Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[C:17]([C:20]1[CH:21]=[C:22]([N:26]=[C:27]=[O:28])[CH:23]=[CH:24][CH:25]=1)(=[O:19])[CH3:18]>>[C:17]([C:20]1[CH:21]=[C:22]([NH:26][C:27]([NH:16][C:10]2[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([C:3]3[N:4]([CH3:7])[N:5]=[CH:6][C:2]=3[Cl:1])[CH:9]=2)=[O:28])[CH:23]=[CH:24][CH:25]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)c1cccc(N=C=O)c1
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C
Product: COc1ccc(NC(=O)Nc2cccc(C(C)=O)c2)cc1-c1c(Cl)cnn1C
Yield: 6 %

Procedure:
3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 3-Acetylphenyl isocyanate in a similar manner as described in Example 1.53, providing 3.7 mg (6%) of Compound 35 (Note: Compound 35 did not precipitate out. Therefore, the CH2Cl2 was removed under reduced pressure, the residue was dissolved in 5 mL DMSO, and purified by preparative HPLC): LCMS m/z (%)=401 (M+H37Cl, 27), 399 (M+H35Cl, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.91 (s, 1H), 8.80 (s, 1H), 8.23 (s, 1H), 7.84 (d, J=8 Hz, 1H), 7.75 (dd, J1=12 Hz, J2=3 Hz, 1H), 7.62 (d, J=8 Hz, 1H), 7.56 (d, J=4 Hz, 1H), 7.49 (s, 1H), 7.43 (t, J=8 Hz, 1H), 7.16 (d, J=8 Hz, 1H), 3.84 (s, 3H), 3.69 (s, 3H), 3.42 (s, 3H).
Reaction SMILES: C(OC([NH:8][NH:9][C:10]([C:12]1[CH:21]=[CH:20][C:15]2[O:16][CH2:17][CH2:18][O:19][C:14]=2[C:13]=1[CH2:22][CH3:23])=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+].O>O>[CH2:22]([C:13]1[C:14]2[O:19][CH2:18][CH2:17][O:16][C:15]=2[CH:20]=[CH:21][C:12]=1[C:10]([NH:9][NH2:8])=[O:11])[CH3:23]
Reactant: CCc1c(C(=O)NNC(=O)OC(C)(C)C)ccc2c1OCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCc1c(C(=O)NN)ccc2c1OCCO2
Temperature: 25 °C
Reaction time: 24 h
Yield: 129.9 %

Procedure:
5.15 g (16 mmol) of N′-(5-ethyl-2,3-dihydro-benzo[1,4]dioxine-6-carbonyl)-hydrazinecarboxylic acid tert-butyl ester were added to a 200 mL round bottom flask. About 20 mL of trifluoroacetic acid were added and the reaction mixture was stirred at room temperature for 24 hours. Then about 40 mL of water were added, followed by the slow addition of cold 10% NaOH/H2O, with stirring, until the acid was neutralized (pH ˜14). The reaction mixture was transferred to a separatory funnel and extracted with ethyl acetate by shaking gently (caution: gas evolution). The ethyl acetate extract was dried and evaporated to yield 5.51 g of a pale, viscous yellow semi-solid. The material was then placed in a 50° C. vacuum oven for about 1 hour to yield 4.62 g of 5-ethyl-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid hydrazide. The t-Boc cleavage is best accomplished with neat trifluoroacetic acid; use of adjunctive solvents always resulted in much lower yields. 1H NMR (CDCl3, 500 MHz) δ (ppm): 7.0 (br, 1H), 6.83 (m, 1H), 6.71 (m, 1H), 4.28 (br s, 4H), 2.76 (m, 2H), 1.6 (br, 2H), 1.17 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[CH2:18][CH2:17][C:12]3(OCC[O:13]3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]2[CH2:18][CH2:17][C:12](=[O:13])[CH2:11][CH2:10]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(CC2CCC3(CC2)OCCO3)cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCC(Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Yield: 64.6 %

Procedure:
To a stirring solution of 8-[(4-fluorophenyl)methyl]-1,4-dioxaspiro[4.5]decane (18 g, 72 mmol) in 100 mL of THF was added 1 M hydrogen chloride in water (70 mL) followed by conc hydrogen chloride (50 mL). The reaction was heated to reflux for 5 h and then cooled to room temperature. The reaction was conc in vacuo to 120 mL and then extracted with ethyl acetate (3×100 mL). The organic layers were combined, washed with sat sodium bicarbonate, brine, dried over sodium sulfate, and conc in vacuo to a colorless oil. The oil was purified by flash chromatography (SiO2, 10:1 hexanes:ethyl acetate) to yield 9.6 g of a colorless oil. MS (ESI) 207 (M+H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH2:8][C:7]1=[O:12])C.O.[NH2:15][NH2:16]>C(O)CCC>[O:12]=[C:7]1[CH2:8][O:9][CH2:10][CH2:11][N:6]1[CH2:5][C:4]([NH:15][NH2:16])=[O:3]
Reactant: CCOC(=O)CN1CCOCC1=O
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: NNC(=O)CN1CCOCC1=O
Yield: 56 %

Procedure:
As described for example 112a, (3-oxo-morpholin-4-yl)-acetic acid ethyl ester in butanol was reacted with hydrazine hydrate at 100° C. for 6 h. Evaporation of all volatiles and chromatography (SiO2, dichloromethane:methanol:aq.ammonia (25%)=100:0:0 to 90:10:1) afforded the title compound as a white solid (yield: 56%). MS: m/e=174.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[O:11]1[C:15]2([CH2:20][CH2:19][CH:18](OS(C)(=O)=O)[CH2:17][CH2:16]2)[O:14][CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:18]2[CH2:19][CH2:20][C:15]3([O:14][CH2:13][CH2:12][O:11]3)[CH2:16][CH2:17]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: CS(=O)(=O)OC1CCC2(CC1)OCCO2
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)ccc1OC1CCC2(CC1)OCCO2
Yield: 34.2 %

Procedure:
In a manner similar to the method described in example 4a, 5-chlorosalicylaldehyde (2.32 g, 14.8 mmol) (Aldrich) reacted with methanesulfonic acid 1,4-dioxa-spiro[4.5]dec-8-yl ester (3.5 g, 14.8 mmol) and K2CO3 in N,N-dimethylformamide to give 5-chloro-2-(1,4-dioxa-spiro[4.5]dec-8-yloxy)-benzaldehyde as a colorless oil (Yield 1.5 g, 34%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[C:13]1([S:19]([CH2:21][CH2:22][CH2:23][CH2:24]Br)=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([S:19]([CH2:21][CH2:22][CH2:23][CH2:24][O:1][C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]3)=[CH:4][CH:3]=2)=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S(CCCCBr)c1ccccc1
Reactant: O=C1CCc2ccc(O)cc2N1
Product: O=C1CCc2ccc(OCCCCS(=O)c3ccccc3)cc2N1

Procedure:
Prepared analogous to Example 4 from 7-hydroxy-3,4-dihydro-carbostyril (see N. Shigematsu et al., Chem. Pharm. Bull. 1961, 970-975) and 4-phenylsulfinyl-butyl bromide.
Reaction SMILES: C[O:2][C:3](=[O:21])/[CH:4]=[CH:5]/[CH:6]=[C:7](/[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)\[C:8]1[S:9][CH:10]=[CH:11][CH:12]=1.[OH-].[Na+]>CO>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13](/[C:7](/[C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:6]/[CH:5]=[CH:4]/[C:3]([OH:21])=[O:2])=[CH:18][CH:17]=1
Reactant: COC(=O)/C=C/C=C(/c1ccc(OC)cc1)c1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(/C(=C/C=C/C(=O)O)c2cccs2)cc1
Yield: 75.9 %

Procedure:
In the manner described in Example 99, (2E,4Z)-5-(4-methoxyphenyl)-5-(2-thienyl)-2,4-pentadienoic acid methyl ester (4.7 g) was saponified in a refluxing mixture of methanol (20 mL) and 2N NaOH (20 mL). After the cooled reaction was worked up in the usual manner, the crude acid was crystallized from 2-propanol to provide 3.4 g of (2E,4Z)-5-(4-methoxyphenyl) -5-(2-thienyl)-2,4-pentadienoic acid, mp 214°-216° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Cl:11][C:12]1[CH:13]=[C:14]([OH:19])[CH:15]=[C:16]([Cl:18])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:11][C:12]1[CH:13]=[C:14]([O:19][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH:15]=[C:16]([Cl:18])[CH:17]=1
Reactant: Oc1cc(Cl)cc(Cl)c1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1Oc1cc(Cl)cc(Cl)c1
Reaction time: 3 h

Procedure:
A mixture of 2-fluoro-1-nitrobenzene (0.7 ml, 6.47 mmol), 3,5-dichloro-phenol (1.56 g, 9.8 mmol) and potassium carbonate (1.35 g, 9.78 mmol) in dimethylformamide (4 ml) was refluxed with stirring for 3 h. After removal of dimethylformamide, the residue was dissolved in ether (20 ml), and washed with sodium hydroxide (5%, 3×20 ml). The organic layers were combined, dried (MgSO4), filtered and evaporated in-vacuo. The product was obtained as a light yellow solid, 0.57 g, 33%. m.p. 78-80° C.; 1H NMR (270 MHz, CDCl3) δ 6.88 (2H, d, J=1.7 Hz, ArHE, ArHG), 7.12 (1H, t, J=1.7 Hz, ArHF), 7.12 (1H, dd, J=1.2, 8.2 Hz, ArHD), 7.32 (1H, td, J=7.4, 1.2 Hz, ArHB), 7.6 (1H, td, J=7.4, 1.7 Hz, ArHC), 8.0 (1H, dd, J=8.2, 1.7 Hz, ArHA).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:32][OH:33])[CH2:6][C:5]([CH2:29][C:30]#[N:31])([N:7]2[CH:11]=[C:10]([C:12]3[C:13]4[CH:20]=[CH:19][N:18](COCC[Si](C)(C)C)[C:14]=4[N:15]=[CH:16][N:17]=3)[CH:9]=[N:8]2)[CH2:4]1.FC(F)(F)C(O)=O.C(N)CN>CO>[OH:1][CH2:2][C:3]1([CH2:32][OH:33])[CH2:4][C:5]([CH2:29][C:30]#[N:31])([N:7]2[CH:11]=[C:10]([C:12]3[C:13]4[CH:20]=[CH:19][NH:18][C:14]=4[N:15]=[CH:16][N:17]=3)[CH:9]=[N:8]2)[CH2:6]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(CO)(CO)C4)c3)ncnc21
Solvent: NCCN
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CC(CO)(CO)C1

Procedure:
3,3-Bis(hydroxymethyl)-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutylacetonitrile (0.022 g, 0.000046 mol) was treated with trifluoroacetic acid (0.5 mL, 0.006 mol) at rt for 30 min and evaporated to dryness. The residue was then mixed with ethylenediamine (0.2 mL, 0.003 mol) in MeOH (1 mL) for 2 h. The reaction was concentrated and purified on prep. LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.15% NH40H) to give the desired product as free base. LCMS calculated for C17H19N6O2(M+H)+: 339.2; Found: 339.3. 1H NMR (300 MHz, CD3OD): δ 8.72 (1H, s), 8.67 (1H, s), 8.39 (1H, s), 7.51 (1H, d, J=3.3 Hz), 6.97 (1H, d, J=3.3 Hz), 3.62 (2H, s), 3.46 (2H, s), 3.36 (2H, s), 2.80 (2H, d, J=13.8 Hz), 2.54 (2H, d, J=13.8 Hz) ppm.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[C:14]([N:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][OH:26])[CH2:19][CH2:18]1)(=[O:16])[CH3:15].C(N(CC)CC)C>ClCCl>[C:2](=[O:3])([O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[O:26][CH2:25][CH2:24][CH2:23][N:20]1[CH2:21][CH2:22][N:17]([C:14](=[O:16])[CH3:15])[CH2:18][CH2:19]1
Reactant: CC(=O)N1CCN(CCCO)CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(CCCOC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Nitrophenyl chloroformate (0.733 g; 3.63 mmol) was added to a solution of 3-(4-acetylpiperazin-1-yl)propanol [Synthesis (1997), 6, 643-648] (0.645 g; 3.46 mmol) and triethylamine (0.51 ml; 3.36 mmol) in dichloromethane (7 ml) under argon atmosphere at 0° C. The mixture was stirred at ambient temperature for 1 hour, evaporated to dryness and purified by flash chromatography, eluting with dichloromethane/ethanol (95/5) to give 3(-4-acetylpiperazino)propyl 4-nitrophenyl carbonate.
Reaction SMILES: Br[C:2]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[C:14]=1[Br:25].[CH3:26][CH2:27][SH:28].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[Br:25][C:14]1[C:15]([O:23][CH3:24])=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=1[CH2:12][N:6]1[CH:5]=[N:4][C:3]2[C:7]1=[N:8][C:9]([NH2:11])=[N:10][C:2]=2[S:28][CH2:27][CH3:26]
Reactant: COc1cc(Cn2cnc3c(Br)nc(N)nc32)c(Br)c(OC)c1OC
Reactant: CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCSc1nc(N)nc2c1ncn2Cc1cc(OC)c(OC)c(OC)c1Br
Temperature: 70 °C

Procedure:
A mixture of 6-bromo-9-(2-bromo-3,4,5-trimethoxy-benzyl)-9H-purin-2-ylamine (see previous example), EtSH, K2CO3 and THF was placed in a pressure vessel and heated to 70° C. for 6 h. Work-up and purification by preparative TLC (EtOAc:hexane 1:1) gave the title compound. HPLC Rt: 6.039 min. 1H-NMR (CDCl3): δ 7.72 (s, 1H), 6.62 (s, 1H), 5.30 (s, 2H), 4.98 (s, 2H), 3.91 (s, 3H), 3.88 (s, 3H), 3.74 (s, 3H), 3.35–3.29 (q, 2H), 1.44–1.41 (t, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])O.[Na+].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1>C(O)C>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[N:12]=3)=[CH:4][C:3]=2[N+:17]([O-:19])=[O:18])=[CH:29][CH:28]=1
Reactant: COc1ccc(N)cc1
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(Nc2ccc(-c3nc4ccccc4o3)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.5 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (300 mg, 1.19 mmol) in ethanol (5 mL) was added sodium hydrogen carbonate (295 mg, 2.32 mmol) and p-anisidine (357 mg, 2.90 mmol), and this was heated to reflux with stirring for 4 hours. After the reaction was complete, this was cooled to room temperature, the precipitated crystals were filtered off, and after washing with water and ethanol the crystals were dried to yield the title compound (359 mg, 86% yield) as orange crystals.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[Cl:13][C:12]1[C:7]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: c1cn[nH]c1
Reactant: Clc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1cccnc1-n1cccn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
A mixture of 2 g of pyrazole, 4.34 g of 2,3-dichloropyridine, 9.58 g of cesium carbonate and 40 ml N,N-dimethylformamide was stirred at 100° C. for 8 hours. The reaction mixture was allowed to cool to room temperature, and water was added thereto. The mixture was extracted with methyl tert-butyl ether three times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 3.57 g of 3-chloro-2-(1H-pyrazol-1-yl)pyridine of the formula:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].II>C(#N)C>[F:11][C:2]([F:1])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][S:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:11])([F:10])[F:1]
Reactant: FC(F)(F)c1ccccc1S
Agent: II
Solvent: CC#N
Product: FC(F)(F)c1ccccc1SSc1ccccc1C(F)(F)F
Temperature: 25 °C
Yield: 88.3 %

Procedure:
A solution of 2-(trifluoromethyl)benzenethiol (0.185 mL, 1.40 mmol) in wet acetonitrile (1:5 water/acetonitrile) was added Iodine (0.178 g, 0.702 mmol) and allowed to stir over night at room temperature. The reaction was concentrated, then diluted with EtOAc and quenched with aqueous sodium thiosulfate, extracted and dried organic with brine, Na2SO4, filtered and concentrated to afford the title compound (219 mg, 44% yield) as a colorless oil.
Reaction SMILES: [S:1]([O:5][C:6]1[C:23]2[C@@H:22]3[C@@H:13]([C@H:14]4[C@@:18]([CH2:20][CH2:21]3)([CH3:19])[C@@H:17]([OH:24])[CH2:16][CH2:15]4)[CH2:12][CH2:11][C:10]=2[CH:9]=[C:8]([O:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:7]=1)([CH3:4])(=[O:3])=[O:2].[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1>[S:1]([O:5][C:6]1[C:23]2[C@@H:22]3[C@@H:13]([C@H:14]4[C@@:18]([CH2:20][CH2:21]3)([CH3:19])[C@@H:17]([O:24][C:30](=[O:32])[CH3:31])[CH2:16][CH2:15]4)[CH2:12][CH2:11][C:10]=2[CH:9]=[C:8]([O:25][S:26]([CH3:29])(=[O:27])=[O:28])[CH:7]=1)([CH3:4])(=[O:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12CC[C@@H]3c4c(cc(OS(C)(=O)=O)cc4OS(C)(=O)=O)CC[C@@H]3[C@@H]1CC[C@@H]2O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1CC[C@H]2[C@H]3CCc4cc(OS(C)(=O)=O)cc(OS(C)(=O)=O)c4[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 72 h

Procedure:
A solution of 200 mg. of 1,3-bis(mesyloxy)-8α-estra-1,3,5(10)-trien-17β-ol in 3 ml. of pyridine is combined with 2 ml. of acetic anhydride and allowed to stand at room temperature for 3 days. Then, the mixture is introduced into ice water, extracted with methylene chloride, washed with water, dried, and evaporated. The residue (180 mg.) is purified by layer chromatography, thus obtaining 150 mg. of 1,3-bis(mesyloxy)-17β-acetoxy-8α-estra- 1,3,5(100-triene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][NH2:26]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:26][NH:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=1)=[O:14]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: NNc1ccccn1
Product: O=C(NNc1ccccn1)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]-N′-pyridin-2-ylisonicotinohydrazide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.5 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.8 mmol of pyridin-2-yl-hydrazine. LC/MS [6.90 min; 450 (M+1)]
Reaction SMILES: [CH3:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[C:11]([OH:13])=[O:12].S(=O)(=O)(O)O.[CH3:19]O>>[CH3:19][O:12][C:11]([C@H:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C@H:2]1[CH3:1])=[O:13]
Reactant: C[C@@H]1c2ccccc2C[C@@H]1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)[C@H]1Cc2ccccc2[C@H]1C
Yield: 91 %

Procedure:
cis-2,3-Dihydro-1-methyl-1H-indene-2-carboxylic acid methyl ester is prepared from cis-2,3-dihydro-1-methyl-1H-indene-2-carboxylic acid (see Example 4) by the standard methods using methanol and concentrated sulphuric acid. Yield 91%.
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1[C:8]([C:9]([O:11]CC)=[O:10])=[C:7]([CH2:14][CH2:15][CH3:16])[C:6]([C:17]([O:19]CC)=[O:18])=[C:5]([C:22]([F:25])([F:24])[F:23])[N:4]=1.[OH-].[K+]>CO>[F:26][CH:2]([F:1])[C:3]1[C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH2:14][CH2:15][CH3:16])[C:6]([C:17]([OH:19])=[O:18])=[C:5]([C:22]([F:25])([F:23])[F:24])[N:4]=1
Reactant: CCCc1c(C(=O)OCC)c(C(F)F)nc(C(F)(F)F)c1C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(C(=O)O)c(C(F)F)nc(C(F)(F)F)c1C(=O)O
Yield: 24.4 %

Procedure:
A mixture of 20.1 g (0.0525 mole) of the product of Example 13, 11.4 g of 85% KOH, and 100 ml of methanol is held at reflux for 19 hours and concentrated. The residue is treated with 200 ml of water and extracted with ether. The aqueous layer is separated and acidified with 30 ml of concentrated HCl. The oily precipitate is extracted into ether and the ether extract is dried and concentrated. The residue is recrystallized from chloroform to give 4.2 g (24%) of the desired product, m.p. 235.5°-236.5° C.
Reaction SMILES: [C:1]1([CH:7]2[S:12][CH2:11][CH2:10][CH2:9][S:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[C:18]1([CH3:26])[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]=[O:25])[CH:19]=1>C1COCC1>[C:1]1([C:7]2([CH:24]([C:20]3[CH:19]=[C:18]([CH3:26])[CH:23]=[CH:22][CH:21]=3)[OH:25])[S:8][CH2:9][CH2:10][CH2:11][S:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2SCCCS2)cc1
Reactant: Cc1cccc(C=O)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cccc(C(O)C2(c3ccccc3)SCCCS2)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
2-Phenyl-[1,3]dithiane (JYC-II-051-A) (10.0 g, 50.9 mmol) in 100 mL of anhydrous THF w a s cooled down to −78° C. nBuLi (22.4 mL of 2.5 M solution in hexanes, 56 mmol) was added dropwise and the mixture was stirred at −78° C. for 1 h. A solution of m-tolualdehyde (6.12 g, 50.9 mmol) in anhydrous THF was added to the mixture dropwise via a cannula at −78° C. under N2 counterflow. The reaction was then warmed up to room temperature and stirred at room temperature overnight. The mixture was quenched with a saturated NH4Cl aqueous solution. The organic phase was washed with H2O and dried over anhydrous MgSO4. The solvent was removed under reduced pressure to give brown oil. The product was purified by column chromatography (silica gel, hexanes:dichloromethane=1:2 (v/v)) to give light yellow oil (12.35 g, 76.6%). 1H NMR (300 MHz, CDCl3, δ): 7.66-7.70 (m, 2H), 7.25-7.33 (m, 3H), 6.98-7.02 (m, 2H), 6.64-6.68 (m, 1H), 6.56 (s, 1H), 4.94 (s, 1H), 2.86 (br s, 1H), 2.58-2.76 (m, 4H), 2.16 (s, 3H), 1.86-1.95 (m, 2H). 13C{1H} NMR (75 MHz, CDCl3, δ): 136.90, 136.74, 135.67, 130.14, 128.43, 128.06, 127.41, 126.86, 126.20, 124.80, 80.39, 65.90, 26.85, 26.62, 24.42, 21.04. HRMS-EI (m/z): [M]+ calcd for C18H20OS2, 316.09556; found, 316.09640.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[CH3:18][NH:19][O:20][CH3:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:21][O:20][N:19]([CH3:18])[C:7](=[O:9])[C:6]1[CH:10]=[C:2]([CH3:1])[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:4][CH:5]=1
Reactant: CNOC
Reactant: Cc1cc(C(=O)O)cnc1OCC(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cnc(OCC(F)(F)F)c(C)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.5 %

Procedure:
A mixture of 5-methyl-6-(2,2,2-trifluoroethoxy)nicotinic acid (2.27 g, 9.67 mmol, Step-1), N,O-dimethylhydroxylamine hydrochloride (1.04 g, 10.64 mmol), HBTU (5.50 g, 14.51 mmol) and triethylamine (5.39 mL, 38.7 mmol) in DCM (30 mL) is stirred at rt for 1.5 hours. The reaction mixture is poured into saturated aqueous sodium hydrogen carbonate (300 mL) and extracted with DCM (500 mL). The organic layer is washed with saturated aqueous sodium hydrogen carbonate (300 mL×2) and dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (4:1) to give 2.03 g (76% yield) of the title compound as colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([CH:11]2[NH:6][C:4](=[O:5])[C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[O:1]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: NC(=O)c1ccccc1O
Product: O=C1NC(c2ccccc2)Oc2ccccc21

Procedure:
2-Hydroxybenzamide was transformed by Method G (using benzaldehyde). M.p. 157–160° C.
Reaction SMILES: C[Si](C)(C)[C:3]1[C:8]([CH2:9][CH2:10][CH:11]=[O:12])=[CH:7][N:6]=[C:5]2[O:13][CH2:14][CH2:15][C:4]=12>CCCC[N+](CCCC)(CCCC)CCCC.C1C=CC([Si-](F)(F)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC.[Cl-].[NH4+]>[CH2:15]1[C:4]2[C:5](=[N:6][CH:7]=[C:8]3[CH2:9][CH2:10][CH:11]([OH:12])[C:3]3=2)[O:13][CH2:14]1
Reactant: C[Si](C)(C)c1c(CCC=O)cnc2c1CCO2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: F[Si-](F)(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: COCCOC
Product: OC1CCc2cnc3c(c21)CCO3
Yield: 70.9 %

Procedure:
To a solution of tetrabutylammonium difluorotriphenylsilicate (43.3 mg, 0.802 mmol) in 1,2-dimethoxyethane (3 mL) heated to 70° C. was added dropwise a solution of 3-[4-(trimethylsilyl)-2,3-dihydrofuro[2,3-b]pyridin-5-yl]propanal (100 mg, 0.401 mmol) in 1,2-dimethoxyethane (1 mL). After dropwise addition, the reaction solution was diluted with saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70→100/0) to give the title compound (50.4 mg, yield 71%).