Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[CH2:3]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1)[CH:4]([CH3:6])[CH3:5].[N+:15]([CH2:18][CH2:19][CH3:20])([O-:17])=[O:16]>C(O)C>[N+:15]([CH:18]([CH2:19][CH3:20])[CH:11]([C:10]1[CH:9]=[CH:8][C:7]([CH2:3][CH:4]([CH3:6])[CH3:5])=[CH:14][CH:13]=1)[OH:12])([O-:17])=[O:16]
Reactant: CC(C)Cc1ccc(C=O)cc1
Reactant: CCC[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCC(C(O)c1ccc(CC(C)C)cc1)[N+](=O)[O-]

Procedure:
The procedure of Example 3 was followed for the reaction of 5 ml of 3.7N potassium hydroxide with 16.2 g of p-isobutylbenzaldehyde and 26.7 g of 1-nitropropane in 7.5 ml of ethanol. Obtained was 20.0 g of a yellow viscous liquid which did not crystallize: ir (film) 2.8 (s), 3.4 (s), 6.4 (s), 7.3 (m), 9.7 (m), 12.4 (m) microns; nmr (CCl4) 7.11 (4H, q), 4.84 (1H, d), 4.42 (1H, sextet), 3.15 (1H, s), 2.44 (2H, d), 1.75 (2H, m), 0.86 (6H, d), 0.83 (3H, t) ppm.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]3[O:34][CH2:33][C:32](=[O:35])[N:31]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:30]=3[CH:41]=2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>O1CCOCC1>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]3[O:34][CH2:33][C:32](=[O:35])[N:31]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:30]=3[CH:41]=2)=[CH:7][CH:6]=1)([OH:4])=[O:2]
Reactant: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(C(=O)OC)cc3)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(C(=O)O)cc3)cc21
Temperature: 80 °C

Procedure:
A solution of 1,200 g of tert-butyl 4-(4-methoxycarbonylphenyl)-3-[4-(3-methoxypropyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate in 20 ml of dioxane is admixed with 10 ml of 2N NaOH. The reaction mixture is heated to 80° C. over 1 hour and subsequently cooled to room temperature. The phases are separated and the aqueous phase is adjusted to pH 2 with 2N HCl (9.5 ml) and extracted with tert-butyl methyl ether (2×40 ml). The organic phases are combined, washed with 50 ml of water, dried over sodium sulphate, filtered and concentrated by evaporation. The residue is recrystallized from 1:1 ethyl acetate/heptane (20 ml). The title compound is obtained as a colourless solid. Rt=4.48.
Reaction SMILES: [CH3:1][C:2]1([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C@H:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]4[NH:16][C:15]3=[O:23])[CH2:10][CH2:9]2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.Cl[C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35]>ClCCl>[O:23]=[C:15]1[N:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:2]3([CH3:1])[CH2:7][CH2:6][N:5]([C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])[CH2:4][CH2:3]3)[CH2:9][CH2:10]2)[C@H:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]2[NH:16]1
Reactant: CC1(N2CCC(N3C(=O)N[C@@H]4CCCC[C@@H]43)CC2)CCNCC1
Reactant: CC(C)OC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)OC(=O)N1CCC(C)(N2CCC(N3C(=O)N[C@@H]4CCCC[C@@H]43)CC2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 41.1 %

Procedure:
To a solution of (cis)-1-[1-(4-methyl-4-piperidyl)-4-piperidyl]-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-2-one (HCl salt, 0.3 g, 0.76 mmol) in dichloromethane (10 mL) at 0° C. was added diisopropylethyl amine (0.315 g, 2.44 mmol) followed by isopropyl chloroformate (0.112 g, 0.92 mmol) dropwise over 30 minutes and stirred at 0° C. for 2 hours. The reaction was quenched with 1N NaOH and aqueous phase extracted with dichloromethane. The combined organic phases were dried and concentrated in vacuo. The residue was then purified by using preparative LC/MS (high pH) to provide the title compound (127 mg, 41%). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.86 (s, 3H), 1.06-1.18 (m, 1H), 1.20 (d, J=6.25 Hz, 6H), 1.27-1.42 (m, 3H), 1.44-1.90 (m, 12H), 1.98-2.26 (m, 2H), 2.77-2.99 (m, 2H), 3.20-3.39 (m, 2H), 3.40-3.72 (m, 5H), 4.16-4.36 (m, 1H), 4.72-4.92 (m, 1H). MS (M+1): 407.30.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21](Br)=[C:15]3[N:14]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O>>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[O:24][CH3:23])=[C:15]3[N:14]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: COc1ccccc1B(O)O
Reactant: CC(C)OC(=O)N1CCN(c2ccn3ncc(Br)c3n2)CC1
Product: COc1ccccc1-c1cnn2ccc(N3CCN(C(=O)OC(C)C)CC3)nc12
Yield: 17.6 %

Procedure:
Prepared similarly to the preparation of example 5.6.9 from 4-(3-bromo-pyrazolo[1,5-a]pyrimidin-5-yl)-piperazine-1-carboxylic acid isopropyl ester (385.0 mg, 1.1 mmol) and 2-methoxyphenylboronic acid [5720-06-9] (191.8 mg, 1.3 mmol) to afford 76.4 mg of yellow powder as a free base, mp. 57-59° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 (d, J=6.32 Hz, 6 H) 3.48-3.54 (m, 4 H) 3.68-3.77 (m, 4 H) 3.87 (s, 3 H) 4.77-4.85 (m, 1 H) 6.76 (d, J=7.83 Hz, 1 H) 6.94-7.07 (m, 2 H) 7.10-7.18 (m, 1 H) 8.38 (dd, J=7.71, 1.64 Hz, 1 H) 8.43 (s, 1 H) 8.71 (d, J=8.08 Hz, 1 H). 13C NMR (100 MHz, DMSO-d6) δ ppm 21.95, 44.07, 55.32, 68.14, 96.93, 101.10, 111.29, 120.48, 121.64, 125.83, 127.67, 136.28, 145.00, 154.31, 155.25, 155.51. LRMS (ESI) m/z 396.1 [(M+H)]+, calc'd for C21H25N5O3: 395.47.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[CH:11]([CH3:19])[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:13].C(=O)([O-])[O-].[Na+].[Na+]>[I-].[K+].CN(C)C=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH:11]([CH3:19])[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:13])=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCOC(=O)C(C)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOC(=O)C(C)Oc1ccc(C=O)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 90.4 %

Procedure:
6.1 g of 4-hydroxybenzaldehyde, 9 g of n-butyl α-chloropropionate, 4 g of sodium carbonate, 0.2 g of potassium iodide and 20 g of dimethyl formamide, were mixed, and the mixture was stirred at 100° C. for 5 hours and then cooled to room temperature. The inorganic salts were filtered off and washed with dimethylformamide. The solution from the washing was combined with the filtrate, followed by concentration and distillation under reduced pressure, whereby 11.3 g of butyl 2-(4-formylphenoxy)propionate was obtained as a colorless transparent liquid. The boiling point was from 135 to 140° C./0.1 mmHg.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.[N+:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])#[C-:19]>C1COCC1>[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]2[O:14][CH:19]=[N:18][C:20]=2[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: [C-]#[N+]CC(=O)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1ncoc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (20 mL, 144 mmol) was added to a solution of 4-chlorobenzoyl chloride (8.4 g, 48 mmol) in THF (100 mL) at 0° C. Ethyl 2-isocyanoacetate (6.0 g, 53 mmol) was added dropwise and the resulting solution was stirred at room temperature for 1 h. The reaction mixture was partitioned between EtOAc and water. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica column with ethyl acetate and hexanes as eluents to give the desired compound. MS (m/z) 252.1 [M+H]+.
Reaction SMILES: C(O[C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2)(=O)C.S(=O)(=O)(O)O.[C:20]1([OH:30])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.C(O)C>C1CCCCC1>[C:5]12([C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:20]=3[OH:30])[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2
Reactant: CC(=O)OC12CC3CC(CC(C3)C1)C2
Reactant: Oc1cccc2ccccc12
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: C1CCCCC1
Product: Oc1c(C23CC4CC(CC(C4)C2)C3)ccc2ccccc12
Yield: 20.7 %

Procedure:
A three-necked 100 ml flask is charged with 2.7 g of 1-acetoxyadamantane and 5 ml of cyclohexane in a nitrogen atmosphere. After complete dissolution, there are introduced 1.4 g of concentrated sulfuric acid. In a single portion there is added a suspension of 2 g of 1-naphthol in 15 ml of cyclohexane and one agitates for 45 minutes. 20 ml of ethanol are added and the mixture is filtered. One washes the residue with ethanol and with water and dries on the filter. After recrystallization with cyclohexane, one obtained 0.8 g of the desired product melting at 209.2°-209.6° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]1([C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)Cl)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(#N)C>[C:7]1([C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C1CCNCC1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1ccc(C(c2ccccc2)(c2ccccc2)N2CCCCC2)cc1
Yield: 31.2 %

Procedure:
Piperidine (1.50 g, 17.6 mmol) (Wako Pure Chemical Industries, Ltd.), triphenylchloromethane (5.40 g, 19.4 mmol) (Wako Pure Chemical Industries, Ltd.), and potassium carbonate (2.68 g, 19.4 mmol) (Wako Pure Chemical Industries, Ltd.) were added to acetonitrile (30 mL) (Wako Pure Chemical Industries, Ltd.), and the mixture was refluxed for 5 hours. A saturated aqueous solution of sodium hydrogen carbonate (Wako Pure Chemical Industries, Ltd.) was added to the reaction solution, and mixture was extracted with ethyl acetate (Wako Pure Chemical Industries, Ltd.). The organic layer was dried with anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of chloroform (Wako Pure Chemical Industries, Ltd.) and n-hexane (Wako Pure Chemical Industries, Ltd.), to thereby obtain the title compound (1.80 g, 31% yield).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]#[N:21])[CH:8]=[N:7][C:6]=2[N:5]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:3]1=[O:4].[Cl:30]N1C(=O)CCC1=O>ClC(Cl)C>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]#[N:21])[C:8]([Cl:30])=[N:7][C:6]=2[N:5]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:28])([CH3:27])[CH3:29])[C:3]1=[O:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1c(=O)c2c(ncn2Cc2ccccc2C#N)n(COCC[Si](C)(C)C)c1=O
Solvent: CC(Cl)Cl
Product: Cn1c(=O)c2c(nc(Cl)n2Cc2ccccc2C#N)n(COCC[Si](C)(C)C)c1=O

Procedure:
Prepared by chlorination of 1-methyl-3-[(2-trimethylsilanyl-ethoxy)methyl]-7-(2-cyano-benzyl)-xanthine with N-chlorosuccinimide in dichloroethane while refluxing.
Reaction SMILES: C(C1C=C(C(C)C)C=C(C(C)C)C=1S(NN=[C:21]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])(=O)=O)(C)C.Br[C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH:37]=[O:38]>>[CH:36]1([CH:37]([OH:38])[C:21]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:22][CH2:23][N:24]([CH3:25])[CH3:26])[CH2:39][CH2:40][CH2:41][CH2:34][CH2:35]1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)NN=C(CCN(C)C)c2ccccc2)c(C(C)C)c1
Reactant: O=Cc1cccc(Br)c1
Product: CN(C)CC=C(c1ccccc1)C(O)C1CCCCC1

Procedure:
By using a method similar to that described in Example 22, but starting from β-dimethylaminopropiophenone 2,4,6-triisopropylbenzenesulphonylhydrazone (20 g) and 3-bromobenzaldehyde (5.6 cc), 1-(3-bromophenyl)-4dimethylamino-2-phenyl-2-buten-1-ol (Z) hydrochloride (11.3 g ) is obtained in the form of a white solid melting at 188° C. after recrystallisation from isopropanol (200 cc).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:32][C:33]1[C:42]2[C:37](=[CH:38][C:39]([OH:45])=[C:40]([O:43][CH3:44])[CH:41]=2)[N:36]=[CH:35][CH:34]=1.[N:46]1[CH:51]=[CH:50][CH:49]=[C:48]([CH2:52][CH2:53][CH2:54]O)[CH:47]=1>C(Cl)Cl>[Cl:32][C:33]1[C:42]2[C:37](=[CH:38][C:39]([O:45][CH2:54][CH2:53][CH2:52][C:48]3[CH:47]=[N:46][CH:51]=[CH:50][CH:49]=3)=[C:40]([O:43][CH3:44])[CH:41]=2)[N:36]=[CH:35][CH:34]=1
Reactant: COc1cc2c(Cl)ccnc2cc1O
Reactant: OCCCc1cccnc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Cl)ccnc2cc1OCCCc1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
Diethyl azodicarboxylate (340 mg, 2 mmol) was added dropwise to a solution of triphenylphosphine (520 mg, 2 mmol), 4-chloro-7-hydroxy-6-methoxyquinoline (265 mg, 1.26mmol), (prepared as described for the starting material in Example 3), and 3-(3-pyridyl)-1-propanol (170 mg, 1.24 mmol) in methylene chloride (10 ml). The mixture was stirred for 1 hour at ambient temperature. The volatiles were removed by evaporation and the residue was purified by column chromatography eluting with methylene chloride/acetonitrile/methanol (50/45/5 increasing to 50/40/10). The purified product was triturated with ether, collected by filtration and dried under vacuum to give 4-chloro-6-methoxy-7-(3-(3-pyridyl)propoxy)quinoline (300 mg, 72%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1Br.[CH2:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[CH2:15].[Cl-].[Li+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH2:15]([C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:11])[O:8][CH2:9][C:10]=2[C:2]=1[Br:1])[CH:14]=[CH2:13]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: O=C1OCc2c1ccc(Br)c2Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCc1ccc2c(c1Br)COC2=O

Procedure:
To a flask charged with 4,5-dibromo-2-benzofuran-1(3H)-one (170 mg, 0.59 mmol) and a stir bar was added allyl tri-n-butyltin (0.18 mL, 0.59 mmol), palladium tetrakis (68 mg, 0.059 mmol), lithium chloride (50 mg, 1.2 mmol), and toluene (5 mL). The mixture was sealed with a condensor, purged three times with nitrogen, and heated to reflux for 16 hours. The reaction was diluted with EtOAc (50 mL), adsorbed onto silica gel, and purified by silica gel flash chromatography to afford 5-allyl-4-bromo-2-benzofuran-1(3H)-one. LC-MS (IE, m/z): 253 [M+1]+;
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].C([O:10][C:11]([NH:13][C@H:14]([C:16]([NH:18][C:19]1[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:22][C:23]1[C:24]([CH3:31])=[C:25]([CH3:30])[C:26](=[O:29])[NH:27][NH+:28]=1)=[O:17])[CH3:15])=O)C>CN(C=O)C.CN(C1C=CN=CC=1)C.O.CC#N>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[F:35][C:34]1[CH:33]=[CH:32][C:21]([CH2:22][C:23]2[C:24]([CH3:31])=[C:25]([CH3:30])[C:26](=[O:29])[NH:27][NH+:28]=2)=[CH:20][C:19]=1[N:18]1[C:16](=[O:17])[CH:14]([CH3:15])[NH:13][C:11]1=[O:10]
Reactant: CCOC(=O)N[C@@H](C)C(=O)Nc1cc(Cc2[nH+][nH]c(=O)c(C)c2C)ccc1F
Agent: CN(C)c1ccncc1
Agent: O=C([O-])C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: Cc1c(Cc2ccc(F)c(N3C(=O)NC(C)C3=O)c2)[nH+][nH]c(=O)c1C
Temperature: 180 °C

Procedure:
To a solution of O2 in DMF (0.1 M) was added DMAP (3 eq) and the mixture was heated in a microwave oven at 180° C. for 2 h. The product was isolated by purification at prep RP-HPLC using H2O (+0.1% TFA) and MeCN (+0.1% TFA) as eluents. The desired fractions were lyophilized to afford the desired compound. 1H NMR (300 MHz, DMSO-d6) δ: 12.67 (1H, s), 8.52 (1H, s), 7.35-7.28 (2H, m), 7.25-7.18 (1H, m), 4.36-4.26 (1H, m), 3.97 (2H, s), 2.06-1.97 (6H, m), 1.38-1.31 (3H, m). MS (ES) C17H18FN4O3 requires: 344. found: 345 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])=[C:5]([C:14]2[S:15][CH:16]=[C:17]([CH2:19][C:20](O)=[O:21])[N:18]=2)[CH:4]=[N:3]1.[O:23]1[CH2:28][CH2:27][CH:26]([CH2:29][NH2:30])[CH2:25][CH2:24]1>>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])=[C:5]([C:14]2[S:15][CH:16]=[C:17]([CH2:19][C:20]([NH:30][CH2:29][CH:26]3[CH2:27][CH2:28][O:23][CH2:24][CH2:25]3)=[O:21])[N:18]=2)[CH:4]=[N:3]1
Reactant: NCC1CCOCC1
Reactant: Cc1ccccc1-c1c(-c2nc(CC(=O)O)cs2)cnn1C
Product: Cc1ccccc1-c1c(-c2nc(CC(=O)NCC3CCOCC3)cs2)cnn1C

Procedure:
Using the compound obtained in step 3 and (tetrahydro-2H-pyran-4-yl)methanamine and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [CH3:1][N:2]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[S:3]1(=[O:5])=[O:4].Cl[CH2:15][C:16]([O:18][CH3:19])=[O:17].CC(C)([O-])C.[K+]>CS(C)=O>[OH:13][C:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[S:3](=[O:5])(=[O:4])[N:2]([CH3:1])[C:15]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)CCl
Reactant: CN1C(=O)c2ccccc2S1(=O)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C

Procedure:
To 27 ml. of dimethylsulfoxide containing 5.18 g. (26.3 mmoles) of N-methylsaccharin and 4.6 ml. (52.5 mmoles) of methyl chloroacetate at 25° C. was added 14.1 g. (126 mmoles) of potassium t-butoxide in 44 ml. of the same solvent at the rate of 0.1 ml. every minute. After 42.2 ml. of the potassium t-butoxide solution had been added the addition was stopped. During the addition the reaction temperature was maintained at about 30°-32° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([CH3:12])[N:9]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:8]=2[CH:21]=1)([OH:3])=O.[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1)([O-:24])=[O:23]>CN(C)C=O>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][N:9]1[C:8]2[CH:21]=[C:4]([C:1](=[O:3])[NH:34][S:31]([C:28]3[CH:27]=[CH:26][C:25]([N+:22]([O-:24])=[O:23])=[CH:30][CH:29]=3)(=[O:33])=[O:32])[CH:5]=[CH:6][C:7]=2[N:11]=[C:10]1[CH3:12]
Reactant: Cc1nc2ccc(C(=O)O)cc2n1Cc1ccccc1Cl
Reactant: NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: Cc1nc2ccc(C(=O)NS(=O)(=O)c3ccc([N+](=O)[O-])cc3)cc2n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.1 %

Procedure:
N,N′-carbonyldiimidazole (0.432 g) is added all at once to an N,N-dimethylformamide (15 ml) solution of 6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole (0.432 g) (example 75), and the solution is stirred for one hour at room temperature. Subsequently, an N,N-dimethylformamide (5 ml) solution of 4-nitrobenzenesulfonamide (0.538 g) and diazabicyclotindecene (0.405 g) is added, and the solution is stirred for 84 hours at 100° C. The reaction solution is cooled and the solvent is removed through evaporation under reduced pressure. When chloroform and hydrochloric acid are added to the residue and the solution is stirred, crystals precipitated. The crystals are separated through filtration, dried, and thus, 1-(2-chlorobenzyl)-2-methyl-6-(4-nitrobenzenesulfonylcarbamoyl)benzimidazole (0.300 g) is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:26])[C:11](=[O:25])[C:12]([CH3:24])=[CH:13][C:14]=2[C:15]([NH:17][O:18][CH2:19][CH2:20][O:21]C=C)=[O:16])=[C:4]([F:27])[CH:3]=1.BrC1C=CC(NC2N(C)C(=O)C(C)=CC=2C(OC)=O)=C(F)C=1.C(OCCON)=C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:26])[C:11](=[O:25])[C:12]([CH3:24])=[CH:13][C:14]=2[C:15]([NH:17][O:18][CH2:19][CH2:20][OH:21])=[O:16])=[C:4]([F:27])[CH:3]=1
Reactant: C=COCCONC(=O)c1cc(C)c(=O)n(C)c1Nc1ccc(Br)cc1F
Agent: C=COCCON
Agent: COC(=O)c1cc(C)c(=O)n(C)c1Nc1ccc(Br)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(=O)NOCCO)c(Nc2ccc(Br)cc2F)n(C)c1=O
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 94 %

Procedure:
Preparation of 2-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-N-(2-(vinyloxy)ethoxy)-1,6-dihydropyridine-3-carboxamide: To a solution of methyl 2-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylate (0.060 g, 0.16 mmol) in THF (2 mL) was added O-(2-vinyloxy-ethyl)-hydroxylamine (0.042 ml, 0.41 mmol). The solution was cooled to 0° C. and lithium bis(trimethylsilyl)amide (0.81 ml, 0.81 mmol, 1 M solution in hexanes) was added dropwise. The reaction mixture was warmed to room temperature. After stirring for 35 minutes the reaction mixture was quenched by the addition of saturated NaHCO3 and partitioned between EtOAc and saturated NaCl. The layers were separated and the organic layer was dried (Na2SO4) and concentrated under reduced pressure. Purification by flash column chromatography (methylene chloride/MeOH, 20:1) gave 0.067 g (94%) pure desired product as an off-white crystalline solid.
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]#[N:16])=[CH:10][CH:9]=1.[N:17]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1[F:30])=[N+:18]=[N-:19]>C(O)(C)(C)C>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[N:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:22][C:21]=3[F:30])[C:15]=2[NH2:16])=[CH:10][CH:9]=1
Reactant: [N-]=[N+]=Nc1ccc(C(F)(F)F)cc1F
Reactant: N#CCc1ccc(N)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Nc1ccc(-c2nnn(-c3ccc(C(F)(F)F)cc3F)c2N)cc1
Yield: 21.3 %

Procedure:
To a stirred and ice-cooled solution of potassium tert-butoxide (1.728 g, 14.626 mmol) in tert-butanol (50 ml), commercial 4-aminophenylacetonitrile (1.418 g, 10.7258 mmol) and 1-azido-2-fluoro-4-trifluoromethyl-benzene (2.000 g, 9.7507 mmol) are added under a nitrogen atmosphere and the reaction mixture is allowed to attain spontaneously room temperature (1 h) and finally refluxed for 6 h. The resulting reaction mixture is concentrated, added water, and extracted with ethylacetate (3×100 ml). The combined organic layers are dried over MgSO4, filtered and evaporated, to afford a dark brown gummy material (3.289 g, 100% mass balance). The crude residue is purified by column chromatography over silica gel (230-400 mesh), eluting with 25% ethylacetate in petroleum ether, to obtain the title compound as a light yellow solid (0.700 g, 21% yield). M.p. 163.6-165.0° C. LC-ESI-HRMS of [M+H]+ shows 338.1021 Da. Calc. 338.102882 Da, dev. −2.3 ppm.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Br.[NH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:34]=[CH:35][C:36](=[O:39])[NH:37][N:38]=2)=[CH:29][CH:28]=1.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(N(CC)CC)C>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:1]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:34]=[CH:35][C:36](=[O:39])[NH:37][N:38]=3)=[CH:29][CH:28]=2)=[O:9])[CH:3]=1
Reactant: NCCCCOc1ccc(-c2ccc(=O)[nH]n2)cc1
Reactant: O=C(O)c1cccnc1
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCCCCOc1ccc(-c2ccc(=O)[nH]n2)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.7 %

Procedure:
868 mg of nicotinic acid, 954 mg of N-hydroxybenzotriazole and triethylamine (1.23 ml) were added to a dimethylformamide solution (50 ml) containing 2.0 g of 6-[4-(4-aminobutoxy)phenyl]pyridazin-3(2H)-one hydrobromide. 1.35 g of 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide was added to the mixture at 0° C., and the resulting mixture was stirred at room temperature for 6 hours and then poured into ice water, and precipitated crystal was collected by filtration. The crystal was recrystallized from ethanol to obtain 1.75 g of 6-[4-(4-(pyridin-3-ylcarbonylamino)butoxy)phenyl]pyridazin-3(2H)-one.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[O:10])[C:5](C)=[CH:6][CH:7]=1.O[C:12]1C(C)=CC(C=O)=CC=1>>[OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[O:10])[CH:5]=[CH:6][C:7]=1[CH3:12]
Reactant: Cc1cc(C=O)ccc1O
Reactant: Cc1ccc(O)cc1C=O
Product: Cc1ccc(C=O)cc1O

Procedure:
4-hydroxy-o-tolualdehyde; 6-hydroxy-m-tolualdehyde; and