Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][NH:5][C:6]1[S:7][C:8](=[CH:12][C:13]2[N:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][C:17](C#N)=[CH:16]3)[C:9](=[O:11])[N:10]=1.C(O[Na])(C)=O.[CH:35]([O:38]C1C=CN=C2C=1N=C(C=C1SC(NC3CC3C3C=CC=CC=3)=NC1=O)C=C2)([CH3:37])[CH3:36]>CC(O)=O>[Cl:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][NH:5][C:6]1[S:7][C:8](=[CH:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([O:38][CH:35]([CH3:37])[CH3:36])[CH:17]=[CH:18][N:19]=3)[N:14]=2)[C:9](=[O:11])[N:10]=1
Reactant: N#Cc1cnc2ccc(C=C3SC(NCc4ccc(F)cc4Cl)=NC3=O)nc2c1
Reactant: CC(C)Oc1ccnc2ccc(C=C3SC(NC4CC4c4ccccc4)=NC3=O)nc12
Agent: CC(=O)O[Na]
Solvent: CC(=O)O
Product: CC(C)Oc1ccnc2ccc(C=C3SC(NCc4ccc(F)cc4Cl)=NC3=O)nc12
Temperature: 100 °C
Yield: 59.5 %

Procedure:
To a mixture of 2-(2-chloro-4-fluoro-benzylamino)-thiazol-4-one (41.4 mg, 0.16 mmol) (see Example 18), AcONa (160 mg, 1.95 mmol), and 8-isopropoxy-[1,5]naphthyridine-2-carbaldehyde (38.9 mg, 0.18 mmol) (see Example 20) in a sealed tube was added AcOH(0.3 mL). The reaction mixture was heated to 100° C. (oil bath) for 3 hrs. The reaction mixture was then cooled to r.t. and triturated with water. The solid was collected by filtration and washed with water, acetone and ether to give 2-(2-chloro-4-fluoro-benzylamino)-5-(8-isopropoxy-[1,5]naphthyridin-2-ylmethylene)-thiazol-4-one as a light brown solid (43.5 mg, 59.5%). HR-ES (+) m/e calcd for C22H18FClN4O2S (M+H)+ 457.0896. found 457.0897.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]4[CH:20]=[C:21]([NH:25]C(=O)C)[CH:22]=[CH:23][CH:24]=4)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[OH-].[Na+]>Cl>[F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]4[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=4)[NH2:25])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CC(=O)Nc1cccc(OCCCN2CCC(c3noc4cc(F)ccc34)CC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1cccc(OCCCN2CCC(c3noc4cc(F)ccc34)CC2)c1
Temperature: 100 °C

Procedure:
A stirred mixture of N-[3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]acetamide (9.2 g, 22 mmol), prepared as described in the previous example, in 15% hydrochloric acid (110 ml) was heated at 100° C. for 2.5 hours until a homogeneous solution resulted. The reaction was cooled to 0° C. in an ice bath and basified with 50% NaOH. The product was extracted with ethyl acetate (3×200 ml). The ethyl acetate solution was washed with water, brine, then dried over Na2SO4. The solvent was removed. The crude product was purified on a flash chromatography column. The product thus obtained was a solid: 6.6 g (80%). Recrystallization from hot ethanol (50 ml) gave 3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-aniline as off-white crystals: 346 g, m.p.=115°-117° C.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][CH2:5][C:6]1[O:10][N:9]=[C:8]([CH:11]([NH:16][C:17](=[O:36])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])=[O:27])=[CH:21][CH:20]=2)[CH2:12][CH:13]([CH3:15])[CH3:14])[CH:7]=1>C(O)(C)(C)C.[OH-].[Na+]>[CH3:14][CH:13]([CH3:15])[CH2:12][CH:11]([C:8]1[CH:7]=[C:6]([CH2:5][CH2:4][C:3]([OH:37])=[O:2])[O:10][N:9]=1)[NH:16][C:17](=[O:36])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])=[O:27])=[CH:21][CH:20]=1
Reactant: COC(=O)CCc1cc(C(CC(C)C)NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)cc2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)NC(CC(C)C)c2cc(CCC(=O)O)on2)cc1
Temperature: 25 °C

Procedure:
A mixture of 3-[3-(3-methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-isoxazol-5-yl]-propionic acid methyl ester (17 mg) in tert-BuOH (1 ml) and 0.1 N NaOH (1 ml) was stirred at room temperature. After 20 h the mixture was concentrated under reduced pressure, dissolved in water (5 ml) and extracted with EtOAc (5 ml×3). The aqueous layer was then acidified to pH 3 with IN HCl and extracted with EtOAc. The combined organics were washed with brine; dried over Na2SO4; filtered and concentrated under reduced pressure to give the title compound as a white amorphous solid. MP=?; MS [M+1]+493.2; 1H nmr (400 MHz, CD3OD) δ0.87 (d, 3H), 0.91 (d, 3H), 1.53-1.66 (m, 3H), 2.26 (s, 3H), 2.64 (t, J=7.4 Hz, 2H), 2.97 (t, J=7.5 Hz, 2H), 3.44 (s, 2H), 5.08 (m, 1H), 6.00 (s, 1H), 6.99 (t, 1H), 7.11-7.36 (m, 6H), 7.59 (d, J=7.9 Hz,1H).
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:9])[CH2:5][N+:6]([O-:8])=[O:7].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>CCOCC>[CH3:9][C:4]([CH2:5][N+:6]([O-:8])=[O:7])=[CH:3][CH2:2][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: C1COCCN1
Reactant: CC(=CCBr)C[N+](=O)[O-]
Solvent: CCOCC
Product: CC(=CCN1CCOCC1)C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 0.1 Mol of 1-bromo-3-methyl-4-nitro-2-butene in ether at 0° C. was added 0.2 Mol of morpholine and stirred at room temperature for two days. The residue, after filtration and evaporation of the solvent, was purified by column chromatography followed by Kugelrohrdistillation at 140°-150° oven temperature and oil pump vacuum. The product obtained was a yellow oil.
Reaction SMILES: [C:1]([CH2:9][C:10]([CH3:12])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=1>CO>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][C:10]([CH3:12])=[N:31]2)=[CH:26][CH:25]=1
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC1=NN(c2ccc(Br)cc2)C(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 1-benzoylacetone (3.63 g, 0.0224 mol) and N,N-diisopropylethylamine (2.88 g, 0.0224 mol) in anhydrous methanol (160 mL), 4-bromophenylhydrazine hydrochloride was added and the resulting mixture was stirred at ambient temperature for 20 hours. The solvent was removed under reduced pressure and the resulting mixture was partitioned between a 5% solution of citric acid solution in water (200 mL) and ethyl acetate (150 mL). The organic phase was successively washed with water (2×200 mL) and brine (150 mL), dried with magnesium sulfate and concentrated. The resulting residue was purified by flash chromatography on silica using ethyl acetate/n-heptane (5:95) as mobile phase to yield 1-(4-bromophenyl)-3-methyl-5-phenyl-4,5-dihydro-1H-pyrazole (4.05 g, 0.0129 mol) as an off-white solid.
Reaction SMILES: [C:1]1([C:6]([C:8]2[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:11]([O:18][CH2:19][C:20]([O:22]C)=[O:21])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>C(O)C.O>[C:1]1([C:6]([C:8]2[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:11]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)COc1ccc(C(=O)c2cccs2)c2c1CCCC2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)COc1ccc(C(=O)c2cccs2)c2c1CCCC2

Procedure:
9 g of the ester according to (b) are dissolved in 100 ml aqueous ethanol. 1.8 g potassium hydroxide dissolved in 25 ml water are added and the mixture refluxed for 8 hours. The ethanol is evaporated and the remaining aqueous phase acidified by addition of mineral acid. The acid is extracted in ethyl ether.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:11]([S:16]([OH:19])(=O)=[O:17])=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CN(C=O)C.C1(C)C=CC=CC=1.S(Cl)([Cl:34])=O>>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:11]([S:16]([Cl:34])(=[O:19])=[O:17])=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1cccc(-c2ccccc2S(=O)(=O)O)c1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccc(-c2ccccc2S(=O)(=O)Cl)c1

Procedure:
3′-Nitrobiphenyl sulfonic acid (2 g) was refluxed in thionyl chloride (30 mL) with a catalytic quantity of DMF (0.5 mL) for 4 hours. Toluene was added and the solvents evaporated under vacuum. The residue was recrystallised from ethyl acetate/petrol to give the title compound as white crystals.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[O:6][CH2:7][CH2:8][NH:9][C:10]([CH2:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11])#[N:2].C(N(CC)CC)C.[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(OCC)(=O)C>CN(C)C=O>[C:29]1([S:35]([N:16]2[CH2:15][CH2:14][CH:13]([CH2:12][C:10]([NH:9][CH2:8][CH2:7][O:6][C:5]3[CH:19]=[CH:20][CH:21]=[C:3]([C:1]#[N:2])[CH:4]=3)=[O:11])[CH2:18][CH2:17]2)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: N#Cc1cccc(OCCNC(=O)CC2CCNCC2)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cccc(OCCNC(=O)CC2CCN(S(=O)(=O)c3ccccc3)CC2)c1
Reaction time: 13 h

Procedure:
430 mg (1.58 mmol) of N-[2-(3-cyanophenoxy)ethyl]piperidine-4-carboxyamide was dissolved in 10 ml of dimethylformamide. 0.2 ml (1.43 mmol) of triethylamine and 253 mg (1.43 mmol) of benzenesulfonyl chloride were added to the solution at 0° C., and they were stirred for 13 hours. After the treatment with ethyl acetate as the extractant in an ordinary manner, the title compound was obtained.
Reaction SMILES: [CH3:1][N:2]=[C:3]([OH:17])[C:4]1[C:5](=[C:9]([Cl:16])[C:10](Cl)=[C:11]([Cl:14])[C:12]=1[Cl:13])[C:6]([OH:8])=[O:7].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:1][N:2]=[C:3]([OH:17])[C:4]1[C:5](=[C:9]([Cl:16])[C:10]([S:26][C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[C:11]([Cl:14])[C:12]=1[Cl:13])[C:6]([OH:8])=[O:7]
Reactant: COc1ccc(S)cc1
Reactant: CN=C(O)c1c(Cl)c(Cl)c(Cl)c(Cl)c1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN=C(O)c1c(Cl)c(Cl)c(Sc2ccc(OC)cc2)c(Cl)c1C(=O)O

Procedure:
41.41 g (138 millimols) of tetrachlorophthalic acid N-methylimide, 19.42 g (138 millimols) of p-methoxythiophenol, 57.43 g of potassium carbonate and 410 ml of tetrahydrofuran are stirred at 25° C. for 24 hours. After evaporation, the residue is acidified and extracted with methylene chloride. After drying and evaporation, the residue is recrystallised from toluene. This yields 35.38 g (64% of theory) of the title imide; melting point 182°-6° C.
Reaction SMILES: C[O:2][C:3](=[O:40])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:26](=[O:39])[NH:27][CH2:28][C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[CH2:31][C:32](=[O:38])[NH:33]3)=[CH:20][C:21]=1[C:22]([F:25])([F:24])[F:23])=[O:16])[CH2:5][NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].O.[OH-].[Li+].Cl>C1COCC1.O>[O:38]=[C:32]1[CH2:31][C:30]2[C:34](=[CH:35][CH:36]=[CH:37][C:29]=2[CH2:28][NH:27][C:26]([C:19]2[S:18][C:17]([C:15]([NH:14][C@@H:4]([CH2:5][NH:6][C:7]([C:9]3[S:10][CH:11]=[CH:12][CH:13]=3)=[O:8])[C:3]([OH:40])=[O:2])=[O:16])=[C:21]([C:22]([F:25])([F:24])[F:23])[CH:20]=2)=[O:39])[NH:33]1
Reactant: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1sc(C(=O)NCc2cccc3c2CC(=O)N3)cc1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C1Cc2c(CNC(=O)c3cc(C(F)(F)F)c(C(=O)N[C@@H](CNC(=O)c4cccs4)C(=O)O)s3)cccc2N1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (S)-2-({5-[(2-oxo-2,3-dihydro-1H-indol-4-ylmethyl)-carbamoyl]-3-trifluoromethyl-thiophene-2-carbonyl}-amino)-3-[(thiophene-2-carbonyl)-amino]-propionic acid methyl ester (53 mg, 0.089 mmol) in THF (5 mL) was added a solution of lithium hydroxide monohydrate (37 mg, 0.89 mmol) in water (6 mL). The mixture was then stirred at room temperature 5 h. The mixture was then acidified with 1N HCl and extracted with EtOAc (×3). The extracts were combined, washed with water and brine, dried over sodium sulfate, filtered, and evaporated to pure product, 0.0466 g (90%). MS m/e 581.0 (M+H+).
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[F:20][C:21]([F:28])([F:27])[C:22](OCC)=[O:23]>C1COCC1>[CH:18]1[C:13]([C:22]([C:21]([F:28])([F:27])[F:20])=[O:23])=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: Clc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(c1ccc(Cl)cc1)C(F)(F)F
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
Under a nitrogen atmosphere, 110 ml of n-butyllithium/hexane solution (0.95M solution) was added to a solution of 20 g of p-bromochlorobenzene in 200 ml of dry THF at -60° C. The reaction solution was stirred at -60° C. for 1 hour and at -20° C. for 30 minutes. A solution of 17.8 g of ethyl trifluoroacetate in 20 ml of dry THF was added to the reaction solution at -60° C., followed by stirring at that temperature for 1 hour. The reaction solution was poured into dilute HCl-ice water and extracted twice with diethyl ether. The ether layers were combined and washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under a reduced pressure and the residue was subjected to distillation under a reduced pressure to obtain 13.1 g of the desired compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].I[CH3:10].[H-].[Na+].O>CN(C=O)C.CCOC(C)=O>[CH3:10][N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc([N+](=O)[O-])cn1
Reaction time: 18 h
Yield: 87.3 %

Procedure:
To a solution of 4-nitro-1H-pyrazole (1.13 g, 10.0 mmol) and iodomethane (1.25 mL, 20.0 mmol) in DMF (12 mL), NaH (60% in mineral oil, 0.600 g, 15.0 mmol) was added. The mixture was stirred for 18 h. Water and EtOAc were added. The organic phase was separated, washed with water, dried over Na2SO4, concentrated in vacuo to give 1-methyl-4-nitro-1H-pyrazole as a solid (1.11 g).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[I-].[Na+].[C:15]1([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Cl)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CN(C)P(N(C)C)(N(C)C)=O>C(O)C.O>[C:15]1([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: ClCCCCCc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCCCCc2ccccc2)cc1
Temperature: 110 °C

Procedure:
A mixture of 18.2 g. of ethyl p-aminobenzoate 10.2 g. of sodium iodide, 10.0 g. of 5-phenylpentyl chloride and 60 ml. of hexamethylphosphoramide is stirred and heated at 110° C. in an oil bath for 20 hours. The mixture is chilled, diluted with 25 ml. of water and 25 ml. of ethanol, chilled and filtered. The solid is washed with 50 ml. of ethanol-water (1:1), with water and once with cold ethanol to give pale yellow crystals, m.p. 63°-64° C. Recrystallization from ethanol gives off-white crystals, m.p. 73°-75° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[O:12][CH3:13])C=C.C[N+]1([O-])CC[O:18][CH2:17]C1.[CH3:22][OH:23]>O.O=[Os](=O)(=O)=O>[OH:23][CH:22]([CH2:17][OH:18])[CH2:1][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[O:12][CH3:13]
Reactant: CO
Reactant: C=CCc1ccc(C#N)cc1OC
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: COc1cc(C#N)ccc1CC(O)CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-allyl-3-methoxybenzonitrile (1.1 g, 6.4 mmol) in 30 mL of methanol and 10 mL of water was added OsO4 (140 mg) and NMO (2.2 g, 16 mmol), and the mixture was stirred at ambient temperature overnight. Remove the methanol under reduced pressure, the residue was dissolved in EtOAc, washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by fast column chromatograph to give 4-(2,3-dihydroxypropyl)-3-methoxybenzonitrile. MS m/z: 208 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[Mg].[CH3:11][C:12]([CH3:14])=[O:13].Cl>CCOCC>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][C:12]([CH3:14])([OH:13])[CH3:11])=[CH:4][CH:3]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CC(C)=O
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)(O)Cc1ccc(Cl)cc1
Yield: 70 %

Procedure:
A solution of 4-chlorobenzyl chloride (165 g; 1.02 mole) in ether (500 ml) was added dropwise during one hour to magnesium (24.3 g; 1.00 mole) in a three-necked flask equipped with stirrer and reflux condenser. The spontaneous reflux was allowed to continue for another hour and the solution was cooled. Acetone (60.0 g, 1.30 mole) was added dropwise and the solution heated to reflux for three hours. After cooling, the reaction mixture was poured out on ice (500 ml) and concentrated hydrochloric acid (92 ml). The phases were separated. The organic phase was washed with water, dried (Na2SO4) and evaporated in vacuum. The residual oil was fractionated affording 1-(4-chlorophenyl)-2-methyl-2-propanol (b.p. 123°-124° C./12 mm Hg; nD25 =1.5300; 128.5 g, 70% yield).
Reaction SMILES: [NH2:1][C:2](=[N:36][C:37](=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:23]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH2:32][CH2:33][OH:34])[C:24]=2[F:35])[C:11]2[NH:15][C:14](=[O:16])[N:13]([C:17]3[N:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:12]=2)=[CH:5][CH:4]=1.C(=O)([O-])O.[K+].[C:50](=[O:62])([O:55][CH:56]1[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]1)[O:51][CH:52](Cl)[CH3:53]>CN(C=O)C>[CH:56]1([O:55][C:50](=[O:62])[O:51][CH:52]([O:16][C:14]2[N:13]([C:17]3[N:18]=[CH:19][CH:20]=[CH:21][N:22]=3)[N:12]=[C:11]([CH:10]([NH:9][C:6]3[CH:7]=[CH:8][C:3]([C:2]([NH2:1])=[N:36][C:37](=[O:44])[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:4][CH:5]=3)[C:23]3[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH2:32][CH2:33][OH:34])[C:24]=3[F:35])[N:15]=2)[CH3:53])[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]1
Reactant: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Reactant: CC(Cl)OC(=O)OC1CCCCC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2nc(OC(C)OC(=O)OC3CCCCC3)n(-c3ncccn3)n2)c1
Temperature: 55 °C
Reaction time: 26 h
Yield: 52.9 %

Procedure:
To a mixture of N-[1-amino-1-(4-{[[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl]amino}phenyl)methylidene]benzamide (Example 1a, 1.0 g) and DMF (20 mL), potassium hydrogen carbonate (1.67 g) and 1-chloroethyl cyclohexyl carbonate (2.76 g) were added, and the resulting mixture was stirred at 55° C. for 26 hours. The reaction solution was filtered, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by NAM silica gel column chromatography (mixed solvent of methanol-ethyl acetate) to obtain the captioned compound (680 mg).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:14][OH:15].[CH3:16][C:17]1([CH3:27])[CH:19]([CH:20]=[C:21]([CH3:23])[CH3:22])[CH:18]1[C:24](Cl)=[O:25].CCCCCC>N1C=CC=CC=1.C(OCC)C>[CH3:16][C:17]1([CH3:27])[CH:19]([CH:20]=[C:21]([CH3:22])[CH3:23])[CH:18]1[C:24]([O:15][CH2:14][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]=1[CH3:1])=[O:25]
Reactant: Cc1c(CO)cccc1-c1ccccc1
Reactant: CC(C)=CC1C(C(=O)Cl)C1(C)C
Solvent: CCCCCC
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)=CC1C(C(=O)OCc2cccc(-c3ccccc3)c2C)C1(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.9 %

Procedure:
A solution of 2.97 g (15.0 mmol) of (2-methyl-3phenylphenyl)methanol in 1.5 ml of pyridine and 10 ml of diethyl ether, was dropwise added to a solution of 2.80 g (15.0 mmol) of 2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarbonyl chloride in 10 ml of diethyl ether, and the mixture was stirred at room temperature for 3 hours. After an addition of 20 ml of hexane thereto, the inorganic salt was filtered off, and the filtrate was concentrated under reduced pressure. The product was purified by column chromatography (silica gel, dichloromethane/hexane=1/2) to obtain 4.23 g of (2-methyl-3-phenylphenyl)methyl 2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylate as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2[C:7](=[CH2:17])[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=O)[CH2:11][C:5]=2[CH:4]=1.Cl.[NH2:21][OH:22].C([O-])(=O)C.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2[C:7](=[CH2:17])[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[N:21][OH:22])[CH2:11][C:5]=2[CH:4]=1
Reactant: C=C1c2ccc(OC)cc2CC(=O)c2ccccc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=C1c2ccc(OC)cc2CC(=NO)c2ccccc21
Yield: 98.1 %

Procedure:
A solution of 2-methoxy-5-methylene-10-oxo-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (9.7 g, 0.0388 mol), hydroxylamine hydrochloride (3.42 g, 0.0492 mol), and sodium acetate (4.26 g, 0.0519 mol) in methanol (194 ml) is heated under reflux for 2 hours. The solvent is removed under reduced pressure, the residue is slurried in water (200 ml), the pH is adjusted to 8 with concentrated aqueous ammonia, and the slurry is extracted with ether (3×105 ml). The combined extracts are dried over MgSO4 and filtered, and the filtrate is evaporated to yield 10.1 g (98%) of crude material. A sample recrystallized from ether has m.p. 125°-127° C.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl[CH2:7][CH2:8][CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[O:19].[F:20][C:21]1[C:33]([F:34])=[C:32]([F:35])[C:31]([F:36])=[C:30]([F:37])[C:22]=1[O:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>CN(C)C=O>[O:19]=[C:11]1[N:10]([CH:9]([N:27]2[CH2:26][CH2:25][CH:24]([O:23][C:22]3[C:30]([F:37])=[C:31]([F:36])[C:32]([F:35])=[C:33]([F:34])[C:21]=3[F:20])[CH2:29][CH2:28]2)[CH2:8][CH3:7])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12]1
Reactant: Fc1c(F)c(F)c(OC2CCNCC2)c(F)c1F
Reactant: O=c1[nH]c2ccccc2n1CCCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(N1CCC(Oc2c(F)c(F)c(F)c(F)c2F)CC1)n1c(=O)[nH]c2ccccc21
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 54.5 %

Procedure:
A mixture of 10 g of sodium bicarbonate, 3.58 g of 1-(3-chloropropyl)-1,3-dihydro-2-oxo-2H-benzimidazole and 60 ml of dimethylformamide was treated with a solution of 4.0 g of 4-(2,3,4,5,6-pentafluorophenoxy)piperidine in 20 ml dimethylformamide and stirred at 75° C. for 1.5 hours. The reaction mixture was then cooled and filtered. The filtrate was poured into water and extracted with ethyl acetate. The organic layer was washed with water followed by a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After filtering, evaporation of the volatiles afforded a residue which was purified by means of high pressure liquid chromatography (silica gel; elution with 5% methanol/dichloromethane). Recrystallization from isopropyl ether afforded 3.6 g (54%) of 1-[1-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl]-4-(2,3,4,5,6-pentafluorophenoxy)piperidine, m.p. 117°-120° C.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]([OH:13])[CH:8]([NH2:12])[C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.[C:14](O)(=O)[CH:15]([CH3:17])[CH3:16]>>[CH:15]([C:17]1[O:13][C:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)=[C:8]([C:9]([OH:11])=[O:10])[N:12]=1)([CH3:16])[CH3:14]
Reactant: CC(C)C(=O)O
Reactant: NC(C(=O)O)C(O)c1ccccc1
Product: CC(C)c1nc(C(=O)O)c(-c2ccccc2)o1

Procedure:
Prepared starting from DL-3-phenylserine hydrate following sequentially general procedures W, X with isobutyric acid, Y and Z. LC-MS-conditions 02: tR=0.90 min; [M+H]+=232.51.