Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1.[F:12][C:13]([F:61])([C:51]([F:60])([F:59])[C:52]([F:58])([F:57])[C:53]([F:56])([F:55])[F:54])[CH2:14][CH2:15][CH2:16][N:17]([CH2:35][CH2:36][CH2:37][C:38]([F:50])([F:49])[C:39]([F:48])([F:47])[C:40]([F:46])([F:45])[C:41]([F:44])([F:43])[F:42])[C:18](=O)[CH2:19][CH2:20][C:21]([F:33])([F:32])[C:22]([F:31])([F:30])[C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25]>O>[F:12][C:13]([F:61])([C:51]([F:59])([F:60])[C:52]([F:57])([F:58])[C:53]([F:54])([F:55])[F:56])[CH2:14][CH2:15][CH2:16][N:17]([CH2:18][CH2:19][CH2:20][C:21]([F:33])([F:32])[C:22]([F:30])([F:31])[C:23]([F:28])([F:29])[C:24]([F:25])([F:26])[F:27])[CH2:35][CH2:36][CH2:37][C:38]([F:50])([F:49])[C:39]([F:48])([F:47])[C:40]([F:46])([F:45])[C:41]([F:44])([F:43])[F:42]
Reactant: O=C(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)N(CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCN(CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 86 %

Procedure:
A 250-ml 3-necked flask equipped with a stir bar, condenser, nitrogen inlet and an addition funnel was charged with LiAlH4 (1.3 g) and 20 ml THF. To the mixture was added a THF (30 ml) solution of N,N-bis(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)-4,4,5,5,6,6,7,7,7-nonafluoroheptanamide (20.6 g, 25.4 mmol) dropwise at RT. The resulting mixture was refluxed for 30 min. After being cooled, the mixture was carefully treated with water (3 ml) to decompose excess LiAlH4. Another 50 ml water were added and the mixture was extracted with ether (3×100 ml). The combined ether extracts were washed with water, dried over Na2SO4, concentrated to give a residue which was distilled to afford tris(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)amine, 17.5 g, yield 86%, bp 153-155° C./270 Pa absolute. 19F NMR (CDCl3) -81.8 (tt, J=10, 3 Hz, 9F), -115.2 (m, 6F), -125.3 (m, 6F), -126.7 (m, 6F) ppm. 1H NMR (CDCl3) 1.92 (m, 6H), 2.10 (m, 6H), 2.48 (t, J=6 Hz, 6H) ppm. 13C NMR (CDCl3) 18.3, 28.7 (t, J=23 Hz), 52.9, 108-123 (m) ppm. Anal. Calcd. for C21H18F27N: C, 31.63; H, 2.28; N, 1.76; F 64.33. Found: C, 31.49; H, 2.52; N, 1.77; F, 64.52. MS (m/e) 550 (M+ -C4F9 (CH2)2, 100%), 512 (0.4%), 462 (0.6%), 362 (0.8%), 290 (11.3%), 276 (1.9%), 219 (0.3%), 169 (3.9%), 119 (7.1%), 69 (23.7%).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[Cl:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][C:37]=1[C:45]([F:48])([F:47])[F:46]>>[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:14]2[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:8])[CH3:9])[C:4]([OH:3])=[O:34])[CH:11]=[C:12]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=3)[CH:13]=2)=[CH:38][C:37]=1[C:45]([F:46])([F:47])[F:48]
Reactant: OB(O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccc(Cl)c(C(F)(F)F)c2)c1

Procedure:
The title compound was prepared from a Suzuki coupling of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (intermediate Example 1g) with 4-chloro-3-trifluoromethyl-phenylboronic acid under the conditions described in Example 1; 1H NMR (400 MHz, MeOD) δ ppm 0.85-0.96 (m, 6H), 1.42-1.54 (m, 1H), 1.65 (ddd, J=13.82, 7.09, 6.97 Hz, 1H), 1.96 (dd, J=13.57, 7.21 Hz, 1H), 3.76 (t, J=7.70 Hz, 1H), 7.56-7.92 (m, 10H); Calcd for C26H21ClF6O2 (M+Na) 537.11, Found 537.
Reaction SMILES: [C:1](Cl)(=[O:10])[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:12]1([C:18]2[NH:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=3[N:22]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C(C)=CC=CC=1C>O1CCCC1>[CH2:3]([O:2][C:1]([N:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=[C:18]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: c1ccc(-c2nc3ccccc3[nH]2)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: O=C(OCc1ccccc1)n1c(-c2ccccc2)nc2ccccc21
Temperature: 50 °C
Reaction time: 20 h
Yield: 72 %

Procedure:
In a nitrogen atmosphere, 107 g of benzyl chlorocarbonate was added dropwise to a solution of 97 g of 2-phenylbenzimidazole and 107 g of 2,6-lutidine in 700 g of tetrahydrofuran, which was heated and stirred at 50° C. for 20 hours. After ordinary aqueous work-up, the insoluble was filtered off. The filtrate was concentrated, washed with hexane, and dried, obtaining 118 g of 1-benzyloxycarbonyl-2-phenylbenzimidazole (yield 72%).
Reaction SMILES: C1C2C(COC([NH:18][NH:19][C:20]([C:22]3[C:23](Cl)=[N:24][C:25]4[C:30]([C:31]=3[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:29][C:28]([Cl:38])=[CH:27][CH:26]=4)=[O:21])=O)C3C(=CC=CC=3)C=2C=CC=1.[NH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1.C(N(CC)CC)C.O>CN(C=O)C>[Cl:38][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[N:24]=[C:23]([N:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)[C:22]([C:20]([NH:19][NH2:18])=[O:21])=[C:31]2[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(NNC(=O)c1c(Cl)nc2ccc(Cl)cc2c1-c1ccccc1)OCC1c2ccccc2-c2ccccc21
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: NNC(=O)c1c(N2CCCCC2)nc2ccc(Cl)cc2c1-c1ccccc1
Temperature: 120 °C
Yield: 38.6 %

Procedure:
A mixture of N′-(2,6-dichloro-4-phenyl-quinoline-3-carbonyl)-hydrazinecarboxylic acid 9H-fluoren-9-ylmethyl ester (130 mg, 211 μmol, Eq: 1.00), piperidine (180 mg, 209 μl, 2.11 mmol, Eq: 10) and triethylamine (64.1 mg, 88.2 μl, 633 μmol, Eq: 3) in DMF (2 ml) was heated to 120° C. for 20 min in a microwave. Water was added and the mixture was extracted with ethyl acetate (3×). The combined extracts were washed with water and brine, dried with Na2SO4 and evaporated. The remaining residue was purified by column chromatography (silica gel, DCM/EtOAc 9:1-4:1) to afford the title compound as light yellow solid (31 mg). MS (ESI): 381.2 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.C([NH:12][S:13]([CH2:16][CH:17]([O:21][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:18][CH2:19][CH3:20])(=[O:15])=[O:14])(C)(C)C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[C:22]([O:21][CH:17]([CH2:18][CH2:19][CH3:20])[CH2:16][S:13]([NH2:12])(=[O:15])=[O:14])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCCC(CS(=O)(=O)NC(C)(C)C)OC(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCCC(CS(N)(=O)=O)OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 32 h
Yield: 84.3 %

Procedure:
Trifluoroacetic acid (200 ml) was added to N-t-butyl-2-benzoyloxy-1-pentanesulfonamide (132.8 g). After stirring for 32 hours at room temperature, the solution was concentrated under reduced pressure. After further adding trifluoroacetic acid (100 ml) and stirring for 16 hours at room temperature, the solution was concentrated under reduced pressure to obtain an oily substance (165 g). This substance was dissolved in ethyl acetate and, after adding a saturated aqueous solution of sodium hydrogencarbonate, the solution was stirred for 15 minutes at room temperature. The organic layer was washed with 5% brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain 2-benzoyloxy-1-pentanesulfonamide (92.8 g).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)=[O:6].[CH2:18](O)[CH2:19][OH:20].C1(C)C=CC(S(O)(=O)=O)=CC=1.[Na]>C1C=CC=CC=1>[CH2:18]1[CH2:19][O:20][CH:4]([CH2:3][CH2:2][Cl:1])[CH:5]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[O:6]1
Reactant: OCCO
Reactant: O=C1CCc2cc(C(=O)CCCCl)ccc2N1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na]
Solvent: c1ccccc1
Product: O=C1CCc2cc(C3OCCOC3CCCl)ccc2N1

Procedure:
10 Grams (39.7 mM) of 6-(4-chlorobutyryl)-3,4-dihydrocarbostyril was dissolved in 300 ml of benzene, then to this solution was added 7.4 g (120 mM) of ethylene glycol and 300 mg of p-toluenesulfonic acid, and the whole mixture was refluxed by heating under dehydrating in Dean-Stark extractor for 6 hours. The reaction mixture was cooled and neutralized with an aqueous solution saturated with sodium hyfrogen carbonate, then extracted with chloroform. The chloroform extract was washed with water then dried with anhydrous magnesium sulfate, then concentrated by removing the solvent by evaporation. The residue thus obtained was purified by means of a silicagel column chromatography (eluent: chloroform:methanol=40:1) to yield 10.5 g of 6-(1-ethylenedioxy-4-chlorobutyl)-3,4-dihydrocarbostyril.
Reaction SMILES: C(O)(C)C.O.[Cl:6][C:7]1[S:8][CH:9]=[C:10]([CH:13]=[O:14])[C:11]=1[Cl:12].[BH4-].[Na+]>ClCCl>[Cl:6][C:7]1[S:8][CH:9]=[C:10]([CH2:13][OH:14])[C:11]=1[Cl:12]
Reactant: O=Cc1csc(Cl)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Solvent: ClCCl
Product: OCc1csc(Cl)c1Cl
Reaction time: 0.75 h
Yield: 90 %

Procedure:
300 ml of isopropanol, 300 ml of water and 200 g of 2,3-dichlorothiophene-4-aldehyde are placed in a 2 liter flask; over a period of 45 minutes, 16 g of sodium borohydride is added in portions. The reaction is exothermic and is cooled to take place at from 35° to 40° C. Subsequently, the two-phase mixture is stirred for 30 minutes at this temperature and then 300 ml of water and 500 ml of dichloromethane are added. After the phases have been separated, the aqueous phase is extracted twice with 250 ml of dichloromethane. The organic phases are washed with 250 ml of water and concentrated. The oily residue is taken up in cyclohexane; there is obtained 182 g (87.3% of theory) of crystalline 2,3-dichloro-4-hydroxymethylthiophene, m.p.: 63° to 65° C.
Reaction SMILES: [NH2:1][CH:2]1[C:16](=[O:17])[N:4]2[C:5]([C:13]([OH:15])=[O:14])=[C:6]([CH:9]=[N:10][O:11][CH3:12])[CH2:7][S:8][C@H:3]12.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH2:23][C:24](Cl)=[O:25].S1C=CC=C1CC(O)=O.S(Cl)(Cl)=O>C(Cl)(Cl)Cl.O.C(N(CC)CC)C>[CH3:12][O:11][N:10]=[CH:9][C:6]1[CH2:7][S:8][C@@H:3]2[CH:2]([NH:1][C:24](=[O:25])[CH2:23][C:19]3[S:18][CH:22]=[CH:21][CH:20]=3)[C:16](=[O:17])[N:4]2[C:5]=1[C:13]([OH:15])=[O:14]
Reactant: CON=CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: O=C(Cl)Cc1cccs1
Agent: O=C(O)Cc1cccs1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CON=CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of 7-amino-3-methoxyiminomethyl-3-cephem-4-carboxylic acid (134 mg) and triethylamine (0.1 ml) in chloroform (1 ml) is added 2-thienylacetyl chloride prepared from 2-thienylacetic acid (78 mg) and thionyl chloride (0.1 ml) in chloroform (1 ml), and the mixture is stirred at room temperature for 2 hours. The reaction mixture is diluted with water, adjusted to pH 2, and extracted with ethyl acetate. The extract solution is washed with water, dried and evaporated under reduced pressure. Treatment of the residue with ether gives 3-methoxyiminomethyl-7-(2-thienylacetamido)-3-cephem-4-carboxylic acid (161 mg; 82%). m.p. 186°-189° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:39][CH2:40][CH3:41])=[C:24]([NH:27][C:28](=[O:38])[CH2:29]P(OCC)(OCC)=O)[CH:25]=3)[N:20]=[CH:19][C:18]=2[C:42]#[N:43])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1(C)C=CC=CC=1.[CH3:61][N:62]1[CH2:66][CH2:65][CH2:64][CH:63]1[CH:67]=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:39][CH2:40][CH3:41])=[C:24]([NH:27][C:28](=[O:38])/[CH:29]=[CH:67]/[CH:63]4[CH2:64][CH2:65][CH2:66][N:62]4[CH3:61])[CH:25]=3)[N:20]=[CH:19][C:18]=2[C:42]#[N:43])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CN1CCCC1C=O
Reactant: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1NC(=O)CP(=O)(OCC)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1NC(=O)/C=C/C1CCCN1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.5 %

Procedure:
N-[4-[[3-Chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]-2-diethoxyphosphoryl-acetamide 1d (3 g, 4.40 mmol) was dissolved in 30 mL of tetrahydrofuran in a dry ice bath, followed by dropwise addition of a solution of lithium bis(trimethylsilyl)amide (1 M) in toluene (9.6 mL, 8.80 mmol). After the mixture was stirred for 30 minutes, a solution of 1-methylpyrrolidine-2-carbaldehyde 10e (1 g, 8.80 mmol) in 5 mL of tetrahydrofuran was added dropwise. The reaction mixture was stirred for another 30 minutes, then warmed up to room temperature and stirred for 24 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound (E)-N-[4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]-3-(1-methylpyrrolidin-2-yl)prop-2-enamide 10 (500 mg, yield 20.8%) as a yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:11](=[O:29])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([O:24][CH2:25][C:26]([NH2:28])=[O:27])=[CH:14][CH:13]=2)(C)(C)C.[ClH:35]>C(OCC)(=O)C>[ClH:35].[NH2:7][CH2:8][C:9]1[N:10]([CH2:30][CH:31]([CH3:32])[CH3:33])[C:11](=[O:29])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([O:24][CH2:25][C:26]([NH2:28])=[O:27])=[CH:14][CH:13]=2
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(OCC(N)=O)cc12
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCOc1c(CN)n(CC(C)C)c(=O)c2ccc(OCC(N)=O)cc12
Yield: 92 %

Procedure:
To a solution of tert-butyl[6-(2-amino-2-oxoethoxy)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.29 g, 0.6 mmol) in ethyl acetate (5 mL) was added, a solution of 4N hydrogen chloride in ethyl acetate (5 mL) and the obtained solution was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, and the precipitated crystals were recrystallized from methanol-diisopropyl ether to give 2-[[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]oxy]acetamide hydrochloride (0.23 g, 92.0%) as crystals.
Reaction SMILES: C(Cl)Cl.CN(C=O)C.[Cl:9][C:10]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:11]=1[C:12]([NH:14][NH:15][C:16](=O)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:19][CH:18]=1)=O.[CH3:38][O:39][C:40]1[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=1.P(Cl)(Cl)Cl>ClC1C=CC=CC=1Cl>[Cl:9][C:10]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:11]=1[C:12]1[N:46]([C:43]2[CH:44]=[CH:45][C:40]([O:39][CH3:38])=[CH:41][CH:42]=2)[C:16]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:19][CH:18]=2)=[N:15][N:14]=1
Reactant: CCCCCCCCOc1ccc(C(=O)NNC(=O)c2cc(Cl)ccc2Cl)cc1
Reactant: COc1ccc(N)cc1
Solvent: CN(C)C=O
Solvent: Clc1ccccc1Cl
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(-c2nnc(-c3cc(Cl)ccc3Cl)n2-c2ccc(OC)cc2)cc1
Temperature: 180 °C
Yield: 33.9 %

Procedure:
Into a 1L round-bottomed flask fitted with a mechanical stirrer, reflux condenser and nitrogen inlet were introduced 2,5-dichloro-N′-[4-(octyloxy)benzoyl]benzohydrazide (40 g, 0.09146 mole, 1 equivalent), p-anisidine (67.60 g, 0.5487 mole, 6 equivalents) and 300 mL 1,2-dichlorobenzene. Mechanical stirring resulted in partial solvation of the solids. Phosphorus trichloride (12.56 g, 0.0146 mole, 1 equivalent) was added and the contents of the flask heated at 180° C. for 12 hrs. The solvent was distilled off under a light vacuum and the residue transferred to a 2L flask with 1L of a 1:1 acetone/heptane mixture. The solid material was filtered off and dissolved in acetone. Enough heptane was added to precipitate a purple-colored oily sludge. Heptane dilution of a test sample of the acetone/heptane layer ensured that the oily sludge had been completely precipitated. The acetone/heptane layer was decanted off and diluted further with a large excess of heptane to precipitate a white solid. This was filtered off, dissolved in acetone and re-precipitated with heptane. Filtration and drying gave 3-(2,5-dichlorophenyl)-4-(4-methoxyphenyl)-5-[4-(octyloxy)phenyl]-4H-1,2,4-triazole (8) (16.25 g, 34% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[C:15]([CH3:23])[C:16]([OH:22])=[CH:17][CH:18]=3)[O:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[C:15]([CH3:23])[C:16]([O:22][C:24](=[O:26])[CH3:25])=[CH:17][CH:18]=3)[O:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(-c2coc3c(C)c(O)ccc3c2=O)cc1OC
Solvent: c1ccncc1
Product: COc1ccc(-c2coc3c(C)c(OC(C)=O)ccc3c2=O)cc1OC
Temperature: 25 °C

Procedure:
3-(3,4-dimethoxy-phenyl)-7-hydroxy-8-methyl-chromen-4-one (9.82 g, 31 mmol), acetic anhydride (62 ml) and pyridine (6.2 ml) were combined in a round bottom flask and heated to reflux. The reaction was cooled to room temperature after 3 hours of heating, and a crystalline solid formed. The solid was filtered and rinsed with H2O (1 L). 1H NMR in d-CDCl3 indicated pale brown crystals was acetic acid 3-(3,4-dimethoxy-phenyl)-8-methyl-4-oxo-4H-chromen-7-yl ester in 90% purity (7.214 g, 71%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I-:25].[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[O:32][CH2:33][C:34]#[C:35][CH2:36]O>ClCCl>[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[O:32][CH2:33][C:34]#[C:35][CH2:36][I:25]
Reactant: OCC#CCOC1CCCCO1
Reactant: [I-]
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: ICC#CCOC1CCCCO1
Reaction time: 0.05 h
Yield: 56.1 %

Procedure:
To a stirred solution of triphenylphosphine (1.4154 g, 5.34 mmol) in anhydrous dichlormethane (20 mL) at room temperature under nitrogen was added imidazole (360 mg, 5.24 mmol), followed by iodide (1.2688 g, 4.95 mmol). The mixture was stirred for three minutes, a solution of 4-(tetrahydro-pyran-2-yloxy)-but-2-yn-1-ol (708.6 mg, 4.16 mmol) in dichloromethane was added dropwise via spring. The resulting mixture was continued to be stirred for 1.5 hours. The mixture was filtered through a pad of Celite. And the solid was washed with dichloromethane. The combined organic filtration was concentrated under reduced pressure. The residue was separated with flash column chromatography on silica using 0-20% EtOAc/hexane to afford 654 mg of product in 56% yield. 1H-NMR (CDCl3): δ 4.77 (t, J=3.0 Hz, 1H), 4.33-4.18 (m, 2 H), 3.85-3.77 (m, 1 H), 3.70 (t, J=2.1 Hz, 2 H), 3.56-3.49 (m, 1 H), 1.85-1.62 (m, 6 H).
Reaction SMILES: [Mg].Cl[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH2:16](Br)[CH3:17].[OH-].[Na+]>CI.CCOCC.[Cu]I>[CH2:16]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)[CH3:17]
Reactant: CCBr
Reactant: CN1CCC(c2ccc(Cl)cc2)CC1
Agent: [Cu]I
Agent: [Mg]
Agent: [Na+]
Solvent: CCOCC
Solvent: CI
Product: CCc1ccc(C2CCN(C)CC2)cc1

Procedure:
A few drops of methyl iodide are added, under nitrogen, to a suspension of 0.5 g of magnesium chips covered with a small amount of absolute ether and, after the reaction has subsided, there is added dropwise at 30° to 35° a solution of 4.2 g of 4-(4-chlorophenyl)-1-methyl-piperidine in 20 ml of absolute ether. When the major part of the magnesium has been dissolved, 100 mg of copper(I)iodide is added; the temperature is lowered to -10°, 2.5 g of ethyl bromide is added, and stirring is maintained over night at -10° to 0°. An addition of 50 ml of 2 N sodium hydroxide solution is then made, the mixture is saturated with sodium chloride, and extraction is performed three times with 50 ml of ether each time. The organic phases are combined, washed until neutral, dried over sodium sulphate and concentrated in vacuo. Distillation of the residue under high vacuum, and chromatography of the fraction boiling at 90°-100° (0.03 mm) on silica gel with chloroform and a small amount of methanol as the eluant yield crude 4-(4-ethylphenyl)-1-methyl-piperidine, which is converted into the hydrochloride, m.p. 209°-210°.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([NH:15]C(=O)OC(C)(C)C)[CH2:11][CH2:10]2)=[N:7][CH:8]=1.[ClH:25]>O1CCOCC1.C1COCC1.O1CCOCC1>[ClH:25].[ClH:25].[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]2)=[N:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(C(F)(F)F)cn2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: NC1CCN(c2ccc(C(F)(F)F)cn2)CC1
Temperature: 25 °C
Yield: 89 %

Procedure:
A mixture of tert-butyl {1-[5-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl}carbamate (1.27 g, 3.68 mmol) in HCl in Dioxane/THF (4M, 1:1; 10 ml) was stirred at rt. After 6.5 h more HCl in Dioxane (4M, 2 ml) was added and the resulting mixture stirred for a further 18 h. The mixture was filtered and the residue was washed with EtOAc to give the title compound (1.04 g, 89%) as a solid. 1H NMR (500 MHz CD3OD): 8.35 (s, 1H), 8.20 (dd, 1H), 7.60 (d, 1H), 4.46 (d, 2H), 3.66-3.56 (m, 1H), 3.48 (td, 2H), 2.28 (d, 2H), 1.90-1.80 (m, 2H); 13C NMR (125 MHz CD3OD): 153.5, 139.2, 136.3, 126.1, 123.9, 121.8, 120.0, 116.2, 115.9, 115.6, 115.3, 113.9, 45.2, 29.1; Mass Spectrum: M+H+ 246.
Reaction SMILES: P(Br)(Br)([Br:3])=O.[NH2:6][C:7]1[C:11]2[C:12](O)=[N:13][CH:14]=[CH:15][C:10]=2[NH:9][N:8]=1.C(=O)(O)[O-].[Na+]>>[Br:3][C:12]1[C:11]2[C:7]([NH2:6])=[N:8][NH:9][C:10]=2[CH:15]=[CH:14][N:13]=1
Reactant: Nc1n[nH]c2ccnc(O)c12
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Product: Nc1n[nH]c2ccnc(Br)c12
Temperature: 70 °C
Yield: 58.1 %

Procedure:
To 3.5 g of POBr3 melted at 45° C. is added 0.4 g of 3-amino-1H-pyrazolo[4,3-c]pyrid-4-ol, and the suspension is then maintained at 70° C. for 4 hours. The resulting mixture is allowed to cool and is hydrolysed, cautiously, with sodium bicarbonate solution. The mixture is extracted with ethyl acetate. The organic phase is isolated and dried over magnesium sulfate, filtered and then concentrated under reduced pressure. 0.33 g of 4-bromo-1H-pyrazolo[4,3-c]pyrid-3-ylamine is obtained in the form of a cream-coloured solid.
Reaction SMILES: [C:1]1([C:7]2[C:11]3[C:12](=[O:21])[C:13](=[O:20])[C:14]4[C:19]([C:10]=3[O:9][N:8]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO>[C:7]([C:11]1[C:10](=[O:9])[C:19]2[C:14]([C:13](=[O:20])[C:12]=1[OH:21])=[CH:15][CH:16]=[CH:17][CH:18]=2)(=[NH:8])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1C(=O)c2c(-c3ccccc3)noc2-c2ccccc21
Solvent: CO
Product: N=C(C1=C(O)C(=O)c2ccccc2C1=O)c1ccccc1
Yield: 57.1 %

Procedure:
A solution of 3-phenyl-4,5-dihydronaphtho-[2,1-d]isoxazole-4,5-dione (40 mg) in methanol (40 ml) is irradiated by light of a high-pressure mercury lamp (1 KW) at room temperature (20°-30°C) for about 1 hour. After removal of the solvent, the residue is chromatographed on alumina and eluted with methylene chloride-methanol (20:1). The eluate is evaporated and the residue is washed with isopropyl ether-ether to give 2-benzimidoyl-3-hydroxy-1,4-naphthoquinone (23 mg). Recrystallization from acetic acid gives pale yellow scales, m.p. 258°-259°C, identical with the product of Example 1.