Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[OH:34][CH:35]1[CH2:40][CH2:39][CH2:38][NH:37][CH2:36]1>>[OH:34][CH:35]1[CH2:40][CH2:39][CH2:38][N:37]([C:2]2[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=2)[C:5]([NH:7][C:8]2[S:9][C:10]3[C:16]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=3[N:12]=2)=[O:6])[CH2:36]1
Reactant: OC1CCCNC1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(N4CCCC(O)C4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 3-hydroxy-piperidine. ES-MS m/e (%): 470 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[O:9]1[CH:13]=[CH:12][N:11]=[CH:10]1>CN(C=O)C.[Cu](I)I.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:10]2[O:9][CH:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(I)cc1
Reactant: c1cocn1
Agent: I[Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: Fc1ccc(-c2ncco2)cc1
Temperature: 25 °C
Yield: 25539.1 %

Procedure:
A solution of 1-fluoro-4-iodobenzene (1 g, 0.0144 mmol) in DMF (15 mL) was purged with argon, and oxazole (6.4 g/3.3 mL, 0.02898 mmol), copper iodide (5.5 g, 0.02898 mmol) and palladium (II) acetate (0.15 g, 0.000724 mmol) was added. The reaction mixture was purged with argon for 5 min and refluxed under argon for 12 h. The solution was cooled to room temperature and diluted with ice cold water (100 mL). The reaction mixture was extracted with ethyl acetate (200 mL) and filtered through Celite® reagent. The organic solvent was dried with sodium sulfate, filtered and the solvent was removed under reduced pressure to obtain crude product. The crude product was purified by Biotage IsoleraOne® column using a 25 g column (7% ethyl acetate in hexane) to give 2-(4-fluorophenyl)oxazole (0.6 g, 26%) as yellow liquid. 1H NMR (400 MHz, DMSO-d6): δ 8.19 (s, 1H), 8.03-7.99 (m, 2H), 7.34 (t, 3H); LC-MS m/z calculated for [M+H]+164.05. found 164.1.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:29]=[CH:30][C:31]([C:34](O)=[O:35])=[N:32][CH:33]=4)=[C:14]([C:16]#[C:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[CH3:37][S:38]([NH2:41])(=[O:40])=[O:39].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:37][S:38]([NH:41][C:34](=[O:35])[C:31]1[CH:30]=[CH:29][C:28]([C:13]2[N:9]3[N:10]=[CH:11][CH:12]=[C:7]([N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[C:8]3=[N:15][C:14]=2[C:16]#[C:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)=[CH:33][N:32]=1)(=[O:40])=[O:39]
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1ccc(-c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1ccc(-c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cn1

Procedure:
A solution of compound 40a (0.20 g, 0.42 mmol), methanesulfonamide (60 mg, 0.63 mmol), dicyclohexylcarbodiimide (90.0 mg, 0.44 mmol) and N,N-dimethylpyridin-4-amine (60.0 mg, 0.49 mmol) in DCM (5 mL) was stirred at rt overnight, then concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel (MeOH/CH2Cl2 (1:20)) to obtain a solid, which was washed with methanol (10 mL) to yield the title compound 28 as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 9.50-9.41 (m, 1H), 8.62 (d, J=8.8 Hz, 1H), 8.41 (d, J=8.4 Hz, 1H), 8.30-8.27 (m, 2H), 8.03-7.99 (m, 2H), 7.82 (t, J=7.6 Hz, 1H), 7.73 (t, J=8.8 Hz, 1H), 7.65 (t, J=7.6 Hz, 1H), 6.51 (d, J=5.6 Hz, 1H), 4.08-3.97 (m, 4H), 3.99-3.80 (m, 4H), 2.96 (s, 3H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C28H23N7O4S: 554.2 (M+H). Found: 554.0.
Reaction SMILES: C(OC(C1C=C([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][S:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:14][CH:13]=2)C=CC=1)=O)C.[CH2:29]([O:31][C:32]([C:34]1[C:35](C2C=CC=C(CSCCO)C=2)=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:33])[CH3:30].C1(O)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:29]([O:31][C:32]([C:34]1[C:39]([C:17]2[CH:12]=[CH:13][CH:14]=[C:15]([CH2:18][S:19][CH2:20][CH2:21][O:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:16]=2)=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:33])[CH3:30]
Reactant: CCOC(=O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Reactant: CCOC(=O)c1ccccc1-c1cccc(CSCCO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Oc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccccc1-c1cccc(CSCCOc2ccccc2)c1

Procedure:
3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethyl ester was prepared as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethyl ester. 3′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethyl ester (2.1 g, 6.64 mmol, 1 eq.) in anhydrous THF was treated with phenol (0.88 g, 9.30 mmol, 1.4 eq.), triphenylphosphine (2.44 g, 9.30 mmol, 1.4 eq.), and diisopropyl azidocarboxylate (1.88 g, 1.83 mL, 9.30 mmol, 1.4 eq.). When complete, the reaction was worked up as described leaving a yellow oil
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([C:11]#[C:12][CH:13]([OH:15])[CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:16].O.[NH3:18]>O1CCOCC1>[NH2:18][C:2]1[N:10]=[C:9]([C:11]#[C:12][CH:13]([OH:15])[CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:16]
Reactant: CC(O)C#Cc1nc(Cl)c2ncn(C)c2n1
Reactant: N
Solvent: C1COCCO1
Solvent: O
Product: CC(O)C#Cc1nc(N)c2ncn(C)c2n1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(6-chloro-9-methyl-9H-purin-2-yl)but-3-yn-2-ol (4.8 g, 20.34 mmol) in dioxane (30 ml) was added 30% w/w water solution of ammonia (60 ml). The reaction mixture was stirred overnight in an autoclave at 70° C. The solution was evaporated at atmospheric pressure at 50° C. and then under reduced pressure. The residue was purified by flash chromatography (DCM/MeOH: 97/3).
Reaction SMILES: F[C:2](F)(F)C([O-])=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][C:16]2[N:20]([CH3:21])[CH:19]=[NH+:18][C:17]=2[C:22]2[CH:27]=[CH:26][C:25]([C@H:28]3[CH2:30][C@@H:29]3[C:31]3[N:32]=[N:33][NH:34][N:35]=3)=[CH:24][CH:23]=2)=[N:13][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.IC>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][C:16]2[N:20]([CH3:21])[CH:19]=[N:18][C:17]=2[C:22]2[CH:23]=[CH:24][C:25]([C@H:28]3[CH2:30][C@@H:29]3[C:31]3[N:32]=[N:33][N:34]([CH3:2])[N:35]=3)=[CH:26][CH:27]=2)=[N:13][CH:14]=1
Reactant: O=C([O-])C(F)(F)F
Reactant: Cn1c[nH+]c(-c2ccc([C@H]3C[C@@H]3c3nn[nH]n3)cc2)c1Sc1ccc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1nnc([C@H]2C[C@@H]2c2ccc(-c3ncn(C)c3Sc3ccc(Cl)cn3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Example 37 (10 mg, 0.024 mmol) and excess potassium carbonate in DMF (0.5 mL) was added 3 drops of iodomethane. The reaction was stirred at rt for 1 h, before filtering and subjecting to purification via reverse phase HPLC. The fractions containing the major product were collected, diluted with ethyl acetate, and washed with aqueous sodium bicarbonate, water, and brine. The organic layer was dried (MgSO4), filtered, and concentrated to afford the title compound. 1H NMR (500 MHz), [CD3OD]: 8.38 (s, 1H), 7.78 (d, 2H), 7.76 (br, 3H), 7.30 (br, 3H), 3.83 (s, 3H), 3.66 (s, 3H), 2.66 (m, 1H), 2.45 (m, 1H), 1.85-1.72 (br, 2H). LCMS: [M+1]+=424. Human FAAH lysate assay: IC50=37 nM
Reaction SMILES: [CH3:1][C:2]1[N:7]2[CH:8]=[N:9][CH:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[Li]CC1N2C=NC=C2C=CC=1.Br[CH2:28][CH2:29][CH2:30][CH2:31][C:32](OCC)([O:36]CC)[O:33][CH2:34][CH3:35]>O1CCCC1.CCCCCC>[CH2:34]([O:33][C:32]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:1][C:2]1[N:7]2[CH:8]=[N:9][CH:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1)=[O:36])[CH3:35]
Reactant: CCOC(CCCCBr)(OCC)OCC
Reactant: Cc1cccc2cncn12
Agent: [Li]CCCC
Agent: [Li]Cc1cccc2cncn12
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)CCCCCc1cccc2cncn12

Procedure:
To a solution of 50 g of 5-methylimidazo[1,5-a]pyridine [J. Org. Chem. 40, 1210 (1975)] in 625 ml of tetrahydrofuran precooled to -75° is added under nitrogen atmosphere 175 ml of 2.4N n-butyllithium in hexane while maintaining temperature below -53°. The solution of 5-(lithiomethyl)imidazo[1,5-a]pyridine, is cooled back to -75° and a solution of 121.8 g of 5-bromo-1,1,1-triethoxypentane in 125 ml of tetrahydrofuran is added rapidly at which time the temperature rises to -60°. The reaction mixture is allowed to warm to -4° over a 45 minute period and evaporated practically to dryness. The residue is partitioned between 500 ml of ethyl ether and 240 ml of 3N hydrochloric acid. The ether solution is further extracted twice with 60 ml of 3N hydrochloric acid; the combined aqueous extract is basified with 100 ml of concentrated ammonia hydroxide and reextracted twice with 200 ml of ethyl ether. The ether extract is dried over magnesium sulfate and evaporated to dryness to give an oil which is distilled under high vacuum to give 5-(5-ethoxycarbonylpentyl)-imidazo[1,5-a]pyridine boiling at 180°-5°/0.12 mm Hg.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[C:11]([CH2:30][CH:31]([CH3:33])[CH3:32])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([C:26]([O:28][CH3:29])=[O:27])=[CH:15][CH:14]=2)=O)(C)(C)C.[ClH:34]>O1CCCC1.C(OCC)(=O)C>[ClH:34].[ClH:34].[NH2:8][CH2:9][C:10]1[C:11]([CH2:30][CH:31]([CH3:33])[CH3:32])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([C:26]([O:28][CH3:29])=[O:27])=[CH:15][CH:14]=2
Reactant: COC(=O)c1ccc2nc(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccccc3)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2nc(CC(C)C)c(CN)c(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a solution of methyl 3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-phenylquinoline-6-carboxylate (0.10 g, 0.22 mmol) in tetrahydrofuran (2 ml) was added 4N solution of hydrogen chloride in ethyl acetate (5 ml), and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from diisopropyl ether-ethyl acetate to give the title compound (0.084 g, yield 90%) as colorless crystals.
Reaction SMILES: [C:1]([C:3](=[CH:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:19][C:20]2[CH:25]=[CH:24][C:23](OC)=[CH:22][CH:21]=2)[C:11]=1[Cl:28])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].C[CH2:30][OH:31].O>>[C:1]([C:3](=[CH:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:31][CH3:30])[C:11]=1[Cl:28])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCOC(=O)C(C#N)=Cc1c(Cl)n(Cc2ccc(OC)cc2)c2ccccc12
Reactant: CCO
Solvent: O
Product: CCOC(=O)C(C#N)=Cc1c(Cl)n(Cc2ccccc2OC)c2ccccc12

Procedure:
To 600 mg of 1-(2-methoxybenzyl)-2-chloroindole-carbaldehyde, slurried in 10 ml of ethanol, was added 608 mg of potassium carbonate and 0.24 ml of ethyl cyanoacetate. After overnight stirring 10 ml of water was added, and the product collected by filtration, washed with water, and dried to give (12a). Yield 630 mg of (12a). M.p. 126°-8° C. (sample recryst. from EtOH/water).
Reaction SMILES: [CH2:1]([N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-])=[CH:9][C:8]=2[N:7]=[CH:6]1)[CH:2]([CH3:4])[CH3:3].C(OC(=O)C)(=[O:21])C>>[CH2:1]([N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([OH:21])[C:8]=2[N:7]=[CH:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)Cn1cnc2c[n+]([O-])c3ccccc3c21
Product: CC(C)Cn1cnc2c(O)nc3ccccc3c21

Procedure:
To 70 ml of acetic anhydride was added 13.0 g (0.0539 mole) of 1-isobutyl-1H-imidazo[4,5-c]quinolin-5-oxide. The solution was heated on a steam bath for 10 minutes, then allowed to cool. The precipitate was separated by filtration, washed with ethanol, and dried. Recrystallization from N,N-dimethylformamide provided 1-isobutyl-1H-imidazo[4,5-c]quinoline-4-ol, m.p. >300° C. Analysis: Calculated for C14H15N3O: %C, 69.7; %H, 6.3; %N, 17.4; Found: %C, 69.8; %H, 6.4; %N, 17.6.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][CH:38]=1)[CH2:5][O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][N:18]2[CH2:22][C@@H:21]([C:23]3[CH:34]=[CH:33][C:26]4[O:27][C:28]([CH3:32])([CH3:31])[O:29][CH2:30][C:25]=4[CH:24]=3)[O:20][C:19]2=[O:35])=[CH:12][CH:11]=1.Cl.[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[N:43][CH:42]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:31][C:28]1([CH3:32])[O:27][C:26]2[CH:33]=[CH:34][C:23]([C@H:21]3[O:20][C:19](=[O:35])[N:18]([CH2:17][CH2:16][C:13]4[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][O:6][CH2:5][C:4]5[CH:3]=[C:2]([NH:1][C:40](=[O:47])[C:41]6[CH:46]=[CH:45][CH:44]=[N:43][CH:42]=6)[CH:38]=[CH:37][CH:36]=5)=[CH:15][CH:14]=4)[CH2:22]3)=[CH:24][C:25]=2[CH2:30][O:29]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOCc5cccc(N)c5)cc4)C(=O)O3)ccc2O1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOCc5cccc(NC(=O)c6cccnc6)c5)cc4)C(=O)O3)ccc2O1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of (5R)-3-[2-(4-{2-[(3-aminobenzyl)oxy]ethoxy}phenyl)ethyl]-5(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one {Example 1 xii)} (100 mg), nicotinoyl chloride hydrochloride (38 mg) and N,N-diisopropylethylamine (67 μL) in DCM (2 mL) was stirred at room temperature under nitrogen for 20 h. The solution was then diluted in DCM, washed with 2M HCl, NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo to give the title compound (136 mg). LCMS RT=3.32 min.
Reaction SMILES: C(N)C1C=CC=CC=1.[F:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1.[CH3:17][C:18]1[N:19]=[C:20]([N:23]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=3)[C:24]2=[O:38])[S:21][CH:22]=1>>[F:9][C:10]1[CH:16]=[CH:15][C:13]([NH:14][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][C:29]([CH2:28][N:25]3[CH2:26][CH2:27][N:23]([C:20]4[S:21][CH:22]=[C:18]([CH3:17])[N:19]=4)[C:24]3=[O:38])=[CH:30][CH:31]=2)=[CH:12][CH:11]=1
Reactant: Nc1ccc(F)cc1
Reactant: Cc1csc(N2CCN(Cc3ccc(C(=O)O)cc3)C2=O)n1
Solvent: NCc1ccccc1
Product: Cc1csc(N2CCN(Cc3ccc(C(=O)Nc4ccc(F)cc4)cc3)C2=O)n1
Yield: 16 %

Procedure:
Following the procedure as describe in Example 8, making variations as required to replace benzylamine with 4-fluoroaniline to react with 4-((3-(4-methylthiazol-2-yl)-2-oxoimidazolidin-1-yl)methyl)benzoic acid, the title compound was obtained as a white powder in 16% yield: mp 206-207° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.74 (d, J=7.2 Hz, 2H), 7.52-7.44 (m, 2H), 7.23 (d, J=7.2 Hz, 2H), 6.90-6.85 (m, 2H), 6.33 (s, 1H), 4.37 (s, 2H), 3.95-3.90 (m, 2H), 3.37-3.31 (m, 2H), 2.16 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.0, 155.9, 146.7, 139.5, 134.2, 127.9, 127.8, 122.6, 115.3, 115.1, 106.9, 47.3, 42.2, 41.8, 16.5; MS (ES+) m/z 411.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](O)=[CH:4][C:3]=1[C:13]([OH:15])=[O:14].Cl.[CH2:17]([OH:19])[CH3:18]>>[OH:19][CH:17]([O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:13]([OH:15])=[O:14])[CH3:18]
Reactant: CCO
Reactant: O=C(O)c1cc(O)c2ccccc2c1O
Agent: Cl
Product: CC(O)Oc1c(C(=O)O)ccc2ccccc12

Procedure:
By refluxing an ethanol solution of 1,4-dihydroxy-2-naphthoic acid under heating and passing hydrogen chloride gas through the solution for 5 hours, 1-hydroxy-ethoxy-2-naphthoic acid having a melting point of 190-195° C was obtained.
Reaction SMILES: [Cl:1][C:2]([Cl:15])=[C:3]1[CH:7]2[C:8]3[C:13]([CH:4]1[CH2:5][CH2:6]2)=[CH:12][CH:11]=[CH:10][C:9]=3[NH2:14].C(N(CC)CC)C.[F:23][CH:24]([F:34])[C:25]1[C:29]([C:30](Cl)=[O:31])=[CH:28][N:27]([CH3:33])[N:26]=1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]([Cl:15])=[C:3]1[CH:7]2[C:8]3[C:13]([CH:4]1[CH2:5][CH2:6]2)=[CH:12][CH:11]=[CH:10][C:9]=3[NH:14][C:30]([C:29]1[C:25]([CH:24]([F:34])[F:23])=[N:26][N:27]([CH3:33])[CH:28]=1)=[O:31]
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: Nc1cccc2c1C1CCC2C1=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: Cn1cc(C(=O)Nc2cccc3c2C2CCC3C2=C(Cl)Cl)c(C(F)F)n1
Temperature: 80 °C
Yield: 83.4 %

Procedure:
9-Dichloromethylene-1,2,3,4-tetrahydro-1,4-methano-naphthalen-5-ylamine (166 g, 35% xylene solution, 0.25 mol), triethylamine (28 g, 0.275 mol) and xylene (13 g) were charged in a reactor and the mixture was heated to 80° C. 3-Difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (182 g, 26% xylene solution, 0.25 mol) was added over 2 hours. After conversion, the product was extracted, concentrated and crystallized in a mixture of xylene/methycyclohexane. 83 g of pure product were isolated. (Purity: 97%, Yield: 82%)
Reaction SMILES: [C:1]([PH:5](=[O:13])[CH:6]([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1>[C:1]([P:5](=[O:13])([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:6]([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(OCC)[PH](=O)C(C)(C)C
Reactant: BrCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(OCC)P(=O)(Cc1ccccc1)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
Tertiary-butyl(diethoxymethyl)phosphine oxide (2.5 g), (0.012 mol) is dissolved in 35 ml of dry tetrahydrofuran and cooled to -78° C. under an argon atmosphere. To this stirred solution is added 9.0 ml of n-butyl lithium (1.6M solution in hexane) and the mixture is stirred at -78° C. for 10 minutes. After this time, a solution of 2.47 g (0.014 mol) of benzyl bromide in 15 ml of dry tetrahydrofuran is added, and the reaction mixture is allowed to warm to room temperature. After stirring for 3 hours at room temperature, 10 ml of saturated ammonium chloride solution is added and the product is extracted into diethyl ether (2×100 ml). The combined organic extracts are dried and evaporated under reduced pressure to give a crude product. This is purified by chromatography on silica, using ethyl acetate as eluent, to give tertiary-butyl(benzyl)(diethoxymethyl) phosphine oxide as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14]([OH:16])=O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C1C=CC=CC=1.C(N(CC)C#CC)C.[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][C:42]=1[O:43][CH3:44])[C:39](=[CH:45][C:46]1[CH:51]=[C:50]([O:52][CH3:53])[C:49]([O:54][CH3:55])=[C:48]([O:56][CH3:57])[CH:47]=1)[NH:38][CH2:37][CH2:36]2>N1C=CC=CC=1>[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][C:42]=1[O:43][CH3:44])/[C:39](=[CH:45]/[C:46]1[CH:51]=[C:50]([O:52][CH3:53])[C:49]([O:54][CH3:55])=[C:48]([O:56][CH3:57])[CH:47]=1)/[N:38]([C:14](=[O:16])[CH2:13][C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:37][CH2:36]2
Reactant: COc1cc2c(cc1OC)C(=Cc1cc(OC)c(OC)c(OC)c1)NCC2
Reactant: COc1cc(CC(=O)O)cc(OC)c1OC
Agent: CC#CN(CC)CC
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: COc1cc2c(cc1OC)/C(=C/c1cc(OC)c(OC)c(OC)c1)N(C(=O)Cc1cc(OC)c(OC)c(OC)c1)CC2

Procedure:
To a suspension of 24 parts of 3,4,5-trimethoxybenzeneacetic acid in 25 parts of benzene is added 7 parts of N,N-diethyl-1-propyne-1-amine, followed by a solution of 12 parts of 3,4-dihydro-6,7-dimethoxy-1-[(3,4,5-trimethoxyphenyl)methylene]isoquinoline [Ber. deut. chem. Ges., 55, 2989 (1922)] in 60 parts of pyridine. The resultant mixture is stirred at room temperatures for 18 hours, whereupon it is consecutively washed with aqueous 5% potassium carbonate, approximately 0.2% hydrochloric acid, and water, then dried over anhydrous sodium sulfate and stripped of solvent by vacuum distillation. The residue, crystallized from methanol, affords (Z)-1,2,3,4-tetrahydro-6,7-dimethoxy-2-(3,4,5-trimethoxybenzeneacetyl)-1-[(3,4,5-trimethoxyphenyl)methylene]isoquinoline melting at 148°-150°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH:9]=[N:10][C:11]3[NH:15][N:14]=[CH:13][C:12]=3[C:7]=2[N:6]2[N:16]=[CH:17][N:18]=[C:5]2[N:4]=1.ClC1C2C=NC3N(CC)N=CC=3C=2N2N=CN=C2N=1.C(O)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(O)C>[C:39]1([CH2:1][O:2][C:3]2[C:8]3[CH:9]=[N:10][C:11]4[NH:15][N:14]=[CH:13][C:12]=4[C:7]=3[N:6]3[N:16]=[CH:17][N:18]=[C:5]3[N:4]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: OCc1ccccc1
Reactant: COc1nc2ncnn2c2c1cnc1[nH]ncc12
Agent: CCn1ncc2c1ncc1c(Cl)nc3ncnn3c12
Solvent: CCO
Product: c1ccc(COc2nc3ncnn3c3c2cnc2[nH]ncc23)cc1

Procedure:
By substituting the 5-chloro-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine of Example 15 for the 5-chloro-8-ethyl-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine and benzyl alcohol for the ethanol in the procedure of Example 4, 5-phenylmethoxy-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:26]1([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][C:16](=[O:18])[N:35]2[CH2:36][CH2:37][N:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:33][CH2:34]2)[CH2:13][CH2:14]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC(=O)O)CC1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC(=O)N2CCN(c3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a colution containing trans-(4-tertbutoxycarbonylamino-cyclohexyl)-acetic acid (15.44 g, 0.06 mol), triethylamine (6.05 g, 0.06 mol) and 1-phenylpiperazine (9.73 g, 0.06 mol) in CH2Cl2 (250 mL) was added EDAC-HCl ((1-ethyl-(3dimethylaminopropyl)-carbodiimide hydrochloride (11.5 g, 0.06 mol)). The reaction mixture was stirred at room temperature 16 hours, then washed with water, 1N NaOH, brine, and dried (MgSO4). The solvent was evaporated, and the residue was chromatographed on a flash silica gel column eluting with CH2Cl2 and then EtOAc. The product fractions were recrystallized from acetonitrile (CH3CN) to yield 12.0 g (50%) of trans-{4-[2-oxo-2-(4-phenyl-piperazin-1-yl)-ethyl]-cylohexyl}-carbamic acid tert-butyl ester as white crystals; mp 197.5-200° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([S:6](Cl)(=[O:8])=[O:7])[N:3]=[CH:2]1.[CH2:10]([C:13]1[NH:14][CH:15]=[CH:16][N:17]=1)[CH2:11][CH3:12]>C1COCC1>[NH:1]1[CH:5]=[C:4]([S:6]([N:14]2[CH:15]=[CH:16][N:17]=[C:13]2[CH2:10][CH2:11][CH3:12])(=[O:8])=[O:7])[N:3]=[CH:2]1
Reactant: O=S(=O)(Cl)c1c[nH]cn1
Reactant: CCCc1ncc[nH]1
Solvent: C1CCOC1
Product: CCCc1nccn1S(=O)(=O)c1c[nH]cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
A round bottom flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet was charged with 10.85 g of imidazole-4-sulfonylchloride and 180 ml of THF. This solution was treated with a solution of 15.4 g 2-n-propylimidazole in 100 ml of THF. The reaction mixture was stirred at room temperature overnight and then refluxed 48 hours. The clear solution was concentrated to an oil and dissolved in water. The opaque solution deposited crystals on standing which were filtered, washed and dried. Recrystallization from ethyl acetate gave 10.61 g of white crystals of 1-(4-imidazolylsulfonyl)-2-n-propylimidazole with mp 163°-4°, λmaxnujol 3.18 (NH), 7.32 (SO2N) and 8.52 μ (SO2N). NMR (DMSO, d6): 660-730 Hz, m, 1H; 496 Hz, d, J = 1.5 Hz, 1H; 477 Hz, d, J = 1.5 Hz, 1H; 447 Hz, d, J = 2 Hz, 1H; 415 Hz, d, J = 2 Hz, 1H; 174 Hz, t, J = 7 Hz, 2H; 82-118 Hz, sextet, J = 7 Hz, 2H; 51 Hz, t, J = 7 Hz, 3H.