Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>ClC1C=CC=CC=1Cl>[CH2:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Oc1ccccc1Cc1ccccc1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccccc3Cc3ccccc3)c2cc1OC
Temperature: 180 °C
Reaction time: 8 h
Yield: 10.5 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (230 mg) and 2-benzylphenol (254 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 180° C. overnight. The reaction solution was cooled to room temperature, and water was added thereto. The mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was then removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using ethyl acetate-hexane to give the title compound (40 mg, yield 10%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])=[O:9].Cl[S:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>>[Cl:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:19]([C:22]1[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:29][CH:30]=1)(=[O:21])=[O:20])=[O:9]
Reactant: Nc1ccccc1C(=O)c1ccc(Cl)cc1Cl
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Product: O=C(O)c1ccc(S(=O)(=O)Nc2ccccc2C(=O)c2ccc(Cl)cc2Cl)cc1

Procedure:
The title compound was prepared from (2-amino-phenyl)-(2,4-dichloro-phenyl)-methanone [Synthesis, (1980) 677-688] and 4-chlorosulfonyl-benzoic acid according to the method described in Example 1.1/c. MS (EI) 451 (MH+).
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](Cl)(=[O:12])[CH2:10][CH3:11].[Al+3].[Cl-].[Cl-].[Cl-].Cl>ClC(Cl)C.O>[CH3:8][S:7][C:1]1[CH:6]=[CH:5][C:4]([C:9](=[O:12])[CH2:10][CH3:11])=[CH:3][CH:2]=1
Reactant: CSc1ccccc1
Reactant: CCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: O
Product: CCC(=O)c1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of thioanisole (5.0 g) and propionyl chloride (3.9 ml) at 0° C. in dichloroethane (80 ml) was added AlCl3 (6.4 g) in portions. The mixture was stirred 12 hours at ambient temperature, poured into water (200 ml) and conc. HCl (2 ml), then extracted with CH2Cl2. The extract was reduced to dryness to provide the title compound mp 60°-61° C. after purification by chromatography on silica gel.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[CH3:12])#[N:2].C(Cl)(=O)C(Cl)=O.[CH3:19][C:20]1[CH:26]=[C:25]([C:27]([F:36])([C:32]([F:35])([F:34])[F:33])[C:28](F)([F:30])[F:29])[CH:24]=[C:23]([CH2:37][CH3:38])[C:21]=1[NH2:22].N1C=CC=CC=1.C(=O)([O-])O.[Na+]>ClCCl.O1CCCC1.CN(C)C=O>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:22][C:21]2[C:20]([CH3:19])=[CH:26][C:25]([C:27]([F:36])([C:32]([F:33])([F:34])[F:35])[C:28]([F:30])([F:29])[C:32]([F:35])([F:34])[F:33])=[CH:24][C:23]=2[CH2:37][CH3:38])=[O:9])=[CH:5][C:4]=1[CH3:12])#[N:2]
Reactant: Cc1cc(C(=O)O)ccc1C#N
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1N
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(C#N)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 200 %

Procedure:
To a solution of 4-cyano-3-methyl-benzoic acid (6.64 g, 41.20 mmol) (prepared according to Bioorganic & Medicinal Chemistry Letters 2004, 14(17), 4585-4589 or EP 1,512,687) and N,N-dimethylformamide (“DMF”) (few drops) in dichloromethane (200 ml) under an atmosphere of nitrogen was added oxalyl chloride (4.18 ml, 49.44 mmol). The reaction mixture was stirred for one hour at ambient temperature and then for 1.5 hours at 60° C. The reaction mixture was concentrated and the residue dissolved in tetrahydrofuran (200 ml). The solution was added drop-wise to a solution of 2-methyl-6-ethyl-4-(heptafluoro-prop-2-yl)-aniline (prepared according to EP 1,006,102) (10.910 g, 30.90 mmol) and pyridine (3.31 ml, 41.20 mmol) in tetrahydrofuran (200 ml). The reaction mixture was stirred for 16 hours at 90° C. Then the reaction mixture was poured into aqueous sodium hydrogen carbonate (1M) and the mixture extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by column chromatography (eluent: ethyl acetate/cyclohexane 1:3) to give the desired compound (15.34 g, 94% yield). 1H-NMR (400 MHz, CDCl3): 7.90 (1H, s), 7.78 (2H, m), 7.53 (1H, s), 7.39 (2H, s), 2.67 (5H, s), 2.35 (3H, s), 1.16 (3H, t) ppm.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:5]=[C:4]2[CH:15]=[CH:16][S:17][C:3]=12.[NH:18]1[CH2:26][CH2:25][CH:21]([C:22]([NH2:24])=[O:23])[CH2:20][CH2:19]1.C([O-])(=O)C.[Na+]>CN1CCCC1=O>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[C:4]3[CH:15]=[CH:16][S:17][C:3]3=[C:2]([N:18]3[CH2:26][CH2:25][CH:21]([C:22]([NH2:24])=[O:23])[CH2:20][CH2:19]3)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: Fc1ccc(-c2cc(Cl)c3sccc3n2)cc1
Reactant: NC(=O)C1CCNCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: NC(=O)C1CCN(c2cc(-c3ccc(F)cc3)nc3ccsc23)CC1
Temperature: 160 °C
Yield: 59.5 %

Procedure:
A mixture of 7-chloro-5-(4-fluorophenyl)thieno[3,2-b]pyridine (68 mg, 0.26 mmole), isonipecotamide (66 mg, 0.52 mmole), and sodium acetate (21 mg, 0.26) in 1-methyl-2-pyrrolidone (3 mL) is stirred and heated in an oil bath at 160° C. for 4 hours. The reaction mixture is then cooled and diluted with EtAc (15 mL), transferred to a separatory funnel, and washed with water (3×15 mL). The organic layer is dried over sodium sulfate and concentrated. The residue is recrystalized with ethyl acetate to give 1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide (55 mg, 60% yield) as a white solid. This material is dissolved in ethyl acetate and HCl saturated ethyl acetate (2 mL) is added. The solution is concentrated to afford the HCl salt as a greasy oil. 1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide hydrochloride (compound 3) is precipitated out of an ether solution, collected by filtration, washed with ether, and dried in vacuo to afford the final product. m.p. 303-305° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:17][C:16](=O)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.S(Cl)([Cl:21])=O>CN(C)C=O>[Cl:21][C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:17]=1
Reactant: O=c1[nH]c(-c2ccccc2Cl)nc2ccccc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Clc1ccccc1-c1nc(Cl)c2ccccc2n1
Temperature: 0 °C

Procedure:
A mixture of 17.5 g of 2-(2-chlorophenyl)quinazolin-4(3H)-one and 130 ml of thionyl chloride was treated as described in Example I with 5 g of dimethylformamide. The mixture was poured into 1000 ml of ice water and stirred until the ice was melted. The solid was collected by filtration and allowed to air-dry overnight. The solid was triturated with 500 ml of boiling cyclohexane. The insoluble solid was removed by filtration and the cyclohexane solution allowed to cool slowly. The solid which separated was collected to give pale yellow needles, m.p. 127°-129°. Recrystallization of the yellow needles from cyclohexane gave 9.9 g of 4-chloro-2-(2-chlorophenyl)quinazoline, m.p. 129.5°-130.5°; ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: [CH2:1]([C:3]1[CH:18]=[C:17]([C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([NH:31][CH2:32]C)[N:25]=3)[O:21][N:20]=2)[CH:16]=[C:15]([CH3:34])[C:4]=1[O:5][CH2:6][C@@H:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])C.[CH3:35]C1N=C(NC)N=C(C(O)=O)C=1.C(N)(=O)C>>[CH3:32][N:31]([CH3:35])[C:26]1[N:25]=[C:24]([C:22]2[O:21][N:20]=[C:19]([C:17]3[CH:16]=[C:15]([CH3:34])[C:4]([O:5][CH2:6][CH:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])=[C:3]([CH3:1])[CH:18]=3)[N:23]=2)[CH:29]=[C:28]([CH3:30])[N:27]=1
Reactant: CNc1nc(C)cc(C(=O)O)n1
Reactant: CCNc1nc(C)cc(-c2nc(-c3cc(C)c(OC[C@@H](O)CNC(=O)CO)c(CC)c3)no2)n1
Agent: CC(N)=O
Product: Cc1cc(-c2nc(-c3cc(C)c(OCC(O)CNC(=O)CO)c(C)c3)no2)nc(N(C)C)n1

Procedure:
rac-N-(3-{4-[5-(2-Dimethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide is prepared in analogy to N—((S)-3-{2-ethyl-4-[5-(2-ethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide using 6-methyl-2-methylamino-pyrimidine-4-carboxylic acid and 2-hydroxy-N-{2-hydroxy-3-(N-hydroxycarbamimidoyl)-2,6-dimethyl-phenoxy]-propyl}-acetamide; LC-MS: tR=0.94 min; [M+H]+=457.31.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:33])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][N:10]=[C:9]2[NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)[N:20]=[CH:19]2)=[O:5])C.[OH-].[Na+].Cl>C1COCC1.CO>[F:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH2:25][N:21]1[C:22]2[C:18](=[CH:17][C:16]([NH:15][C:9]3[C:8]4=[C:7]([CH3:33])[C:6]([C:4]([OH:5])=[O:3])=[CH:14][N:13]4[N:12]=[CH:11][N:10]=3)=[CH:24][CH:23]=2)[CH:19]=[N:20]1
Reactant: CCOC(=O)c1cn2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c2c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C(=O)O)cn2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12
Temperature: 60 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A flask equipped with mechanical stirrer was charged with 4-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-5-methyl-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid ethyl ester (19) (1 equiv), THF (4 volumes) and MeOH (2.5 volumes). The suspension was cooled to 5 C and 50% NaOH (5.3 equiv.) solution was slowly added maintaining the temperature below 15° C. The resulting solution was warmed to 60° C. for 4 h, and then cooled to 25° C. THF (7 volumes) was charged to the reaction and concentrated HCl (9.95 equiv.) was slowly added maintaining the temperature below 35° C. to pH 3. The resulting slurry was stirred at ambient temperature overnight, and then filtered. The filter cake was washed with H2O (3×5 volumes) and dried on the filter for 1 h. The filter cake was washed with heptane (1×1 volume) and dried under vacuum at 50° C. to afford the product in 88% yield as an off-white solid.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Br:6][C:7]1[CH:15]=[C:11]([C:12]([OH:14])=O)[C:10]([OH:16])=[CH:9][CH:8]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([OH:16])=[C:11]([CH:15]=1)[C:12]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:14]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: CCNCC
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1cc(Br)ccc1O
Temperature: 50 °C
Reaction time: 12 h

Procedure:
Diethylamine (2.39 mL, 23.0 mmol) was added to a solution of 5-bromosalicylic acid (1.000 g, 4.61 mmol), EDC (1.33 g, 6.91 mmol), HOAt (0.627 g, 4.61 mmol) and DMF (20.0 mL) and the system was flushed with argon. The tube was sealed and the mixture stirred at 50° C. for 12 h. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was separated and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a brown oil. This oil was purified via column chromatography on silica gel (RediSep 40 g column, gradient elution with 0-50% ethyl acetate-hexane) to afford 5-bromo-N,N-diethyl-2-hydroxybenzamide as an off-white solid. MS m/z=272.1, 274.1 [M+H]+. Calcd for C11H14BrNO2: 272.1.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[S:10]1[CH2:16][C:14](=[O:15])[NH:13][C:11]1=S.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:11]1[S:10][CH2:16][C:14](=[O:15])[N:13]=1
Reactant: NCc1ccccc1Cl
Reactant: O=C1CSC(=S)N1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CSC(NCc2ccccc2Cl)=N1

Procedure:
Similar procedure as described in example 10c was used, starting with 2-chloro-benzylamine, rhodanine, mercuric chloride and DIEA to give 2-(2-chloro-benzylamino)-thiazol-4-one. LC-MS m/e 241 (MH+).
Reaction SMILES: C(OC[CH:10]1[CH2:15][O:14][CH:13]([N:16]2[CH:23]=[CH:22][C:20]([NH2:21])=[N:19][C:17]2=[O:18])[CH2:12][S:11]1)C1C=CC=CC=1.B(Cl)(Cl)Cl.CO.C(Cl)Cl.[C:33](=O)(O)[O-:34].[Na+]>C(Cl)Cl>[OH:34][CH2:33][SH:11]1[CH2:10][CH2:15][O:14][CH:13]([N:16]2[CH:23]=[CH:22][C:20]([NH2:21])=[N:19][C:17]2=[O:18])[CH2:12]1
Reactant: Nc1ccn(C2CSC(COCc3ccccc3)CO2)c(=O)n1
Reactant: O=C([O-])O
Agent: ClB(Cl)Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Nc1ccn(C2C[SH](CO)CCO2)c(=O)n1
Temperature: -78 °C

Procedure:
1-(5-benzyloxymethyl-1,4-oxathian-2-yl)cytosine (0.12 g) was dissolved in methylene chloride (10 ml), and the solution was cooled to -78° C. To the solution, 1M boron trichloride solution (3.7 ml) was added dropwise, and the resultant mixture was stirred at the same temperature for 4 hours. Mixed solvent of methanol-methylene chloride (1/1, 8 ml) was added thereto, and sodium bicarbonate was added to neutralize the reaction mixture. Upon raising the temperature of the reaction mixture to room temperature, the solvent was distilled off under reduced pressure to obtain white solid.
Reaction SMILES: [OH:1][C:2]1[C:9]([N+:10]([O-])=O)=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:13].NN>CO.O.O.O.O.O.O.[Fe](Cl)Cl>[NH2:10][C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([CH3:13])[C:2]=1[OH:1])[C:6]#[N:7]
Reactant: Cc1cc(C#N)cc([N+](=O)[O-])c1O
Agent: Cl[Fe]Cl
Agent: NN
Solvent: CO
Solvent: O
Product: Cc1cc(C#N)cc(N)c1O
Temperature: 70 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
Iron chloride hexahydrate (9.6 mg), 4-hydroxy-3-methyl-5-nitrobenzonitrile (126 mg), and 77 mg of activated carbon were suspended in 5 ml of methanol and heated under N2 at 70° C. for 10 min. Hydrazine (0.11 ml) was then added slowly and the mixture was stirred for 2 h at 70° C. The mixture was then cooled to room temperature and filtered through a plug of Celite, eluting with methanol. The eluent was concentrated in vacuo and the residue was purified on a 2×1500 micron preparative TLC plate, eluting with ethyl acetate (Rf=0.24), to provide 101 mg (96%) of the title compound. Mass spectrum (ESI) 150.1 (M+1). 1H NMR (500 MHz, CDCl3): □ 6.93 (s, 1H), 6.91 (s, 1H), 5.21 (bs, 1H), 3.76 (bs, 2H), 2.42 (s, 3H).
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].C(NC(C)C)(C)C.[Cl-].[Li+].ICCCC.[OH:20][CH:21]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH:22]([N:24]([CH3:35])[C:25](=[O:34])[CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[CH3:23]>>[OH:20][CH:21]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[CH:22]([N:24]([CH3:35])[C:25](=[O:34])[CH:26]([CH2:2][CH2:3][CH2:4][CH3:5])[CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[CH3:23]
Reactant: [Li]CCCC
Reactant: CC(C(O)c1ccccc1)N(C)C(=O)CCC1CCCCC1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCCCI
Solvent: CC(C)NC(C)C
Product: CCCCC(CC1CCCCC1)C(=O)N(C)C(C)C(O)c1ccccc1
Yield: 53 %

Procedure:
A solution of 2.5M nBuLi in hexanes (5.8 mL, 14.5 mmol), diisopropylamine (2.0 mL, 14.5 mmol), lithium chloride (1.6 g, 39 mmol), iodobutane (130 μL, 6.4 mmol) and the product from Example 1315A (2.0 g, 6.4 mmol) were allowed to react in a manner similar to that described by A. G. Myers et al., Journal of the American Chemical Society 1994, 116: 9361-9362. The crude residue was chromatographed (silica gel; EtOAc/hexanes, 1:4) to afford the title compound as a yellow oil (1.2 g, 53%). MS (CI/NH3) m/z: 360 (M+H)+.
Reaction SMILES: [CH3:1][C@@:2]12[CH:11]3[CH2:12][CH:13]=[C:14]4[C@@H:19]5[CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][CH2:23][C@:18]5([C:26]([OH:28])=[O:27])[CH2:17][CH2:16][C@@:15]4([CH3:29])[C@:10]3([CH3:30])[CH2:9][CH2:8][C@H:7]1[C@@:6]([OH:32])([CH3:31])[C@@H:5]([OH:33])[CH2:4][CH2:3]2.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:67]([NH2:79])[CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH3:78]>C1COCC1.C(Cl)(Cl)Cl.C1CCCCC1.C(OC(=O)C)C>[CH2:67]([NH-:79])[CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH3:78].[CH3:1][C@@:2]12[CH:11]3[CH2:12][CH:13]=[C:14]4[C@@H:19]5[CH2:20][C:21]([CH3:24])([CH3:25])[CH2:22][CH2:23][C@:18]5([C:26]([OH:28])=[O:27])[CH2:17][CH2:16][C@@:15]4([CH3:29])[C@:10]3([CH3:30])[CH2:9][CH2:8][C@H:7]1[C@@:6]([OH:32])([CH3:31])[C@@H:5]([OH:33])[CH2:4][CH2:3]2
Reactant: CCCCCCCCCCCCN
Agent: CC1(C)CC[C@]2(C(=O)O)CC[C@]3(C)C(=CCC4[C@@]5(C)CC[C@H](O)[C@@](C)(O)[C@@H]5CC[C@]43C)[C@@H]2C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCC[NH-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Gypsogenin (1.30 g, 2.76 mmol) was dissolved in dry THF (40 mL) under argon atmosphere at room temperature. DIEA (1.5 ML, 8.28 mmol) and HBTU (1.30 g, 3.31 mmol) were added to the above solution and reaction mixture was stirred for 1 hr at room temperature to produce an intermediate complex. Dodecylamine (614 mg, 3.31 mmol) was added to the reaction mixture which was further stirred for 48 hours at room temperature. TLC using cyclohexane-ethylacetate (1:1) as mobile phase showed the completion of reaction. The reaction was diluted with chloroform, washed with water, dried over sodium sulfate and concentrated to a solid. Column chromatographic purification of crude product on silica gel G using cyclohexane-ethylacetate (3:1 to 2:1) as mobile phase gave pure dodecylamide derivative of gypsogenin in 65% yield. m.p. 85-87° C.
Reaction SMILES: [CH:1]1CC(C(CC)CC=O)C[CH:5]=1.[CH:12]1([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[O:22])[CH2:16][CH2:15][CH:14]=[CH:13]1.C([Mg]Br)C.S(=O)(=O)(O)O>O.O1CCCC1>[OH:22][CH:21]([CH2:1][CH3:5])[CH2:20][CH2:19][CH2:18][CH2:17][CH:12]1[CH2:16][CH2:15][CH:14]=[CH:13]1
Reactant: CCC(CC=O)C1CC=CC1
Reactant: O=CCCCCC1C=CCC1
Agent: CC[Mg]Br
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Product: CCC(O)CCCCC1C=CCC1
Temperature: -30 °C

Procedure:
All work is performed an inert atmosphere using anhydrous tetrahydrofuran. The starting material, 3-(5-cyclopenten-3-yl) valeraldehyde {2-cyclopentene-1-pentanal} (75 g, 0.493 moles) is diluted in tetrahydrofurar (750 ml) and cooled in a -30° C. ethanol/dry ice bath. Ethyl magnesium bromide (0.493 moles) is added dropwise to the stirring reaction mixture for a period of over 2 hours. The mixture is warmed to 0° C. and water (100 ml), followed by 15% sulfuric acid (200 ml), is added and the organic phase separated. The aqueous layer is extracted with ether (2×300 ml) and the organic extracts are combined. The volume is reduced and the residue washed with brine (400 ml). The product is dried over anhydrous sodium sulfate and the remaining solvent removed under vacuum leaving a clear yellow oil. The crude product is chromatographed on silica gel and subsequently kugelrohred under vacuum leaving clear, colorless oil (10.2 g, 0.056 moles).
Reaction SMILES: [C:1]([C:3]1[C:20](F)=[CH:19][CH:18]=[CH:17][C:4]=1[O:5][C:6]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])#[N:2].O.[NH2:23][NH2:24].C(N(C(C)C)C(C)C)C>O1CCOCC1>[NH2:2][C:1]1[C:3]2[C:20](=[CH:19][CH:18]=[CH:17][C:4]=2[O:5][C:6]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:7]=2[C:8]([O:10][CH3:11])=[O:9])[NH:24][N:23]=1
Reactant: COC(=O)c1ccc(F)cc1Oc1cccc(F)c1C#N
Reactant: NN
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)c1ccc(F)cc1Oc1cccc2[nH]nc(N)c12

Procedure:
A mixture of EXAMPLE 428A (14.8 g), hydrazine monohydrate (2.74 mL) and N-ethyl-N-isopropylpropan-2-amine (18 mL) in dioxane (150 mL) was heated at 90° C. overnight. The solvent was removed, and the residue was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate three times. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting from 80%-100% ethyl acetate in hexanes to give the title compound.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[C:8]([NH:9]C=O)=[CH:7][CH:6]=[N:5]1.Cl>CO>[F:1][CH2:2][CH2:3][N:4]1[C:8]([NH2:9])=[CH:7][CH:6]=[N:5]1
Reactant: O=CNc1ccnn1CCF
Agent: Cl
Solvent: CO
Product: Nc1ccnn1CCF
Reaction time: 3.5 h
Yield: 93 %

Procedure:
To a solution of [1-(2-fluoroethyl)-1H-pyrazol-5-yl]formamide (15.7 g) in methanol (78 ml) was added concentrated hydrochloric acid (21 ml) at room temperature. The reaction mixture was stirred for 3.5 hours and evaporated in vacuo. The residue was dissolved in ethyl acetate and washed with aqueous sodium hydrogen carbonate solution. The organic layer was dried over magnesium sulfate and concentrated in vacuo to give 1-(2-fluoroethyl)-1H-pyrazol-5-amine (12 g).
Reaction SMILES: [CH3:1][OH:2].[H-].[Na+].I[C:6]1[C:18]2[S:17][C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[C:14]=2[C:13]([C:23]2[CH:28]=[CH:27][C:26]([O:29]S(C)(=O)=O)=[CH:25][CH:24]=2)=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[CH:11]2.Cl>CN(C)C=O.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:6]1[C:18]2[S:17][C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[C:14]=2[C:13]([C:23]2[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=2)=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[CH:11]2
Reactant: CO
Reactant: CS(=O)(=O)Oc1ccc(-c2c3ccccc3c(I)c3sc4ccccc4c23)cc1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c2ccccc2c(-c2ccc(O)cc2)c2c1sc1ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To cold (ice bath) anhydrous methanol (13.2 mL) was added sodium hydride (80% by weight suspension in mineral oil, 1.70 g, 56.6 mmol) in three portions. After stirring in the cold for 0.5 hours and at ambient temperature for 50 minutes copper II chloride (0.251 g, 1.87 mmol) and solution of methanesulfonic acid 4-(6-iodo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-phenyl ester (3.00 g, 5.66 mmol) in dry N,N-dimethylformamide (24 mL) were added. The reaction mixture was heated at reflux for approximately 3 hours, cooled to room temperature, diluted with water (400 mL), acidified with 10% hydrochloric acid and extracted with diethyl ether. The extracts were combined, silica gel was added and the solvent removed. The adsorbate was flash chromatographed (40/60 petroleum ether/methylene chloride) to provide the title compound as a white solid (1.82 g, 90%): mp 218-223° C. (dec); NMR (CDCl3); δ 8.27 (ddd, J=8, 1, 1 Hz, 1H), 7.80 (ddd, J=8, 1, 1 Hz, 1H), 7.65 (ddd, J=8, 1, 1 Hz, 1H), 7.57 (ddd, J=8, 7, 1 Hz, 1H), 7.40 (ddd, J=8, 7, 1 Hz, 1H), 7.36 (ddd, J=8, 7, 1 Hz, 1H), 7.30-7.26 (m, 2H), 7.13-7.07 (m, 3H), 6.85 (ddd, J=8, 1, 1 Hz, 1H), 4.98 (s, 1H), 4.21 (S, 3H); MS (EI): [M+], 356 (100%); Anal. Calc. for C23H16O2S: C, 77.50, H, 4.52, N, 0.00; Found C, 76.79, H, 4.61, N, 0.11.