Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.[CH2:13]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:14]1[CH:22]=[CH:21][C:20]2[O:19][CH2:18][O:17][C:16]=2[CH:15]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][C:10]([N:26]2[CH2:27][CH2:28][N:23]([CH2:13][C:14]3[CH:22]=[CH:21][C:20]4[O:19][CH2:18][O:17][C:16]=4[CH:15]=3)[CH2:24][CH2:25]2)=[O:12])=[CH:6][CH:7]=1
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Reactant: O=C(O)CNc1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CNc1ccc(O)cc1)N1CCN(Cc2ccc3c(c2)OCO3)CC1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of N-(4-hydroxyphenyl)glycine (11.38 g, 68.1 mmol) in N,N-dimethylformamide (DMF) (150 mL) were added under ice cooling 1-piperonylpiperazine (15.0 g, 68.1 mmol), 1-hydroxybenzotriazole monohydrate (10.43 g, 68.1 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (15.66 g, 81.7 mmol), and the resulting solution was stirred for 30 minutes under ice cooling and for 4.5 hours at room temperature. The reaction solution was concentrated under reduced pressure. To the residue was added a saturated sodium bicarbonate solution (400 mL), and extracted with ethyl acetate (400 mL). The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated, to leave the resulting product solidified in a powdered form. Ethyl acetate was added, and the resulting product was filtered off and washed with ethyl acetate, to thereby yield 18.58 g of the title compound.
Reaction SMILES: C(O)(=[O:3])C.[CH3:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][O:25][P:26]1([O:32][CH2:31][C@H:30]([CH2:33][N:34]2[C:39](=[O:40])[N:38]=[C:37]([NH2:41])[CH:36]=[CH:35]2)[O:29][CH2:28]1)=[O:27]>[OH-].[Na+]>[CH3:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][O:25][P:26]([OH:32])([CH2:28][O:29][C@H:30]([CH2:31][OH:3])[CH2:33][N:34]1[C:39](=[O:40])[N:38]=[C:37]([NH2:41])[CH:36]=[CH:35]1)=[O:27]
Reactant: CC(=O)O
Reactant: CCCCCCCCCCCCCCCCOCCCOP1(=O)CO[C@@H](Cn2ccc(N)nc2=O)CO1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCOCCCOP(=O)(O)CO[C@H](CO)Cn1ccc(N)nc1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
As described in U.S. Pat. No. 6,716,825, in Step 1 of the scheme above, cidofovir was suspended in N,N-DMF and N,N′-dicyclohexyl-4-morpholine-carboxamide was added. The mixture was stirred overnight to dissolve the cidofovir. The clear solution was then charged to an addition funnel and slowly added (30 min) to a stirred, hot pyridine (60° C.) solution containing 1,3-dicyclohexyl carbodiimide. The resulting reaction mixture was stirred at 100° C. for 16 h, cooled to room temperature and the solvents were removed under reduced pressure. The reaction mixture was adsorbed on silica gel and the product was purified by flash column chromatography using gradient elution (CH2Cl2 and MeOH) followed by 5:5:1 CH2Cl2/MeOH/H2O. The fractions containing the product were combined and concentrated in vacuo. The product, the DCMC salt of cyclic cidofovir was isolated in a 44% yield. In step 2, a solution of cyclic cidofovir DCMC salt in dry N,N-DMF was charged with 1-bromo-3-hexadecyloxypropane and the mixture was stirred and heated at 80° C. for 6 h. The solution was concentrated in vacuo, the residue adsorbed on silica gel and purified by flash column chromatography using gradient elution (CH2Cl2 and ethanol). The product was eluted with 90:10 CH2Cl2/EtOH. The fractions containing pure product were concentrated in vacuo. Hexadecyloxypropyl-cyclic cidofovir was obtained in a 55% yield. In Step 3, hexadecyloxypropyl-cyclic cidofovir was dissolved in 0.5M NaOH and stirred at room temperature for 1.5 h. 50% aqueous acetic acid was then added dropwise to adjust the pH to 9. The precipitated hexadecyloxypropyl-cidofovir was isolated by filtration, rinsed with water, and dried. The product was crystallized from 3:1 p-dioxane/water to give hexadecyloxypropyl-cidofovir (HDP-CDV, i.e, CMX001).
Reaction SMILES: P(Cl)(Cl)[Cl:2].O[CH2:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][C:15]=2[C:28]#[N:29])[CH:10]=[CH:11][CH:12]=1>CN(C=O)C>[Cl:2][CH2:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][C:15]=2[C:28]#[N:29])[CH:10]=[CH:11][CH:12]=1
Reactant: COc1cc2ncc(C#N)c(Nc3cccc(CO)c3)c2cc1OC
Reactant: ClP(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2ncc(C#N)c(Nc3cccc(CCl)c3)c2cc1OC
Temperature: 27.5 °C
Yield: 81.3 %

Procedure:
To 14 ml of DMF was added phosphorous trichloride (0.70 ml, 8.0 mmol) with stirring at 25-30° C. After 60 m, the mixture was cooled to 0° C., and a suspension of 4-[3-(hydroxymethyl)phenylamino]-6,7-dimethoxy-3-quinolinecarbonitrile (1.34 g, 4.0 mmol) in 6 ml of DMF was added. The mixture was warmed to 25° C., stirred 15 m, recooled in ice bath, and partitioned with methylene chloride-aqueous sodium bicarbonate. The organic layer was washed with water, dried, and concentrated to give 1.15 g of an amber solid; NMR (CDCl3) δ 4.79(s, CH2Cl).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:22][OH:23])=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7]([S:12]([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.C(N(C(C)C)C(C)C)C.CS(C)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]2[N:7]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:6]=[CH:5][C:4]=2[C:3]=1[CH:22]=[O:23]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(CO)c(Cl)cc(C)c32)cc1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C=O)c(Cl)cc(C)c32)cc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a solution of (5-chloro-7-methyl-1-tosyl-1H-indol-4-yl)methanol (3.3 g, 9.5 mmol) and N-ethyl-diisopropylamine (8.3 mL, 47.3 mmol) in CH2Cl2 (20 mL)/DMSO (1 mL) was added SO3.Py (4.5 g, 28.4 mmol) at 0° C. The mixture was stirred at 0° C. for 2.5 h, and then stirred at room temperature for 15 h. The reaction was quenched by MeOH. The mixture was stirred for 1 h. The mixture was partially concentrated. The mixture was diluted with H2O, and then the resulted solid was collected by filtration. The resulting residue was triturated with MeOH to give the title compound. 1H NMR (400 MHz, ACETONITRILE-d3) δ 10.56 (s, 1H), 8.00 (d, J=3.80 Hz, 1H), 7.62 (d, J=3.80 Hz, 1H), 7.60 (d, J=8.60 Hz, 2H), 7.35 (d, J=8.60 Hz, 2H), 7.22 (s, 1H), 2.60 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: [N:1]1([C:5]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:27]=[C:28]([OH:30])[CH:29]=3)[C:17]([NH:19][C:20]3[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=3)=[O:18])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.O[CH:32]1[CH2:36][CH2:35][O:34][C:33]1=[O:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[N:1]1([C:5]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:27]=[C:28]([O:30][CH:32]4[CH2:36][CH2:35][O:34][C:33]4=[O:37])[CH:29]=3)[C:17]([NH:19][C:20]3[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=3)=[O:18])=[CH:9][CH:8]=2)=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: Cc1cnc(NC(=O)c2cc(O)cc(Oc3ccc(C(=O)N4CCC4)nc3)c2)cn1
Reactant: O=C1OCCC1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(OC3CCOC3=O)c2)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-[6-(Azetidine-1-carbonyl)pyridin-3-yl]oxy-5-hydroxy-N-(5-methylpyrazin-2-yl)benzamide (Intermediate 1) (203 mg, 0.5 mmol), 3-hydroxyoxolan-2-one (CAS no. 19444-84-9) (0.078 mL, 1 mmol) and triphenyl phosphine (262 mg, 1 mmol) in anhydrous THF (10 mL) under argon at 0° C. was treated dropwise with DIAD (0.20 mL, 1 mmol). The mixture allowed to warm to room temperature and stirred for 16 hours. The solvent was removed by evaporation under reduced pressure and the residue was purified by chromatography on silica eluting with 0-4% methanol:DCM to give product (212 mg 86%). 1H NMR δ (400 MHz, CDCl3) 2.29 (quintet, 2H), 2.40-2.48 (m, 1H), 2.50 (s, 3H), 2.69-2.78 (m, 1H), 4.18 (t, 2H), 4.33 (q, 1H), 4.49 (t, 1H), 4.64 (t, 2H), 4.99 (t, 1H), 6.89 (s, 1H), 7.18 (s, 1H), 7.33 (d, 1H), 7.36 (s, 1H), 8.06 (d, 1H), 8.08 (s, 1H), 8.28 (s, 1H), 8.41 (s, 1H), 9.46 (s, 1H); m/z 490 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].[N:8]1([C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=2)[CH:12]=[CH:11][N:10]=[CH:9]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:5][CH2:17][C:16]1[CH:15]=[CH:14][C:13]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Reactant: COC(CN)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(CNCc1ccc(-n2ccnc2)cc1)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To a solution of 2,2-dimethoxyethylamine (526 mg) and 4-(1H-imidazol-1-yl)benzaldehyde (861 mg) in methanol (25 ml) was added acetic acid (600 mg), and the mixture was stirred at room temperature for 1 hour. To the mixture was added, under ice-cooling, sodium triacetoxyborohydride (1.59 g), and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated, and to the residue was added 1 N sodium hydroxide solution. The mixture was extracted with dichloromethane, dried and concentrated to give colorless oil of the title compound (1.21 g).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[C:5]([C:9]([O:11]CC)=[O:10])[S:6][C:7]=1[I:8])#[N:2].[OH-].[Na+]>O1CCCC1.O>[C:1]([C:3]1[C:4]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[C:5]([C:9]([OH:11])=[O:10])[S:6][C:7]=1[I:8])#[N:2]
Reactant: CCOC(=O)c1sc(I)c(C#N)c1-c1ccc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(I)sc(C(=O)O)c1-c1ccc(Cl)cc1Cl
Reaction time: 8 h
Yield: 111.2 %

Procedure:
To a solution of ethyl 4-cyano-3-(2,4-dichlorophenyl)-5-iodothiophene-2-carboxylate (1.44 g, 0.00318 mol) in tetrahydrofuran (20 mL) and water (10 mL) was added a solution of 1.00M sodium hydroxide in water (16 mL). The solution was allowed to stir overnight. The reaction was quenched with a solution of 1N HCl (18 mL) and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the crude title compound (1.50 g, 100%) used directly in the next reaction. LCMS: (FA) ES−, 422. 1H NMR (400 MHz, d6-DMSO) δ: 7.68 (d, 1H, J=2.0 Hz), 7.46-7.34 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH:11](C=O)[C:10](=[O:17])[C:9]=2[CH:8]=[C:7]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].C(NC1C=CC(S([N:45]=[N+:46]=[N-])(=O)=O)=CC=1)(=O)C>C(N(CC)CC)C>[N+:45](=[C:11]1[CH2:12][CH2:13][C:14]2[N:6]([CH2:5][C:4]3[CH:28]=[CH:29][C:30]([Cl:31])=[C:2]([Cl:1])[CH:3]=3)[C:7]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[CH:8][C:9]=2[C:10]1=[O:17])=[N-:46]
Reactant: O=CC1CCc2c(cc(C(=O)OCc3ccccc3)n2Cc2ccc(Cl)c(Cl)c2)C1=O
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CCN(CC)CC
Product: [N-]=[N+]=C1CCc2c(cc(C(=O)OCc3ccccc3)n2Cc2ccc(Cl)c(Cl)c2)C1=O
Reaction time: 18 h
Yield: 62.3 %

Procedure:
Triethyl amine (0.36 mL) was added dropwise to a solution of benzyl 1-(3,4-dichlorobenzyl)-5-formyl-4-oxo-4,5,6,7-tetrahydroindole-2-carboxylate (0.5 g) and p-acetamidobenzenesulphonyl azide (305 mg) at room temperature, and stirred for 18 hours to give a brown solution. The solvent was removed in vacuo to afford a brown oil. Purification by column chromatography, using iso-hexane : 20% ethyl acetate as eluent afforded the title compound as a pale yellow solid (0.31 g, 62%), NMR d(CDCl3) 2.80 (2H, t), 3.05 (2H, t), 5.13 (2H, s), 5.57 (2H, s), 6.76 (1H, dd), 7.05 (1H, s), 7.20-7.40 (7H, m); M/z (+) 456, 454 (M+).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[OH:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[CH:15]([C:14]1[CH:17]=[CH:18][C:11]([O:10][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:12][CH:13]=1)=[O:16]
Reactant: N#Cc1ccc(F)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(Oc2ccc(C=O)cc2)cc1
Temperature: 130 °C
Reaction time: 18 h
Yield: 49.3 %

Procedure:
Combine 4-fluorobenzonitrile (3.96 g, 32.7 mmol), 4-hydroxybenzaldehyde (3.99 g, 32.7 mmol), dimethyl acetamide (100 mL), and potassium carbonate (6.8 g, 49 mmol), stir, and heat to 130° C. After 18 h, cool to ambient temperature, partially remove the solvent in vacuo, and dilute with 100 mL of water. Extract the aqueous solution with diethyl ether (3× 150 mL), wash the organic phase with water (2× 100 mL), and brine (100 mL). Dry the organic phase over magnesium sulfate, filter, and concentrate under vacuum. Purify via a Biotage Flash 40L system, using a gradient: 5:95 hexanes/ethyl acetate to 50:50 hexanes/ethyl acetate to give the title compound (3.6 g, 49%) as a white solid: 1H NMR (chloroform-d): 9.95 (s, 1H), 7.92 (d, 2H), 7.68 (d, 2H), 7.14 (m, 4H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[N:10]([CH3:46])[C:11](=[O:45])[CH2:12][N:13]([C:30]1[CH:35]=[CH:34][C:33](B2OCC(C)(C)CO2)=[CH:32][C:31]=1[CH3:44])[CH2:14][C:15]([NH:17][CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH3:22])=[O:16].[CH3:47][O:48][C:49](=[O:57])[C:50]1[CH:55]=[CH:54][C:53](Br)=[N:52][CH:51]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.[Cl-].[Cl-].[Pd+2]>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[N:10]([CH3:46])[C:11](=[O:45])[CH2:12][N:13]([C:30]1[CH:35]=[CH:34][C:33]([C:53]2[CH:54]=[CH:55][C:50]([C:49]([O:48][CH3:47])=[O:57])=[CH:51][N:52]=2)=[CH:32][C:31]=1[CH3:44])[CH2:14][C:15]([NH:17][CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:21][CH3:22])=[O:16]
Reactant: COC(=O)c1ccc(Br)nc1
Reactant: CCN(CCNC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1ccc(B2OCC(C)(C)CO2)cc1C)C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCN(CCNC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1ccc(-c2ccc(C(=O)OC)cn2)cc1C)C(=O)OC(C)(C)C
Yield: 71 %

Procedure:
The compound (510 mg, 0.802 mmol) obtained in step A, 6-bromonicotinic acid methyl ester (208 mg, 0.962 mmol), bis(tricyclohexylphosphine)palladium(II)dichloride (59 mg, 0.080 mmol) and 1.27 mol/l aqueous potassium phosphate solution (0.95 ml) were dissolved in 1,4-dioxane (4 ml), and the mixture was heated under reflux for 8 hr. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried over sodium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (ethyl acetate-methanol) to give the title compound (375 mg, yield 71%) as a brown oil.
Reaction SMILES: O[CH:2]=[C:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=O.Cl.[F:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[CH:17][CH:16]=1.Cl>C(O)C>[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:4]3[C:5]4[C:10]([CH2:11][C:3]=3[CH:2]=[N:22]2)=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:17][CH:16]=1
Reactant: O=C1C(=CO)Cc2ccccc21
Reactant: NNc1ccc(F)cc1
Agent: Cl
Solvent: CCO
Product: Fc1ccc(-n2ncc3c2-c2ccccc2C3)cc1

Procedure:
2-Hydroxymethylene indan-1-one, (Example 1(ii) (a) (4.004 g; 250 mmol), p-fluorophenyl hydrazine hydrochloride (Aldrich) (4.106 g; 25.25 mmol) 10M hydrochloric acid (1 cm3) and ethanol (30 cm3), were heated under reflux for 19 hours. After cooling, the solvent was evaporated under reduced pressure, then taken up in dichloromethane and washed with 2M NaOH. The organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo. Purification by Kugelrohr distillation (140° C.; 0.01 mmHg) afforded a yellow solid, m.p. 104-105° C.
Reaction SMILES: [CH3:1][C:2]1(O)[CH2:7][CH2:6][C@@H:5]([C:8]([CH3:10])=[CH2:9])[CH:4]=[CH:3]1.[CH3:12][C:13]1[CH:14]=[C:15]([OH:20])[CH:16]=[C:17]([CH:19]=1)[OH:18].O.O.C(O)(=O)C(O)=O>C1(C)C=CC=CC=1.C(OCC)C>[C:8]([CH:5]1[CH:4]([C:14]2[C:13]([CH3:12])=[CH:19][C:17]([OH:18])=[CH:16][C:15]=2[OH:20])[CH:3]=[C:2]([CH3:1])[CH2:7][CH2:6]1)([CH3:10])=[CH2:9]
Reactant: C=C(C)[C@H]1C=CC(C)(O)CC1
Reactant: Cc1cc(O)cc(O)c1
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C=C(C)C1CCC(C)=CC1c1c(C)cc(O)cc1O
Reaction time: 5 h
Yield: 154.8 %

Procedure:
(4R)-1-Methyl-4-isopropenylcyclohex-2-ene-1-ol (300 mg, 2 mmoles) was dissolved in toluene (20 ml) and 5-methylresorcinol (248 mg, 2 mmoles) was added in diethyl ether (5 ml). Oxalic acid dihydrate (252 mg, 2 mmoles) was added and the reaction mixture heated with stirring at 80° for 5 hours. The reaction mixture was allowed to cool and diluted with diethyl ether (30 ml). The ether solution washed twice with aqueous sodium bicarbonate and dried over anhydrous magnesium sulphate. The solvents were evaporated under reduced pressure to give the crude product as a brown oil (800 mg). The product was purified using a silica column eluted with ethyl acetate:isohexane 1:9 going to ethyl acetate:isohexane 2:8.
Reaction SMILES: [CH2:1]([O:19][CH2:20][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])(O)[CH3:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].S(Br)([Br:45])=O.[Na].C(=O)(O)[O-]>CN(C)C=O>[Br:45][CH2:22][CH:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:20][O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=S(Br)Br
Reactant: CCCCCCCCCCCCCCCCCCOCC(C)(O)OCCCCCCCCCCCCCCCCCC
Agent: O=C([O-])O
Agent: [Na]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOCC(CBr)OCCCCCCCCCCCCCCCCCC
Temperature: 100 °C

Procedure:
To a solution of 15 g of 1,2-dioctadecyloxy-2-propanol in 450 ml of dimethylformamide 21 g of thionylbromide were added dropwise while stirring and cooling, after which the reaction mixture was heated at 100° C for 5 hours. After cooling down, the resultant mixture was slowly poured into 400 ml of 5% sodium-bicarbonate solution. The aqueous solution was extracted with 4 × 150 ml of diethylether, after which the ether extract was consecutively washed with water, 5% sodium bicarbonate solution and water. After drying on sodium sulphate the solvent was removed under vacuum. The coarse product thus obtained was purified by means of column chromatography. The yield was 14 g of 1-bromo-2,3-dioctadecyloxypropane with a melting point of 38°-38.8° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=1>C(O)C.O1CCCC1.CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]1
Reactant: COc1ccc2[nH]cc(C3=CCN(C)CC3)c2c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCO
Product: COc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Reaction time: 96 h
Yield: 97.2 %

Procedure:
5-Methoxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)indole (9.00 g, 37 mmol) was dissolved in 190 mL of ethanol/tetrahydrofuran/methanol (10:10:1). 10% palladium on carbon (2.2 g) was added, and the reaction mixture was hydrogenated at 40 p.s.i. in a Parr shaker for 96 hours. The mixture was filtered through celite, the catalyst was washed with ethanol, and the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel (5-10% 2M ammonia-methanol/dichloromethane) to provide 8.79 g (97%) of the title compound. MS(m/e): 245 (M+). EA calculated for C14H19N3O: C, 68.54; H, 7.81; N, 17.13. Found: C, 68.40; H, 7.52; N, 16.90.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([CH:47]=[CH:48][CH:49]=2)[C:43](OC)=[O:44])=[N:8]1.O.[OH-].[Li+].[F:53][C:54]1[CH:61]=[CH:60][C:57]([CH2:58][NH2:59])=[CH:56][CH:55]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O1CCCC1.O1CCCC1.O>[F:53][C:54]1[CH:61]=[CH:60][C:57]([CH2:58][NH:59][C:43]([C:42]2[CH:47]=[CH:48][CH:49]=[C:40]([C:9]3[C:10]4[C:15](=[CH:14][CH:13]=[C:12]([C:16]5[N:20]=[CH:19][N:18]([C:21]([C:28]6[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=6)([C:34]6[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=6)[C:22]6[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=6)[N:17]=5)[CH:11]=4)[N:7]([CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[N:8]=3)[CH:41]=2)=[O:44])=[CH:56][CH:55]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCc1ccc(F)cc1)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 85.8 %

Procedure:
To a stirred solution of methyl 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}benzoate (0.431 g, 0.667 mmol) in a tetrahydrofuran/water mixture (2.70 mL/1.62 mL) was added lithium hydroxide monohydrate (0.0840 g, 2.00 mmol) and the mixture heated at 60° C. for 21 h. To this mixture was added tetrahydrofuran (2.00 mL), 4-fluorobenzylamine (0.212 mL, 1.86 mmol), 1-hydroxybenzotriazole hydrate (0.251 g, 1.86 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.356 g, 1.86 mmol). This reaction mixture was stirred for 18 h at ambient temperature. The mixture was extracted with ethyl acetate (2×). The combined organic extracts were washed with aqueous saturated sodium bicarbonate, followed by brine, dried over anhydrous sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography with 30-60% ethyl acetate/hexanes gave the title compound (0.423 g, 86% yield). ES-MS (m/z) 497 [M+1(−Tr)]+.
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:6](=[CH:9][CH2:10][CH3:11])[C:7]#[N:8])[CH2:4][CH3:5].[CH2:12](Cl)[CH:13]=[CH2:14]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH2:9]([C:6]([CH2:12][CH2:13][CH3:14])([CH:3]=[CH:4][CH3:5])[C:7]#[N:8])[CH:10]=[CH2:11]
Reactant: CCC=C(C#N)CCC
Reactant: C=CCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=CCC(C#N)(C=CC)CCC
Temperature: 80 °C
Yield: 35.9 %

Procedure:
Into a 250 ml 4-neck flask equipped with stirrer, reflux cooler and dropping funnel, 20 g (0.5 moles) of solid sodium hydroxide, 80 ml of toluene and 5 g of tetrabutylammonium bromide are first introduced and heated to 80° C. To this 2-phase system, a mixture of 50 g (0.41 moles) of 2-propyl-2-pentenenitrile and 31.4 g (0.41 moles) of allyl chloride were added in doses within 30 minutes. The reaction mixture was maintained for 2 more hours at a temperature of 75° C. Further work proceeded as in Example 1. A yield of 24 g of desired product, corresponding to 29.4% of the theoretical, was obtained.