Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([C:10]#[N:11])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]1([CH3:18])[CH:17]=CC=[CH:14][CH:13]=1.B(O)(O)O>C(O)CCC>[C:1]1([S:7]([C:10]2[CH:14]=[CH:13][C:12]([CH3:18])=[CH:17][N:11]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1
Reactant: N#CS(=O)(=O)c1ccccc1
Agent: OB(O)O
Solvent: CCCCO
Product: Cc1ccc(S(=O)(=O)c2ccccc2)nc1
Temperature: 119 °C
Yield: 94 %

Procedure:
First, 9.00 g (107 mmol) of tiglic aldehyde and 8.35 g (50.0 mmol) of benzenesulfonyl cyanide were introduced to the same reaction vessel as in Example 1. Toluene (15 ml) as the solvent and butanol (1.5 ml) were added, and 0.30 g (4.85 mmol) of boric acid was added. Then the mixture was heated under reflux for 4 hours while agitating at an internal temperature of 119° C. in a nitrogen atmosphere, separating and removing water that was produced. After this solution was cooled to room temperature, the low-boiling components, such as solvent, etc., were removed under reduced pressure and the resulting concentrate was cooled in an ice bath to precipitate crystals. The crystals were filtered with a glass filter and washed with 10 ml toluene that had been cooled to 5° C. or lower. Then the crystals were dried for 2 hours in vacuo to give 11.1 g of 2-benzenesulfonyl-5-methylpyridine as colorless crystals (purity of 99%, yield of 94% based on benzenesulfonyl cyanide).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][CH2:13][CH2:14][CH2:15][S:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1.C(=O)=O.CC(C)=O.[OH-].[Na+]>C(Cl)Cl>[Cl:12][CH2:13][CH2:14][CH2:15][S:16]([C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[O:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=[N+]([O-])c1ccc(SCCCCl)cc1
Agent: O=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(S(=O)CCCCl)cc1
Reaction time: 2 h
Yield: 4.2 %

Procedure:
A solution of m-chloroperoxybenzoic acid (80% 16.6 g, 86.3 mmol) in methylene chloride (100 mL) was added dropwise to a solution of 1-[(3-chloropropyl)thio]-4-nitrobenzene (20.0 g, 86.3 mmol) in methylene chloride (20 mL) maintained at -78° C. (dry ice/acetone bath). After 2 h the reaction was allowed to warm to ambient temperature (~1 h) and 200 mL of 10% aqueous sodium hydroxide was added. The layers were allowed to separate and the aqueous layer was extracted (100 mL) with methylene chloride. The combined organic extracts were washed (water, 100 mL), dried (MgSO4) and concentrated in vacuo. A 1.0 g sample of the residue (21.2 g) was chromatographed (Chromatatron, SiO2 4000 μ, 99/1 methylene chloride:methanol) to give 0.89 g (88%) of white solid, mp 72.5°-74.5° C.
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CO.CN(C=O)C>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: NO
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1ccc(C)cn1
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccc(N(CCCCCCC(=O)NO)c2ccccn2)nc1
Reaction time: 72 h
Yield: 75 %

Procedure:
HONH2 (50% aqueous, 1 mL) was added to II (50 mg, 0.15 mmol) in MeOH (1 mL) and DMF (0.5 mL) at rt. The reaction mixture was stirred for 72 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (3×5 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:2 to 100:8) to furnish III as a pale brown oil (37 mg, 75%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7](I)=[CH:6][C:3]=1[C:4]#[N:5].[Cl-].[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][Zn+].NC1C=CC(CC2C=CC=CC=2)=CC=1C#N>>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[Cl:12])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(I)ccc1N
Reactant: Clc1ccccc1C[Zn+]
Agent: N#Cc1cc(Cc2ccccc2)ccc1N
Agent: [Cl-]
Product: N#Cc1cc(Cc2ccccc2Cl)ccc1N

Procedure:
From 9 (488 mg, 2 mmol) and 2-chlorobenzylzinc chloride (0.5 Min THF, 10 mL, 5 mmol) by the same methods as 10a; white powder (272 mg, 62%), mp 79-80° C.; 1H NMR (CDCl3) δ 3.96 (s, 2H, CH2), 4.79 (br s, 2H, NH2), 6.69 (d, J=8.8 Hz, 1H, H-3), 7.12-7.19 (m, 5H, aromatic protons), 7.20 (s, 1H, H-6).
Reaction SMILES: [Br:1][C:2]1[C:7](=O)[NH:6][C:5]([CH:9]2[CH2:11][CH2:10]2)=[N:4][C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].S(Cl)(Cl)=O.C[N:22](C)C=O>>[NH2:22][C:7]1[N:6]=[C:5]([CH:9]2[CH2:11][CH2:10]2)[N:4]=[C:3]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]=1[Br:1]
Reactant: CCOC(=O)c1nc(C2CC2)[nH]c(=O)c1Br
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1nc(C2CC2)nc(N)c1Br
Temperature: 125 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 5-bromo-2-cyclopropyl-1,6-dihydro-6-oxo-4-pyrimidine-carboxylate (i.e. the product of Step B) (1.07 g, 3.7 mmol) in N,N-dimethylformamide (15 mL) was added thionyl chloride (0.54 mL, 7.5 mmol). The reaction mixture was stirred for 2 h. The solvent was removed with a rotary evaporator. The residue was dissolved in dichloromethane, washed with saturated aqueous sodium bicarbonate and dried (Na2SO4). The solvent was removed with a rotary evaporator. The residue was dissolved in tetrahydrofuran (2 mL), and a methanolic solution of ammonia (7 N, 2 mL) was added. The reaction mixture was placed in a sealed vial and heated in a microwave reactor at 125° C. for 2 h. The reaction mixture was allowed to stand over the weekend. Dichloromethane was added and the reaction mixture was filtered. The solvent was removed with a rotary evaporator. The residue was purified by MPLC (10→30% ethyl acetate in hexanes as eluant) to afford the title product, a compound of the present invention, as a white solid (0.52 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]=2)[C:6](=[S:19])[NH:5][C:4](=[O:20])[CH:3]=1.[N:21]([O-])=O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)(=O)C.O>[NH2:21][C:3]1[C:4](=[O:20])[NH:5][C:6](=[S:19])[N:7]([CH2:8][CH2:9][C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]=2)[C:2]=1[NH2:1]
Reactant: O=N[O-]
Reactant: Nc1cc(=O)[nH]c(=S)n1CCc1nc2ccccc2[nH]1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1c(N)n(CCc2nc3ccccc3[nH]2)c(=S)[nH]c1=O
Reaction time: 0.83 h
Yield: 50.5 %

Procedure:
To 6-amino-1-[2-(1H-benzimidazol-2-yl)ethyl]-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (0.55 g, 1.9 mmol, obtained from Example 12(b)) in acetic acid (5 mL) was added, dropwise, a solution of sodium nitrite (0.15 g, 2.1 mmol) in water (1.3 mL). After 50 min, sodium dithionite (0.67 g, 3.8 mmol) was added and the reaction stirred for 20 min, followed by evaporation of acetic acid in vacuo and addition of water (50 mL). The precipitated solid was collected by filtration, washed with water and dried in vacuo, providing the title compound (0.29 g, 50% yield). This material was used in the next step without further purification. MS (ESI)-m/z 303 (M+1).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][C:10]2[C:11]([NH2:16])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)[CH3:3].C1COCC1.[H-].[Na+].Cl[CH2:27][CH2:28][S:29](Cl)(=[O:31])=[O:30]>O>[CH3:3][CH:2]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][C:10]2[C:11]3=[N:16][S:29](=[O:31])(=[O:30])[CH2:28][CH2:27][N:12]3[CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)[CH3:1]
Reactant: CC(C)c1ccc(OCc2cccnc2N)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1ccc(OCC2=CC=CN3CCS(=O)(=O)N=C23)cc1
Reaction time: 1 h
Yield: 36.8 %

Procedure:
A mixture of 3-{[4-(1-methylethyl)phenoxy]methyl}pyridin-2-amine (600 mg) and dehydrated THF (10 ml) was added to a mixture of sodium hydride (60%, 495 mg), 2-chloroethanesulfonyl chloride (1211 mg) and dehydrated THF (10 ml) at room temperature. The reaction mixture was stirred for 1 hr, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (methanol/ethyl acetate) to give the title compound (303 mg) as a white solid. The obtained solid was crystallized from THF-diisopropyl ether to give a white solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:6][CH2:5][O:4]1.[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>C(Cl)Cl.N1C=CC=CC=1>[CH3:17][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:1][CH2:2][CH:3]2[CH2:6][CH2:5][O:4]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: OCC1CCO1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CCO2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-hydroxymethyloxetane (TCI-US, 2.0 g, 23 mmol) in 10 mL of CH2Cl2 and 10 mL of pyridine was added p-toluenesulfonyl chloride (6.5 g, 34 mmol) in portions over 15 minutes. The mixture was stirred at ambient temperature for 3 hours and was quenched with 10 mL of saturated, aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with three 5 mL portions of CH2Cl2. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification via column chromatography (SiO2, 70% hexanes in ethyl acetate) afforded the title compound. MS (DCI/NH3) m/z 243 (M+H)+, 260 (M+NH4)+.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH:3]([CH3:5])[CH3:4].C(Br)CC(C)C.[Mg].[O:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[O:21][C@@H:22]1[C@@:42]2([CH3:43])[C:26](=[CH:27][CH:28]=[C:29]3[C@@H:41]2[CH2:40][CH2:39][C@@:38]2([CH3:44])[C@H:30]3[CH2:31][CH2:32][C@@H:33]2[CH:34]([CH:36]=[O:37])[CH3:35])[CH2:25][C@@H:24]([O:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][O:47]2)[CH2:23]1.[OH-].[Na+]>O1CCCC1>[O:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[O:21][C@@H:22]1[C@@:42]2([CH3:43])[C:26](=[CH:27][CH:28]=[C:29]3[C@@H:41]2[CH2:40][CH2:39][C@@:38]2([CH3:44])[C@H:30]3[CH2:31][CH2:32][C@@H:33]2[C@H:34]([CH3:35])[CH:36]([OH:37])[CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4])[CH2:25][C@@H:24]([O:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][O:47]2)[CH2:23]1
Reactant: CC(C)CC[Mg]Br
Reactant: CC(C=O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Agent: [Mg]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)CCBr
Product: CC(C)CCC(O)[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To 20 ml of a tetrahydrofuran solution of the isoamylmagnesium bromide prepared from 2.27 g of isoamyl bromide and 0.48 g of magnesium was slowly added a solution of 5.12 g of 1α, 3β-bis(tetrahydropyran-2-yloxy)pregna-5,7-diene-20-carbaldehyde in 30 ml of tetrahydrofuran under ice-cooling. After the addition, the mixture was further stirred at 0° C. for 1 hour. To the reaction mixture thus obtained was added 2N aqueous sodium hydroxide solution, followed by extraction with diethyl ether. The extract was washed with aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The low-boiling fraction was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography. The procedure yielded 4.84 g of 1α,3β-bis(tetrahydropyran-2-yloxy)cholesta-5,7-dien-22-ol (yield: 83%) showing the following physical property.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:11]2[CH2:13][O:12]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH2:28]>C(O)(C)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[CH2:9][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:11]([OH:12])[CH2:13][NH:28][CH2:27][C:26]1[CH:29]=[CH:30][CH:31]=[C:24]([O:23][CH3:22])[CH:25]=1
Reactant: COc1cccc(CN)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1
Solvent: CC(C)O
Product: COc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)OC(C)(C)C)c1
Temperature: 22.5 °C

Procedure:
tert-Butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, EXAMPLE 3, 245 mg, 0.82 mmol) is suspended in isopropyl alcohol (6 mL) and 3-methoxybenzylamine (160 microL, 1.22 mmol) is added with stirring at 20-25 degrees C. This mixture is heated to gentle reflux (bath temp 85 degrees C.) under nitrogen for 2 hours, whereupon the resulting mixture is concentrated under reduced pressure to give the title compound. The title compound is purified by flash chromatography (2-5% methanol/methylene chloride; gradient elution) to give purified title compound.
Reaction SMILES: [OH-].[K+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.Cl.[CH2:13]([N:20]1[CH2:25][CH2:24][CH2:23][C:22](=O)[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CO>[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]=[C:22]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:3][CH:4]=2)[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C1CCCN(Cc2ccccc2)C1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C1=C(c2c[nH]c3ccccc23)CN(Cc2ccccc2)CC1
Temperature: 65 °C

Procedure:
KOH (2.12 g, 37.8 mmole), indole (1.0 g, 8.54 mmole) and 1-benzyl-3-piperidone hydrochloride (4.82 g, 21.34 mmole) were suspended in methanol (20 ml) and heated for 8 hours at 65° C. under argon. Water (40 ml) was added dropwise at RT to the mixture over a period of 40 minutes. The methanol was distilled off and the aqueous phase was extracted with EE (3×20 ml). The organic phase was dried with Na2SO4 and concentrated by evaporation. 3-(1-benzyl-1,2,5,6-tetrahydropyridine-3-yl)-1H-indole was purified by chromatography with cyclohexane/EE (1:1). The product was obtained as a yellow solid in a yield of 860 mg (35%) and an m.p. of 105°-107° C.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:20])[N:4]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:5](CC2C=CC=CC=2)=[CH:6][CH:7]=1.[K+].[Br-].[CH3:23]OC(=O)CN1C(CCC2C=CC=CC=2)=CC=C(N)C1=O>>[NH2:1][C:2]1[C:3](=[O:20])[N:4]([CH:15]([CH3:23])[C:16]([O:18][CH3:19])=[O:17])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cn1c(Cc2ccccc2)ccc(N)c1=O
Reactant: COC(=O)Cn1c(CCc2ccccc2)ccc(N)c1=O
Agent: [Br-]
Agent: [K+]
Product: COC(=O)C(C)n1cccc(N)c1=O

Procedure:
A mixture of 2(S) methyl-2[3-benzyloxycarbonylamino-1,2-dihydro-2-oxo-1-pyridyl)propionate (49a) (2.75 g, 8.33 mmol), methanol (100 ml), and 10% palladium on carbon (300 mg) was stirred under an atmosphere of hydrogen for 30 min. The mixture was filtered and concentrated to afford 1.63 g (100%) of a colorless solid: 1H NMR (d6-DMSO) δ 8.35 (1H, brs), 7.46 (1H, d), 7.22 (1H, d), 6.29 (1H, t), 5.22 (1H, q), 3.63 (3H, s), 1.55 (3H, d). The following compounds were prepared in a similar manner: Methyl [3-amino-6-benzyl-1,2-dihydro-2-oxo-1-pyridyl]acetate (50b). 100% yield as a grey solid: mp. 134-6° C.; IR (KBr) 3418, 3312, 1723, 1658, 1596, 1548, 1435, 1290, 1245, 1011; 1H NMR (d6-DMSO) δ 7.25 (5H, m), 6.45 (1H, d, J=7.4), 5.92 (1H, d, J=7.4), 5.00 (2H, s), 4.63 (2H, s), 3.88 (2H, s), 3.51 (3H, s). Methyl[3-amino-1,2-dihydro-2-oxo-6-phenethyl-1-pyridyl]acetate (50c). 99% yield as a viscous oil: IR (KBr) 3456, 341, 2953, 1745, 1649, 1600, 1548, 1219;
Reaction SMILES: Cl[C:2]1[CH:37]=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][CH2:5][N:6]([C:11]1[N:16]=[C:15]2[O:17][C:18]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)=[C:19]([C:20]([NH:22][CH3:23])=[O:21])[C:14]2=[CH:13][C:12]=1[CH:31]1[CH2:33][CH2:32]1)[S:7]([CH3:10])(=[O:9])=[O:8].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:46]1COC[CH2:47]1.O>[Pd]>[CH:31]1([C:12]2[CH:13]=[C:14]3[C:19]([C:20]([NH:22][CH3:23])=[O:21])=[C:18]([C:24]4[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=4)[O:17][C:15]3=[N:16][C:11]=2[N:6]([CH2:5][CH2:4][C:3]2[CH:34]=[CH:35][CH:36]=[CH:37][C:2]=2[CH:46]=[CH2:47])[S:7]([CH3:10])(=[O:8])=[O:9])[CH2:32][CH2:33]1
Reactant: C1CCOC1
Reactant: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCc3ccccc3Cl)S(C)(=O)=O)c(C3CC3)cc12
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=Cc1ccccc1CCN(c1nc2oc(-c3ccc(C)cc3)c(C(=O)NC)c2cc1C1CC1)S(C)(=O)=O
Temperature: 120 °C

Procedure:
Combined 6-(N-(2-chlorophenethyl)methylsulfonamido)-5-cyclopropyl-N-methyl-2-(p-tolyl)furo[2,3-b]pyridine-3-carboxamide (38 mg, 0.071 mmol), Potassium phosphate Tribasic (nH2O) (244 mg, 1.059 mmol) and Pd-catalyst (42.4 mg, 0.071 mmol) in 3.4 mL 2:1 THF/water. Heated at 120° C. μwave for 20 min. Added water 50 mL and extracted 4× with EtOAc. Conc on vac. Taken up in DMF/ACN/drop of water Purified via HPLC C18 40-75% ACN/water (0.1% NH4OH)40 mL/min over 20 min to give 10.4 mg 5-cyclopropyl-N-methyl-2-(p-tolyl)-6-(N-(2-vinylphenethyl)methylsulfonamido)furo[2,3-b]pyridine-3-carboxamide
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:8]([F:10])[F:9])=[N:4][NH:5][C:6]=1[CH3:7].C(Cl)(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:27]1[CH:32]=[CH:31][CH2:30][CH2:29][CH2:28]1>>[Br:1][C:2]1[C:3]([CH:8]([F:10])[F:9])=[N:4][N:5]([CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][O:27]2)[C:6]=1[CH3:7]
Reactant: C1=COCCC1
Reactant: Cc1[nH]nc(C(F)F)c1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1c(Br)c(C(F)F)nn1C1CCCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-bromo-3-(difluoromethyl)-5-methyl-1H-pyrazole (1.40 g, 6.63 mmol) in chloroform (30.0 mL, 0.375 mol) was added p-toluenesulfonic acid monohydrate (0.13 g, 0.66 mol) at 0° C. Dihydropyran (0.91 mL, 0.010 mol) was added and stirred at 25° C. for 2 h. The reaction was extracted with ethyl acetate and the organic extracts were washed with NaHCO3, water, saturated NaCl, dried (MgSO4) and concentrated in vacuo. The compound was chromatographed on silica gel using 10% EtOAc/hexanes to give the desired product. 1H NMR (CDCl3): δ 6.51-6.78 (t, 1H), 5.31 (dd, 1H), 4.01 (m, 1H), 3.65 (m, 1H), 2.40 (m, 1H), 2.35 (s, 3H), 2.21 (m, 1H), 1.95 (m, 1H), 1.50-1.70 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[NH2:22])=[CH:10][CH:9]=[CH:8][N:7]=1.[CH2:26]([S:28](Cl)(=[O:30])=[O:29])C>C(Cl)Cl.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[NH:22][S:28]([CH3:26])(=[O:30])=[O:29])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: Nc1cnccc1CCCOc1cccnc1Oc1cccc(Cl)c1
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cnccc1CCCOc1cccnc1Oc1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 38.4 %

Procedure:
2-(3-Chlorophenoxy)-3-[3-(3-aminopyridin-4-yl)propoxy]pyridine (0.15 g, 0.42 mmol) obtained in Example 25 is dissolved in methylene chloride (5 ml) and pyridine (0.34 ml), and thereto is added ethylsulfonyl chloride (0.04 ml, 0.50 mmol) under ice-cooling, and the mixture is stirred for 3 hours. To the mixture is added ice-water (20 ml), and the mixture is extracted with ethyl acetate (50 ml×2). The organic layer is washed with a saturated aqueous sodium hydrogen carbonate solution (20 ml×2) and a saturated brine (20 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by basic silica gel column chromatography (eluent: chloroform/methanol), and further recrystallized from diethyl ether to give the title compound (0.07 g) as colorless crystals, m.p. 131-133° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](F)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].IC1C(=O)C2C(=CC([O:49][C:50]([F:53])([F:52])[F:51])=CC=2)OC=1C1C=CC=CC=1>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][C:23]([O:49][C:50]([F:53])([F:52])[F:51])=[CH:24][CH:25]=4)[O:20][C:19]=3[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=c1c(I)c(-c2ccccc2)oc2cc(OC(F)(F)F)ccc12
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(OC(F)(F)F)ccc4c3=O)cc2)CCC1
Yield: 100 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 3-iodo-2-phenyl-7-trifluoromethoxy-chromen-4-one was reacted to give the title compound as a beige solid (83 mg, 100%). LCMS (Method B): RT=5.11 min, [M+Na]+=574.
Reaction SMILES: [C:1]([Si:5]([CH3:13])([CH3:12])[O:6][CH2:7][CH2:8][CH2:9][S:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].[O-:14]I(=O)(=O)=O.[Na+]>O.CO>[C:1]([Si:5]([CH3:12])([CH3:13])[O:6][CH2:7][CH2:8][CH2:9][S:10]([CH3:11])=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSCCCO[Si](C)(C)C(C)(C)C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CS(=O)CCCO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 20 h

Procedure:
A solution of tert-butyldimethyl(3-(methylthio)propoxy)silane (0.1 mol) in water/MeOH (3:2, 500 mL) at 0° C. was added sodium (meta)periodate (˜30 g). The reaction mixture was stirred first at 0° C. for 20 hours, then at room temperature for 3 hours. The reaction mixture was then filtered and the filtrate was concentrated under reduced pressure to remove the most of the organic solvent. The aqueous residue was then extracted with CHCl3 (2×) and the combined organic extracts were dried with anhydrous sodium sulfate. The organic phase was decanted and concentrated to yield the title compound as an oil which solidified to provide a white solid upon standing (17.65 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=2)=[CH:4][CH:3]=1.C.O.NN>C(O)(C)C.[Fe](Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: O
Solvent: CC(C)O
Product: Cc1ccc(-c2cccc(N)c2)cc1
Temperature: 65 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
4′-Methyl-3-nitro-biphenyl (1.9 g) dissolved in isopropyl alcohol (30 mL) and iron (III) chloride (0.19 g) added followed by charcoal (0.19 g). Mixture heated to 65° C. before adding hydrazine hydrate (7.6 mL) slowly for 45 minutes under nitrogen. Mixture stirred for a further 2 hours at 70° C. Mixture filtered and washed with ethyl acetate. Organics combined and washed with water (50 mL) and brine (50 mL) before drying over sodium sulfate, filtering and evaporating to dryness to leave a yellow solid (1.55 g, 95%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[CH:10][C:9]=1[N+:13]([O-:15])=[O:14].[C:16](OC(=O)C)(=O)[CH3:17]>O>[N+:13]([C:9]1[CH:10]=[N:11][N:12]2[C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:1]=[C:16]2[CH3:17])([O-:15])=[O:14]
Reactant: Nc1ccccc1-c1[nH]ncc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: Cc1nc2ccccc2c2c([N+](=O)[O-])cnn12
Yield: 50 %

Procedure:
20.4 g (0.1 mole) of 5-(o-aminophenyl)-4-nitropyrazole are heated with 100 ml of acetic anhydride for 2 hours under reflux. The solution obtained is poured into water, the precipitate that solidifies is filtered off, washed with water, dried, then boiled in a ten times' quantity of xylene for 5 hours. Thus, 11.4 g (50%) of 1-nitro-5-methylpyrazolo[1,5-c]quinazoline are obtained. M.p.: 178°-179° C.