Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na+:1].N1(C[CH2:8][O:9][C:10]2[CH:18]=[CH:17][C:16]([C:19]3[S:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[C:20]=3[CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][N:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)=[CH:31][CH:30]=3)=[CH:15][C:11]=2[C:12]([O-:14])=[O:13])CCCC1.ClC[CH2:45][CH2:46][C:47]([O:49]C)=[O:48]>>[Na+:1].[Na+:1].[C:47]([CH2:46][CH2:45][CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:16]([C:19]2[S:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[C:20]=2[CH2:28][C:29]2[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)=[CH:33][CH:34]=2)=[CH:15][C:11]=1[C:12]([O-:14])=[O:13])([OH:49])=[O:48].[C:47]([CH2:46][CH2:45][CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:16]([C:19]2[S:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[C:20]=2[CH2:28][C:29]2[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)=[CH:33][CH:34]=2)=[CH:15][C:11]=1[C:12]([O-:14])=[O:13])([OH:49])=[O:48]
Reactant: COC(=O)CCCCl
Reactant: O=C([O-])c1cc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)ccc1OCCN1CCCC1
Agent: [Na+]
Product: O=C(O)CCCOc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1C(=O)[O-]
Yield: 54 %

Procedure:
The title compound was prepared in 54% yield by essentially following the procedures outlined in above in Example 1, Part A, from the phenol of Example 1, Part I, above, and methyl 4-chlorobutyrate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[NH:21][C:22]1[C:27](C(O)=O)=[CH:26][N:25]=[CH:24][N:23]=1.C([N:33]([CH2:36]C)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:45])C=CC=CC=1.O>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:12]2)(=[O:9])=[O:10])=[CH:4][C:3]=1[N:21]1[C:36](=[O:45])[NH:33][C:27]2[C:22]1=[N:23][CH:24]=[N:25][CH:26]=2
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cncnc1Nc1cc(S(=O)(=O)N2CCCc3ccccc32)ccc1Cl
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: O=c1[nH]c2cncnc2n1-c1cc(S(=O)(=O)N2CCCc3ccccc32)ccc1Cl
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 4-chloropyrimidine-5-carboxylate (0.4 g), 2-chloro-5-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)aniline (0.69 g) and sodium hydride (55%, 98 mg) in 1-methyl-2-pyrrolidone (8 mL) was stirred at 100° C. for 2 hours. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1−2/1) to give ethyl 4-[2-chloro-5-(3,4-dihydroquinolin-1(2H)-yl sulfonyl)phenylamino]pyrimidine-5-carboxylate (0.42 g). To this material were added ethanol (8 mL), tetrahydrofuran (2 mL) and 5 mol/L aqueous sodium hydroxide solution (1.77 mL), and the mixture was stirred at room temperature for 3 days. The reaction mixture was acidified by adding 1 mol/L hydrochloric acid, and the precipitated crystals were collected by filtration. The crystals were washed with water, and dried under reduced pressure to give 4-[2-chloro-5-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)phenylamino]pyrimidine-5-carboxylic acid (0.37 g). The obtained 4-[2-chloro-5-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)phenylamino]pyrimidine-5-carboxylic acid (0.1 g) was dissolved in 1,4-dioxane (2 mL). To the solution were added triethylamine (0.094 mL) and diphenylphosphoryl azide (0.058 mL), and the mixture was stirred at 100° C. for 3 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/2−ethyl acetate) to give the title compound (80 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13].ClC1C=CC=C(C(OO)=[O:22])C=1>C(Cl)Cl>[O:22]1[CH:12]([CH2:11][CH2:10][CH2:9][CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH2:13]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCCCCOC1CCCCO1
Solvent: ClCCl
Product: C(CCC1CO1)COC1CCCCO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 11.57 g of 6-(2-tetrahydropyranyloxy)-hex-1-ene in 200 ml of methylene chloride is added 10.8 g m-chloroperbenzoic acid and the mixture is stirred at room temperature for 18 h. The reaction is quenched by the addition of saturated aqueous sodium bicarbonate solution followed by saturated sodium sulfite solution. The organic phase is dried, filtered and evaporated to give a clear oil which is purified by chromatography over silica gel using hexane/ether (4:1) as eluent to obtain 1,2-epoxy-6-(2-tetrahydropyranyloxy)-hexane; IR (CH2CH2): 1450, 1135, 1033 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5](C#N)=[C:4]([CH3:10])[CH:3]=1.C([O:15][CH:16]([N:20]([CH3:22])C)N(C)C)(C)(C)C>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:8][CH:9]=1)[C:16](=[O:15])[NH:20][CH:22]=[CH:10]2
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: Cc1cc(Br)ccc1C#N
Product: O=c1[nH]ccc2cc(Br)ccc12
Temperature: 140 °C
Reaction time: 2 h

Procedure:
A solution of 4-bromo-2-methylbenzonitrile (26 g) dissolved in 1-tert-butoxy-N,N,N′,N′-tetramethylmethanediamine (47.9 mL) was stirred at 140° C. for 2 h (flask open to evaporate t-butanol). The reaction mixture was cooled to room temperature, diluted with water (600 mL), and extracted with ethyl acetate (500 mL). The aqueous was further extracted with ethyl acetate (250 mL), the combined organics were washed with water (500 mL), brine (150 mL), dried (MgSO4) filtered and evaporated. The residual oil was dissolved in ethanol (250 mL) at 80° C. and treated with 37% hydrochloric acid (250 mL) at such a rate as to maintain a solution. The reaction mixture was stirred at 110° C. for 3 h, cooled to room temperature, diluted with water (600 mL) and the resulting suspension stirred for 2 h and filtered. The filtered solid was slurried in diethyl ether (400 mL) for 2 h, filtered and dried to give the subtitle compound (26.4 g) as a solid.
Reaction SMILES: [CH:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([O:12][CH3:13])=[O:11])=[O:2].[F:14][C:15]([F:19])([F:18])[CH2:16]I>>[CH:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]([CH2:16][C:15]([F:19])([F:18])[F:14])[C:4]=1[C:10]([O:12][CH3:13])=[O:11])=[O:2]
Reactant: COC(=O)c1[nH]c(C)c(C)c1C=O
Reactant: FC(F)(F)CI
Product: COC(=O)c1c(C=O)c(C)c(C)n1CC(F)(F)F

Procedure:
The title compound was prepared as pale brown crystals in 5.5% yeild in a similar procedure to that described in Referential Example 9 by using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and 1,1,1-trifluoro-2-iodoethane.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[NH2:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.CC(N(C)C)=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:9][C@@H:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:15]([OH:17])=[O:16])=[CH:3][CH:4]=1
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: Brc1ccc(Br)cc1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C)C[C@H](Nc1ccc(Br)cc1)C(=O)O
Temperature: 95 °C

Procedure:
To 1,4-dibromobenzene (16.1 g, 68.25 mmol), L-leucine (2.984 g, 22.75 mmol), potassium carbonate (4.71 g, 34.13 mmol), and copper iodide (650 mg, 3.41 mmol) was added dry DMA (N,N-dimethylacetamide, 100 mL). The reaction flask was thoroughly degassed with dry nitrogen and heated at 95° C. for 3 days. Water and hexane were added and the organic phase was separated and discarded (to remove excess 1,4-dibromobenzene). The pH of the aqueous phase was adjusted to 3 and the product was extracted with EtOAc (3×), dried on Na2SO4, concentrated in vacuo, and purified by flash chromatography over silica gel (EtOAc/Hex/AcOH, 3/7/1% then 4/6/1%) to afford (2S)-2-(4-bromoanilino)-4-methylpentanoic acid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([CH:10]3[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]3)[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[OH-].[Na+]>ClCCl.FC(F)(F)C(O)=O.O>[O:1]1[C:5]2[CH:6]=[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3ccoc3c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc2ccc(C3CCNCC3)cc2o1
Temperature: 15 °C
Reaction time: 1 h
Yield: 112.9 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of tert-butyl 4-(1-benzofuran-6-yl)piperidine-1-carboxylate (compound 63.4, 200 mg, 0.66 mmol) in dichloromethane (3 mL) and trifluoroacetic acid (1 mL). The resulting solution was stirred at 15° C. for 1 hour, then the pH was carefully adjusted to =9 with aqueous sodium hydroxide (2 M). The mixture was diluted with H2O (20 mL) and the layers were separated. The aqueous phase was extracted with dichloromethane (4×20 mL) and the combined organic layers were washed with brine (30 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to yield the title compound as a brown oil (150 mg, crude).
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH:3]([C:14]([OH:16])=[O:15])[NH:2]1.[OH-].[K+].[CH:19](I)([CH3:21])[CH3:20].[C:23](=[S:25])=[S:24]>>[CH:19]([S:25][C:23]([N:2]1[CH:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH2:1]1)=[S:24])([CH3:21])[CH3:20]
Reactant: S=C=S
Reactant: O=C(O)C1Cc2c([nH]c3ccccc23)CN1
Reactant: CC(C)I
Agent: [K+]
Agent: [OH-]
Product: CC(C)SC(=S)N1Cc2[nH]c3ccccc3c2CC1C(=O)O

Procedure:
In the same manner as described in Example 6, (3RS)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (3.24 g), KOH (96%, 1.75 g), carbon disulfide (0.91 ml) and isopropyl iodide (1.8 ml) are reacted and treated. The product is crystallized from chloroform to give the title compound (1.59 g) as colorless needles, m.p. 188°-190° C.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[C:16]([Cl:18])[C:15]([Cl:19])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1C=C(C)C(C)=C[C:29]=1[C:30]([OH:32])=[O:31])(=O)C1C=CC=CC=1>>[Cl:18][C:16]1[CH:17]=[C:9]2[C:10](=[CH:14][C:15]=1[Cl:19])[C:11](=[O:12])[O:13][C:29]([C:30]([OH:32])=[O:31])=[C:1]2[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C(=O)O)c(C(=O)c2ccccc2)cc1C
Reactant: O=C(O)c1cc(Cl)c(Cl)cc1C(=O)c1ccccc1
Product: O=C(O)c1oc(=O)c2cc(Cl)c(Cl)cc2c1-c1ccccc1

Procedure:
2-Benzoyl-4,5-dichlorobenzoic acid, in place of 2-benzoyl-4,5-dimethyl-benzoic acid, was reacted and treated in the same manner as in Process 1 of Reference Example 29 to yield 6,7-dichloro-4-phenylisocoumarin-3-carboxylic acid [melting point 243°-244° C. (recrystallized from ethyl acetate-isopropyl ether)]. This compound was reacted and treated in the same manner as in Process 2 of Reference Example 29 to yield the title compound as colorless crystals.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[F:8][C:9]([F:18])([F:17])[C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=1)[NH2:13].C(N(CC)CC)C.O>CCOCC>[CH3:3][C:2]([CH3:5])([CH3:4])[C:1]([NH:13][C:12]1[CH:14]=[CH:15][CH:16]=[C:10]([C:9]([F:8])([F:17])[F:18])[CH:11]=1)=[O:6]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)C(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 98.3 %

Procedure:
A solution of pivaloyl chloride (3.62 g; 30 mmol) in 40 ml dry ether was added dropwise at room temperature to a mixture of 3-trifluoromethyl-aniline (4.83 g, 30 mmol) and triethylamine (4.25 ml, 30.5 mmol). This was stirred at room temperature for a period of 14 hours and then poured into 200 ml water, extracted with ether (2×100 ml). The combined ether extracts were washed successively with 0.5 HCl (100 ml); water (2×50 ml); 7% KOH (100 ml) and water (2×50 ml). The ether solution was dried with MgSO4 and concentrated in vacuo to give a white solid (7.23 gm, 98%, m.p. 112.5° C.). The 2,2-dimethyl-3'-trifluoromethyl-propionanilide was recrystallized with dichloromethane and petroleum ether mixture.
Reaction SMILES: C[C:2]1[C:7]([OH:8])=C[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.C[O:16][CH2:17][C:18]([O:20][CH3:21])=O.[H-].[Na+].S(O)(O)(=O)=O.N1(C(=N)N)CCOC[CH2:30]1>C1(C)C=CC=CC=1>[CH3:21][O:20][C:18]1[C:17]([OH:16])=[N:5][C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:3][C:2]=1[CH2:7][O:8][CH3:30]
Reactant: COCC(=O)OC
Reactant: N=C(N)N1CCOCC1
Reactant: Cc1nc(N2CCOCC2)ncc1O
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COCc1nc(N2CCOCC2)nc(O)c1OC

Procedure:
The 4-methyl-2-morpholino-5-pyrimidinol (D represents methyl) can be prepared by reacting methyl methoxyacetate with sodium hydride in toluene and the product is then reacted with 4-morpholinecarboximidamide sulfate to give 5-methoxy-6-methoxymethyl-2-morpholino-4-pyrimidinol. This latter compound is converted to 4-chloro-5-methoxy-6-methoxymethyl-2-morpholinopyrimidine by reaction with phosphorus oxychloride. The ring chlorine and the methoxy group in the methoxymethyl group are replaced with hydrogen on reduction with zinc in 1 normal NaOH and reaction with sodium ethylmercaptide in dimethylformamide then yields the desired pyrimidinol.
Reaction SMILES: [Si]([O:5][S:6]([C:9]([F:12])([F:11])[F:10])(=[O:8])=[O:7])(C)(C)C.[Br-].[Li+:14].CC([N-]C(C)C)C.C1COCC1>C(Cl)Cl>[O:5]([S:6]([C:9]([F:12])([F:11])[F:10])(=[O:8])=[O:7])[Li:14]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: [Li+]
Agent: CC(C)[N-]C(C)C
Agent: [Br-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: [Li]OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Me3SiOTf (0.90 ml, 5.0 mmol ) was added at −78° C. to a solution of iminiun bromide 3f (1.83 g, 5.0 mmol) in CH2Cl2 (30 ml). The suspension was warmed to room temperature and stirred for 1 hour. After evaporation of the solvent, a solid residue was obtained. Then to a 1/1 mixture of LDA and iminium triflate (5.0 mmol), 30 ml of THF was added at −78° C. The suspension was warmed to room temperature and stirred for 30 min. After evaporation of the solvent under vacuum, a solid residue containing carbene Cf and LiOTf was obtained. 1H NMR (thf-d8, 25° C.): 7.00-7.20 (m, 3H, Har), 3.34 (m, 1H, CHCH3), 2.85 (sept, 2H, CHCH3, J=6.9), 1.85-1.96 (m, 1H, CH2), 1.29-1.62 (m, 3H, CH2), 1.18 (d, 3H, CHCH3, J=6.9), 1.14 (d, 3H, CHCH3, J=6.9), 1.11 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.00 (d, 3H, CHCH3, J=6.6), 0.98 (d, 3H, CHCH3, J=6.3), 0.94 (d, 3H, CHCH3, J=6.3). 13C NMR (thf-d8, 25° C.): 322.00 (C), 144.45 (Car), 144.02 (Car), 142.35 (Car), 126.86 (Car), 123.44 (Car), 123.37 (Car), 56.15 (CH), 41.88 (C), 28.39, 28.26, 27.95, 27.12 (CH2), 26.88 (CH2), 26.47, 24.64, 23.91, 22.21, 21.70, 18.34.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)=O)=[C:4]([O:28][CH3:29])[CH:3]=1>ClCCl.O>[F:1][C:2]1[CH:3]=[C:4]([O:28][CH3:29])[C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:13]=[C:14]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=3)[C:26]=2[CH:27]=1
Reactant: COC(=O)c1ccc(C(=O)Nc2ccccc2Oc2ccc(F)cc2OC)cc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(C2=Nc3ccccc3Oc3c(OC)cc(F)cc32)cc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 6.5 %

Procedure:
A stirring mixture of title compound 92 (2 g, 5.06 mmol) in polyphosphoric acid (4.76 ml, 41.7 mmol) was heated at 130° C. for 3 h. The reaction mixture was cooled, diluted with dichloromethane and water and stirred overnight. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over MgSO4, filtered and solvent evaporated. The crude residue was purified via ISCO (0-25% Hex/EtOAc; 40 g silica gel column) to afford title compound 93 (125 mg, 6.5%) as a light yellow solid. LRMS (ESI): (calc) 377.11 (found) 378.4 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:9]=2[C:10](=[O:12])[CH:11]=1)=[O:5])[CH3:2].Br[CH2:19][CH2:20][CH2:21][Cl:22].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:16]=[C:15]([O:17][CH2:19][CH2:20][CH2:21][Cl:22])[CH:14]=[CH:13][C:9]=2[C:10](=[O:12])[CH:11]=1)=[O:5])[CH3:2]
Reactant: ClCCCBr
Reactant: CCOC(=O)c1cc(=O)c2ccc(O)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(=O)c2ccc(OCCCCl)cc2o1
Yield: 72.4 %

Procedure:
A mixture of 23.4 g (0.1 mole) of 7-hydroxy-4-oxo-4H-1-benzopyran-2-carboxylic acid ethyl ester, 31.6 g (0.2 mole) of 1-bromo-3-chloropropane and 41.5 g (0.3 mole) of anhydrous potassium carbonate in 500 ml of acetone was heated at reflux for 20 hr. The mixture was cooled and filtered through Celite. The filtrate was concentrated under reduced pressure to give a solid residue. The solid was triturated with petroleum ether (30°-60° C.), collected by filtration, and recrystallized from 2-propanol to yield 22.5 g (73%) of white solid, m.p. 107°-108° C.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C.[CH3:22][C:23]1[C:37]([CH3:38])=[CH:36][C:26]2[NH:27][C:28]([C:30]3[C:34]([NH2:35])=[CH:33][NH:32][N:31]=3)=[N:29][C:25]=2[CH:24]=1.[N:39]1([CH2:44][C:45](O)=[O:46])[CH:43]=[N:42][N:41]=[N:40]1>CN(C)C=O>[CH3:38][C:37]1[C:23]([CH3:22])=[CH:24][C:25]2[NH:29][C:28]([C:30]3[C:34]([NH:35][C:45](=[O:46])[CH2:44][N:39]4[CH:43]=[N:42][N:41]=[N:40]4)=[CH:33][NH:32][N:31]=3)=[N:27][C:26]=2[CH:36]=1
Reactant: O=C(O)Cn1cnnn1
Reactant: Cc1cc2nc(-c3n[nH]cc3N)[nH]c2cc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2nc(-c3n[nH]cc3NC(=O)Cn3cnnn3)[nH]c2cc1C
Reaction time: 72 h
Yield: 9.2 %

Procedure:
A stirred solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (295.7 mg) and diisopropylethylamine (269 μl) in dimethylformamide (10 ml) were treated with 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine [100 mg, Example 233(c)] and 2-(1H-1,2,3,4-tetraazol-1-yl) acetic acid (197.8 mg). The reaction mixture was stirred for 72 hours then treated further with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (295.7 mg), diisopropylethylamine (269 μl) and 2-(1H-1,2,3,4-tetraazol-1-yl) acetic acid (197.8 mg). Stirring was continued for a further 48 hours then the reaction mixture was partitioned between ethyl acetate and water. The organic phase was evaporated and the residue was treated with 1N potassium hydroxide in a mixture of methanol and tetrahydrofuran (1:4, 8 ml). After 1 hour this mixture was extracted with ethyl acetate. The extract was washed with brine, then dried over magnesium sulfate and then evaporated to dryness. The residue was subjected to preparative HPLC to give N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-2-(1H-1,2,3,4-tetraazol-1-yl)-acetamide (13.7 mg) as an off-white solid. MS: 338.14 (M+H)+. HPLC (METHOD B1): RT=7.26 minutes.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=O)=[CH:9][C:4]=2[NH:3][CH:2]=1.[C:12]1([CH2:18][CH2:19][NH2:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:20][CH2:19][CH2:18][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: NCCc1ccccc1
Reactant: O=Cc1ccc2nc[nH]c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: c1ccc(CCNCc2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from benzimidazol-5-carbaldehyde (146 mg; 1 mmol; 1 eq.), phenylethylamine (0.126 ml; 1 mmol; 1 eq.); NaBH(AcO)3 (318 mg; 1.5 mmol; 1.5 eq.) and AcOH (0.095 ml; 1.5 mmol; 1.5 eq.) as described above. Yield: 0.040 g (16%); MS m/z: 252.2 [M+H]+; 1H-NMR (400 MHz, DMSO d6): δ 3.30 (br s, 4H); 3.81 (s, 2H); 7.12-7.27 (m, 9H); 8.13-8.14 (m, 1H); 12.30 (br s, 1H); HPLC (METHOD [A]): rt doublepeak 6.77/6.60 min (93.7%)
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1>ClC(Cl)Cl>[ClH:3].[Cl:3][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: O=S(Cl)Cl
Reactant: OCCOc1ccccn1
Solvent: ClC(Cl)Cl
Product: Cl
Product: ClCCOc1ccccn1
Temperature: 5 °C
Reaction time: 1 h
Yield: 132.4 %

Procedure:
Thionyl chloride (0.55 ml, 7.55 mmol) was added to a solution of 2-(2-hydroxyethoxy)pyridine (700 mg, 5.04 mmol), (J. Org. Chem. 1977, 42, 1500), in trichloromethane (20 ml) at 5° C. The mixture was stirred for 1 hour at 5° C, allowed to warm to ambient temperature and stirred for a further 1 hour. The volatiles were removed by evaporation and by azeotroping with toluene to give 2-(2-chloroethoxy)pyridine hydrochloride (970 mg, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][NH2:13])[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20].[C:21](OCC)(OCC)(OCC)[CH3:22]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:21]([CH3:22])=[N:13][N:12]=[C:7]1[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20]
Reactant: NNc1cc(-c2ccccc2Cl)c2cc(Cl)ccc2n1
Reactant: CCOC(C)(OCC)OCC
Solvent: Cc1ccccc1C
Product: Cc1nnc2cc(-c3ccccc3Cl)c3cc(Cl)ccc3n12

Procedure:
In the manner given in Preparation 5, 6-chloro-2-hydrazino-4-(o-chlorophenyl)quinoline and triethyl orthoacetate in xylene were refluxed to give 7-chloro-1-methyl-5-(o-chlorophenyl)-s-triazolo[4,3-a]quinoline.
Reaction SMILES: [F:1][C:2]1[C:3]([C@@H:8]([NH:19][C:20]([C:22]2[N:27]=[CH:26][C:25]([O:28][CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])=[CH:24][CH:23]=2)=[O:21])[C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[C:3]([C@@H:8]([NH:19][C:20]([C:22]2[N:27]=[CH:26][C:25]([O:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:24][CH:23]=2)=[O:21])[C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:16])[F:18])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(C(=O)N[C@@H](c2ccc(C(F)(F)F)cc2)c2ncccc2F)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COc1ccc(C(=O)N[C@@H](c2ccc(C(F)(F)F)cc2)c2ncccc2F)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the (S)-tert-butyl 2-((6-(((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)carbamoyl)pyridin-3-yl)oxy)acetate from above in DCM (0.5 mL), was added TFA (0.550 mL, 7.40 mmol). The resulting mixture was then stirred at rt for 1 h. The mixture was then concentrated and MeOH (1 mL) was added. The mixture was purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the title compound as a white solid. 1H NMR (400 MHz, MeOH) δ ppm 8.55 (d, J=4.7 Hz, 1H), 8.42 (d, J=2.5 Hz, 1H), 8.08 (d, J=8.8 Hz, 1H), 7.59-7.72 (m, 5H), 7.42-7.55 (m, 2H), 6.68 (d, J=1.6 Hz, 1H), 4.89 (s, 2H). MS (ESI pos. ion) m/z: 450.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[CH:4][C:3]=1[CH2:14]O.P(Br)(Br)[Br:17]>ClCCl>[Br:17][CH2:14][C:3]1[CH:4]=[C:5]([CH2:8][N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: BrP(Br)Br
Reactant: CCN(CC)Cc1ccc(Cl)c(CO)c1
Solvent: ClCCl
Product: CCN(CC)Cc1ccc(Cl)c(CBr)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {2-chloro-5-[(diethylamino)methyl]phenyl}methanol (3.0 g, 13.2 mmol) in anhydrous dichloromethane (80 mL) was added dropwise phosphorus tribromide (2.5 mL, 26.4 mmol). The mixture was stirred at room temperature overnight. The solvent was evaporated. The residue was dried in vacuo, affording {[3-(bromomethyl)-4-chlorophenyl]methyl}diethylamine. The product was used without further purification.