Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1]/[CH:2]=[CH:3]/[CH:4]([OH:6])[CH3:5].C(N(CC)CC)C.[Cl:14][CH2:15][C:16](Cl)=[O:17]>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[I:1]/[CH:2]=[CH:3]/[CH:4]([O:6][C:16](=[O:17])[CH2:15][Cl:14])[CH3:5]
Reactant: CC(O)/C=C/I
Reactant: O=C(Cl)CCl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(/C=C/I)OC(=O)CCl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
57.1 g (0.25 mol) of (2RS,3E)-4-iodo-3-buten-2-ol (86 percent, produced according to Example 2) was dissolved in 400 ml of toluene under argon, cooled to 0° C. and mixed with 2.4 g (20 mmol) of 4-(dimethylamino)pyridine. Then the mixture was cooled to -5° C., mixed with 11.07 g of triethylamine and cooled again to -10° C. After drop-by-drop addition of a first portion of 12.4 g of chloroacetyl chloride within 15 minutes (exothermic reaction) and another 0.5 hour of stirring, the same amounts of triethylamine and chloroacetyl chloride were instilled in succession. Again after 0.5 hour finally a third portion each was instilled, thus, altogether there were 33.21 g of triethylamine and 37.2 g chloroacetyl chloride added. Triethylammonium chloride precipitated during the addition of chloroacetyl chloride. After the final addition the mixture was stirred 1.5 hours more at -5° C. and then heated to room temperature. After another 3 hours the triethylammonium chloride was filtered off and washed with toluene. The filtrate was washed twice with 80 ml of 0.1M hydrochloric acid each. The aqueous phase was reextracted once with 50 ml of toluene. The combined organic phases were dried on magnesium sulfate, filtered and concentrated by evaporation on a rotary evaporator. The yield was 72.4 g (crude product, still contains some toluene). Further data on the product is:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:21](C#N)=[C:20]([N:24]=[CH:25][N:26]([CH3:28])C)[NH:19][N:18]=2)=[CH:13][CH:12]=1>CO>[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[C:21]3[C:20](=[N:24][CH:25]=[N:26][C:28]=3[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[C:3]([Cl:2])[CH:4]=3)[NH:19][N:18]=2)=[CH:15][CH:16]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CN(C)C=Nc1[nH]nc(-c2ccc(N)cc2)c1C#N
Agent: Cl
Solvent: CO
Product: Nc1ccc(-c2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1

Procedure:
With the exclusion of moisture, 62 mg (0.38 mmol) of 3-chloro-aniline hydrochloride (see Step 14.4) are added to 92 mg (0.36 mmol) of N'-[3-(4-amino-phenyl)-4-cyano-1H-pyrazol-5-yl]-N,N-dimethylformamidine in 1 ml of methanol and the reaction mixture is boiled under reflux for 28 hours. The light-yellow reaction solution is cooled, concentrated by evaporation and chromatographed (SiO2, methylene chloride/ethanol [10:1]). Crystallization from isopropanol yields 3-(4-amino-phenyl)-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine; TLC: Rf =0.33 (methylene chloride:methanol=10:1); FAB-MS: (M)+ =336; HPLC: TRet (Grad20-100)=9.2, TRet (Grad5-40)=18.8.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]2[N:7]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[CH2:8][C@@H:9](OS(C3C=CC(C)=CC=3)(=O)=O)[C@H:5]2[O:4][CH2:3]1.[CH3:31][NH2:32]>C(O)C>[OH:1][C@@H:2]1[C@H:6]2[N:7]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[CH2:8][C@H:9]([NH:32][CH3:31])[C@H:5]2[O:4][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CN(C(=O)OCc3ccccc3)[C@H]3[C@@H]2OC[C@@H]3O)cc1
Reactant: CN
Solvent: CCO
Product: CN[C@H]1CN(C(=O)OCc2ccccc2)[C@H]2[C@@H]1OC[C@@H]2O
Temperature: 25 °C
Yield: 35 %

Procedure:
A stirred solution of tosylate (34b) (200 mg, 0.46 mmol) and methylamine in ethanol (33% wt, 6 mL) was heated in a sealed pressure vessel at 150° C. for 72 hours. The mixture was then allowed to cool to ambient temperature then solvents removed in vacuo. The residue was dissolved in dichloromethane (20 mL), washed with water (15 mL) then dried (Na2SO4), filtered and reduced in vacuo. Flash chromatography over silica, eluting with dichloromethane:methanol mixtures 97:3 to 95:5 gave methylaminoalcohol (57) as a pale yellow solid (47 mg, 35%). TLC (Rf=0.22, DCM:MeOH 93:7), HPLC-MS 293.1 [M+H]+, 315.2 [M+Na]+, 607.3 [2M+Na]+; δH (500 MHz, CDCl3) mixture of rotamers major:minor 3:2; 2.42 (1.8H, s, NHCH3 major), 2.3 (1.2H, s, NHCH3 minor), 3.14-3.16 (1H, m, CHNHCH3), 3.35-4.48 (7H, m, OCH2CHOH, CHCHCHCH2NCbz), 5.06 and 5.22 (0.8H total, each d, J=12.22 Hz, Cbz minor), 5.12 (1.2H, s, Cbz major), 7.27-7.37 (5H, m, aromatic CH).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH2:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[F:17][C:18]([F:37])([F:36])[O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[C:27][CH2:28][CH2:29][CH2:30]OS(C)(=O)=O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:15][CH2:30][CH2:29][CH2:28][C:27]#[C:26][C:23]3[CH:24]=[CH:25][C:20]([O:19][C:18]([F:17])([F:36])[F:37])=[CH:21][CH:22]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2ccc(N)cc21
Reactant: CS(=O)(=O)OCCCC#Cc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccc2ccc(NCCCC#Cc3ccc(OC(F)(F)F)cc3)cc21
Temperature: 70 °C
Reaction time: 14 h
Yield: 13 %

Procedure:
A suspension of (6-amino-indol-1-yl)-acetic acid ethyl ester (50 mg, 0.23 mmol, WO 2003041714 A1), methanesulfonic acid 5-(4-trifluoromethoxy-phenyl)-pent-4-ynyl ester (148 mg, 0.46 mmol) and potassium carbonate (63 mg, 0.46 mmol) in DMF (1 ml) was stirred for 3 h at ambient temperature and for 14 h at 70° C. The reaction mixture was poured onto ethyl acetate/ice water 1/1, the layers were separated and the aqueous layer was extracted two times with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (silica gel, heptane/AcOEt) to give 16 mg (0.03 mmol, 15%) of the title compound as yellow oil.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:6]=[C:7]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[O:8][C:9]1[C:10]([CH2:21][CH3:22])=[N:11][N:12]([CH2:16][C:17](OC)=[O:18])[C:13]=1[CH2:14][CH3:15]>C(O)C>[Cl:4][C:5]1[CH:6]=[C:7]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[O:8][C:9]1[C:10]([CH2:21][CH3:22])=[N:11][N:12]([CH2:16][C:17]([NH:2][NH2:3])=[O:18])[C:13]=1[CH2:14][CH3:15]
Reactant: CCc1nn(CC(=O)OC)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCc1nn(CC(=O)NN)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Yield: 70624 %

Procedure:
Hydrazine hydrate (520 μL, 10.9 mmol) was added to a solution of the ester (780 mg, 2.18 mmol) of Example 9 in ethanol (25 ml) and the resulting mixture was heated under reflux for 18 hours. After cooling, the precipitate was collected by filtration and washed with ether (50 ml) to afford the title compound (550 g) as a white solid, m.p. >250° C.
Reaction SMILES: [CH:1]([C:4]1[C:13]2[CH:12]=[C:11]([NH:14][C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)[C:10]([O:26][CH2:27][CH2:28][CH3:29])=[CH:9][C:8]=2[C:7]([CH3:31])([CH3:30])[CH2:6][CH:5]=1)([CH3:3])[CH3:2].[CH:32](=O)[CH3:33]>>[CH2:32]([N:14]([C:11]1[C:10]([O:26][CH2:27][CH2:28][CH3:29])=[CH:9][C:8]2[C:7]([CH3:31])([CH3:30])[CH2:6][CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:13]=2[CH:12]=1)[C:15]1[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=1)[CH3:33]
Reactant: CC=O
Reactant: CCCOc1cc2c(cc1Nc1ccc(C(=O)OCC)cc1)C(C(C)C)=CCC2(C)C
Product: CCCOc1cc2c(cc1N(CC)c1ccc(C(=O)OCC)cc1)C(C(C)C)=CCC2(C)C
Yield: 70 %

Procedure:
Following General Procedure D, ethyl 4-(8-isopropyl-5,5-dimethyl-3-n-propoxy-5,6-dihydronaphthalen-2-ylamino)benzoate (Compound 117, 0.18 g, 0.43 mmol) was reacted with acetaldehyde to afford 0.14 g (70%) of the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:16])=O.CN(C=O)C>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C:10]([Cl:16])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)COCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)COCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of benzyloxyacetic acid (4.6 g, 28.0 mmol, 4.0 mL) in DCM (52 mL) was added oxalyl chloride (7.7 g, 61 mmol, 5.3 mL) and a drop of DMF. The reaction mixture was stirred at room temperature for 4 h. Excess of oxalyl chloride was removed in vacuo to give benzyloxy-acetyl chloride. The crude acyl chloride was diluted into DCM (100 mL) and triethylamine (5.3 mL, 41.6 mmol, 4.2 g) was added followed by 4-fluoroaniline (3.5 g, 32 mmol, 3.0 mL). The reaction mixture was stirred at RT overnight. The reaction was then quenched with 1 M aqueous HCl (100 mL), dried and concentrated in vacuo to give 7.1 g (95%) of 2-benzyloxy-N-(4-fluoro-phenyl)-acetamide (33) as a yellow oil which was used in the next step without purification. The structure was confirmed by 13C NMR (75 MHz, CDCl3) δC 69.2, 73.5, 115.4 (d, JCF=22 Hz), 121.4 (d, JCF=7 Hz), 127.9, 128.2, 128.5, 132.5 (d, JCF=3 Hz), 136.3, 157.6, 160.8, and 167.5.
Reaction SMILES: O1C2C=CC=CC=2OB1.[Br:10][C:11]1[C:12]([N:27]2[CH2:32][CH2:31][C:30](=[C:33]([CH3:35])[CH3:34])[CH2:29][CH2:28]2)=[C:13]([C:19](=[O:26])[C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:14]([CH3:18])=[N:15][C:16]=1[CH3:17].CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1>C1(C)C=CC=CC=1>[Br:10][C:11]1[C:12]([N:27]2[CH2:32][CH2:31][C:30](=[C:33]([CH3:35])[CH3:34])[CH2:29][CH2:28]2)=[C:13]([C@H:19]([OH:26])[C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:14]([CH3:18])=[N:15][C:16]=1[CH3:17]
Reactant: CC(C)=C1CCN(c2c(Br)c(C)nc(C)c2C(=O)C(=O)OC(C)C)CC1
Agent: B1Oc2ccccc2O1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: Cc1ccccc1
Product: CC(C)=C1CCN(c2c(Br)c(C)nc(C)c2[C@H](O)C(=O)OC(C)C)CC1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
The 1.0 mL of benzo[d][1,3,2]dioxaborole (567 mg, 4.72 mmol) was added to a nitrogen purged solution of isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-(propan-2-ylidene)piperidin-1-yl)pyridin-3-yl)-2-oxoacetate (1.0 g, 2.36 mmol) and 0.95 mL of (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (262 mg, 0.95 mmol) in toluene (20 mL) at −60° C. and allowed to warm to −15° C. before being placed in the freezer overnight. The reaction was quenched with 1M Na2CO3, diluted with EtOAc, and stirred for 30 min. The organic layer was washed with sat'd Na2CO3 solution, brine and dried (MgSO4). The crude product was charged (DCM) to a 80 g ISCO silica gel cartridge and gradient elution (0-60% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-(propan-2-ylidene)piperidin-1-yl)pyridin-3-yl)-2-hydroxyacetate 1.0 g (100%). 1H NMR (500 MHz, DMSO-d6) δ 5.90 (d, J=3.3 Hz, 1H), 4.95 (dt, J=12.3, 6.2 Hz, 1H), 3.43-3.41 (m, 2H), 3.23 (t, J=10.6 Hz, 1H), 2.86 (d, J=10.3 Hz, 1H), 2.56-2.51 (m, 2H), 2.51 (s, 3H), 2.38 (s, 3H), 2.16-2.08 (m, 2H), 1.67 (s, 6H), 1.15 (d, J=6.2 Hz, 3H), 1.08 (d, J=6.2 Hz, 3H). UPLC (M+H)=427.2.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][CH:6]1[CH2:11][C:10](=[O:12])[O:9][C:7]1=[O:8].[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.S(=O)(=O)(O)O>ClCCCl.Cl>[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:10](=[O:12])[CH2:11][CH:6]([CH3:5])[C:7]([OH:9])=[O:8]
Reactant: Fc1ccc(-c2ccccc2)c(F)c1
Reactant: CC1CC(=O)OC1=O
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Al+3]
Solvent: ClCCCl
Product: CC(CC(=O)c1ccccc1-c1ccc(F)cc1F)C(=O)O
Temperature: 15 °C
Yield: 42 %

Procedure:
A solution is prepared by dissolving 33.2 g anhydrous aluminum chloride (0.25 moles) and 21.6 g methylsuccinic acid anhydride (0.188 moles) in 190 ml of 1,2-dichloroethane. The solution is cooled to 15° C. and is treated under stirring and cooling with a solution of 47.5 g of 2,4-difluorobiphenyl (0.25 moles) in 50 ml of 1,2-dichloroethane, at a rate such that the temperature of the reaction mixture does not exceed 20° C. The mixture is then stirred for an additional 3 hours at 20° C., for 1 hour at 40° to 45° C., is cooled to 20° C., and is then poured slowly, under stirring, into a mixture of 500 g ice in 250 ml of concentrated hydrochloric acid. The resulting precipitate is collected on a filter, and the organic layer of the filtrate is separated and washed with 5% aqueous sodium hydroxide solution (4×100 ml). The alkaline extracts are combined and the precipitate is dissolved in the extracts. A moderately turbid solution is obtained, which is filtered with active carbon to obtain a clear filtrate. The clear filtrate is acidified to approximately pH 1 with 50% sulfuric acid. The crude product precipitate is separated, washed with water, and purified by crystalization from 160 ml of 65% acetic acid, to yield 24.0 g of the title compound (42% of theoretical yield) with a melting point of 150°-152° C.
Reaction SMILES: [H-].[K+].[OH:3][CH2:4][C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][C:8]=2[CH:9]=1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CCCCCC.C1C=CC=CC=1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:16]([O:3][CH2:4][C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][C:8]=2[CH:9]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1ccc2oc(CO)cc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: c1ccccc1
Solvent: O
Solvent: CCCCCC
Product: N#Cc1ccc2oc(COCc3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
A dispersion of potassium hydride (0.990 g, 5.04 mmol) in 20% mineral oil was washed by decantation with anhydrous hexane, then was resuspended in anhydrous benzene (25 ml). This suspension was added at 0° C. and under inert atmosphere with a solution of 2-(hydroxymethyl)benzofuran-5-carbonitrile (0.671 mg, 3.89 mmol) in benzene (10 ml) stirring at room temperature for 15 min, then with benzyl bromide (0.825 ml) and a catalytic amount of tetrabutylammonium iodide. The mixture was left under stirring at room temperature for 4 h, then added with water (50 ml) and extracted with ethyl acetate (4×50 ml). The organic phase was dried and the solvent removed, to obtain a crude which was purified by chromatography through a silica gel column, eluting with n-hexane:ethyl acetate mixtures of increasing polarity, thereby recovering 1.087 g of the title compound as a yellowish oil (82% yield).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][OH:14].[CH3:15][O:16][C:17]([C:19]1[S:23][N:22]=[C:21](O)[CH:20]=1)=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:15][O:16][C:17]([C:19]1[S:23][N:22]=[C:21]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])[CH:20]=1)=[O:18]
Reactant: COC(=O)c1cc(O)ns1
Reactant: Cc1onc(-c2ccccn2)c1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)ns1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
To a solution of (5-methyl-3-pyridin-2-yl-isoxazol-4-yl)-methanol (360 mg, 1.9 mmol) in THF (10 mL) was added 3-hydroxy-isothiazole-5-carboxylic acid methyl ester (300 mg, 1.9 mmol) and triphenylphosphine (594 mg, 1.9 mmol) at 0° C. under an argon atmosphere. Then diethyl azodicarboxylate (˜40% in toluene, 0.95 mL, 1.9 mmol) was added and the reaction mixture was stirred overnight at room temperature. Concentration and purification by chromatography (silica, heptane:ethyl acetate=4:1 to 1:4) afforded the title compound (350 mg, 56%) as a white solid. MS: m/e=332.2 [M+H]+.
Reaction SMILES: C([O-])(=O)C.[NH4+].[CH2:6]([N:13]1[CH2:18][CH:17]([CH2:19][CH3:20])[C:16](=O)[C:15]([CH2:23][CH3:24])([CH3:22])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([BH3-])#[N:26].[Na+]>CO>[NH2:26][CH:16]1[CH:17]([CH2:19][CH3:20])[CH2:18][N:13]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:14][C:15]1([CH2:23][CH3:24])[CH3:22]
Reactant: CCC1CN(Cc2ccccc2)CC(C)(CC)C1=O
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCC1CN(Cc2ccccc2)CC(C)(CC)C1N
Temperature: 0 °C
Reaction time: 24 h

Procedure:
Ammonium acetate (8.0 g, 104 mmol) was added to the stirred solution of 1-benzyl-3,5-diethyl-3-methyl-4-piperidone (2.5 g, 9.65 mmol) in methanol (25 ml) and stirring was continued for 24 hr at ambient temperature. The resulting mixture was cooled at 0° C. and sodium cyanoborohydride (0.69 g, 11.2 mmol) was added to it. Cooling was removed after 10 min. and resulting mixture was stirred for 20 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water, acidified with conc. HCl (pH 2) and extracted with ethyl acetate to remove impurities. The aqueous layer was basified with 1M sodium hydroxide solution (pH 9) and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to furnish 4-amino-1-benzyl-3,5-diethyl-3-methylpiperidine as an oil. Yield 2.1 g (84%), C17H28N2, m/z 261 (M+1).
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=2)[CH:6]=[CH:5][CH:4]=[C:3]([OH:7])[CH:2]=1.Br[CH2:16][CH2:17][CH2:18][OH:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:19][CH2:18][CH2:17][CH2:16][O:14][C:10]1[CH:9]=[C:8]([C:1]2[CH:6]=[CH:5][CH:4]=[C:3]([OH:7])[CH:2]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Oc1cccc(-c2cccc(O)c2)c1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OCCCOc1cccc(-c2cccc(O)c2)c1

Procedure:
26.0 g (0.140 mol) of biphenyl-3,3′-diol and 10.0 g of 3-bromo-1-propanol are dissolved in 300 ml of acetone, and, after addition of 19.3 g (0.140 mol) of potassium carbonate, the mixture is heated under reflux overnight. The batch is subsequently filtered and evaporated, and the residue is chromatographed on silica gel with toluene/ethyl acetate (1:1), giving 3′-(3-hydroxypropoxy)biphenyl-3-ol as colourless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([C@H:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]([NH2:16])=[O:15])[C:7]2=[O:12].CN(C)C=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[Cl:61][C:62]1[CH:63]=[C:64]([C@H:69]([CH3:73])[C:70](O)=[O:71])[CH:65]=[CH:66][C:67]=1[Cl:68]>>[NH2:16][C:14](=[O:15])[C@H:13]([N:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:70](=[O:71])[C@H:69]([C:64]2[CH:65]=[CH:66][C:67]([Cl:68])=[C:62]([Cl:61])[CH:63]=2)[CH3:73])[C:7]1=[O:12])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NC(=O)[C@@H](c1ccccc1)n1ccc2c(N)cccc2c1=O
Reactant: C[C@H](C(=O)O)c1ccc(Cl)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](C(=O)Nc1cccc2c(=O)n([C@@H](C(N)=O)c3ccccc3)ccc12)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round bottom flask was charged with (R)-2-(5-amino-1-oxoisoquinolin-2(1H)-yl)-2-phenylacetamide (120 mg, 0.00041 mol), N,N-dimethylformamide (1.5 mL, 0.019 mol), N,N-diisopropylethylamine (0.1 mL, 0.0008 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.3 g, 0.0008 mol) and (S)-2-(3,4-dichlorophenyl)propanoic acid (0.11 g, 0.00049 mol) and the reaction stirred at room temperature overnight. The solvent was removed and the residue purified by flash chromatography and again by preparative HPLC (reverse phase) to obtain the product as a white solid. MS m/z=495.2 (M+H). 1H NMR (400 MHz; DMSO-d6) δ 9.98 (s, 1H), 8.13-8.11 (d, J=8.37 Hz, 1H), 8.03 (s, 1H), 7.74-7.72 (d, J=7.90 Hz, 1H), 7.64-7.63 (d, J=2.06 Hz, 1H), 7.61-7.59 (d, J=7.94 Hz, 1H), 7.55 (s, 1H), 7.50-7.33 (m, 6H), 7.00-6.98 (d, J=8.02 Hz, 1H), 6.74 (s, 1H), 6.39-6.37 (d, J=8.02 Hz, 1H), 4.02-3.96 (q, J=7.01 Hz, 1H), 1.45-1.43 (d, J=7.55 Hz, 3H).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[N:12]=[C:11]2[S:13][C:14]3[CH2:15][NH:16][CH2:17][CH2:18][C:19]=3[C:10]2=[C:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:8]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:4][CH3:5])[CH3:2].[C:35](Cl)(=[O:39])[O:36][CH2:37][CH3:38].C(=O)([O-])[O-].[K+].[K+].O1CCCC1>O>[CH2:4]([N:3]([CH2:6][C:7]1[N:12]=[C:11]2[S:13][C:14]3[CH2:15][N:16]([C:35]([O:36][CH2:37][CH3:38])=[O:39])[CH2:17][CH2:18][C:19]=3[C:10]2=[C:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:8]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:1][CH3:2])[CH3:5]
Reactant: CCOC(=O)c1c(CN(CC)CC)nc2sc3c(c2c1-c1ccc(OC)c(OC)c1)CCNC3
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(CN(CC)CC)nc2sc3c(c2c1-c1ccc(OC)c(OC)c1)CCN(C(=O)OCC)C3
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.2 %

Procedure:
A mixture of the compound obtained in Example 5A (1.12 g), ethyl chlorocarbonate (0.35 g), potassium carbonate (0.47 g) and tetrahydrofuran (20 ml) was stirred at room temperature for 3 hours. The reaction mixture was poured over water and extracted with ethyl acetate; the ethyl acetate layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1, v/v) to yield ethyl 2-(N,N-diethylaminomethyl)-4-(3,4-dimethoxyphenyl)-7-ethoxycarbonyl-5,6,7,8-tetrahydrothieno[2,3-b:5,4-c']dipyridine-3-carboxylate (for structural formula, see below) (0.89 g, 56%), which was then recrystallized from ethyl acetate-hexane to yield colorless prismatic crystals having a melting point of 119 to 120° C. ##STR54##
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7](I)[C:3]=1[C:4]([OH:6])=[O:5].[N:13]1[NH:14][N:15]=[CH:16][CH:17]=1>>[F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]([N:14]2[N:15]=[CH:16][CH:17]=[N:13]2)[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1c(I)ccc(F)c1F
Reactant: c1cn[nH]n1
Product: O=C(O)c1c(-n2nccn2)ccc(F)c1F

Procedure:
The title compound was synthesized following the same general protocol as described in Example A11 using 2,3-difluoro-6-iodobenzoic acid and 2H-1,2,3-triazole. ESI-MS (m/z): 226 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[C:11]([C:18]3[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])=[N:12][O:13][C:14]=2[CH:15]([CH3:17])[CH3:16])[CH:5]=[CH:4][C:3]=1[C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[C:32]([C:36]([O:38]C)=[O:37])=[CH:31][CH:30]=[CH:29]2.C1COCC1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[C:11]([C:18]3[C:19]([Cl:25])=[CH:20][CH:21]=[CH:22][C:23]=3[Cl:24])=[N:12][O:13][C:14]=2[CH:15]([CH3:17])[CH3:16])[CH:5]=[CH:4][C:3]=1[C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[C:32]([C:36]([OH:38])=[O:37])=[CH:31][CH:30]=[CH:29]2
Reactant: COC(=O)c1cccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3Cl)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3c(C(=O)O)cccc3c2)c(Cl)c1
Temperature: 65 °C
Yield: 42.7 %

Procedure:
A solution of methyl 6-[2-chloro-4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxylate (0.36 g, 0.62 mmol), 6.5 mL of THF, 3.5 mL of methanol and 1.3 mL of 1 N NaOH was stirred for 18 h at rt. The reaction mixture was heated to 65° C. for 2 hours. The solution was allowed to cool to room temperature and the pH was adjusted with 1N HCl. The solution was concentrated and the residue was extracted with ethyl acetate. The organic layer was dried with MgSO4, filtered, and the filtrate was concentrated to give the crude product as oil. The crude material was purified by flash chromatography (silica gel, gradient hexane to hexanes/ethyl acetate, 1:1) to afford the title compound as a white foam (0.15 g, 67%). 1H NMR (DMSO-d6): 13.13 (s, 1H), 8.87 (d, J=9 Hz, 1H), 8.19-8.14 (m, 2H), 7.97 (m, 1H), 7.64-7.53 (m, 5H), 7.36 (d, J=9 Hz, 1H), 7.04 (m, 1H), 6.86-6.84 (m, 1H), 4.92 (s, 2H), 3.48 (septet, J=7 Hz, 1H), 1.33 (d, J=7 Hz, 6H). HRMS C30H22Cl3NO4 m/z 566.0693 (M+H)+Cal; 566.0687 (M+H)+Obs.