Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@@H:10]3[O:19][C@@H:9]3[C:8]=2[CH:20]=1)([O-:3])=[O:2].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][CH2:29][C:30]1[N:31]=[N:32][N:33]([CH3:35])[N:34]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@H:10]([OH:19])[C@@H:9]([N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[Cl:21])[CH2:29][C:30]3[N:31]=[N:32][N:33]([CH3:35])[N:34]=3)[C:8]=2[CH:20]=1)([O-:3])=[O:2]
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H]2O[C@H]21
Reactant: Cn1nnc(CNc2ccccc2Cl)n1
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](N(Cc2nnn(C)n2)c2ccccc2Cl)[C@H]1O
Yield: 15 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using the epoxide compound (450 mg, 1.6 mmol) obtained in step 1 of example 2 and N-(2-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=2:1), to give desired compound (118 mg, yield: 15%).
Reaction SMILES: C1(C(=[N:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[C:20]([C:25]([C:30]2[N:31]=[CH:32][N:33](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:34]=2)([OH:29])[CH:26]([CH3:28])[CH3:27])[CH:19]=[CH:18]3)C2C=CC=CC=2)C=CC=CC=1.NC1C=C2C(=CC=1)C=C(C(C1N=CN(C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)C=1)(O)C(C)C)C=C2.[CH3:94][S:95](Cl)(=[O:97])=[O:96].[OH-].[Na+]>ClCCl.N1C=CC=CC=1>[OH:29][C:25]([C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([NH:14][S:95]([CH3:94])(=[O:97])=[O:96])[CH:24]=[CH:23]2)([C:30]1[N:31]=[CH:32][NH:33][CH:34]=1)[CH:26]([CH3:28])[CH3:27]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)C(O)(c1ccc2cc(N=C(c3ccccc3)c3ccccc3)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC(C)C(O)(c1ccc2cc(N)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)C(O)(c1ccc2cc(NS(C)(=O)=O)ccc2c1)c1c[nH]cn1
Reaction time: 0.5 h

Procedure:
In a similar manner to that described in Example 51-(ii), a reaction was carried out by using 1-{6-[(diphenylmethylene)amino]naphthalen-2-yl}-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (2.0 g) to give crude product containing 1-(6-aminonaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol as a pale yellow oily substance. The crude product was dissolved in dichloromethane (10 ml). To the solution were added pyridine (0.71 ml) and methanesulfonyl chloride (0.34 ml) under ice cooling, and the mixture was stirred for 30 min. To the mixture was added 0.1N-aqueous solution of sodium hydroxide, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent, hexane:ethyl acetate=1:1) to give the titled compound (1.16 g) as a pale yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[OH-].[K+].O.Cl[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[Cl:23]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[Cl:23][C:15]1[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=1[O:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=1
Reactant: OCc1cccc(F)c1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)c(Cl)c1
Temperature: 60 °C
Yield: 62.7 %

Procedure:
To a mixture of 3-fluorobenzyl alcohol (7.88 g, 62.5 mmol), Aliquot 336 (8.08 g, 20.0 mmol), potassium hydroxide (3.51 g, 62.5 mmol) and water (40 mL) were added toluene (80 mL) and 1,2-dichloro-4-nitrobenzene (10.0 g, 52.1 mmol). The mixture was heated to 60° C. overnight with vigorous stirring. The mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, and the solvent was removed in vacuo. The residue was triturated with hot petroleum ether and tert-butyl methyl ether to yield 9.20 g (63%) of the title compound.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:8][CH:7](Br)[C@H:6]1[F:21])(=[O:3])[CH3:2].[Cl:22][C:23]1[C:24]([NH2:30])=[N:25][C:26](=[O:29])[NH:27][CH:28]=1.S([O-])([O-])(=O)=O.[NH4+].[NH4+]>C(Cl)Cl.C[Si](C)(C)N[Si](C)(C)C>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:8][C@@H:7]([N:27]2[CH:28]=[C:23]([Cl:22])[C:24]([NH2:30])=[N:25][C:26]2=[O:29])[C@H:6]1[F:21])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1[C@H](F)C(Br)O[C@@H]1COC(=O)c1ccccc1
Reactant: Nc1nc(=O)[nH]cc1Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(=O)O[C@H]1[C@H](F)[C@H](n2cc(Cl)c(N)nc2=O)O[C@@H]1COC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a solution of 3-O-acetyl-5-O-benzoyl-2-deoxy-2-fluoro-D-arabinofuranosyl bromide (3.6 g, 0.01 mol) in methylene chloride (50 ml) is added a methylene chloride solution of 5-chloro-tris(trimethylsilyl)cystosine [prepared from 4.3 g, 0.03 mol. of 5-chlorocytosine as follows: a mixture of 5-chlorocytosine and 5-15 mg of ammonium sulfate in 43 ml of hexamethyldisilazane is heated to reflux until a clear solution is obtained. The excess hexamethyldisilazane is removed by evaporation in vacuo and the residue is dissolved in 25 ml of methylene chloride]. The mixture is stirred for 5 days at room temperature. Methanol (7 ml) is added to the reaction mixture, and the suspension is filtered through a Celite pad which is thoroughly washed with methylene chloride. The combined filtrate and washings are evaporated to dryness in vacuo and the residue is crystallized from ethanol to give 860 mg of 1-(3-O-acetyl-5-O-benzoyl-2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-chlorocytosine, m.p. 233°.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[C:5]([C:15]#[N:16])=[C:6]([C:13]#[N:14])[C:7]([Cl:12])=[C:8](Cl)[C:9]=1[Cl:10].[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O.CC(C)=O>[Cl:12][C:7]1[C:6]([C:13]#[N:14])=[C:5]([C:15]#[N:16])[C:4]([Cl:3])=[C:9]([Cl:10])[C:8]=1[O:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Oc1ccccc1
Reactant: N#Cc1c(Cl)c(Cl)c(Cl)c(Cl)c1C#N
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: N#Cc1c(Cl)c(Cl)c(Oc2ccccc2)c(Cl)c1C#N
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of potassium hydroxide (11.2 parts) in water (22 parts) was added dropwise to a stirred solution of 3,4,5,6-tetra-chloro-1,2-dicyanobenzene (26.6 parts) and phenol (9.4 parts) in acetone (100 parts) at 0° C. The solution was stirred at 60° C. for 2 hours before pouring into water (500 parts). The aqueous mixture was extracted with dichloromethane (3×500 parts). The dichloromethane extracts were washed with water (3×200 parts), dried over anhydrous Na2SO4, filtered and the dichloromethane was removed under reduced pressure to leave a brown solid. The solid was recrystallised from butan-1-ol. 3,5,6-Trichloro-l,2-dicyano-4-phenoxybenzene (17 parts) was obtained as a brown solid, m.p. 147°-150° C.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:15]=[CH:14][O:13][CH:12]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]1([C:11]2[CH:15]=[CH:14][O:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Brc1ccoc1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: c1ccc(-c2ccoc2)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
To a solution of phenylboronic acid (15 g, 123.02 mmol) in dioxane (150.0 mL) and water (3.0 mL) was added 3-bromofuran (16.3 g, 110.91 mmol), K3PO4 (43 g, 202.57 mmol) and Pd(PPh3)4 (6.0 g, 5.19 mmol) with stirring for 2 h at 90° C. in an oil bath maintained with an inert atmosphere of nitrogen. The reaction mixture was concentrated under reduced pressure to give the residue, which was purified by silica gel column chromatography eluting with 1% ethyl acetate in petroleum ether to afford 3-phenylfuran as a white solid (15 g, 85%).
Reaction SMILES: ClCCl.[S:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[C:13]([OH:15])=[O:14].[F:16][C:17]([F:25])=[C:18]([CH3:24])[CH2:19][CH2:20][CH2:21][CH2:22]O.CN(C1C=CC=CN=1)C>O>[S:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[C:13]([O:15][CH2:22][CH2:21][CH2:20][CH2:19][C:18]([CH3:24])=[C:17]([F:25])[F:16])=[O:14]
Reactant: CC(CCCCO)=C(F)F
Reactant: O=C(O)c1nc2ccccc2s1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: O
Product: CC(CCCCOC(=O)c1nc2ccccc2s1)=C(F)F
Reaction time: 20 h
Yield: 43.8 %

Procedure:
To 4 ml of dichloromethane were dissolved 0.24 g (1.3 mmol) of benzothiazole-2-carboxylic acid, manufactured by a method described in “J. Amer. Chem. Soc.”, page 2328 (1949), 0.17 g (1.1 mmol) of 6,6-difluoro-5-methyl-5-hexenol and 0.13 g (1.1 mmol) of dimethylaminopyridine, followed by the addition of 0.38 g (2.0 mmol) of N-ethyl-N′-3-dimethyl-aminopropylcarbodiimide (WSC) hydrochloric acid salt at room temperature and stirring at the same temperature for 20 hours. The reaction liquid was then poured in water and extracted with dichloromethane. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:6) to obtain 0.15 g (yield: 43%) of 6,6-difluoro-5-methyl-5-hexenyl benzothiazole-2-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]([O:14][CH3:15])=[O:13].[Br:16]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(C)ccc2ccccc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(CBr)ccc2ccccc12
Temperature: 25 °C

Procedure:
A solution of methyl 2-methyl-1-naphthoate (1.277 g, 6.377 mmol), N-bromosuccinimide (1.14 g, 6.38 mmol) and 2,2′-azobis(isobutyronitrile) (10 mg) in carbon tetrachloride (10 ml) was heated under reflux for 0.5 hr. After cooling the reaction solution to room temperature, the white precipitate was removed by filtration, and the precipitate was washed with diethyl ether. The solvent of the collected filtrate was evaporated under reduced pressure to give a crude product of methyl 2-bromomethyl-1-naphthoate as a pale-yellow liquid. The obtained liquid, thiophenol (0.84 g, 7.65 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (1.14 ml, 7.65 mmol) were stirred in acetonitrile (20 ml) overnight at room temperature. The solvent of the reaction solution was evaporated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=20/1-9/1) to give the objective substance.
Reaction SMILES: N1C=CCC(=NC=CC(OCC)=O)C=1.C1([C:18]2[N:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26](OCC)=[O:27])=[CH:20][N:19]=2)CC1>>[N:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=[O:27])[CH:22]=[N:23][CH:18]=1
Reactant: CCOC(=O)C=Cc1cnc(C2CC2)nc1
Agent: CCOC(=O)C=CN=C1C=NC=CC1
Product: O=CC=Cc1cncnc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 13 by substituting ethyl 3-(5-pyridiminyl)acrylate (prepared as described in WO0066566) for the ethyl 3-(2-cyclopropylpyrimidin-5-yl)acrylate of Reference Example 13. MS 135 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N:10][C:11](=O)[NH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.CN(C=O)C.P(Cl)(Cl)([Cl:22])=O.C(Cl)(Cl)Cl>>[Cl:22][C:11]1[N:12]=[N:13][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[CH:9][N:10]=1
Reactant: O=c1ncc(-c2cccc(F)c2)n[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Fc1cccc(-c2cnc(Cl)nn2)c1
Yield: 21 %

Procedure:
A mixture of 6-(3-fluoro-phenyl)-2H-[1,2,4]triazin-3-one (15.2 g, 79.5 mmol, crude) and 2 ml of DMF in 250 ml of 1:1 phosphorous oxychloride-chloroform was maintained at reflux overnight. The mixture was then concentrated at reduced pressure, diluted with methylene chloride and poured onto ice with stirring. When the ice melted the mixture was neutralized with sodium bicarbonate solution, and the layers were separated, the aqueous layer was extracted with dichloromethane once, the combined organic layer was washed with water, dried and concentrated to a brown oil which was purified by column chromatography (eluting with pure petroleum) to give title compound as a pale yellow solid (3.5 g, 21.0%): 1H NMR (CDCl3): δ 8.88 (s, 1H), 7.87-7.82 (m, 2H), 7.60-7.52 (m, 1H), 7.32-7.27 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:19])=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@@H:8]1[C:12]([O:14][CH3:15])=[O:13])=[O:6].[CH3:20][O:21][C:22]1[C:23](=O)[C:24](=[O:28])[C:25]=1[O:26]C.C(OCC)(=O)C>C(O)C>[OH:19][C:3]1[C:2]([NH:1][C:23]2[C:24](=[O:28])[C:25](=[O:26])[C:22]=2[O:21][CH3:20])=[CH:18][CH:17]=[CH:16][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@@H:8]1[C:12]([O:14][CH3:15])=[O:13])=[O:6]
Reactant: COC(=O)[C@H]1CCCN1C(=O)c1cccc(N)c1O
Reactant: COc1c(OC)c(=O)c1=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1CCCN1C(=O)c1cccc(Nc2c(OC)c(=O)c2=O)c1O
Temperature: 50 °C
Yield: 33.9 %

Procedure:
A mixture of 2.64 g (10 mmol, 1 eq) of methyl (R)-1-(3-amino-2-hydroxybenzoyl)pyrrolidine-2-carboxylate and 2.84 g (20 mmol, 2.0 eq) of 3,4-dimethoxy-3-cyclobutene-1,2-dione in 80 ml of ethanol was heated at 50° C. for four and a half hours. The residue was taken up with ethyl acetate and washed three times with a 1 M aqueous sodium dihydrogen phosphate solution. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The oil was chromatographed on silica gel (300 g prepacked column) eluted with heptane/ethyl acetate (gradient). 1.27 g of methyl (R)-1-[2-hydroxy-3-(2-methoxy-3,4-dioxocyclobut-1-enylamino)benzoyl]pyrrolidine-2-carboxylate were obtained in the form of white solid. Yield=34%.
Reaction SMILES: [CH:1]1([C:4]2[N:5]([CH3:12])[CH:6]=[C:7]([C:9]([OH:11])=O)[N:8]=2)[CH2:3][CH2:2]1.[NH2:13][C@@H:14]([CH3:31])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[C:27]([F:29])[C:24]([C:25]#[N:26])=[C:23]([Cl:30])[CH:22]=2)=[N:17]1>>[Cl:30][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:9]([C:7]3[N:8]=[C:4]([CH:1]4[CH2:2][CH2:3]4)[N:5]([CH3:12])[CH:6]=3)=[O:11])[CH3:31])[N:17]=2)[CH:28]=[C:27]([F:29])[C:24]=1[C:25]#[N:26]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: Cn1cc(C(=O)O)nc1C1CC1
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cn(C)c(C2CC2)n1

Procedure:
The title compound was prepared using the procedure described in Example 32(e) starting from 2-cyclopropyl-1-methyl-1H-imidazole-4-carboxylic acid (260 mg, 1.56 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzo-nitrile (435 mg, 1.56 mmol). Yield 123 mg. 1H-NMR (400 MHz; DMSO-d6): δ 0.81-0.91 (m, 4H), 1.08 (d, 3H), 1.95 (m, 1H), 3.65 (s, 3H), 4.27-4.38 (m, 3H), 7.01 (s, 1H), 7.46 (s, 1H), 7.69 (d, 1H), 7.87 (d, 2H), 7.96 (s, 1H).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)=[N:7][C:6]=1[CH:26]1[CH2:28][CH2:27]1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH:26]1([C:6]2[C:5]([CH2:4][OH:3])=[C:10]([C:11]([F:12])([F:14])[F:13])[CH:9]=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:17][CH:16]=3)[N:7]=2)[CH2:28][CH2:27]1
Reactant: CCOC(=O)c1c(C(F)(F)F)cc(-c2ccc(OC(F)(F)F)cc2)nc1C1CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCc1c(C(F)(F)F)cc(-c2ccc(OC(F)(F)F)cc2)nc1C1CC1

Procedure:
In analogy to the procedure described in example 43D], 2-cyclopropyl-6-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-nicotinic acid ethyl ester was treated with lithium aluminium hydride to give the title compound as colorless crystals.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([CH3:35])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:10][CH:9]=1)[CH3:6])C.[OH-].[Na+]>CO>[CH3:35][C:5]([O:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:24]=[CH:25][C:26]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:27][CH:28]=3)[O:20][C:21]=2[CH3:22])=[CH:12][CH:13]=1)([CH3:6])[C:4]([OH:36])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1
Reaction time: 0.5 h
Yield: 67 %

Procedure:
2-Methyl-2-{4-[2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethoxy]phenoxy}propionic acid ethyl ester (12.0 g, 24.7 mmol) was dissolved in methanol (200 mL) and 2N NaOH (150 mL) was added. The resulting cloudy solution became clear after 30 min and the reaction was stirred vigorously overnight. The solution was concentrated under reduced pressure, diluted with H2O (100 mL) and acidified to pH=1 with 5N HCl. The mixture was extracted with ethyl acetate (2×200 mL), dried (MgSO4), and concentrated under reduced pressure to provide an oil. The oil (8.23 g) was recrystallized from ethyl acetate (24 mL) and hexanes (56 mL) to afford 2-methyl-2-{4-[2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethoxy]phenoxy}propionic acid (7.57 g, 67%) as colorless needles after drying at 50° C. under vacuum for 6 h: Rf=0.14 in 35% ethyl acetate/hexanes; mp 123-124° C.; 1H NMR (400 MHz, CDCl3) δ8.05 (d, J=8.0 Hz, 2H), 7.67 (d, J=8.0 Hz, 2H), 7.66-7.63 (m, 2H), 7.46 (t, J=7.6 Hz, 2H), 7.38 (t, J=7.6 Hz, 11H), 6.91-6.79 (m, 4H), 4.21 (t, J=6.4 Hz, 2H), 3.01 (t, J=6.4 Hz, 2H), 2.40 (s, 3H), 1.53 (s, 6H); MS m/e calculated. for C28H28NO5 (M++1) 458.2, found 458.2.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17](Br)=[C:16]([CH2:21][CH3:22])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:23](=[O:25])=[O:24].O>CCCCCC.O1CCCC1.C1(C)C=CC=CC=1>[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:23]([OH:25])=[O:24])=[C:16]([CH2:21][CH3:22])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCc1cc(OCc2ccccc2)ccc1Br
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1cc(OCc2ccccc2)ccc1C(=O)O
Yield: 51.1 %

Procedure:
A 1.59 mol/L solution of n-butyllithium in n-hexane (2.28 mL) was added to a solution of 4-benzyloxy-1-bromo-2-ethylbenzene (0.96 g) in tetrahydrofuran (5.35 mL) at −78° C. with stirring. The mixture was stirred for 1.5 hrs at that temperature, poured to dry ice (33 g) slowly, and then tetrahydrofuran (2 mL) was added. The mixture was stirred at room temperature for 40 minutes, and water, toluene and tetrahydrofuran were added. The organic layer was separated, and extracted with a 1 mol/L aqueous solution of sodium hydroxide. These aqueous layers were combined, and was adjusted to pH 3 with an addition of concentrated hydrochloric acid. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford the title compound (0.432 g).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.I[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[C:21](=[O:39])[N:22]([C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[C:29]([C:35]([F:38])([F:37])[F:36])[CH:28]=2)[C:23](=[O:26])[C:24]=1[CH3:25]>O1CCCC1.C(OCC)(=O)C>[C:31]([C:30]1[CH:33]=[CH:34][C:27]([N:22]2[C:23](=[O:26])[C:24]([CH3:25])=[C:20]([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][N:4]3[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]3)[C:21]2=[O:39])=[CH:28][C:29]=1[C:35]([F:38])([F:37])[F:36])#[N:32]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC1=C(CCCCCI)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1=C(CCCCCN2CCN(C(=O)OC(C)(C)C)CC2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Temperature: 25 °C
Reaction time: 168 h
Yield: 98 %

Procedure:
1.56 g of 1,1-dimethylethyl piperazine-1-carboxylate was added under a nitrogen atmosphere to a solution of 2.0 g of 4-[2,5-dihydro-3-(5-iodopentyl)-4-methyl-2,5-dioxo-1H-pyrrol-1-yl]-2-(trifluoromethyl)benzonitrile in 53 ml of tetrahydrofuran, and this mixture was stirred for 7 days at room temperature. For working-up, it was diluted with ethyl acetate and washed with semi-saturated sodium bicarbonate solution. After drying on sodium sulfate and concentration by evaporation, it was chromatographed with methanol/dichloromethane on silica gel, and thus 2.2 g of the title compound was obtained as a yellowish oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:18]3[CH2:22][CH2:21][O:20][CH2:19]3)[C:4]=2[N:5]=[CH:6][N:7]=1.F[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1>>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:24]4[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=4)=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:18]3[CH2:22][CH2:21][O:20][CH2:19]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2c1c(-c1ccc(O)cc1)cn2C1CCOC1
Reactant: O=Cc1ccc(F)cc1
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccc(C=O)cc3)cc1)cn2C1CCOC1

Procedure:
In a similar manner to Example 9, 4-[4-amino-7-(3-tetrahydrofuryl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenol was reacted with 4-fluorobenzaldehyde to give 4-[4-(4-amino-7-(3-tetrahydrofuryl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenoxy]benzaldehyde.
Reaction SMILES: C1(C[C:8]2[N:12](CCCO)[C:11]3[CH:17]=[CH:18][CH:19]=[CH:20][C:10]=3[N:9]=2)C=CC=CC=1.S(Cl)(Cl)=O>ClC(Cl)Cl>[NH:9]1[C:10]2[CH:20]=[CH:19][CH:18]=[CH:17][C:11]=2[N:12]=[CH:8]1
Reactant: OCCCn1c(Cc2ccccc2)nc2ccccc21
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: c1ccc2[nH]cnc2c1
Reaction time: 4 h

Procedure:
To a stirred mixture of 40 parts of 2-(phenylmethyl)-1H-benzimidazole-1-propanol and 225 parts of trichloromethane are added dropwise 30 parts of sulfinyl chloride. Upon completion, stirring is continued for 4 hours at reflux temperature. The reaction mixture is evaporated and the residue is boiled in water. The solution is filtered over hyflo and the filtrate is alkalized with ammonium hydroxide. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane. The product is filtered off and dried, yielding 1-(3-chloropropyl)-2-phenylmethyl)-1H-benzimidazole; mp. 112° C.