Azzindani/Open_Reaction_Data huggingface dataset:
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][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:35][CH2:36][CH:37]([OH:40])[CH2:38][CH3:39].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[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][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:24](=[O:26])[O:40][CH:37]([CH2:38][CH3:39])[CH2:36][CH3:35])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CCC(O)CC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCC(CC)OC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Yield: 57.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 3-pentanol (23 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (40 mg, yield 53%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:25])[CH2:9][CH2:10][CH:11]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:18][C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[C:4]([CH3:26])[CH:3]=1.[CH3:27][N:28](C)C=O>Cl.O>[C:27]([C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:25])[CH2:9][CH2:10][CH:11]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[O:18][C:19]3[C:24]2=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:4]([CH3:26])[CH:3]=1)#[N:28]
Reactant: CN(C)C=O
Reactant: Cc1cc(Br)ccc1C(=O)CCC1c2ccccc2Oc2ccccc21
Agent: Cl
Solvent: O
Product: Cc1cc(C#N)ccc1C(=O)CCC1c2ccccc2Oc2ccccc21
Reaction time: 24 h

Procedure:
A solution of cuprous cyanide (2.7 g, 30.5 mmol) and 1-(4-bromo-2-methylphenyl)-2-(9H-xanthen-9-ylmethyl)ethanone (10 g, 25.4 mmol) in dry dimethylformamide (80 ml) was heated to reflux under an atmosphere of nitrogen. After 24 h, further cuprous cyanide (2 g, 22.3 mmol) was added and reflux continued for another 20 h. The reaction mixture was cooled and a solution of ferric chloride (8.6 g, 52.9 mmol) in aqueous hydrochloric acid (2M, 200 ml) added. The resulting solution was diluted with water (400 ml) and extracted twice with diethyl ether, the combined extracts were washed with water (5×) and a saturated solution of sodium chloride. The organic phase was dried over magnesium sulphate, filtered and evaporated to a yellow oil. Purified on flash silica eluting with hexane-dichloromethane (4:1 then 3:2 then 1:1) to give 1-(4-cyano-2-methylphenyl)-2-(9H-xanthen-9-ylmethyl)ethanone as a yellow oil. Sample crystallised from hexane m.p. 138°-141° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20](F)=[N:21][CH:22]=3)[C:9]=2[F:24])[CH:5]=[CH:6][CH:7]=1.[N+](C1C=C(B(O)O)C=CC=1)([O-])=[O:26].N12[CH2:47][CH2:46][CH2:45][N:44]=[C:43]1CCCCC2>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([N:44]4[CH2:43][CH2:47][CH:46]([OH:26])[CH2:45]4)=[N:21][CH:22]=3)[C:9]=2[F:24])[CH:5]=[CH:6][CH:7]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: COc1ccc(Cc2ccc(F)nc2)c(F)c1-c1cccc(Cl)c1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Solvent: ClCCl
Product: COc1ccc(Cc2ccc(N3CCC(O)C3)nc2)c(F)c1-c1cccc(Cl)c1
Temperature: 100 °C

Procedure:
To 5-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine (P-456, 0.3 g, 0.87 mmol) and 3-pyrrolidinol (2) (0.15 g, 1.74 mmol) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.66 g, 4.34 mmol). The reaction mixture was stirred and heated at 100° C. for 2.5 h, cooled to room temperature, diluted with dichloromethane (8 mL), washed with 0.5 N HCl (2×4 mL), dried with Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography using 5% methanol in dichloromethane to afford 0.27 g (75%) of P-601 as white solid. 1H NMR (DMSO-d6, 400 MHz): 7.95 (s, 1H), 7.2-7.46 (m, 6H), 6.91 (d, J=8.4 Hz, 1H), 6.35 (d, J=8.4 Hz, 1H), 4.9 (d, J=3.6 Hz, 1H), 4.32-4.4 (m, 1H), 3.76 (s, 2H), 3.71 (s, 3H), 3.12-3.45 (m, 4H), 1.8-2.05 (m, 2H) ppm; MS (APCI+): 413.1 (M+1), LC-MS: 91.6%.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][N:3]=[N:2]1.C(N(CC)CC)C.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.C([NH+](CC)CC)C>C1COCC1>[C:13]([N:1]1[CH:5]=[N:4][N:3]=[N:2]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: c1nnn[nH]1
Agent: CC[NH+](CC)CC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(c1ccccc1)n1cnnn1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a stirring suspension of 1H-tetrazole (7.0 g, 0.1 mol) and triethylamine (15 ml, 0.12 mol) in anhydrous THF (300 ml), in a bath maintained at 0° C., was added benzoyl chloride (99%, 12.8 ml, 0.11 mol) slowly over 30 min. When addition was complete, the mixture was stirred for an additional 45 min. A precipitate formed, identified as triethylammonium hydrochloride (using NMR spectroscopy), was removed by filtration through a pad of Celite 545. The solvent was removed under reduced pressure while the bath temperature was maintained below 30° C. A residual oil was obtained. Crystallization of the residual oil in hexanes yielded N-benzoyltetrazole as colorless crystals. The crystals were removed by filtration, washed with hexanes (2×15 ml) and dried under vacuum for approximately 15 hours at room temperature. Yield: 15 g, 86%; m.p. 56-58iC; 1H NMR, (CDCl3) δ 9.43 (s, 1H), 8.26-8.22 (d, J=, 2H), 7.79-7.54 (m, 3H); 13C NMR, (CDCl3) 162.9, 143.7, 136.3, 132.7, 129.7 and 129.5. HRMS: (FAB) for C8H7N4O (MH+) 175.0620, found 175.0627.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH2:13])=[NH:12].[Cl:14][C:15]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:16]=1[CH:17]=[C:18]([C:21]#[N:22])[C:19]#[N:20]>>[NH2:22][CH2:21][C:18]1[C:19]([NH2:20])=[N:12][C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[N:13][C:17]=1[C:16]1[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:15]=1[Cl:14]
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Reactant: N=C(N)c1ccc2ccccc2c1
Product: NCc1c(N)nc(-c2ccc3ccccc3c2)nc1-c1ccc(Cl)cc1Cl

Procedure:
The title compound, MS: m/e=394.9 (M+H+), was prepared from naphthalene-2-carboxamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[N:10][C:11]([Cl:15])=[CH:12][C:13]=1[I:14])(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[Cl:15][C:11]1[N:10]=[CH:9][C:8]([NH2:7])=[C:13]([I:14])[CH:12]=1
Reactant: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1I
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Nc1cnc(Cl)cc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
A solution of (6-chloro-4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester (8.6 g, 24.3 mmol) dissolved in CH2Cl2 was treated with 4 N HCl/dioxane (100 mL) and stirred at room temperature for 2 hours. The reaction mixture was diluted with CH2Cl2 and washed with 2 N NaOH. The organic layer was dried over MgSO4 and concentrated to give the product as a solid (6.2 g, 100%).
Reaction SMILES: [H-].[Na+].C(O)C.[Cl-].[CH2:7]([O:9][C:10](=[O:40])[CH2:11][O:12][C:13]1[CH:38]=[CH:37][C:16]([CH2:17][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:15][C:14]=1[CH3:39])[CH3:8].[CH3:41][C:42]1[N:43]=[C:44]([C:49]2[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][CH:50]=2)[S:45][C:46]=1[CH:47]=O>O>[CH2:7]([O:9][C:10](=[O:40])[CH2:11][O:12][C:13]1[CH:38]=[CH:37][C:16]([CH:17]=[CH:47][C:46]2[S:45][C:44]([C:49]3[CH:50]=[CH:51][C:52]([C:55]([F:58])([F:56])[F:57])=[CH:53][CH:54]=3)=[N:43][C:42]=2[CH3:41])=[CH:15][C:14]=1[CH3:39])[CH3:8]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Reactant: CCOC(=O)COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1C
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)COc1ccc(C=Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium hydride (0.040 g, 60% dispersion in mineral oil) was added to anhydrous ethanol (20 ml) followed by [4-(2-ethoxy-2-oxoethoxy)-3-methylbenzyl](triphenyl)phosphonium chloride (intermediate 18, 0.45 g) after 10 minutes. After a further 10 minutes 4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carbaldehyde (intermediate 2, 0.24 g) was added and the reaction mixture stirred at ambient temperature for 3 hours. The reaction mixture was treated with water and then the mixture extracted with chloroform. The chloroform solution was separated with a hydrophobic frit and excess aldehyde removed using 3-[4-(hydrazinosulfonyl)phenyl]propionyl AM resin (0.50 g). The crude product remaining after this treatment was purified by Biotage™ chromatography using a mixture of petroleum ether:ethyl acetate (5:1) as eluent to give the title compound as a mixture of E and Z isomers.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:31])[CH2:16][NH:17][C@H:18]([CH3:30])[CH2:19][C:20]2[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=2)[C:23]([O:25][CH3:26])=[O:24])=[CH:11][C:10]=1[CH2:32][OH:33])C1C=CC=CC=1>[Pd].C(O)C>[NH3:17].[OH:31][C@H:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([CH2:32][OH:33])[CH:11]=1)[CH2:16][NH:17][C@H:18]([CH3:30])[CH2:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)c1cccc(C[C@@H](C)NC[C@H](O)c2ccc(OCc3ccccc3)c(CO)c2)c1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1cccc(C[C@@H](C)NC[C@H](O)c2ccc(O)c(CO)c2)c1
Product: N
Temperature: 25 °C
Reaction time: 18 h
Yield: 187.4 %

Procedure:
A suspension of methyl 3-[(2R)-2-({(2R)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-hydroxyethyl}amino)propyl]benzoate (Preparation 61) (6.83 g, 15.2 mmol) and 10% palladium on carbon (683 mg) in ethanol (100 ml) was stirred under an atmosphere of hydrogen (60 psi) at room temperature for 18 hours. The catalyst was filtered off through arbocel and the filtrate concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (95:5:0.5 changing to 90:10:1, by volume) to give the title compound as a pale yellow gum (5.12 g). 1H NMR (400 MHz, CD3OD): δ=7.85-7.83 (1H, m), 7.79 (1H, s), 7.36-7.35 (2H, m), 7.20 (1H, s), 7.02-6.99 (1H, dd), 6.68-6.65 (1H, d), 4.61-4.58 (1H, m), 4.60 (2H, s), 3.90 (3H, s), 2.97-2.87 (2H, m), 2.80-2.62 (3H, m), 1.08-1.07 (3H, d) ppm. LRMS (electrospray): m/z [M+H]+ 360, [M+Na]+ 382, [M−H]− 358.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:33])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][CH2:19][CH2:20][CH2:21][N:22]4C(=O)C5=CC=CC=C5C4=O)=[CH:14][CH:13]=3)[O:11][C:6]=2[C:5]([F:34])=[CH:4][C:3]=1[F:35]>CN(C)C=O.CO.O.NN>[NH2:1][C:2]1[C:7]2[C:8](=[O:33])[CH:9]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([NH:18][CH2:19][CH2:20][CH2:21][NH2:22])=[CH:16][CH:17]=3)[O:11][C:6]=2[C:5]([F:34])=[CH:4][C:3]=1[F:35]
Reactant: Nc1c(F)cc(F)c2oc(-c3ccc(NCCCN4C(=O)c5ccccc5C4=O)cc3)cc(=O)c12
Agent: NN
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: NCCCNc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1
Reaction time: 1.5 h

Procedure:
600 mg of Compound 23 was dissolved in 75 ml of a mixed solvent of dimethylformamide and methanol (1:1), 0.613 ml of hydrazine monohydrate was added and the mixture was stirred at 50° to 60° C. for 1.5 hours. Additional 0.307 ml of hydrazine monohydrate was added and the mixture was stirred at 50° to 60° C. for 10 minutes. The reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (chloroform:methanol:aqueous ammonia =9:1:1) to give Compound 24 which was dissolved in ethanol, a 5.5N hydrochloric acid-isopropylalcohol solution was added, and the precipitated crystals were collected by filtration to give 331 mg (69%) of Compound 24.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:2]=[CH2:3].[PH2:13]([OH:15])=[O:14].C1C(C(OOC(C)(C)C)=O)=CC=CC=1.CCCCCCC>C(O)(C)C.O>[CH2:5]([O:4][CH2:1][CH2:2][CH2:3][PH:13](=[O:14])[OH:15])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=[PH2]O
Reactant: C=CCOCCCCCCCC
Agent: CC(C)(C)OOC(=O)c1ccccc1
Solvent: CCCCCCC
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCCOCCC[PH](=O)O
Reaction time: 0.5 h

Procedure:
Allyloxyoctane of step a) (15 g, 0.0882 mols), 50% hypophosphorous acid (15 mL, 0.0882 mols) and tert-butyl perbenzoate (1 mL) in 100 mL isopropyl alcohol are heated at 100° C. for 26 hrs. After completion of the reaction, a mixture of 200 mL n-heptane and water (1:1) is added and the mixture is stirred for 30 minutes. The organic phase is separated and is washed with water. It is dried over Na2SO4 and concentrated to give 16.2 g of oily product. The characterization of the crude material by 1H and 31P NMR shows the formation of product with 63% purity.
Reaction SMILES: Br[C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:22]5[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:23]5)=[N:19][C:18]4=[O:31])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:34]([F:37])([F:36])[F:35])[CH:3]=1.[CH:38]1(B(O)O)[CH2:40][CH2:39]1>>[CH:38]1([C:2]2[CH:33]=[CH:32][C:5]([CH2:6][N:7]3[C:15]4[C:10](=[CH:11][C:12]([CH:16]=[C:17]5[S:21][C:20]([N:22]6[CH2:23][CH2:24][N:25]([CH2:28][CH2:29][OH:30])[CH2:26][CH2:27]6)=[N:19][C:18]5=[O:31])=[CH:13][CH:14]=4)[CH:9]=[N:8]3)=[C:4]([C:34]([F:35])([F:37])[F:36])[CH:3]=2)[CH2:40][CH2:39]1
Reactant: O=C1N=C(N2CCN(CCO)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Br)cc2C(F)(F)F)c1
Reactant: OB(O)C1CC1
Product: O=C1N=C(N2CCN(CCO)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(C3CC3)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Cyclopropyl-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-hydroxy-ethyl)piperazin-1-yl]-thiazol-4-one was prepared from 5-[1-(4-bromo-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-thiazol-4-one and cyclopropyl boronic acid following General Procedure F.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[CH2:34][C:35](Cl)=[O:36]>C1(C)C=CC=CC=1.O>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:21][C:35](=[O:36])[CH2:34][C:30]4[S:29][CH:33]=[CH:32][CH:31]=4)[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(Cl)Cc1cccs1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Cc1cccs1)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Temperature: 50 °C
Yield: 53.5 %

Procedure:
(R)—N2-indan-1-yl-quinoline-2,6-diamine (0.10 g, 0.36 mmol), triethylamine (0.055 mL, 0.4 mmol) and 2-thiophenacetyl chloride (0.049 mL, 0.4 mmol) were dissolved in toluene (3.0 mL). The reaction mixture was heated to 50° C. for 10 h. The reaction mixture was diluted with water and extracted with dichloromethane (3×). The combined organic phases were dried on sodium sulfate and evaporated. The crude product was purified by column chromatography (silica gel, heptane ethyl acetate 4:1/2:1/1:1/1:2). The title compound (0.077 g, 53%) was obtained as a yellow solid; MS: m/e=400.6 (M+H+).
Reaction SMILES: N1C2C(=CC=CC=2)C=CC1=O.[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1.[N+:22]([O-])([OH:24])=[O:23]>>[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=1[N+:22]([O-:24])=[O:23]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccc(Br)cc1
Agent: O=c1ccc2ccccc2[nH]1
Product: O=C(O)c1ccc(Br)c([N+](=O)[O-])c1
Yield: 95 %

Procedure:
In one method the starting quinolinone carboxylic acid 22 building block used for the synthesis of compounds comprising Formulae (I)-(X) was prepared as described in Scheme 9. The commercially available 4-bromobenzoic acid 42 was nitrated under standard conditions using fuming nitric acid to give the 4-bromo-3-nitrobenzoic acid 43 in over 95% yield. The benzoic acid 43 was coupled with ethyl acrylate 44 in the presence of palladium acetate catalyst and ligand triphenylphosphine using triethylamine as base in DMF to afford the corresponding nitro substituted benzoic acid derivative 45 in over 90% yield. The reductive cyclization of the compound 45 under hydrogenation conditions using palladium over activated carbon as catalyst under hydrogen atmosphere at around 50 psi pressure gave the quinolinone carboxylic acid 22 in over 95% yield.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1.[CH2:15]([C:17]1[CH:18]=[C:19]([CH3:29])[C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[N:21][CH:22]=1)[CH3:16]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:26]2[CH2:27][CH2:28][N:23]([C:20]3[C:19]([CH3:29])=[CH:18][C:17]([CH2:15][CH3:16])=[CH:22][N:21]=3)[CH2:24][CH2:25]2)=[O:8])=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)O
Reactant: CCc1cnc(N2CCNCC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 76.1 %

Procedure:
Using 4-bromo-2-methanesulfonylbenzoic acid (2.76 g) and 1-(5-ethyl-3-methylpyridin-2-yl)piperazine (1.85 g) described in Preparation Example 81 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (3.20 g) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22]/[CH:23]=[CH:24]/[C:25]3[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=3)[C:28]#[N:29])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH:40]([CH3:46])[C:41]([O:43][CH2:44][CH3:45])=[O:42].O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH:40]([CH3:46])[C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:22]/[CH:23]=[CH:24]/[C:25]3[CH:32]=[CH:31][CH:30]=[C:27]([C:28]#[N:29])[CH:26]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC/C=C/c3cccc(C#N)c3)cc2)CC1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)N(C/C=C/c1cccc(C#N)c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
To a solution of 3-[3-[N-[4-(1-t-butoxycarbonylpiperidin-4-yloxy)phenyl]amino]-1-(E)-propenyl]benzonitrile (1200 mg) in N,N-dimethylformamide (20 ml) were added potassium carbonate (1710 mg) and ethyl 2-bromopropionate (1.5 ml). The mixture was stirred at 100° C. for 12 hours. After addition of water, the reaction mixture was extracted with ethyl acetate. The extract was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=2/1 as an eluant to give the desired compound (882 mg, yield 60%) as a yellow oil.
Reaction SMILES: C[N:2]([CH3:14])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][N:8]=1)=O.N[C:16]1[CH:20]=C[NH:18][N:17]=1>C(O)(=O)C>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:18]3[N:17]=[CH:16][CH:20]=[C:14]3[N:2]=[CH:3][CH:4]=2)=[N:8][CH:9]=1
Reactant: Cc1ccc(C(=O)C=CN(C)C)nc1
Reactant: Nc1cc[nH]n1
Solvent: CC(=O)O
Product: Cc1ccc(-c2ccnc3ccnn23)nc1

Procedure:
A mixture of 0.01 mole of 3-dimethylamino-1-(5-methyl-2-pyridyl)-2-propen-1-one and 0.01 mole of 3-aminopyrazole in glacial acetic acid is refluxed for 8 hours and worked up as for Example 53 to give the product of the example.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH3:12][N+:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1SC.[CH2:25]([N:32]1[C:36](=[O:37])[CH2:35][S:34][C:33]1=[N:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][C:46]=1[NH:47][CH2:48][CH3:49])[C:42]#[N:43])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([N:32]1[C:36](=[O:37])[C:35](=[C:14]2[CH:15]=[CH:16][C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:13]2[CH3:12])[S:34][C:33]1=[N:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][C:46]=1[NH:47][CH2:48][CH3:49])[C:42]#[N:43])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CSc1ccc2ccccc2[n+]1C
Reactant: CCNc1ccc(C#N)cc1N=C1SCC(=O)N1Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(C#N)cc1N=C1SC(=C2C=Cc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 45, intermediate 1-methyl-2-methylthioquinolinium p-toluenesulfonate was condensed with 3-(3-benzyl-4-oxothiazolidin-2-ylideneamino)-4-ethylaminobenzonitrile to afford the title compound. 1H-NMR (CDCl3): δ 7.41-7.58 (4H, m), 7.20-7.38 (9H, m), 6.49 (1H, d), 5.16 (2H, s), 3.79 (3, br s), 3.01 (2H, q), 1.02 (3H, t); MS(ESI): 492 (MH+).
Reaction SMILES: [H-].[Na+:2].[C:3]([O:6][CH2:7][CH3:8])(=[O:5])[CH3:4].[CH:9](OCC)=[O:10]>C(OC(C)C)(C)C>[CH2:7]([O:6][C:3](=[O:5])/[CH:4]=[CH:9]\[O-:10])[CH3:8].[Na+:2]
Reactant: CCOC(C)=O
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)OC(C)C
Product: CCOC(=O)/C=C\[O-]
Temperature: 45 °C
Reaction time: 8 h

Procedure:
Sodium hydride (21.79 g, 545 mmol) was suspended in isopropyl ether (378 mL) in a 3-neck flask equipped with a thermometer adapter, addition funnel and a capped neck. Ethyl acetate (44.4 mL, 454 mmol) was added slowly via syringe through the capped neck. An internal temperature of 45° C. was maintained. Ethyl formate (78 mL, 962 mmol) was added via the addition funnel slowly, maintaining the temperature at 42° C. The reaction was allowed to stir overnight, at which point solid had crashed out. This solid was filtered and washed with ethyl ether (2×100 mL) and hexanes (200 mL) and the solid was dried to give the title compound.
Reaction SMILES: ClCC[CH2:4][CH:5]([O:11]C(=O)C)CCCCC.C(Br)CCCC.[Cl:21][CH2:22][CH2:23][CH2:24][C:25](=[O:34])[CH2:26][CH2:27][CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31].ClCCCC(O)CCCCC(F)(F)F>>[Cl:21][CH2:22][CH2:23][CH2:24][CH:25]([O:34][C:5](=[O:11])[CH3:4])[CH2:26][CH2:27][CH2:28][CH2:29][C:30]([F:31])([F:32])[F:33]
Reactant: CCCCCC(CCCCl)OC(C)=O
Reactant: O=C(CCCCl)CCCCC(F)(F)F
Agent: OC(CCCCl)CCCCC(F)(F)F
Solvent: CCCCCBr
Product: CC(=O)OC(CCCCl)CCCCC(F)(F)F

Procedure:
By following the procedure described for 1-chloro-4-acetoxynonane (Example A) but substituting 1-bromo-5,5,5-trifluoropentane for amyl bromide, there is obtained in succession: 1-chloro-9,9,9-trifluoro-4-nonanone, 1-chloro-9,9,9-trifluoro-4-nonanol, and 1-chloro-4-acetoxy-9,9,9-trifluoronane.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1[CH3:12])#[N:2].C(Cl)(=O)C([Cl:16])=O>ClCCl.CN(C)C=O>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:16])=[O:8])=[CH:5][C:4]=1[CH3:12])#[N:2]
Reactant: Cc1cc(C(=O)O)ccc1C#N
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Cl)ccc1C#N
Reaction time: 3 h

Procedure:
The crude product of 4-cyano-3-methylbenzoic acid (1.0 g) was suspended in dichloromethane. To the mixture, oxalyl chloride (1.2 g) and an catalytic amount of N,N-dimethylformamide (2 to 3 drops) were added under ice cooling. After adjusting to room temperature, the reaction solution was stirred for three hours. The solvent was distilled off under reduced pressure to obtain 4-cyano-3-methylbenzoyl chloride as a crude product (1.0 g).