Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([C:12]([CH2:15][CH2:16][N:17]4[CH2:22][CH2:21][N:20]([C:23]5[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][N:24]=5)[CH2:19][CH2:18]4)=[C:13]([CH3:14])[N:8]3[CH2:7][CH2:6][CH2:5]2)[CH:11]=1.C(N(CC)CC)C.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)(Cl)Cl>[C:37]([NH:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([C:12]([CH2:15][CH2:16][N:17]4[CH2:22][CH2:21][N:20]([C:23]5[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][N:24]=5)[CH2:19][CH2:18]4)=[C:13]([CH3:14])[N:8]3[CH2:7][CH2:6][CH2:5]2)[CH:11]=1)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Cc1ccnc(N2CCN(CCc3c(C)n4c5c(cc(N)cc35)CCC4)CC2)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccnc(N2CCN(CCc3c(C)n4c5c(cc(NC(=O)c6ccccc6)cc35)CCC4)CC2)c1
Yield: 23.7 %

Procedure:
2 g of 8-amino-5,6-dihydro-2-methyl-1-{2-[4-(4-methylpyridin-2-yl)piperazin-1-yl]-ethyl}-4H-pyrrolo-[3,2,1-ij]quinoline (preparation see Example 20) were dissolved in 25 ml of chloroform. 1.45 ml of triethylamine and then, dropwise, 1.075 g of benzoyl chloride were added to the solution without exceeding a temperature of 20° C. in this process. The reaction mixture was allowed to react at room temperature for hour. To work up the reaction mixture, it was washed with 20 ml of 10% aqueous sodium hydroxide solution until neutral, dried and evaporated. The crude product obtained was purified by chromatography on a small silica gel column using toluene/ethanol 95:5 as the eluent. After recrystallization from ethanol, 0.6 g of 8-benzoylamino-5,6-dihydro-2-methyl-1-{2-[4-(4-methylpyridin-2-yl)-piperazin-1-yl]-ethyl}-4H-pyrrolo[3,2,1-ij]quinoline was obtained as a cream-colored powder. This was converted into the corresponding 0.5-hydrochloride having a melting point of 218° C. as described in Example 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:25])[N:11]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]O.C(Br)(Br)(Br)[Br:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:27][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:10]([NH:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])=[O:25]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCCCCN(CCCCCO)C(=O)Nc1ccc(F)cc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCCN(CCCCCBr)C(=O)Nc1ccc(F)cc1F
Reaction time: 3 h
Yield: 100 %

Procedure:
Part D. To a solution of N'-(2,4-difluorophenyl)-N-heptyl-N-5-hydroxypentylurea (15.0 g, 0.042 mol) and carbon tetrabromide (16.75 g, 0.051 mol) in methylene chloride (350 mL) under a nitrogen atmosphere at ambient temperature, a solution of triphenylphosphine (13.24 g, 0.051 mol) in methylene chloride (100 mL) was added slowly. The reaction mixture was stirred for 3 hours and was concentrated in vacuo to give crude viscous oil. The product was purified by flash chromatography on silica gel (400 mL) eluting with hexane:ethyl acetate (90:10::v:v) to give N-(5-bromopentyl)-N'-(2,4-difluorophenyl)-N-heptylurea as a viscous colorless oil (17.5 g, 0.042 mol). 1H NMR (CDCl3) δ8.14-8.00 (m,1H), 6.92-6.79 (m,2H), 6.35 (bs,1H), 3.49-3.25 (m,6H), 1.99-1.26 (m,16H), 0.92 (t,3H,J=6.7 Hz).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH2:9][CH2:8][CH2:7]2)(=[O:3])[CH3:2].[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][N:22]=2)=[CH:17][CH:16]=1>>[CH3:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:22]=[CH:23][C:24]([C:25]([N:10]3[C:11]4[C:6](=[CH:5][C:4]([C:1](=[O:3])[CH3:2])=[CH:13][CH:12]=4)[CH2:7][CH2:8][CH2:9]3)=[O:26])=[CH:28][CH:29]=2)=[CH:19][CH:20]=1
Reactant: CC(=O)c1ccc2c(c1)CCCN2
Reactant: Cc1ccc(-c2ccc(C(=O)O)cn2)cc1
Product: CC(=O)c1ccc2c(c1)CCCN2C(=O)c1ccc(-c2ccc(C)cc2)nc1

Procedure:
Using 6-acetyl-1,2,3,4-tetrahydroquinoline and 6-(4-methylphenyl)nicotinic acid, 1-[1-[[6-(4-methylphenyl)-3-pyridinyl]carbonyl]-1,2,3,4-tetrahydro-6-quinolinyl]ethanone was obtained as pale yellow powder by the same procedure as in Reference Example 5.
Reaction SMILES: [CH2:1]([N:3]([CH2:8][CH3:9])[C:4](=[O:7])[CH2:5]O)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:29]N1C(=O)CCC1=O.C(N(CC)C(C)C)(C)C>ClCCl>[Br:29][CH2:5][C:4]([N:3]([CH2:8][CH3:9])[CH2:1][CH3:2])=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCN(CC)C(=O)CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(CC)C(=O)CBr
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
Under a nitrogen atmosphere, N,N-diethyl-2-hydroxy-acetamide (42 mg, 0.320 mmol) was dissolved in dichloromethane (1.5 mL) and the mixture was cooled to 0° C. Triphenylphosphine (125.9 mg, 0.480 mmol) and N-bromosuccinimide (85.4 mg, 0.480 mmol) were added in order and the mixture was stirred at room temperature for 3.5 hours. The mixture was warmed to room temperature and 2-bromo-N,N-diethylacetamide was prepared in situ. To the mixture, solution of No. 5447725 (Compound G; 56 mg, 0.080 mmol) in dichloromethane (1.0 mL) was added dropwise under a nitrogen atmosphere. N,N-Diisopropylethylamine (69.7 μL, 0.40 mmol) was then added at room temperature, and the mixture was stirred under feflux for 14 hours. After completing the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with water and a saturated brine and dried over anhydrous sodium sulfate. After the organic layer was filtered and the solvent was distilled off, the residue was then purified by HPLC (water with 0.05% TFA-acetonitrile with 0.05% TFA) to obtain 31.2 mg (42% yield) of the triester form.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:14]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])[CH2:11][CH:10]2[N:22]([CH3:37])[C:23](=[O:36])[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([C:32]([F:35])([F:34])[F:33])[CH:25]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:38]1([S:41](Cl)(=[O:43])=[O:42])[CH2:40][CH2:39]1>>[CH:38]1([S:41]([N:19]2[CH2:20][CH2:21][CH:16]([C:14]([N:12]3[CH2:13][CH:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[CH:10]([N:22]([CH3:37])[C:23](=[O:36])[C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([C:32]([F:33])([F:34])[F:35])[CH:25]=4)[CH2:11]3)=[O:15])[CH2:17][CH2:18]2)(=[O:43])=[O:42])[CH2:40][CH2:39]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCNCC3)CC2c2ccc(Cl)c(Cl)c2)cc1C(F)(F)F
Product: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCN(S(=O)(=O)C4CC4)CC3)CC2c2ccc(Cl)c(Cl)c2)cc1C(F)(F)F

Procedure:
In analogy to the procedure described for the synthesis of example 140, the title compound N-[(3RS,4SR)-1-(1-Cyclopropanesulfonyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide was prepared from N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using cyclopropanesulfonylchloride instead of ethanesulfonyl chloride and was obtained as a off-white foam. MS m/e: 662.2 [M]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[C:10]([O:14][C:15]([N:17]1[C:22](=[O:23])[CH2:21][CH2:20][CH2:19][C@@H:18]1[C:24]([OH:26])=[O:25])=[O:16])([CH3:13])([CH3:12])[CH3:11].[CH2:27]1COCC1>>[CH3:27][O:26][C:24](=[O:25])[C@H:18]([NH:17][C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])[CH2:19][CH2:20][CH2:21][C:22]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:23]
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1C(=O)CCC[C@@H]1C(=O)O
Product: COC(=O)[C@@H](CCCC(=O)c1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Reaction time: 1.5 h

Procedure:
In nitrogen atmosphere, 4-chlorophenyl magnesium bromide (1.0 M, diethylether solution, 42 mL) was added to a THF solution (120 mL) of (R)-6-oxopiperidine-1,2-dicarboxylic acid 1-tert-butyl ester (CAS Register No. 183890-36-0, 9.00 g) over 20 min at −78° C. The resulting reaction solution was stirred at −78° C. to −40° C. for 1.5 hr and then quenched with a saturated ammonium chloride aqueous solution at −40° C. To this reaction solution, water was added. The resulting mixture was extracted with ethyl acetate. The obtained extract solution was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: heptane-ethyl acetate system) to give 9.53 g of (R)-2-tert-butoxycarbonylamino-6-(4-chlorophenyl)-6-oxohexanoic acid methyl ester. To an ethyl acetate solution (90 mL) of the (R)-2-tert-butoxycarbonylamino-6-(4-chlorophenyl)-6-oxohexanoic acid methyl ester (9.53 g), a 4 N hydrogen chloride-ethyl acetate solution (90 mL) was added at room temperature. The resulting reaction solution was stirred at room temperature for 12 hr and then concentrated under reduced pressure. A saturated sodium hydrogencarbonate aqueous solution was added to the residue for basification, and then chloroform was added thereto. The resulting reaction solution was stirred at room temperature for 2 hr. The organic layer was separated, dried over magnesium sulfate, and concentrated under reduced pressure. To a methanol solution (150 mL) of the residue, sodium cyano borohydride (3.29 g) and then acetic acid (4.27 mL) were added at 0° C. The resulting reaction solution was stirred at 0° C. for 1 hr and further at room temperature for 1 hr, and then a saturated sodium hydrogencarbonate aqueous solution was added thereto. The resulting mixture was extracted with chloroform. The obtained extract solution was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: heptane-ethyl acetate system) and further solidified from a heptane-diisopropylether system to give 2.47 g of the title compound. The physical property values of this compound were as follows:
Reaction SMILES: [CH3:1][N:2]([CH3:26])[N:3]=[C:4]([CH:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)[CH3:7])[CH3:5].C([N-]C(C)C)(C)C.[Li+].[CH:35](=[O:37])[CH3:36].O.C(Cl)Cl>C1COCC1>[CH3:26][N:2]([CH3:1])[N:3]=[C:4]([CH2:5][CH:35]([OH:37])[CH3:36])[CH:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)[CH3:7]
Reactant: CC=O
Reactant: CC(=NN(C)C)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(O)CC(=NN(C)C)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reaction time: 1 h

Procedure:
To a solution of 3-[4-(4-trifluoromethylphenoxy)phenoxy]-2-butanone N,N-dimethylhydrazone (5.4 mmol) in THF (15 ml) under nitrogen is added lithium diisopropylamide (6.6 mmol) in THF (15 ml) at 0° for 4 hours. The resulting solution is cooled to -78°, and to it is added ethanal (6.6 mmol). After 1 hour at -78°, the reaction mixture is allowed to warm to 0° and is poured into water/methylene chloride (3:1). The organic phase is separated (3X), and the combined organic extracts are dried over sodium sulfate and concentrated to give 5-hydroxy-2-[4-(4-trifluoromethylphenoxy)phenoxy]-3-hexanone N,N-dimethylhydrazone (cpd. 25, Table C).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18].O>ClCCl>[CH2:20]([O:19][C:17]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1)=[O:18])[CH3:21]
Reactant: CCOC(=O)Cl
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)N1CCC(c2c[nH]c3ccccc23)CC1
Reaction time: 2 h

Procedure:
To a suspension of 30 g (0.15 mol) of 3-piperidin-4-yl-1H-indole and 28 mL (0.2 mol) in 185 ml of anhydrous dichloromethane, 17 ml (0.18 mol) of ethyl chloroformate were added dropwise keeping the temperature of the reaction below 20° C. After 2 h at room temperature, the crude mixture was poured into 100 ml of water. The organic layer was separated and dried with sodium sulphate. After filtration, the solvent was removed under reduced pressure affording 39 g (95% of yield) of the expected product.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([CH2:19]Br)[CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:7][CH:8]=1)#[N:2].[N-:21]=[N+:22]=[N-:23].[Na+].O.C(OCC)(=O)C>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([CH2:19][N:21]=[N+:22]=[N-:23])[CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)c1cc(CBr)cc(-c2cccc(C#N)c2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(CN=[N+]=[N-])cc(-c2cccc(C#N)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
In 33 ml of dimethylformamide, was dissolved 1.1 g of the compound obtained in Example 5. To the resulting solution, was slowly added 325 mg of sodium azide. The obtained reaction solution was stirred at room temperature for 2 hours, and 80 ml of water and 120 ml of ethyl acetate were then added thereto to extract organic substances. The aqueous layer was extracted with 100 ml of ethyl acetate twice. The resulting extract was washed with saturated brine and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure to afford 925 mg (95%) of the title compound as a light-yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]2[N:18](C(OC(C)(C)C)=O)[CH:19]=[CH:20][C:13]=12.[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([O:38][CH3:39])=[C:33]([N:35]=[C:36]=[O:37])[CH:34]=1>C(Cl)Cl>[ClH:28].[O:38]([C:32]1[CH:31]=[CH:30][C:29]([Cl:28])=[CH:34][C:33]=1[NH:35][C:36]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]2[NH:18][CH:19]=[CH:20][C:13]=12)=[O:37])[CH3:39]
Reactant: CC(C)(C)OC(=O)n1ccc2c(Cn3ccc4c(N)cccc43)ccnc21
Reactant: COc1ccc(Cl)cc1N=C=O
Solvent: ClCCl
Product: COc1ccc(Cl)cc1NC(=O)Nc1cccc2c1ccn2Cc1ccnc2[nH]ccc12
Product: Cl
Reaction time: 8 h

Procedure:
To a solution of 4-[(4-amino-1H-indol-1-yl)methyl]-1-(t-butyloxycarbonyl)-1H-pyrrolo[2,3-b]pyridine (450 mg) in DCM was added 5-chloro-2-methoxyphenyl isocyanate (Int-4, 275 mg, 1.5 mmol). The mixture was stirred overnight, then concentrated, and purified by flash column chromatography to give the desired product 1-(2-methoxyl-5-chlorophenyl)-3-{1-[1-(t-butyloxycarbonyl)-1H-pyrrolo[2, 3-1)]pyridin-4-ylmethyl]-1H-indol-4-yl}urea (540 mg, 80% for two steps).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[CH3:11][S:12][C:13]1[N:18]=[CH:17][C:16]2=[CH:19][CH:20]=[CH:21][N:15]2[N:14]=1.BrC1N2C(C=NC(SC)=N2)=CC=1>>[CH3:11][S:12][C:13]1[N:18]=[CH:17][C:16]2=[CH:19][CH:20]=[C:21]([CH:8]=[O:9])[N:15]2[N:14]=1
Reactant: CN(C)C=O
Reactant: CSc1ncc2cccn2n1
Agent: CSc1ncc2ccc(Br)n2n1
Solvent: O=P(Cl)(Cl)Cl
Product: CSc1ncc2ccc(C=O)n2n1
Temperature: 80 °C
Yield: 78.6 %

Procedure:
To a cooled (0° C.) mixture of Phosphoryl chloride (55 mL, 0.59 mol) and N,N-Dimethylformamide (27 mL, 0.35 mol) was added 2-Methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (3.70 g, 0.0224 mol) in N,N-Dimethylformamide (55 mL, 0.71 mol). The addition was added to ensure that the temperature of the reaction stayed below 20° C. After complete addition of 7-Bromo-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine, the mixture was heated at 80° C. and was allowed to stir until HPLC showed consumption of starting material (−1 hour). The reaction was then poured over ice water and was neutralized with saturated sodium bicarbonate. Organics were then extracted with ethyl acetate and combined extracts were dried over magnesium sulfate, filtered and reduced to afford 3.40 g of 2-Methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine-7-carbaldehyde which was used without further purification. 1H NMR (400 MHz, DMSO, d6) δ 10.41 (s, 1H), 9.25 (s, 1H), 7.43 (d, 1H, J=4.96 Hz), 7.05 (d, 1H, J=5.00 Hz), 2.59 (s, 3H).
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[OH:2].[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(OCC)(=O)C>[S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[NH+:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH+:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccncc1
Reactant: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: O=S(=O)([O-])[O-]
Product: c1cc[nH+]cc1

Procedure:
To a mixture of dry ethyl acetate (1 l) and concentrated sulphuric acid (25 l, 0.469 mol) was added slowly, with stirring, dry pyridine (50 ml, 0.620 mol). The mixture was cooled and the precipitate of pyridinium sulphate produced was separated from the ethyl acetate by decanting, rinsed with a portion of dry ethyl acetate and vacuum dried at 60° C. to yield 85 g (100% yield) of product. The product (85 g, 0.480 mol) was dissolved in dry dimethylformamide (250 ml) to provide a 1.921M pyridinium sulphate solution, herein designated as pyridinium sulphate reagent. The reagent was stored in a hermetically sealed amber bottle over anhydrous calcium sulphate (25 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:19][C:20]1[CH:35]=[CH:34][C:23]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[CH:22][C:21]=1[O:36][CH3:37].ClCCl>O1CCOCC1.CO>[CH2:27]([O:26][C:24]([C:23]1[CH:34]=[CH:35][C:20]([NH:19][C:2]2[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=2)=[C:21]([O:36][CH3:37])[CH:22]=1)=[O:25])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COc1cc(C(=O)OCc2ccccc2)ccc1N
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc(C(=O)OCc2ccccc2)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Temperature: 100 °C
Reaction time: 30 h

Procedure:
2 g (9.217 mmol) 2,4-dichloro-5-trifluoromethylpyrimidine are dissolved in 4 ml dioxane and combined with 6.01 g (18.430 mmol) caesium carbonate and 2.16 g (7.363 mmol) benzyl 4-amino-3-methoxybenzoate (WO 9825901). This suspension is stirred for 30 h at 100° C. The suspension is combined with 50 ml dichloromethane and methanol and filtered to remove the insoluble constituents. The solvent is eliminated in vacuo and the residue is purified by column chromatography. The carrier used is silica gel and the eluant used is a mixture of 85% cyclohexane and 15% ethyl acetate.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH2:22][CH2:23][CH3:24])=[C:8]([C:16]([CH:19]([OH:21])[CH3:20])=[CH:17][CH:18]=1)[O:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[OH:25][C:26]1[C:31]([CH2:32][CH2:33][CH3:34])=[C:30]([SH:35])[CH:29]=[CH:28][C:27]=1[C:36](=[O:38])[CH3:37].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[C:36]([C:27]1[CH:28]=[CH:29][C:30]([S:35][CH2:2][CH2:3][CH2:4][O:5][C:6]2[C:7]([CH2:22][CH2:23][CH3:24])=[C:8]([C:16]([CH:19]([OH:21])[CH3:20])=[CH:17][CH:18]=2)[O:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[C:31]([CH2:32][CH2:33][CH3:34])[C:26]=1[OH:25])(=[O:38])[CH3:37]
Reactant: CCCc1c(S)ccc(C(C)=O)c1O
Reactant: CCCc1c(OCCCCl)ccc(C(C)O)c1OCCCC(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c(SCCCOc2ccc(C(C)O)c(OCCCC(=O)O)c2CCC)ccc(C(C)=O)c1O
Temperature: 0 °C
Yield: 35.9 %

Procedure:
A mixed solution of 55.9 mg of (-)-4-[3-(3-chloropropoxy)-6-(1-hydroxyethyl)-2-propylphenoxy] butanoic acid, 39.3 mg of (2-hydroxy-4-mercapto-3-propylphenyl) ethanone, 51.7 mg of potassium carbonate and 1 ml of dimethylformamide was stirred at room temperature for 6 hours. The reaction mixture was poured into ice water, acidified with 1N-hydrochloric acid, and extracted with ethyl acetate. After washed with water and saturated aqueous solution of sodium chloride, the organic layer was dried over anhydrous sodium sulfate and subjected to distillation off of the solvent under reduced pressure to afford residue, which was then purified through silica gel column chromatography (methylene chloride: methanol=20:1) and further purified through preparative thin layer chromatography (methylene chloride: methanol=15:1) to afford 29.8 mg of yellow oily matter as the title compound (35.9%). [α]D20 -13.8° (c=2.98, ethanol)
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[NH:19][N:18]=[N:17][N:16]=3)[CH:10]=2)[C:4]=1[OH:20].[N:21]([O-])=O.[Na+].[CH3:25][C:26]1([CH3:42])[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([N:35]3[C:39](=[O:40])[CH2:38][C:37]([CH3:41])=[N:36]3)[CH:33]=2)[CH2:28][CH2:27]1.C(=O)(O)[O-].[Na+]>Cl.C(O)C>[CH3:25][C:26]1([CH3:42])[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([N:35]3[C:39](=[O:40])[C:38](=[N:21][NH:2][C:3]4[C:4]([OH:20])=[C:5]([C:9]5[CH:14]=[CH:13][CH:12]=[C:11]([C:15]6[NH:19][N:18]=[N:17][N:16]=6)[CH:10]=5)[CH:6]=[CH:7][CH:8]=4)[C:37]([CH3:41])=[N:36]3)[CH:33]=2)[CH2:28][CH2:27]1
Reactant: CC1=NN(c2ccc3c(c2)C(C)(C)CC3)C(=O)C1
Reactant: Nc1cccc(-c2cccc(-c3nnn[nH]3)c2)c1O
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC1=NN(c2ccc3c(c2)C(C)(C)CC3)C(=O)C1=NNc1cccc(-c2cccc(-c3nnn[nH]3)c2)c1O
Yield: 73.7 %

Procedure:
3-Amino-3′-(1H-tetrazol-5-yl)-biphenyl-2-ol hydrochloride 8f (290 mg, 1.0 mmol) was dissolved in hydrochloric acid (3.4 mL, 1 mol/L) followed by dropwise addition of 1.2 mL of aqueous sodium nitrite (73 mg, 1.05 mmol) upon cooling by an ice-water bath. After the mixture was reacted at room temperature for 10 minutes, 2-(3,3-dimethyl-indan-5-yl)-5-methyl-2,4-dihydro-pyrazol-3-one 8i (218 mg, 0.9 mmol), sodium bicarbonate (1.26 g, 15 mmol) and 4.4 mL of ethanol were added successively. Then the reaction mixture was reacted for 10 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered and the filter cake was washed with 20 mL of water and then dissolved in 20 mL of water. Upon cooling by an ice-water bath, the mixture was adjusted to pH<5 with concentrated hydrochloric acid. The mixture was filtered and dried to obtain the title compound 2-(3,3-dimethyl-indan-5-yl)-4-{[2-hydroxy-3′-(1H-tetrazol-5-yl)-biphenyl-3-yl]-hydrazono}-5-methyl-2,4-dihydro-pyrazol-3-one 8 (336 mg, yield 73.8%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Cl[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[N:44]([CH3:49])[CH:45]=[C:46]([CH3:48])[N:47]=2)=[CH:38][C:37]=1[CH3:50].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:41]([CH3:42])=[CH:40][C:39]([C:43]6[N:44]([CH3:49])[CH:45]=[C:46]([CH3:48])[N:47]=6)=[CH:38][C:37]=5[CH3:50])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Cc1cn(C)c(-c2cc(C)c(Cl)c(C)c2)n1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6nc(C)cn6C)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-(4-chloro-3,5-dimethyl-phenyl)-1,4-dimethyl-imidazole following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 7): tR=0.98 min; Mass spectrum (ESI+): m/z=541 [M+H]+.