Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]([S:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=O)[CH:15]=1>>[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:1][C:2]2[CH:3]=[CH:4][C:5]([S:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=2)[CH:15]=1
Reactant: O=Cc1cccnc1
Reactant: COC(=O)CSc1ccc(N)cc1
Product: COC(=O)CSc1ccc(NCc2cccnc2)cc1

Procedure:
Following the procedure described in Example 9, (4-aminothiophenoxy)-acetic acid, methyl ester (Preparation 8) is reacted with 3-pyridinecarboxaldehyde (B-5A wherein m is 1) to yield the titled product.
Reaction SMILES: Cl[CH:2]([CH3:15])[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1.[F:16][C:17]([F:26])([F:25])[C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>>[F:12][C:11]([F:14])([F:13])[C:7]1[CH:6]=[C:5]([NH:4][CH2:3][CH:2]([NH:21][C:20]2[CH:22]=[CH:23][CH:24]=[C:18]([C:17]([F:16])([F:25])[F:26])[CH:19]=2)[CH3:15])[CH:10]=[CH:9][CH:8]=1
Reactant: CC(Cl)CNc1cccc(C(F)(F)F)c1
Reactant: Nc1cccc(C(F)(F)F)c1
Product: CC(CNc1cccc(C(F)(F)F)c1)Nc1cccc(C(F)(F)F)c1
Yield: 76.6 %

Procedure:
N-(β-chloropropyl)-3-trifluoromethyl-aniline is reacted with 3-trifluoromethylaniline as described in Example 16, point (c) to obtain 1,2-bis(3'-trifluoromethylphenyl-amino)propane with a yield of 76.6%. The dihydrochloride of this base melts at 116°-120° C.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:4]=[C:5]([C:20]2[CH:21]=[CH:22][C:23]([C:26]#[N:27])=[N:24][CH:25]=2)[CH:6]=[C:7]([NH:9][C:10]2[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][N:11]=2)[CH:8]=1>[Pd].C(O)C>[ClH:1].[NH2:27][CH2:26][C:23]1[N:24]=[CH:25][C:20]([C:5]2[CH:6]=[C:7]([NH:9][C:10]3[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][N:11]=3)[CH:8]=[C:3]([CH3:2])[CH:4]=2)=[CH:21][CH:22]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(C#N)nc2)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(CN)nc2)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
HCl (4 M in dioxanes, 0.844 mL, 3.38 mmol) followed by palladium on carbon (599 mg, 0.281 mmol) were added to a mixture of 5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridine-2-carbonitrile (1.00 g, 2.81 mmol) and ethanol (200 mL). The reaction mixture was purged and flushed with H2(g) and was stirred under 1 atm of H2(g) for 3.5 hours at room temperature. The reaction mixture was filtered through CELITE, washed with ethanol and ethyl acetate and concentrated under reduced pressure to afford N-{3-[6-(Aminomethyl)pyridin-3-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine hydrochloride as a yellow powder. MS APCI calc'd for C18H17F3N5 [M+H]+ 360. found 360.
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:20]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:5]=1.N1CCCCC1>CN(C=O)C>[NH2:1][C@H:2]([C:20]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])[CH:5]=1
Reactant: CC(C)(C)OC(=O)n1cc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)NCc2ccccc2)c2ccccc21
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1cc(C[C@H](N)C(=O)NCc2ccccc2)c2ccccc21
Yield: 82.3 %

Procedure:
To the mixture of Fmoc-Trp(Boc)-OH (205 mg, 0.39 mmol) and benzylamine (165 μL, 1.51 mmol) in DMF (5 mL) was added TBTU (249 mg, 0.77 mmol) and N,N-diisopropylethylamine (340 μL, 1.95 mmol). The reaction was stirred for 2 hours at room temperature. The solvent was removed in vacuo and the residue was purified by flash column silica gel chromatography (2:1, hexane:ethyl acetate) to yield the Fmoc-Trp(Boc)-NHBn (151 mg, 63%). The solution of Fmoc-Trp(Boc)-NHBn (151 mg, 0.25 mmol) and piperidine (0.5 mL) in DMF (2 mL) was stirred for 1 hour at room temperature. The solvent was removed in vacuo and the crude product was purified by flash column silica gel chromatography (from ethyl acetate to 5% methanol in ethyl acetate) to afford the NH2-Trp(Boc)-NHBn (81 mg, 80%). Compound 16 (23 mg, 0.04 mmol) was dissolved in DMF (2 mL) and NH2-Trp(Boc)-NHBn (72 mg, 0.18 mmol), TBTU (33 mg, 0.10 mmol), and N,N-diisopropylethylamine (37 μL, 0.21 mmol). The mixture was stirred for 4 hours at room temperature before removing the solvent under reduced pressure. The crude product was purified by flash chromatography using ethyl acetate as eluent to afford 17 (24 mg, 63%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH2:6][CH:7]([C:9]([F:12])([F:11])[F:10])O)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:33]1(=[O:43])[NH:37][C:36](=[O:38])[C:35]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:34]12.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH2:6][CH:7]([C:9]([F:12])([F:11])[F:10])[N:37]1[C:36](=[O:38])[C:35]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:34]2[C:33]1=[O:43])[CH3:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCOC(=O)CCC(O)C(F)(F)F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CCC(N1C(=O)c2ccccc2C1=O)C(F)(F)F

Procedure:
To a solution of 30 mmole of 4-trifluoromethyl-4-oxobutyric acid ethyl ester in 20 ml of ethanol cooled to 0° C. is added 30 mmole of sodium borohydride. The reaction mixture is stirred at 0° C. for 4 hours then acidified with M HCl to a pH of 1. The solvent is evaporated under reduced pressure and the residue is partitioned between water and ether. The organic phase is washed with brine, dried over magnesium sulfate and concentrated to give 4-trifluoromethyl-4-hydroxybutyric acid ethyl ester. A mixture of 20 mmole of 4-trifluoromethyl-4-hydroxybutyric acid ethyl ester, 22 mmole of triphenylphosphine, 20 mmole of phthalimide and 22 mmole of diethyl azodicarboxylate in 60 ml of tetrahydrofuran is heated at reflux temperature under nitrogen for 24 hours. The solvent is evaporated under reduced pressure, and the residue chromatographed on silica gel to give 4-trifluoromethyl-4-phthalimidobutyric acid ethyl ester. A suspension of 30 mmole of 4-trifluoromethyl-4-phthalimidobutyric acid ethyl ester in 20 ml of concentrated HCl is heated at reflux temperature for 24 hours. The solid which separates on cooling is filtered, and the filtrate concentrated under reduced pressure. The residue is dissolved in the minimum quantity of water, and the pH of the solution adjusted to 5 by the addition of sodium hydroxide. Acetone is added, and the precipitated 4-amino-4-trifluoromethylbutyric acid collected by filtration.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].CC1(C)C(C)(C)OB([C:34]2[CH:35]=[C:36]([C:40]3([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:42][CH2:41]3)[CH:37]=[CH:38][CH:39]=2)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.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>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:38]5[CH:37]=[C:36]([C:40]6([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])[CH2:42][CH2:41]6)[CH:35]=[CH:34][CH:39]=5)[C:3]([CH3:25])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: CC(C)(C)OC(=O)NC1(c2cccc(B3OC(C)(C)C(C)(C)O3)c2)CC1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(C2(NC(=O)OC(C)(C)C)CC2)c1
Temperature: 120 °C

Procedure:
N-(6-Chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (110 mg, 0.300 mmol) was dissolved in 3 mL of 1,2-dimethoxyethane (DME) in a microwave reactor tube. tert-Butyl 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropylcarbamate (50% pure, 280 mg, 0.390 mmol), 0.4 mL of an aqueous 2 M potassium carbonate solution, and tetrakis(triphenylphospine)palladium(0) (Pd(PPh3)4, 17 mg, 0.015 mmol) were added and the reaction mixture was heated at 120° C. in a microwave reactor for 20 minutes. The resulting material was cooled to room temperature, filtered, and the layers were separated. The organic layer was evaporated to dryness and the residue was purified on silica gel utilizing a gradient of 0-30% ethyl acetate in hexanes to yield tert-butyl 1-(3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)phenyl)cyclopropylcarbamate. This material was then dissolved in 3 mL of dichloromethane containing 1 mL of trifluoroacetic acid (TFA) and was allowed to stir for 15 min at room temperature. The mixture was evaporated to dryness, dissolved in a minimum of N,N-dimethylformamide, and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield N-(6-(3-(1-aminocyclopropyl)phenyl)-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 463.2, found; 464.0 (M+1)+ Retention time 1.39 minutes.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([C:13]2[C:14]([CH2:35][O:36][CH3:37])=[N:15][N:16]3[C:21]([C:22]4[C:27]([O:28][CH3:29])=[CH:26][C:25]([CH2:30][O:31][CH3:32])=[CH:24][C:23]=4[O:33][CH3:34])=[CH:20][CH:19]=[CH:18][C:17]=23)C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.Cl.[OH-].[Na+]>C(OCC)(=O)C>[CH:1]1([CH2:4][NH:5][C:13]2[C:14]([CH2:35][O:36][CH3:37])=[N:15][N:16]3[C:21]([C:22]4[C:23]([O:33][CH3:34])=[CH:24][C:25]([CH2:30][O:31][CH3:32])=[CH:26][C:27]=4[O:28][CH3:29])=[CH:20][CH:19]=[CH:18][C:17]=23)[CH2:3][CH2:2]1
Reactant: COCc1cc(OC)c(-c2cccc3c(N(CC4CC4)C(=O)OC(C)(C)C)c(COC)nn23)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COCc1cc(OC)c(-c2cccc3c(NCC4CC4)c(COC)nn23)c(OC)c1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
The obtained tert-butyl N-cyclopropylmethyl-N-[7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-(methoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]carbamate was dissolved in ethyl acetate (5 mL) without purification, and then 4N hydrochloric acid (ethyl acetate solution; 10 mL) was added thereto and the reaction mixture was stirred for 30 minutes at 40° C. The reaction mixture was neutralized with a 5N aqueous sodium hydroxide solution while cooling with ice, and then the reaction mixture was extracted with ethyl acetate and the organic extract was washed with water and brine. The organic extract was dried over anhydrous magnesium sulfate and filtered, the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography and the title compound (95 mg) was obtained as a yellow oil from the n-hexane:ethyl acetate (2:3) fraction.
Reaction SMILES: [Te:1]([Cl:5])(Cl)([Cl:3])[Cl:2].[CH3:6][O:7][C:8]([CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]>C(Cl)(Cl)(Cl)Cl>[CH3:6][O:7][C:8]([CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([Te:1]([Cl:5])([Cl:3])[Cl:2])=[CH:14][CH:13]=1)=[O:9]
Reactant: COC(=O)COc1ccccc1
Reactant: Cl[Te](Cl)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)COc1ccc([Te](Cl)(Cl)Cl)cc1
Yield: 96.1 %

Procedure:
Tellurium tetrachloride (11.36 g, 0.042 mol) and methyl phenoxy acetate (21.00 g, 0.127 mol) were refluxed in carbon tetrachloride (175 ml) for 18 h. The reaction solution was filtered while still hot, the filtrate cooled in an ice bath and the resulting solid filtered to afford p-methoxycarbonylmethoxyphenyltellurium trichloride (16.11 g, 96%) δ(CDCl3 /DMSO d6) 8.38 (2H,d,9Hz), 6.90 (2H,d,9 Hz), 4.67 (2H,s), and 3.77 (3H,s). No attempt was made to purify this compound and it was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[N:15]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=4)[CH:13]=[C:12]([C:24]([OH:26])=O)[C:8]=3[NH:9][C:10]=2[CH:11]=1.Cl.CN.Cl.[CH3:31][N:32](C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[N:15]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=4)[CH:13]=[C:12]([C:24]([NH:32][CH3:31])=[O:26])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: COc1ccc(-c2cc(C(=O)O)c3[nH]c4cc(OC)ccc4c3n2)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: CNC(=O)c1cc(-c2ccc(OC)cc2)nc2c1[nH]c1cc(OC)ccc12
Reaction time: 8 h
Yield: 66.7 %

Procedure:
A mixture of 7-methoxy-2-(4-methoxyphenyl)-5H-pyrido[3,2-b]indole-4-carboxylic acid (Example 127D) (60 mg, 0.17 mmol), methylamine hydrochloride (19 mg, 0.28 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodimide hydrochloride (43 mg, 0.22 mmol), and 1-hydroxybenzotriazole hydrate (30 mg, 0.22 mmol) in a vial was flushed with nitrogen and dimethylformamide (0.5 mL) followed by triethylamine (38 μL, 0.28 mmol) were added. After stirring overnight, the reaction was diluted with methanol and the product was isolated by preparative HPLC (100×30 mm Luna C18 column, gradient elution starting with A:B=10:90 and ending with A:B=70:30 [A=10 mM NH4OAc in 5% aqueous acetonitrile; B=10 mM NH4OAc in 95% aqueous acetonitrile] over 20 min) followed by removal of the solvents. This gave 7-methoxy-2-(4-methoxyphenyl)-N-methyl-5H-pyrido[3,2-b]indole-4-carboxamide (41 mg, 63% yield) as a yellow solid. MS (ESI) m/z 362.3 (M+H). 1H NMR (MeOD) δ ppm 8.26 (1H, d, J=8.55 Hz), 8.00-8.04 (2H, m), 7.98 (1H, s), 7.17 (1H, d, J=2.14 Hz), 7.07-7.10 (2H, m), 6.92 (1H, dd, J=8.70, 2.29 Hz), 3.94 (3H, s), 3.89 (3H, s), 3.06 (3H, s).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([C:18]([F:21])([F:20])[F:19])=[N:16][N:17]=2)[N:14]=1.[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:7]2[CH2:8][CH:4]3[CH:5]([CH2:1][N:2]([C:9]4[CH:10]=[CH:11][C:12]5[N:13]([C:15]([C:18]([F:20])([F:21])[F:19])=[N:16][N:17]=5)[N:14]=4)[CH2:3]3)[CH2:6]2)=[CH:25][CH:24]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CC4CNCC4C3)nn12
Reactant: O=Cc1ccc(Cl)cc1
Product: FC(F)(F)c1nnc2ccc(N3CC4CN(Cc5ccc(Cl)cc5)CC4C3)nn12

Procedure:
Reductive amination of 6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-chlorobenzaldehyde was carried out according to General Synthetic Method 10. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[2-[(4-chlorophenyl)methyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[Cl:11].[CH2:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][CH2:20][C:21](Cl)=[O:22])[CH2:14][CH2:13]1>C(Cl)(Cl)(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH:15]1([CH2:18][CH2:19][CH2:20][C:21]([C:6]2[CH:5]=[C:4]([Cl:11])[C:3]([O:2][CH3:1])=[CH:8][C:7]=2[O:9][CH3:10])=[O:22])[CH2:16][CH2:17][CH2:12][CH2:13][CH2:14]1
Reactant: COc1ccc(Cl)c(OC)c1
Reactant: O=C(Cl)CCCC1CCCCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(OC)c(C(=O)CCCC2CCCCC2)cc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
10 g of 2,4-dimethoxychlorobenzene and 10.93 g of 4-cyclohexanebutyryl chloride obtained in step 1 of Preparation 1.1 in 100 ml of CCl4 are mixed together at 0° C. and 6.35 ml of TiCl4 are added. After stirring for 2 hours at 0° C., the mixture is poured onto ice-cold 1N HCl solution and the organic phase is then separated out by settling and washed with 0.5N NaOH. After drying over MgSO4 and evaporation of the solvent, 20 g of the expected product are obtained.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[N+:18]([O-:20])=[O:19])(=O)OCC)C.C1OCCOCCOCCOCCOC1.[H-].[Na+].[O:38]1[CH2:43][CH2:42][C:41](=O)[CH2:40][CH2:39]1>C1COCC1.O>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH:9]=[C:41]2[CH2:42][CH2:43][O:38][CH2:39][CH2:40]2)=[C:11]([N+:18]([O-:20])=[O:19])[CH:12]=1
Reactant: O=C1CCOCC1
Reactant: CCOP(=O)(Cc1ccc(OC)cc1[N+](=O)[O-])OCC
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C=C2CCOCC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
To a solution of diethyl-(4-methoxy-2-nitrobenzyl)phosphonate (3 g; 9.89 mmol; 1 eq) and 15-crown-5 (196.31 μL; 0.99 mmol; 0.1 eq) in THF (30 mL) at 0° C. is added portionwise sodium hydride (431.65 mg; 9.89 mmol; 1 eq). After 15 min, a solution of tetrahydro-2H-pyran-4-one (990.43 mg; 9.89 mmol; 1 eq) in THF (30 mL) is added dropwise at 0° C. After stirring at room temperature for 3 h, the reaction is complete. The mixture is diluted with water at 0° C. and the product is extracted with EtOAc. The organic layer is washed with saturated aqueous NaHCO3 and brine then dried over MgSO4. The solvent is removed under reduced pressure and the yellow residue is washed with pentane (to remove the oil from NaH) to afford 1.8 g (73%) of the title compound as an orange powder. 1H NMR (DMSO-d6) δ 7.53 (d, J=2.3 Hz, 1H), 7.32-7.24 (m, 2H), 6.39 (s, 1H), 3.84 (s, 3H), 3.67-3.63 (m, 2H), 3.55-3.51 (m, 2H), 2.34-2.31 (m, 2H), 2.19-2.16 (m, 2H). HPLC (max plot) 87%; Rt 3.96 min.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].C[O-].[Na+].Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[N:15][N:14]=1>O1CCOCC1>[OH:2][C:1]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[O:5][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[N:15][N:14]=1
Reactant: Oc1cccc(O)c1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Agent: C[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Oc1cccc(Oc2nnc(Cc3ccncc3)c3ccccc23)c1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
A solution of 0.2 g (1.82 mmol) resorcinol in 5 ml dioxane is spiked with 0.37 ml 5.4 M methanolic sodium methylate solution (2 mmol) The crystalline residue is then suspended in 5 ml dioxane, 0.511 g (2 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine is added, and the reaction mixture stirred under nitrogen atmosphere for 18 h at 120° C. After cooling to RT and filtration, the filtrate is evaporated under vacuum, and the residue purified by means of flash chromatography on silica gel with particle size 0.04-0.06 mm, using acetate and ethyl acetate/methanol mixtures (50:1 and 25:1). The product-containing fractions are evaporated under vacuum, the crystalline residue suspended in about 5 ml dichloromethane, and filtered. Title compound is obtained after drying of the crystallizate under HV (6 h, 100° C.); m.p. 206-207° C.; ESI-MS: (M+H)+=330.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[C:3]=1[C:10](=[O:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23]>O1CCCC1>[OH:1][C:2]1[C:7]([CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[C:3]=1[C:10](=[O:12])[CH3:11]
Reactant: CC(C)=CCCl
Reactant: CC(=O)c1c(O)cc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)c1c(O)cc(O)c(CC=C(C)C)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
In 250 ml of anhydrous tetrahydrofuran was dissolved 50.0 g of 2',4',6'-trihydroxyacetophenone, and 123.1 g of anhydrous potassium carbonate was added to the solution and the mixture was stirred at room temperature for 30 minutes. Then, 37.2 g of 1-chloro-3-methyl-2-butene was added dropwise to the mixture over a period of 20 minutes and reaction was carried out at room temperature for 24 hours. After the reaction, the reaction mixture was extracted with 2 l of ethyl acetate and the solvent was removed from the ethyl acetate layer by distillation, and the residue was recrystallized from a benzene/petroleum ether mixed solvent to obtain 38.6 g (yield=55.0%) of 2',4',6'-trihydroxy-3'-(3-methyl-2-butenyl)acetophenone in the form of a yellow prism.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1([C:11](OC)=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].C(OCC)(=O)C>C(OCC)C>[CH3:1][O:2][CH2:3][CH2:4][C:5]1([CH2:11][OH:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COCCC1(C(=O)OC)CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COCCC1(CO)CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of EXAMPLE 88A (7.0 g) in diethyl ether (30 mL) was added dropwise to a suspension of LiAlH4 (1.32 g) in diethyl ether (50 mL). Once the addition was finished, the mixture was refluxed for 90 minutes. Then cooled to 0° C. and 2N NaOH (50 mL) was added slowly. Once a semi-solid appeared at the bottom of the flask, ethyl acetate (300 mL) was added and the mixture was stirred vigorously for 30 minutes. The top clear layer was decanted and more ethyl acetate (200) mL) was added to the mixture and stirred for another 15 minutes. The top organic layer was decanted and combined with the previous one. The combined organic layers were washed with 2N aqueous NaOH, water, brine and dried over Na2SO4. Filtration and evaporation of solvent gave the title compound.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:32])[C:16]([N:18]2[CH2:23][CH:22]3[C@@:20]([CH2:24][OH:25])([CH2:21]3)[C@@H:19]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>C(Cl)Cl>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]([N:15]([CH3:32])[C:16]([N:18]2[CH2:23][CH:22]3[C@@:20]([CH2:24][O:25][S:43]([CH3:42])(=[O:45])=[O:44])([CH2:21]3)[C@@H:19]2[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:17])[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H](c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N(C)C(=O)N1CC2C[C@@]2(CO)[C@@H]1c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N(C)C(=O)N1CC2C[C@@]2(COS(C)(=O)=O)[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
To a stirred solution of Intermediate 35, 4 isomers, one being (1S,2S)-1-Hydroxymethyl-2-phenyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid [(R)-1-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide (0.28 g, 0.57 mmol) and triethylamine (0.13 mL, 0.96 mmol) in methylene chloride (6 mL) at 0° C. was added methanesulfonyl chloride (0.06 mL, 0.79 mmol). The reaction was allowed to warm to room temperature and stir for 2 hours. The reaction was washed with cold 0.5N HCl and the phases separated. The methylene chloride was washed with cold 0.5N NaOH, washed with brine, and dried over sodium sulfate, filtered and concentrated to give the title compound as a pink foam (0.32 g, quantitative yield). This material was processed without further purification.