solution is refluxed with excess α-aminopropionaldehyde dimethyl acetal. After cooling excess butanol is removed by vacuum distillation and the residue is crystallized from ethyl acetate-hexane to give 2-[[7-chloro-5-(2-pyridyl)-3H-1,4-benzodiazepin-2-yl]amino]propionaldehyde dimethyl acetal.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:17]([NH2:19])=[O:18])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.[C:20]1([CH3:29])[CH:25]=[CH:24][CH:23]=[C:22]([C:26](O)=[O:27])[CH:21]=1>ClCCCl.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH3:29][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[C:26]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:17]([NH2:19])=[O:18])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1)=[O:27]
Reactant: NC(=O)n1c(-c2ccc(N)cc2)cc2ccccc21
Reactant: Cc1cccc(C(=O)O)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: Cc1cccc(C(=O)Nc2ccc(-c3cc4ccccc4n3C(N)=O)cc2)c1
Temperature: 60 °C

Procedure:
To the solution of 2-(4-amino-phenyl)-indole-1-carboxylic acid amide (125.5 mg, 0.5 mmol, 1 eq) and m-toluic acid (68.8 mg, 0.5 mmol, 1 eq) in anhydrous DCE (4 mL) was added DMAP (12.2 mg, 0.2 eq) and EDC (115.2 mg, 1.2 eq). The reaction mixture was heated at 60° C. for 1.5 hours. It was then cooled to room temperature, diluted with ethyl acetate, washed subsequently with aqueous NH4Cl, saturated aqueous NaHCO3, brine, and lastly dried with anhydrous sodium sulfate. The upper liquor was decanted, concentrated, and the solid residue was treated with EtOAC-Hex(2:1) with stirring. 2-{4-[(3-methylbenzoyl)amino]phenyl}-1H-indole-1-carboxamide was obtained as slightly brown solid upon filtration in amount of 165 mg (89%).
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4]1.F[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1>O1CCOCC1>[CH:3]1([O:8][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: OC1CCCC1
Reactant: N#Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: N#Cc1ccc(OC2CCCC2)cc1
Temperature: 100 °C
Yield: 80.1 %

Procedure:
Suspend sodium hydride (336 mg, 2.8 mmol, 60% suspension in mineral oil) in anhydrous 1,4-dioxane (10 mL) under nitrogen atmosphere. Add cyclopentanol (620 mg, 7.2 mmol) and stir the resulting solution for 30 min. Add the preformed solution (3.35 mL, 2.4 mmol) to neat 4-fluorobenzonitrile (240 mg, 2 mmol) in a microwave tube and heat the sealed mixture at 100° C. for 30 min. Cool to room temperature and concentrate in vacuo. Purify by chromatography on silica gel eluting with isohexane/EtOAc (95:5 to 1:1 gradient) to obtain the desired intermediate (300 mg, 80%). GC-MS m/z: 187 (M+).
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]#[N:16])[CH:10]=1)(=[O:3])[CH3:2].[C:17](OC)(=[O:25])[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[SH:20].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[S:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[C:17](=[O:25])[N:16]=2)[CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCCC1c1ccnc(C#N)c1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCCC1c1ccnc(-c2nc(=O)c3ccccc3s2)c1
Yield: 47.4 %

Procedure:
4-(1-Acetyl-2-pyrrolidinyl)-2-pyridinecarbonitrile (0.32 g, 1.5 mmol) and methyl thiosalicylate (1.02 g, 6.0 mmol) were dissolved in toluene (4 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. The mixture was refluxed for 24 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-methanol (8:1, v/v) were collected, concentrated and recrystallized from diethyl ether-methanol to give the titled compound (0.25 g, 48%) as white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Br-:8].[Br:9][CH2:10][CH2:11][CH2:12][N+:13]([CH2:20][CH2:21][CH3:22])([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16].CN(C=O)C>C(OCC)C>[Br-:9].[Br-:8].[CH2:17]([N+:13]([CH2:12][CH2:11][CH3:10])([CH2:14][CH2:15][CH3:16])[CH2:20][CH2:21][CH2:22][N+:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)[CH2:18][CH3:19]
Reactant: CCC[N+](CCC)(CCC)CCCBr
Reactant: Cc1ccncc1
Agent: [Br-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCC[N+](CCC)(CCC)CCC[n+]1ccc(C)cc1
Yield: 38.1 %

Procedure:
4-Methylpyridine (307 mg, 3.3 mmol), (3-bromopropyl)tripropylammonium bromide (1.0 g, 2.9 mmol), and 4 mL DMF were stirred at 100° C. in a pressure vessel for 14 h. After cooling down, the reaction mixture was added dropwise to a vigorously stirred diethyl ether (100 mL). The oily precipitates formed was collected and further purified by column chromatography (SiO2, gradient from 1:4 to 1:1 MeOH/CH2Cl2) to furnish 1-(3-tripropylammoniopropyl)-4-methylpyridinium dibromide as a colorless solid (484 mg, 38%). 1H NMR (400 MHz, CD3OD): δ 1.03 (t, J=7.0 Hz, 9 H), 1.77 (m, 6 H), 2.51 (m, 2 H), 2.70 (s, 3 H), 3.28 (m, 6 H), 3.49 (m, 2 H), 4.72 (t, J=7.8 Hz, 2 H), 7.99 (d, J=6.4 Hz, 2 H), 8.99 (d, J=6.4 Hz, 2 H); HRMS (FAB+): m/z=357.1906 [M-Br]+ (calcd for C18H34BrN2: 357.1900).
Reaction SMILES: [CH3:1][C:2]1[O:7][C:6]([C:8]([O:10]CC)=[O:9])=[CH:5][C:4](=[O:13])[CH:3]=1.[O-]CC.[Na+].[Na].[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C.O>[O:13]=[C:4]1[CH:3]=[C:2]([CH:1]=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5]1
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)c1cc(=O)cc(C)o1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(=O)cc(C=Cc2ccccc2)o1

Procedure:
A solution of this ester (3.6 g) in ethanol (100 ml) was added to a solution of sodium ethoxide prepared by dissolving sodium (0.1 g) in ethanol (100 ml). Benzaldehyde (2.45 ml) was added and the stirred mixture was heated at 80°-90° C. for an hour, cooled, diluted with water (800 ml) and washed with ether. The aqueous phase was acidified with 2M hydrochloric acid and extracted with ethyl acetate. The extract was dried and evaporated and the solid residue was recrystallised from dimethylformamide-water to give the title product (mp 227°-228° C. with decomposition).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH2:13][CH:14]=C)[C:11]=1[OH:12])[O:8][C:7](=[O:16])[CH:6]=[CH:5]2>CCOC(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]2=[C:10]2[CH:13]=[CH:14][O:12][C:11]=12)=[O:16]
Reactant: C=CCc1c(O)c(C)cc2ccc(=O)oc12
Solvent: CCOC(C)=O
Product: Cc1cc2ccc(=O)oc2c2ccoc12
Reaction time: 0.33 h

Procedure:
The 6-methyl-7-hydroxy-8-allylcoumarin (VII) (1.7 g) was dissolved in EtOAc (150 ml) and into the solution, cooled in an ice bath, a stream of ozonized oxigen was bubbled until 1.1 times the stoichiometric amount of ozone was reached. The solution was then immediately submitted to hydrogenation in the presence of Pd 10% on CaCO3 (0.3 g) and the mixture stirred until the rapid absorption of hydrogen ceased. The catalyst was removed by filtration, the solvent evaporated at reduced pressure, and the residue treated with 85% H3PO4 (60 ml). The reaction mixture was then placed into a thermostatic bath at 100° C. for 20 min, chilled, diluted with H2O (200 ml) and extracted with CHCl3. From the dried (Na2SO4) organic phase the solvent was evaporated under reduced pressure and the residue chromatographed on a silica gel column by eluting with CHCl3, yielding the 6-methylangelicin (XIX), crystallized from MeOH (0.18 g; m.p. 164°-5° C.). ##STR24##