Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:25])[CH:5]=[C:6]([NH:8][C:9]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][C:19]([C:22](O)=[O:23])([CH3:21])[CH3:20])=[CH:16][CH:17]=2)=[O:10])[CH:7]=1.Cl.C[O:28][C:29](=[O:35])[C@H:30]([CH:32]([CH3:34])[CH3:33])[NH2:31].O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH3:25][C:4]1[CH:5]=[C:6]([NH:8][C:9]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([CH3:20])([CH3:21])[C:22]([NH:31][CH:30]([CH:32]([CH3:34])[CH3:33])[C:29]([OH:28])=[O:35])=[O:23])=[CH:14][CH:13]=2)=[O:10])[CH:7]=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(C)cc(NC(=O)Cc2ccc(OC(C)(C)C(=O)O)cc2)c1
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(NC(=O)Cc2ccc(OC(C)(C)C(=O)NC(C(=O)O)C(C)C)cc2)c1

Procedure:
Using RSR13 acid (1.5 g, 4.4 mmol), valine methyl ester hydrochloride (739 mg, 4.4 mmol) and 1-hydroxybenzotriazole hydrate (635 mg, 4.8 mmol), N-methylmorpholine (666 mg, 6.5 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.01 g, 5.3 mmol) in dimethylformamide (30 mL), the three isomers were prepared in 1.9 g yield (99%).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[C:8]([CH:16](Br)[CH:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>CN(C)C=O.CCCCCC>[C:8]([CH:16]=[C:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)(=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: c1nc[nH]n1
Reactant: O=C(c1ccccc1)C(Br)C(Br)c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=C(C=C(c1ccccc1Cl)n1cncn1)c1ccccc1
Temperature: 100 °C

Procedure:
This Example illustrates the preparation of compound no. 3 of Table I. 1,2,4-Triazole (4.64 g) in dry dimethylformamide (10 ml) was added slowly to a suspension of sodium hydride (2.88 g of 50% dispersion in mineral oil, washed free of oil with dry petrol) in dry dimethylformamide (10 ml) with cooling and stirring. A solution of 1-benzoyl-1,2-dibromo-2-(o-chlorophenyl) ethane (8.45 g) in dry dimethylformamide (10 ml) was then added and the mixture heated at 100° C. for 1 hour. The mixture was poured into cold water (1 liter) and extracted with ether. The ether extracts were dried and evaporated to give a yellow oil. This was dissolved in hexane and the solution cooled to -15° C. The light yellow fibrous crystals were filtered off to give 1-benzoyl-2-o-chlorophenyl-2-(1,2,4-triazol-1-yl)-ethylene (compound no. 3 of Table I) having a melting point of 79°-81° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]1(=[O:14])[O:13][C:11](=[O:12])[CH2:10][CH2:9]1.CCN(CC)CC>C1COCC1>[O:14]=[C:8]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: O=C1CCC(=O)O1
Reactant: Nc1ccccn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)CCC(=O)Nc1ccccn1

Procedure:
The compound 2-aminopyridine (5 g; 53.02 mmol) is dissolved in 80 ml of THF and heated at 80° C. for 15 hours in the presence of succinic anhydride (5.3 g; 53.08 mmol) and a catalytic amount of Et3N (0.7 ml). A white solid is observed with precipitates in the reaction mixture and is suction-filtered off, corresponding to the title product.
Reaction SMILES: CC[Mg+].[Br-].Br[C:6]1[N:10]([CH3:11])[CH:9]=[N:8][CH:7]=1.CON(C)[C:15](=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH3:25])[CH:17]=1>C(Cl)Cl>[CH3:11][N:10]1[C:6]([C:15]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH3:25])[CH:17]=2)=[O:26])=[CH:7][N:8]=[CH:9]1
Reactant: CON(C)C(=O)c1ccc([N+](=O)[O-])c(C)c1
Reactant: Cn1cncc1Br
Agent: CC[Mg+]
Agent: [Br-]
Solvent: ClCCl
Product: Cc1cc(C(=O)c2cncn2C)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of EtMgBr (3.0 M in diethylether, 8.5 mL, 25.69 mmol) was added dropwise, over a 25 minute period to a solution of 5-bromo-1-methyl-1H-imidazole (4.1 g, 25.69 mmol) in dry DCM (25 mL). The mixture was stirred at room temperature for 15 minutes, cooled in an ice-brine bath and N-methoxy-N,3-dimethyl-4-nitrobenzamide (4.8 g, 21.41 mmol. Intermediate 13: step a) dissolved in 10 mL of DCM was added dropwise. A dark brown solid mass formed. The ice bath was removed and the mixture stirred at room temperature for 48 hours. Water was added to the suspension followed by 6 M aqueous HCl slowly to neutralize the mixture (pH=6-7). More DCM was added and the layers were separated. The organic layer was dried over Na2SO4, filtered and concentrated. Et2O was added, the slurry sonicated, and the precipitates filtered to provide the title compound as a tan solid.
Reaction SMILES: O.NN.[CH2:4]([N:6]([CH2:41][CH3:42])[C:7]([C:9]1[N:13]=[C:12]([CH2:14][N:15]2[C:19](=O)[C:18]3=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]3C2=O)[N:11]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2C(=O)C2C=CC=CC=2)[N:10]=1)=[O:8])[CH3:5]>C(O)C>[CH2:4]([N:6]([CH2:41][CH3:42])[C:7]([C:9]1[N:13]=[C:12]2[CH2:14][N:15]=[C:19]([C:18]3[CH:17]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:31]3[CH:30]=[C:29]([Cl:32])[CH:28]=[CH:27][C:26]=3[N:11]2[N:10]=1)=[O:8])[CH3:5]
Reactant: CCN(CC)C(=O)c1nc(CN2C(=O)c3ccccc3C2=O)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1
Agent: NN
Solvent: O
Solvent: CCO
Product: CCN(CC)C(=O)c1nc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
An amount of 1.05 g (0.021 mole) of hydrazine hydrate is added to a solution of 5.41 g (0.01 mole) of N,N-diethyl-1-(2-benzoyl-4-chlorophenyl)-5-(phthalimidomethyl)-1H-1,2,4-triazole-3-carboxamide in 150 ml of ethanol, and the reaction mixture stirred for 16 hours at room temperature and for a further 5 hours at 60°. The formed phthalic acid hydrazide is then filtered off, and the filtrate concentrated in vacuo to dryness. Ice water is added to the residue, and extraction performed twice with ethyl acetate. The organic phase is washed twice with ice cold 1N sodium hydroxide solution, once with ice cold 1N hydrochloric acid solution, and twice with water. After drying of the solution over sodium sulphate, the solvent is evaporated off in vacuo. After recrystallisation from benzene/cyclohexane, the residue yields N,N-diethyl-6-phenyl-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-carboxamide, M.P. 175°-177°.
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[CH2:14]([CH:21]1[CH:26]([OH:27])[CH2:25][CH2:24][CH2:23][N:22]1[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>CC(C)=O>[CH2:14]([CH:21]1[C:26](=[O:27])[CH2:25][CH2:24][CH2:23][N:22]1[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCN1CCCC(O)C1CCCCCCC
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CCCCCCCCN1CCCC(=O)C1CCCCCCC
Reaction time: 6 h
Yield: 34.6 %

Procedure:
Jones' reagent (116.1 ml) was added dropwise to a stirred solution of 2-n-heptyl-3-hydroxy-1-n-octyl-piperidine (16.6 g) in acetone (160 ml) at room temperature. The reaction mixture was stirred for 6 hours and filtered through kieselguhr. The residue was washed several times with ether and the combined organic solutions were extracted with 5% sodium hydroxide solution. The aqueous phase was washed with ether and the combined organic phases were washed with water, dried over magnesium sulphate and evaporated in vacuo. The product was purified by chromatography to give 2-n-heptyl-1-n-octyl-piperidin-3-one as a yellow gum (5.71 g, 34% yield).
Reaction SMILES: [CH:1]([N:3]1[CH:8]([C:9]([O:11]CC)=[O:10])[CH2:7][CH:6]([CH3:14])[CH2:5][C:4]1([OH:20])[C:15]([O:17]CC)=[O:16])=[O:2].[OH-].[Na+]>C(O)C>[CH:1]([N:3]1[CH:8]([C:9]([OH:11])=[O:10])[CH2:7][CH:6]([CH3:14])[CH2:5][C:4]1([OH:20])[C:15]([OH:17])=[O:16])=[O:2]
Reactant: CCOC(=O)C1CC(C)CC(O)(C(=O)OCC)N1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1CC(C(=O)O)N(C=O)C(O)(C(=O)O)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 134.7 %

Procedure:
A mixture of 143 mg of the product of Example 18, 2 ml of ethanol and 1 ml of N sodium hydroxide was stirred for 15 hours at ambient temperature to obtain 155 mg of product which was taken up in water, filtered and lyophilized to obtain 146 mg of the desired product with a Rf=0.35 (butanol-acetic acid-ethanol 4-2-2).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[CH3:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>COCCOC.CCOC(C)=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:17]([O:16][C:14]([NH:13][C@@H:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:21])[CH:27]=2)=[CH:3][CH:4]=1)[C:10]([OH:12])=[O:11])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Br)cc1)C(=O)O
Reactant: Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cc1cccc(-c2ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc2)c1
Temperature: 25 °C

Procedure:
(S)-3-(4-bromophenyl)-2-(tert-butoxycarbonylamino)propanoic acid (2.0 g, 5.81 mmol), 3-methylphenylboronic acid (0.948 g, 6.97 mmol), Pd(PPh3)4 (0.336 g, 0.291 mmol) and 2M NaCO3 aqueous solution (4.36 mL) were stirred in 1,2-dimethoxyethane (30 mL) at 80° C. for 2.5 hours. After being cooled to room temperature, the reaction mixture was diluted with EtOAc and washed with 1M HCl and brine. The organic layer was dried over Na2SO4, concentrated under reduced pressure, and purified by silica gel flash column chromatography (10% MeOH in DCM/DCM) to give(S)-2-(tert-butoxycarbonylamino)-3-(3′-methylbiphenyl-4-yl)propanoic acid. MS: m/z (MH+-Boc) 256. Retention time=1.45 min. (condition A).
Reaction SMILES: [Cl:1][CH2:2][C:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1)=[O:4].[CH3:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>C(OCC)(=O)C>[Cl-:1].[C:13]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][C:3](=[O:4])[CH2:2][N+:17]2([CH3:16])[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:7][CH:8]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)Nc1ccc(OC(=O)CCl)cc1
Reactant: CN1CCCC1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(OC(=O)C[N+]2(C)CCCC2)cc1
Product: [Cl-]
Temperature: 25 °C
Yield: 97 %

Procedure:
4-Acetamidophenyl 2-chloroacetate [2] (1.138 g, 5 mmol) and N-methylpyrrolidine (0.511 g, 6 mmol) were suspended in 50 ml of anhydrous ethyl acetate and refluxed for 48 hrs. After cooling to room temperature the white precipitate was filtered, washed with ethylacetate and diethylether and dried under reduced pressure to give [4] in 97% yield. The product was pure according to 1H NMR and was directly subjected to the next step without further purification. The desired compound is isolated as a colourless powder. 1H-NMR (300 MHz, d6-DMSO) δ(ppm)=10.48 (s, 1H), 7.72 (d, J=8.90 Hz, 2H), 7.17 (d, J=8.90 Hz, 2H), 4.91 (s, 2H), 3.75 (m, 4H), 3.26 (s, 3H), 2.13 (m, 4H), 2.06 (s, 3H). 13C-NMR (75 MHz, d6-DMSO) δ(ppm)=168.8, 164.8, 144.4, 138.2, 121.9, 120.2, 65.5, 62.0, 49.7, 24.3, 21.7. mp 186° C. (dec), T5%onset 197° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH2:35])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4].[C:38](O)(=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40]>>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH:35][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Reactant: CC(C)(C)C(=O)O
Product: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)C(C)(C)C)cc1
Yield: 86 %

Procedure:
The title compound was prepared from 5-n-butyl-2,4-dihydro-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-2-[2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Example 16, Step C), according to the procedure of Example 43 except that pivalic acid was used as the acid. Excess pivalic acid was removed by 10% aq. KHCO3. The crude product was purified by flash chromatography (gradient elution using 1-5% MeOH/CH2Cl2) to afford a 86% yield of the desired compound as a white solid, homogeneous by TLC in 5% MeOH/CH2C2 ; mass spectrum (FAB) m/e 615 (M+1)+ ; mp 176°-178° C.
Reaction SMILES: F[CH:2](F)[C:3]([OH:5])=O.[F:7][C:8]1[CH:32]=[CH:31][C:11]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([CH2:29][NH2:30])[CH:27]=4)[CH:22]=[CH:21]3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.C(=O)(O)[O-].[Na+].[C:38](OCC)(=O)[CH3:39]>CN(C)C=O>[F:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][CH2:13][N:14]2[CH2:15][CH2:16][CH:17]([N:20]3[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([CH2:29][N:30]5[CH2:39][CH2:38][CH2:2][C:3]5=[O:5])[CH:27]=4)[CH:22]=[CH:21]3)[CH2:18][CH2:19]2)=[CH:31][CH:32]=1
Reactant: CCOC(C)=O
Reactant: O=C(O)C(F)F
Reactant: NCc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCCN1Cc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1
Yield: 65 %

Procedure:
Under ice cooling, N,N′-carbonyldiimidazole (160 mg) was added to a solution of difluoroacetic acid (96 mg) in dimethylformamide (5 ml) and the resultant mixture was stirred for 30 min. Next, a solution of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-aminomethylindole (150 mg) obtained in Example 322-3) in dimethylformamide (5 ml) was added thereto and the resultant mixture was stirred at room temperature for 2 hr. Then a saturated aqueous solution of sodium bicarbonate and ethyl acetate were added to the reaction mixtures. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (120 mg) as a white powder (yield: 65%).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[CH:19][N:20]3[C@@H:23]3[CH2:27][C@H:26]([NH:28][C:29](=[O:32])[CH2:30][OH:31])[C@@H:25]([OH:33])[C@H:24]3[OH:34])=[C:16]([NH:35][CH2:36][CH:37]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:15]=2)[CH2:10]1.[N:50]([C:53]1[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=1)=[C:51]=[O:52]>C1COCC1>[C:44]1([CH:37]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:36][NH:35][C:16]2[N:15]=[C:14]([N:11]3[CH2:12][CH2:13][C@@H:9]([NH:8][C:51]([NH:50][C:53]4[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=4)=[O:52])[CH2:10]3)[N:22]=[C:21]3[C:17]=2[N:18]=[CH:19][N:20]3[C@@H:23]2[CH2:27][C@H:26]([NH:28][C:29](=[O:32])[CH2:30][OH:31])[C@@H:25]([OH:33])[C@H:24]2[OH:34])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)CO)[C@@H](O)[C@H]4O)c3n2)C1
Reactant: O=C=Nc1cccnc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O
Temperature: 50 °C

Procedure:
A solution of N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-hydroxy-acetamide trifluoroacetate (0.2 g, 0.28 mmol) in dry THF (10 ml) is treated with TEA (113 mg, 1.12 mmol) followed by 3-isocyanato-pyridine (38 mg, 0.31 mmol). The reaction mixture is heated at 50° C. overnight. The solvent is removed in vacuo and purification by reverse phase column chromatography (Isolute™ C18, 10-50% acetonitrile in water −0.1% TFA) affords the product. The product is further purified by dissolving in MeOH and treating with saturated sodium bicarbonate solution. The mixture is passed through a pre-washed (400 ml MeOH followed by 400 ml water) eluting with 0.5% ammonia 880: water (100 ml) followed by water (400 ml) and finally MeOH to afford the title compound. (MH+ 693.4)
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[C:7]([O:12][CH2:13][O:14][CH3:15])[CH:6]=1.CN(C)CCN(C)C.[Li]CCCC.C[O:30][C:31]1[CH2:35][CH2:34][C:33](=O)[CH:32]=1.Cl>C1COCC1>[CH3:15][O:14][CH2:13][O:12][C:7]1[CH:6]=[C:5]([O:4][CH2:3][O:2][CH3:1])[CH:10]=[CH:9][C:8]=1[C:33]1[CH2:34][CH2:35][C:31](=[O:30])[CH:32]=1
Reactant: COCOc1ccc(Br)c(OCOC)c1
Reactant: COC1=CC(=O)CC1
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOc1ccc(C2=CC(=O)CC2)c(OCOC)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 12.7 %

Procedure:
1,3-Bis(methoxymethoxy)-4-bromobenzene (1.0 g) was dissolved in THF (20 ml) and cooled to −78° C. under argon. N,N,N′,N′-Tetramethylethylene diamine was added followed by dropwise addition of n-BuLi (3.4 ml of a 2.2M solution in hexanes) over 10 mins. After stirring at −78° C. for 1 hr, a solution of 3-methoxy-2-cyclopentene-1-one (605 mg) in THF (5 ml) was added slowly. The reaction mixture was stirred at −78° C. for 1 hr before warming to 0° C. 1M HCl (20 ml) was added, and after 10 min the mixture was extracted with ethyl acetate (2×50 ml). The combined organic phases were washed with brine (30 ml), dried over magnesium sulfate, and concentrated in vacuo. The crude residue was purified by flash column chromatography (SiO2, ethyl acetate/petrol, 1:1 v/v) to furnish the title compound as yellow oil (128 mg, 13%); m/z (ES+) 279 (M+1)+.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH3:5][N:6]([CH3:15])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([CH3:14])[N:8]=1>O1CCCC1.C(=O)([O-])O.[Na+]>[N:13]([C:10]1[CH:11]=[CH:12][C:7]([N:6]([CH3:5])[CH3:15])=[N:8][C:9]=1[CH3:14])=[C:1]=[S:2]
Reactant: S=C(Cl)Cl
Reactant: Cc1nc(N(C)C)ccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(N(C)C)ccc1N=C=S
Temperature: 0 °C
Reaction time: 2 h
Yield: 43.2 %

Procedure:
Thiophosgene (1.3 mL, 16.7 mmol) was added dropwise to a stirred mixture of N2,N2,6-trimethylpyridine-2,5-diamine (2.30 g, 15.2 mmol) in tetrahydrofuran (20 mL) and saturated aqueous sodium hydrogen carbonate (20 mL) at 0° C., and the mixture was stirred at 0° C. for 2 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with diisopropyl ether to give the title compound as a pale yellow powder (1.27 g, 6.57 mmol, 43%).
Reaction SMILES: C([O:8][N:9]1[CH2:13][CH2:12][NH:11][C:10]1=[N:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([O:22][CH3:23])[C:16]=1[Cl:24])C1C=CC=CC=1.Cl>C(O)C.[Pd]>[ClH:21].[Cl:24][C:16]1[C:17]([O:22][CH3:23])=[CH:18][CH:19]=[C:20]([Cl:21])[C:15]=1[N:14]=[C:10]1[NH:11][CH2:12][CH2:13][N:9]1[OH:8]
Reactant: COc1ccc(Cl)c(N=C2NCCN2OCc2ccccc2)c1Cl
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1ccc(Cl)c(N=C2NCCN2O)c1Cl
Reaction time: 2 h

Procedure:
A solution of 20.14 g of 1-(benzyloxy)-2-(2,6-dichloro-3-methoxyphenyl)imino-imidazolidine in 100 ml of ethanol is treated with 6.5 ml of concentrated hydrochloric acid and 1.0 g of palladium/carbon and hydrogenated at room temperature. After 2 hours, the solution is filtered and the filtrate is evaporated in vacuo. The residual material is taken up in acetone and heated to boiling under reflux. There is obtained 2-[(2,6-dichloro-3-methoxyphenyl)imino]-1-hydroxyimidazolidine hydrochloride of melting point 215°-217°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=2[Cl:19])[N:12]=[C:11]([C:21]([OH:23])=[O:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]([N:27]([CH:31]([CH3:33])[CH3:32])[CH2:28][CH2:29]O)([CH3:26])[CH3:25]>S(Cl)(Cl)=O>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=2[Cl:19])[N:12]=[C:11]([C:21]([O:23][CH2:29][CH2:28][N:27]([CH:31]([CH3:33])[CH3:32])[CH:24]([CH3:26])[CH3:25])=[O:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(OCc2ccccc2)c2c(Cl)cc(Cl)cc2n1
Reactant: CC(C)N(CCO)C(C)C
Solvent: O=S(Cl)Cl
Product: CC(C)N(CCOC(=O)c1cc(OCc2ccccc2)c2c(Cl)cc(Cl)cc2n1)C(C)C

Procedure:
Treatment of 4-benzyloxy-5,7-dichloroquinoline-2-carboxylic acid (1 g, Example 33b) with thionyl chloride (10 ml) followed by 2-(diisopropylamino)ethanol (1.63 ml) as described in Example 33c gave 2-diisopropylaminoethyl 4-benzyloxy-5,7-dichloroquinoline-2-carboxylate (0.85 g). δ (360 MHz, DMSO-d6) 0.98 (12H, 2d, CH3), 2.77 (2H, t, CH2N), 3.01 (2H, m, C-H), 4.27 (2H, t, CO2CH2), 5.49 (2H, s, OCH2), 7.38 (1H, d, p-ArH), 7.44 (2H, t, m-ArH), 7.58 (2H, d, o-ArH), 7.72 (1H, s, 3-H), 7.81 (1H, d, 6-H) and 8.21 (1H, d, 8-H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C:13]2([CH2:18][OH:19])[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.FC(F)(F)C1C=CC(C2(C[O:36][S:37]([CH3:40])(=O)=[O:38])CCCC2)=CC=1>>[CH3:40][S:37]([O:19][CH2:18][C:13]1([C:5]2[CH:4]=[C:3]([C:2]([F:20])([F:21])[F:1])[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1)(=[O:38])=[O:36]
Reactant: OCC1(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCCC1
Reactant: CS(=O)(=O)OCC1(c2ccc(C(F)(F)F)cc2)CCCC1
Product: CS(=O)(=O)OCC1(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCCC1

Procedure:
(1-(3,5-bis(trifluoromethyl)phenyl)cyclopentyl)methyl methanesulfonate (458) was synthesized from ((1-(3,5-bis(trifluoromethyl)phenyl)cyclopentyl)methanol (457) following the procedure described for methanesulfonic acid 1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl ester (240).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2].Cl.[CH2:16]([O:18][C:19](=[O:30])[C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:25](=[O:29])[C@H:26]([CH3:28])[NH2:27])[CH3:17].C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[CH2:16]([O:18][C:19](=[O:30])[C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:25](=[O:29])[C@H:26]([CH3:28])[NH:27][C:12]([C:10]1[N:11]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=[CH:8][CH:9]=1)=[O:14])[CH3:17]
Reactant: CCOC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N
Reactant: CCOC(=O)c1cccc(C(=O)O)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1cccc(C(=O)N[C@@H](C)C(=O)N2CCC[C@H]2C(=O)OCC)n1
Reaction time: 0.33 h
Yield: 49.6 %

Procedure:
To a stirred solution of 4.31 g (0.022 mol) of 6-ethoxycarbonyl-2-pyridinecarboxylic acid in 100 ml of anhydrous pyridine, there are added 5.5 g (0.022 mol) of L-alanyl-L-proline ethyl ester hydrochloride and 4.6 g of N,N'-dicyclohexyl carbodiimide. Stirring is continued for 20 minutes at room temperature, and the bulky precipitate of dicyclohexyl urea is filtered and washed with acetone. The solvent from the filtrate and washings is distilled off under reduced pressure and the crude product obtained is purified by column chromatography over silica gel using chloroform:acetone (10:1) as eluant. The isolated solid is crystallized from an acetone/isopropyl ether/petroleum ether mixture, to give 4.27 g of the desired product as acicular crystals (yield: 53%).
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:6]2[N:7]=[C:8]([C:10]3[CH:11]=[N:12][C:13]([N:16]([CH3:18])[CH3:17])=[N:14][CH:15]=3)[O:9][C:5]=2[CH:4]=1.CN(C)C1N=CC(C2OC3C=CC(O)=CC=3N=2)=CC=1>>[CH3:17][N:16]([CH3:18])[C:13]1[N:14]=[CH:15][C:10]([C:8]2[O:9][C:5]3[CH:4]=[C:3]([OH:2])[CH:20]=[CH:19][C:6]=3[N:7]=2)=[CH:11][N:12]=1
Reactant: COc1ccc2nc(-c3cnc(N(C)C)nc3)oc2c1
Agent: CN(C)c1ccc(-c2nc3cc(O)ccc3o2)cn1
Product: CN(C)c1ncc(-c2nc3ccc(O)cc3o2)cn1

Procedure:
The title compound was synthesized from 5-(6-Methoxy-1,3-benzoxazol-2-yl)-N,N-dimethylpyrimidin-2-amine according to the general procedure as described for 2-[6-(dimethylamino)pyridin-3-yl]-1,3-benzoxazol-5-ol to give 30.3 mg: 1H NMR δ ppm 9.85 (br. s, 1H) 8.97 (s, 2H) 7.51 (d, 1H) 7.05 (d, 1H) 6.82 (dd, 1H) 3.22 (s, 6 H); MS m/z 257 (M+H).