Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][C:3]=1[CH3:10].[CH2:11]([O:13][P:14]([CH2:19][CH:20]1[CH2:22][O:21]1)(=[O:18])[O:15][CH2:16][CH3:17])[CH3:12].[Cl-].[NH4+]>C1COCC1.[Cu]I>[CH2:16]([O:15][P:14]([CH2:19][CH:20]([OH:21])[CH2:22][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:10])[CH:4]=1)(=[O:18])[O:13][CH2:11][CH3:12])[CH3:17]
Reactant: CCOP(=O)(CC1CO1)OCC
Reactant: Cc1cc([Mg]Br)ccc1F
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOP(=O)(CC(O)Cc1ccc(F)c(C)c1)OCC
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 86.6 %

Procedure:
To a solution of 4-fluoro-3-methylphenylmagnesium bromide (0.5M in Et2O, 15.5 mL, 7.75 mmol) in THF (10 mL) at −30° C. was added copper (I) iodide, CuI (196 mg, 1.03 mmol) and the reaction mixture was stirred for 10 minutes. The reaction mixture was warmed to −15° C. and oxiranylmethyl-phosphonic acid diethyl ester (1 g, 5.2 mmol) in THF (10 mL) was added. The reaction mixture was stirred at 0° C. for 2 h. Saturated aqueous ammonium chloride was added and the product was extracted into EtOAc. The organic solution was dried (MgSO4), filtered and concentrated. Purification by medium pressure chromatography (20% EtOAc in hexanes to 70% EtOAc in hexanes) provided [3-(4-fluoro-3-methyl-phenyl)-2-hydroxy-propyl]-phosphonic acid diethyl ester (1.37 g).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:25]1[C:30]2([CH2:35][CH2:34][N:33]([CH2:36][C:37]3[C:38]([F:46])=[C:39]([CH2:43][CH2:44][OH:45])[CH:40]=[CH:41][CH:42]=3)[CH2:32][CH2:31]2)[CH2:29][NH:28][CH2:27][CH2:26]1.[CH3:47][CH2:48][CH:49]([C:52]1[S:53][CH:54]=[C:55]([C:57](O)=[O:58])[N:56]=1)[CH2:50][CH3:51].C(N(CC)CC)C>CN(C=O)C.[Cl-].[Na+].O.O>[F:46][C:38]1[C:39]([CH2:43][CH2:44][OH:45])=[CH:40][CH:41]=[CH:42][C:37]=1[CH2:36][N:33]1[CH2:34][CH2:35][C:30]2([O:25][CH2:26][CH2:27][N:28]([C:57]([C:55]3[N:56]=[C:52]([CH:49]([CH2:50][CH3:51])[CH2:48][CH3:47])[S:53][CH:54]=3)=[O:58])[CH2:29]2)[CH2:31][CH2:32]1
Reactant: CCC(CC)c1nc(C(=O)O)cs1
Reactant: OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCC(CC)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4F)CC3)C2)cs1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
HATU (0.35 g) was added to a colourless solution of 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)-2-fluorophenyl)ethanol [Example 9, step b] (0.364 g), 2-(pentan-3-yl)thiazole-4-carboxylic acid [Carboxylic Acid 3] (0.141 g) and triethylamine (0.30 mL) in DMF (10 mL), pre-cooled in ice-water. The resulting yellow mixture was stirred in ice-water for 1 hour, then at room temperature for 1 hour. The solution was poured into a mixture of water and brine and extracted twice with ethyl acetate. The combined organic extracts were washed three times with water, once with brine, then dried (MgSO4), filtered and concentrated onto flash silica in vacuo. The resulting powder was purified by flash chromatography on silica eluted with triethylamine:methanol:dichloromethane (1:2:97) to afford the subtitled compound. Yield 0.324 g.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:4]#[N:5].[CH3:12][O:13][C:14]1[C:15]2[C:20]([C:21]([O:32][CH3:33])=[C:22]3[C:27]=1[CH:26]=[C:25]([S:28](Cl)(=[O:30])=[O:29])[CH:24]=[CH:23]3)=[CH:19][CH:18]=[CH:17][CH:16]=2.ClCCl>C(N(CC)CC)C>[CH3:12][O:13][C:14]1[C:15]2[C:20]([C:21]([O:32][CH3:33])=[C:22]3[C:27]=1[CH:26]=[C:25]([S:28]([O:1][N:2]=[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:4]#[N:5])(=[O:30])=[O:29])[CH:24]=[CH:23]3)=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: N#CC(=NO)c1ccccc1
Reactant: COc1c2ccccc2c(OC)c2cc(S(=O)(=O)Cl)ccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c2ccccc2c(OC)c2cc(S(=O)(=O)ON=C(C#N)c3ccccc3)ccc12
Yield: 93.8 %

Procedure:
From a mixture of 1.26 g of 2-hydroxyimino-2-phenylacetonitrile, 2.91 g of 9,10-dimethoxyanthracene-2-sulfonyl chloride, 50 ml of dichloromethane, and 0.87 g of triethylamine was obtained 3.61 g of a yellow solid product by the same procedures as in Example 1. The light irradiation was carried out on this compound in the same way as in Example 1, and the leuco dye of the above formula (VI) was added. The compound became a brilliant blue color, and the generation of an acid was observed.
Reaction SMILES: CC1(C)CO[CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17]([CH2:18][C@@H:19]([OH:30])[C@@H:20]5[O:29][C@@H:21]53)=[CH:16][CH:15]=4)[CH2:12][CH2:11]2)[CH3:9])[O:4]C1.CC1(C)COC(C([C@@H]2[C@]3(C)[C@H]([C@H]4[C@H](CC3)[C@]3(C)C(C[C@@H](O)[C@@H]5O[C@@H]53)=C[C@H]4O)CC2)C)OC1>>[O:29]1[C@H:20]2[C@H:19]([OH:30])[CH2:18][C:17]3[C@:22]([CH3:23])([C@@H:21]12)[C@@H:24]1[C:14]([C@H:13]2[C@:27]([CH3:28])([CH2:26][CH2:25]1)[C@@H:10]([CH:8]([CH:5]=[O:4])[CH3:9])[CH2:11][CH2:12]2)=[CH:15][CH:16]=3
Reactant: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C=C4C[C@@H](O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Product: CC(C=O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Yield: 58.4 %

Procedure:
The procedure of Example 36 was repeated except that 2.2 mg (0.005 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-5,7-dien-3β-ol was used in lieu of 2.2 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregn-5-ene-3β,7α-diol to give 1.0 mg of 1α,2α-epoxy-3β-hydroxypregna-5,7-diene-20-carbaldehyde (yield: 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[N:63]1[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=1[CH:69]1[CH2:73][CH2:72][CH2:71][NH:70]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:70]1[CH2:71][CH2:72][CH2:73][CH:69]1[C:64]1[CH:65]=[CH:66][CH:67]=[CH:68][N:63]=1)=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: c1ccc(C2CCCN2)nc1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(Nc1ncnc2cc(C(=O)N3CCCC3c3ccccn3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 2-(pyridin-2-yl)-pyrrolidine in DMSO at ambient temperature.
Reaction SMILES: FC(F)(F)COP([CH2:13][C:14]([O:16][CH3:17])=[O:15])(=O)OCC(F)(F)F.C1OCCOCCOCCOCCOCCOC1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[N:55]1([CH2:60][C:61]([C:63]2[CH:64]=[C:65]([CH:68]=[CH:69][CH:70]=2)[C:66]#[N:67])=O)[CH:59]=[CH:58][CH:57]=[N:56]1>O1CCCC1>[C:66]([C:65]1[CH:64]=[C:63](/[C:61](/[CH2:60][N:55]2[CH:59]=[CH:58][CH:57]=[N:56]2)=[CH:13]\[C:14]([O:16][CH3:17])=[O:15])[CH:70]=[CH:69][CH:68]=1)#[N:67]
Reactant: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Reactant: N#Cc1cccc(C(=O)Cn2cccn2)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)/C=C(/Cn1cccn1)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 32.4 %

Procedure:
To a solution of bis(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate (0.39 ml, 1.87 mmol) in 5 ml anhydrous tetrahydrofuran was added a solution of 18-crown-6 (2 g, 7.8 mmol) in 5 ml anhydrous tetrahydrofuran. Reaction was cooled to −78° C. to which a 0.5M solution of potassium bis(trimethylsilyl)amide in toluene (0.93 ml, 1.87 mmol) was added all at once. The reaction mixture was stirred at −78° C. for 20 minutes after which a solution of 3-[2-(1H-1-pyrazolyl)acetyl]-benzonitrile (330 mg, 1.56 mmol) in 5 ml anhydrous tetrahydrofuran was added dropwise over several minutes. Reaction was gradually allowed to warm to room temperature and stirred for 5 hours. Reaction was then quenched with a saturated ammonium chloride solution (10 ml) and extracted with 2×25 ml diethyl ether. Combined organic layers were washed with 2×25 ml water, 2×25 ml saturated brine solution, dried over magnesium sulfate, filtered and concentrated to a brown residue. Crude residue was chromatographed on silica gel using a gradient of 5% EtOAc in hexane containing 0.1% triethylamine to 20% EtOAc in hexane containing 0.1% triethylamine to give methyl (E)-3-(3-cyanophenyl)-4-(1H-1-pyrazolyl)-2-butenoate (135 mg, 32%) as a clear oil after drying. H1NMR (CDCl3) 3.521 (s, #H); 4.98 (s, 2H); 5.694 (s, H); 6.237-6.247 (t, H); 7.296-7.593 (m, 6H). NOE experiment confirmed the stereochemical configuration.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:11]=2[CH:12]=O)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH2:22]([NH2:24])[CH3:23]>>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:11]=2[CH2:12][NH:24][CH2:22][CH3:23])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Br)cc1-c1ccc(C(F)(F)F)cc1C=O
Reactant: CCN
Product: CCNCc1cc(C(F)(F)F)ccc1-c1cc(Br)cnc1OC

Procedure:
2-(5-Bromo-2-methoxy-pyridin-3-yl)-5-trifluoromethyl-benzaldehyde and ethylamine (2M in THF) as described in Example 3, Step 3 to provide [2-(5-bromo-2-methoxy-pyridin-3-yl)-5-trifluoromethyl-benzyl]-ethyl-amine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([CH2:26][CH:27]=[CH2:28])=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O>C1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[C:19]([CH:26]=[CH:27][CH3:28])=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: C=CCc1c([N+](=O)[O-])ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: c1ccccc1
Product: CC=Cc1c([N+](=O)[O-])ccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)CO2
Yield: 74 %

Procedure:
To a solution of 10.0 g (24.0 mmole) of (R)-[8-allyl-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate in 700 mL of benzene was added 1.03 g of bis(acetonitrile)dichloropalladium (II) and the mixture was refluxed under nitrogen for 48 hours. The catalyst was then removed by filtration and the filtrate concentrated in vacuum to a brown oil. Column chromatography on silica gel with methylene chloride as eluant gave 7.2 g of the title compound as a mixture of E and Z isomers. A sample of {(2R)-7-nitro-8[(E)-1-propenyl]-2,3-dihydro-1,4-benzo-dioxin-2-yl}methyl 4-methylbenzenesulfonate was obtained as a yellow solid (m.p. 105-106° C.) by evaporation of a pure E isomer-containing fraction.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:3]1.[OH-].[Na+].CC[O-].[Na+].[CH:20]([O-:22])=[O:21].[NH4+]>CCO.[Pd].CC(O)=O>[CH2:12]([O:11][C:9](=[O:10])[CH2:8][CH:5]1[CH2:6][CH2:7][CH:2]([C:20]([OH:22])=[O:21])[CH2:3][CH2:4]1)[CH3:13]
Reactant: O=C[O-]
Reactant: CCOC(=O)CC1CCC(=O)CC1
Agent: [Pd]
Agent: CC[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)CC1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A three liter round bottom flask was charged with ethyl (4-oxocyclohexyl)acetate (100 g, 0.588 mol) and ethanol (400 mL). Sodium hydroxide (25.8 g, 0.645 mol) was added, and the reaction was stirred at room temperature for 1 hour. Next, triethyl phosphonoacetate (128 mL, 0.645 mol) was added, and the reaction was then cooled to 0° C. A solution of NaOEt in EtOH (21% solution, 242 mL) was added dropwise to the reaction over 1 hour. The reaction was warmed to room temperature and stirred for 1 hour. HOAc (84 mL) was added, followed by ammonium formate (74 g) and 5% Pd/C (10 g). The reaction was heated to 60° C. for 6 hours and then cooled to room temperature. The solids were filtered off and the filtrate was concentrated. The residue was taken up in EtOAc (2 L) and washed with 1N HCl (2×500 mL), H2O (500 mL), and brine (500 mL). The organic layer was concentrated to an oil and azeotroped with toluene (2 L). The residue was purified by flash chromatography on silica gel (0 to 50% EtOAc/Hexanes containing 1% HOAc). This afforded 4-(2-ethoxy-2-oxoethyl)cyclohexanecarboxylic acid as a mixture of cis and trans isomers.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[N:12]1[CH:13]=[CH:14][C:9]([CH2:8][C:7]2[CH:15]=[CH:16][C:4]([NH2:1])=[CH:5][CH:6]=2)=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])c1ccc(Cc2ccncc2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(Cc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 41.6 %

Procedure:
A solution of 4-(4-nitro-benzyl)-pyridine (24 mmol, 5.1 g) in MeOH (15 mL) was hydrogenated in the presence of 500 mg palladium (10% on activated carbon). After stirring at r.t. for 20 h the reaction mixture was filtered through Celite 521. The filter aid was washed with MeOH several times. The filtrate was evaporated to dryness to afford 4-pyridin-4-ylmethyl-phenylamine (1.84 g) as a grey solid. Anal. RP-HPLC indicated a single product. A solution of this product in MeOH (15 mL) was cooled on an ice bath and was treated first with HCl (conc. 1.75 mL) followed by addition of cyanamide (50% aq soln.; 5 mL). The reaction mixture was heated at reflux for 18 h. The solvent was evaporated and the residue was washed with EtOAc/MeOH (2:1, v/v) to afford N-(4-pyridin-4-ylmethyl-phenyl)-guanidine hydrochloride (2.25 g) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.[Li]CCCC.C(O[B:16]1[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]1)(C)C>C1COCC1.[NH4+].[Cl-]>[CH3:1][N:2]1[C:6]([B:16]2[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]2)=[CH:5][CH:4]=[N:3]1
Reactant: Cn1cccn1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
To a solution of 1-methylpyrazole (4.1 g, 50 mmole) in THF (100 mL) at 0° C. was added n-BuLi (2.2M in THF, 55 mmole). The reaction solution was stirred for 1 hour at RT and then cooled to −78° C. [J. Heterocyclic Chem. 41, 931 (2004)]. To the reaction solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (12.3 mL, 60 mmole). After 15 min at −78° C., the reaction was allowed to warm to 0° C. over 1 hour. The reaction was diluted with saturated NH4Cl solution and extracted with DCM. The organics were dried over Na2SO4 and concentrated under vacuum to afford a tan solid (8.0 g, 76%) which was used without further purification. LCMS (ES) m/z 127 (M+H)+ for [RB(OH)2]; 1H NMR (CDCl3, 400 MHz) δ 7.57 (s, 1H), 6.75 (s, 1H), 4.16 (s, 3H), and 1.41 (s, 12H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[CH:15]=1.[Cl:23][C:24]1[N:29]=[CH:28][C:27]([C:30]([C:32]2[N:33]([CH3:37])[CH:34]=[N:35][CH:36]=2)=[O:31])=[CH:26][CH:25]=1>>[Cl:23][C:24]1[N:29]=[CH:28][C:27]([C:30]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=[C:5]3[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[CH:15]=2)([C:32]2[N:33]([CH3:37])[CH:34]=[N:35][CH:36]=2)[OH:31])=[CH:26][CH:25]=1
Reactant: Cn1cncc1C(=O)c1ccc(Cl)nc1
Reactant: CCOc1cccc(-c2cc(OC)nc3ccc(Br)cc23)c1
Product: CCOc1cccc(-c2cc(OC)nc3ccc(C(O)(c4ccc(Cl)nc4)c4cncn4C)cc23)c1
Yield: 52.1 %

Procedure:
Following the same procedure as that described in example 1E, 6-bromo-4-(3-ethoxy-phenyl)-2-methoxy-quinoline (2 g, 5.59 mmol) and (6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methanone (1.48 g, 6.70 mmol) generated the title compound of 26A (1.458 g, 52% yield).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:11]([Sn](CCCC)(CCCC)C=C)[CH2:12]CC.O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[N+:8]([C:7]1[C:2]([CH:11]=[CH2:12])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1ncccc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a solution of 2-chloro-3-nitropyridine (20 g, 126.15 mmol) in 1, 4 dioxane (378 mL) was added tributyl vinyl tin (48 g, 151.38 mmol). The reaction mixture was degassed using nitrogen for 30 min. Bis-(triphenylphosphin)palladium(II)-chloride (4.4 g, 6.3 mmol) was added to the reaction mixture. Reaction mass was stirred at 110° C. for overnight. The reaction mixture was cooled to rt. Water was added to the reaction mass and extracted with EtOAc. Organic layer was washed with brine and dried over Na2SO4. The organic layer was concentrated in vacuo and purified by column chromatography on silica gel using 0-5% EtOAc in hexane to give 3-nitro-2-vinylpyridine: 1H NMR (400 MHz, DMSO-d6) δ 5.741 (dd, J=2.0 Hz, J=10.4 Hz, 1H), 6.536 (dd, J=2.4 Hz, J=16.8 Hz, 1H), 7.134-7.202 (m, 1H), 7.593 (dd, J=4.4 Hz, J=8.4 Hz, 1H), 8.388 (dd, J=1.6 Hz, J=8.4 Hz, 1H), 8.857 (dd, J=0.8 Hz, J=4.4 Hz, 1H); LC-MS (ESI) m/z 151.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[NH:23][C:22]2=[O:35])[CH2:17][CH2:16]1.[CH2:36](I)[CH2:37][CH2:38][CH3:39]>>[CH2:36]([N:23]1[C:24]2[C:29](=[CH:28][C:27]([N+:32]([O-:34])=[O:33])=[CH:26][CH:25]=2)[C:30](=[O:31])[N:21]([CH:18]2[CH2:19][CH2:20][N:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)[C:22]1=[O:35])[CH2:37][CH2:38][CH3:39]
Reactant: CCCCI
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc([N+](=O)[O-])cc5c4=O)CC3)c2cc1OC
Product: CCCCn1c(=O)n(C2CCN(c3ncnc4cc(OC)c(OC)cc34)CC2)c(=O)c2cc([N+](=O)[O-])ccc21
Yield: 61 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 334.6 mg (0.7 mmol) of Compound 24 was used and butyl iodide was used in place of methyl iodide. As a result, 228.9 mg (yield: 61%) of Compound 4 was obtained as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:10]([CH2:12][C:13](OCC)=[O:14])#[N:11].N1CCCCC1>CCO>[CH:7]1[CH:6]=[C:3]2[CH:4]=[C:12]([C:10]#[N:11])[C:13]([NH:1][C:2]2=[CH:9][CH:8]=1)=[O:14]
Reactant: Nc1ccccc1C=O
Reactant: CCOC(=O)CC#N
Solvent: CCO
Solvent: C1CCNCC1
Product: N#Cc1cc2ccccc2[nH]c1=O
Temperature: 75 °C

Procedure:
To a solution of o-aminobenzaldehyde (Sigma) (5.80 g, 48 mmol) in 250 mL of EtOH was added ethyl cyanoacetate (Aldrich) (6.20 mL, 58 mmol) followed by piperidine (Aldrich) (1.4 mL, 14 mmol) at RT. The reaction was heated at 75° C. for 15 h then cooled to RT. The solid was filtered, washed with EtOH and dried in vacuo to give a pale yellow crystalline solid. MS m/z: 171 (M+1); 169 (M−1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]([CH3:16])=[C:9]2[C:10](=[O:14])[NH:11][CH2:12][CH2:13][N:8]2[N:7]=1)=O)[CH3:2].Cl[C:18]1[C:19](CO)=NN2CCN[C:23](=O)[C:22]=12.ClC1C(COC2C=CC=CC=2)=NN2CCNC(=O)C=12>>[CH3:16][C:15]1[C:6]([CH2:4][O:3][C:1]2[CH:23]=[CH:22][CH:18]=[CH:19][CH:2]=2)=[N:7][N:8]2[CH2:13][CH2:12][NH:11][C:10](=[O:14])[C:9]=12
Reactant: O=C1NCCn2nc(CO)c(Cl)c21
Reactant: CCOC(=O)c1nn2c(c1C)C(=O)NCC2
Agent: O=C1NCCn2nc(COc3ccccc3)c(Cl)c21
Product: Cc1c(COc2ccccc2)nn2c1C(=O)NCC2

Procedure:
The compound was prepared from 3-methyl-4-oxo-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine-2-carboxylic acid ethyl ester using the methods described in the preceding examples 77 (3-chloro-2-hydroxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one) and 78 (3-chloro-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one).
Reaction SMILES: [CH2:1]([C:4]1[C:12]2[N:11]=[C:10]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[N:9]([CH2:22][CH2:23][CH2:24][CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].[C:37]1([CH2:43][CH2:44][CH2:45]Cl)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C)C=O>[CH2:1]([C:4]1[C:12]2[N:11]=[C:10]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[N:9]([CH2:22][CH2:23][CH2:24][CH:25]3[CH2:26][CH2:27][N:28]([CH2:45][CH2:44][CH2:43][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH2:29][CH2:30]3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC1CCNCC1
Reactant: ClCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC1CCN(CCCc2ccccc2)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
In a 50 ml round bottom flask, under a nitrogen atmosphere, were added 4-(prop-2-enyl)-2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-4-yl)propyl]benzimidazole (898 mg, 2.12 mmol), potassium carbonate (1.46 g, 10.58 mmol), 3-(phenyl)propyl chloride (0.2 ml, 506 mg, 2.54 mmol) and N,N-dimethylformamide (7 ml). The resulting mixture was heated to 60° C. and maintained at this temperature overnight. The progress of the reaction was monitored by thin layer chromatography. An additional 1 equivalent of potassium carbonate and 0.2 ml of 3-(phenyl)propyl chloride were added and the resulting contents were stirred at 60° C. for an additional two hours. The reaction was quenched by the addition of water. The aqueous fraction was extracted wtih ethyl acetate. The organic fractions were combined, washed with water, and then dried over sodium sulfate. The solvents were removed in vacuo. The desired title product was further purified by radial chromatography.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11]([N:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=[CH:6][CH:5]=1)([O-])=O.[OH-].[K+]>Cl.C(O)C.O.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11]([N:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=[CH:6][CH:5]=1
Reactant: CN(C)S(=O)(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CN(C)S(=O)(=O)Cc1ccc(N)cc1
Reaction time: 3 h
Yield: 107.3 %

Procedure:
To a solution of 22.3 g of crude 4-nitro-N,N-dimethyl-benzenemethanesulfonamide (contaminated with dimethylamine hydrochloride as described above) in 45 mL of 2N hydrochloric acid, 100 mL of ethanol and 200 mL of water was added 5.0 g of 10% palladium on carbon. The mixture was hydrogenated in a Parr apparatus at 60 to 50 psi for three hours. The mixture was filtered and the ethanol removed in vacuo. The resulting aqueous solution was treated with 15% aqueous potassium hydroxide. Precipitate began forming at pH four. Addition of potassium hydroxide was continued until the pH had reached nine. The product was isolated by filtration and dried for sixteen hours at 65° C. at 0.05 mm Hg to give 21.0 g (83%, two steps) of 4-amino-N,N-dimethylbenzenemethanesulfonamide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[N:8][CH:9]=1)([O-])=O>[Pd].CO>[N:10]1([C:7]2[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH:14]=[N:13][CH:12]=[N:11]1
Reactant: O=[N+]([O-])c1ccc(-n2cncn2)nc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(-n2cncn2)nc1

Procedure:
5-nitro-2-(1H-1,2,4-triazol-1-yl)pyridine (100 mg, 0.523 mmol) from step 1 of this example was added Pd/C (111 mg, 0.105 mmol) and methanol (5.2 mL). Set the reaction on Parr Shaker at 50 psi (345 kPa) for overnight. The solution was filtered through CELITE and rinsed with methanol to give the title compound as a white solid.