Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[C:3]12([CH2:9][O:10][C:11]3[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=3)[CH2:8][CH:7]1[CH2:6][NH:5][CH2:4]2.[F:22][C:23]([F:34])([F:33])[C@H:24]1[CH2:29][CH2:28][C@H:27]([C:30](O)=[O:31])[CH2:26][CH2:25]1.N1C2C(=CC=CC=2)C=C1C(O)=O>>[F:22][C:23]([F:33])([F:34])[C@H:24]1[CH2:25][CH2:26][C@H:27]([C:30]([N:5]2[CH2:6][CH:7]3[C:3]([CH2:9][O:10][C:11]4[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=4)([CH2:8]3)[CH2:4]2)=[O:31])[CH2:28][CH2:29]1
Reactant: CCOC(=O)c1ncccc1OCC12CNCC1C2
Reactant: O=C(O)[C@H]1CC[C@H](C(F)(F)F)CC1
Agent: Cl
Agent: O=C(O)c1cc2ccccc2[nH]1
Product: CCOC(=O)c1ncccc1OCC12CC1CN(C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1)C2

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 1 using ethyl 3-(3-azabicyclo[3.1.0]hexan-1-ylmethoxy)picolinate dihydrochloride (EXAMPLE 88, Step 2) and trans-4-(trifluoromethyl)cyclohexanecarboxylic acid instead of (R)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride and indole-2-carboxylic acid.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[H-].[Na+].Cl[C:9]1[O:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1.O>CN(C)C=O>[O:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[O:4][CH2:3][CH2:2][CH2:1][OH:5]
Reactant: OCCCO
Reactant: Clc1nc2ccccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCCOc1nc2ccccc2o1

Procedure:
To a stirred solution of 1,3-propanediol (65 g) in dimethylformamide (60 ml) was added sodium hydride (3.0 g, 60% dispersion in oil) portionwise. The mixture was stirred until effervescence had ceased. A solution of 2-chlorobenzoxazole (11.4 g) in dimethylformamide (30 ml) was added dropwise. The reaction mixture was stirred at room temperature overnight. The mixture was added to water (600 ml) and extracted with ethyl acetate (3×300 ml). The combined organic extracts were washed with water (2×300 ml), brine (2×300 ml), dried (MgSO4), filtered and evaporated to dryness. The title compound was obtained as an oil following chromatography on silica gel in 3% methanol in dichloromethane.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][CH2:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)([CH3:12])[CH3:11])=[CH:4][C:3]=1C.ClC1N=NC(Cl)=CC=1[C:28]([NH2:30])=[O:29].FC1C=CC(C(C)(C)CN)=CC=1.C(N(C(C)C)CC)(C)C>CC#N>[Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][CH2:9][C:10]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)([CH3:11])[CH3:12])=[C:4]([C:28]([NH2:30])=[O:29])[CH:3]=1
Reactant: Cc1cc(NCC(C)(C)c2ccc(F)cc2)nnc1Cl
Reactant: NC(=O)c1cc(Cl)nnc1Cl
Agent: CC(C)(CN)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(CNc1nnc(Cl)cc1C(N)=O)c1ccc(F)cc1
Yield: 78 %

Procedure:
Using a similar procedure as was used for 6-chloro-N-(2-(4-fluorophenyl)-2-methylpropyl)-5-methylpyridazin-3-amine in example 14, 3,6-dichloropyridazine-4-carboxamide (2.6 g, 13 mmol, 1.0 equiv), (2-(4-fluorophenyl)-2-methylpropan-1-amine (2.5 g, 15 mmol, 1.1 equiv), and diisopropylethylamine (2.8 mL, 16 mmol, 1.2 equiv) in CH3CN (54 mL) was heated at 60-90° C. for 48 hours. The product was purified over silica gel with 100% EtOAc to give the desired product (3.4 g, 78%) as a yellow foamy solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:8][C:9]1[C:10](=[O:36])[CH:11]=[C:12]([C:15](=[O:35])[CH2:16][O:17][P:18]([OH:34])([N:20]2[C:23](=[O:24])[C@@H:22]([NH:25]C(=O)OC(C)(C)C)[C@@H:21]2[CH3:33])=[O:19])[NH:13][CH:14]=1.[K].C1(OC)C=CC=CC=1>ClCCl.C1(C)C=CC=CC=1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:25][C@@H:22]1[C:23](=[O:24])[N:20]([P:18]([O:17][CH2:16][C:15]([C:12]2[NH:13][CH:14]=[C:9]([OH:8])[C:10](=[O:36])[CH:11]=2)=[O:35])(=[O:19])[OH:34])[C@H:21]1[CH3:33]
Reactant: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1P(=O)(O)OCC(=O)c1cc(=O)c(O)c[nH]1
Agent: [K]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: C[C@H]1[C@H](N)C(=O)N1P(=O)(O)OCC(=O)c1cc(=O)c(O)c[nH]1
Reaction time: 0.05 h

Procedure:
Trifluoroacetic acid (3 ml) was added to a 5° C. stirred suspension of (2S-trans)-[1-[[2-(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)-2-oxoethoxy]hydroxyphosphinyl]-2-methyl-4-oxo-3-azetidinyl]carbamic acid, 1,1-dimethylethyl ester, monopotassium salt (375 mg) in 4 ml of dry dichloromethane containing 1 ml of anisole. After about three minutes, the solid dissolved and the mixture was stirred for 1.25 hours at 5° C. TLC indicated the reaction was essentially complete. Toluene (2 ml) was added and the mixture was concentrated in vacuo to a viscous brown oil. The oil was washed twice with hexane, then triturated with ether. The resultant solid was washed twice with ether and dried in vacuo to afford 0.437 g of crude title compound, which was used directly in the next step.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[N:8]=[CH:9][N:10]3[C@H:15]2[CH2:19][CH2:18][C@@H:17]([CH2:20][OH:21])[O:16]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:29](Cl)(=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>CN(C)C1C=CN=CC=1.C(#N)C>[CH:1]1([CH2:4][NH:5][C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[N:8]=[CH:9][N:10]3[C@H:15]2[CH2:19][CH2:18][C@@H:17]([CH2:20][O:21][C:29](=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[O:16]2)[CH2:2][CH2:3]1
Reactant: CCCCCC(=O)Cl
Reactant: OC[C@@H]1CC[C@H](n2cnc3c(NCC4CC4)ncnc32)O1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCC(=O)OC[C@@H]1CC[C@H](n2cnc3c(NCC4CC4)ncnc32)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.7 %

Procedure:
6-(Cyclopropylmethylamino)-9-[(2R,5S)-tetrahydro-5-(hydroxymethyl)-2-furyl]-9H-purine (0.503 g, 1.7 mmoles), triethylamine (2.0 mL, 14 mmoles, Aldrich Chemical Co., Madison, Wis.), and 4-dimethylaminopyridine (10 mg, 0.1 mmoles, Aldrich Chemical Co., Madison, Wis.) were dissolved in 50 mL acetonitrile. Hexanoyl chloride (980 μl, 7.0 mmoles, Aldrich Chemical Co., Madison, Wis.) was added and the reaction was stirred at room temperature for 3 hours. The reaction was quenched with methanol and solvents were evaporated in vacuo. The residue was dissolved in 25 mL ethyl acetate and undissolved salts were removed by filtration. After evaporation of the ethyl acetate, the residue was dissolved in methanol and passed over a silica gel column (4.8×13 cm). The product containing fractions were combined, concentrated, and chromatographed on a Chromatotron (4 mm silica gel plate) with a mixture of hexane:acetone (8:2). The product was further purified on the Chromatotron (2 mm silica gel plate) with a mixture of chloroform:acetone (99:1). Lyophilization afforded 0.268 g of 6-(cyclopropylmethylamino)-9-[(2R,5S)-5-[(hexanoyloxy)methyl]-tetrahydro-2-furyl]-9H-purine as an oil (40% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14](=[O:17])[N:15]=[N:16][C:12]3=[CH:11][C:10](=[O:18])[N:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:8]=2[CH:25]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14](=[O:17])[N:15]=[N:16][C:12]3=[CH:11][C:10](=[O:18])[N:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:8]=2[CH:25]=1
Reactant: [H][H]
Reactant: O=c1cc2nnc(=O)n-2c2ccc([N+](=O)[O-])cc2n1-c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2c(c1)n(-c1ccccc1)c(=O)cc1nnc(=O)n2-1

Procedure:
33.5 g of 8-nitro-6-phenyl-1H-s-triazolo[4,3-a] [1,5]-benzodiazepine-1,5-dione in 100 ml of ethanol containing 2.0 g of 10% palladium-on-charcoal is hydrogenated at room temperature at an initial hydrogen pressure of 50 p.s.i. The reaction is stopped when 0.3 moles of hydrogen has been absorbed; the suspension is filtered and the filtrate evaporated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([C:15]3([C:19]([OH:21])=[O:20])[CH2:18][CH2:17][CH2:16]3)[NH:8][CH2:7][CH2:6][C:5]2=1.[C:22](Cl)(=[O:24])[CH3:23]>>[C:22]([N:8]1[CH2:7][CH2:6][C:5]2[C:4]3[C:12](=[CH:13][CH:14]=[C:2]([Cl:1])[CH:3]=3)[NH:11][C:10]=2[CH:9]1[C:15]1([C:19]([OH:21])=[O:20])[CH2:16][CH2:17][CH2:18]1)(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: O=C(O)C1(C2NCCc3c2[nH]c2ccc(Cl)cc32)CCC1
Product: CC(=O)N1CCc2c([nH]c3ccc(Cl)cc23)C1C1(C(=O)O)CCC1

Procedure:
The procedure is as in Example 55, using as substrate the compound of Example 32 and as reagent acetyl chloride.
Reaction SMILES: C(O)COCCO.[OH-].[K+].[CH3:10][C:11]([CH3:20])([CH3:19])[C:12]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)=O.O.NN>Cl.O>[CH3:10][C:11]([CH3:20])([CH3:19])[CH2:12][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)C(=O)c1cccs1
Agent: Cl
Agent: NN
Agent: [K+]
Solvent: OCCOCCO
Solvent: O
Product: CC(C)(C)Cc1cccs1
Yield: 93.1 %

Procedure:
To 45 mL of diethylene glycol was added 5.04 g (90 mmol) of KOH, and the mixture was stirred until solution was complete. To this was added 5.05 g (30 mmol) of 2.2-dimethyl-1-thiophenyl-1-propanone (Lancaster Chemical Co.), and 3.75 g of hydrazine monohydrate, and the reaction was stirred at reflux for 48 hours. The solution was cooled, diluted with 100 mL of 1N HCl and 100 mL of water, and extracted with pentane. The extract was dried over MgSO4, filtered and concentrated to give 4.31 g of the title product. NMR (CDCl3) δ:0.95 (s, 9H), 2.70 (s, 2H), 6.75 (dd, 1H, J=1, J=4 Hz), 6.98 (dd, 1H, J=4, J=6 Hz), 7.12 (dd, 1H, J=1, J=6 Hz).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:18])[N:15]=[C:16]([CH3:17])[C:3]=12.[F-:19].[K+]>CN(C=O)C>[F:19][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:18])[N:15]=[C:16]([CH3:17])[C:3]=12
Reactant: Cc1nn(C)c2nnc(-c3ccccc3)c(Cl)c12
Reactant: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nn(C)c2nnc(-c3ccccc3)c(F)c12
Temperature: 120 °C
Reaction time: 16 h
Yield: 29.1 %

Procedure:
A suspension of 4-chloro-1,3-dimethyl-5-phenyl-pyrazolo[3,4-c]pyridazine (44 mg, 0.17 mmol), potassium fluoride (50 mg, 0.85 mmol) in dry DMF (1 mL) was stirred at 120° C. for 16 h. The reaction mixture was purified by preparative HPLC to provide Compound 24 (12 mg).
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[CH3:8][CH:9]([CH3:26])[C:10]([O:12][CH2:13][CH2:14][O:15][C:16](ON1C(=O)CCC1=O)=[O:17])=[O:11]>>[OH:4][CH2:3][C@@H:2]([NH:1][C:16]([O:15][CH2:14][CH2:13][O:12][C:10](=[O:11])[CH:9]([CH3:8])[CH3:26])=[O:17])[C:5]([OH:7])=[O:6]
Reactant: CC(C)C(=O)OCCOC(=O)ON1C(=O)CCC1=O
Reactant: N[C@H](CO)C(=O)O
Product: CC(C)C(=O)OCCOC(=O)N[C@H](CO)C(=O)O
Yield: 40.3 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, D-serine (252 mg, 2.4 mmol) and (2,5-dioxoazolidinyloxycarbonyloxy)ethyl 2-methylpropanoate (546 mg, 2.0 mmol) were reacted to provide 212 mg (40% yield) of the title compound (29) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (CDCl3, 400 MHz): δ=6.79 (m, 1H), 6.03 (t, 0.2H), 5.58 (br s, 1H), 4.41 (m, 1H), 4.05 (m, 1H), 3.94 (m, 1H), 2.57 (m, 1H), 1.48 (2d, 3H), 1.19 (2d, 6H). MS (ESI) m/z 281.11 (M+NH4)+; 286.11 (M+Na)+; 262.12 (M−H)−.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][O:11][NH:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[C:16]=1[NH:23][C:24]1[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=1[F:31])=[O:14])C)(C)(C)C.[ClH:33]>>[ClH:33].[F:22][C:17]1[C:16]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=2[F:31])=[C:15]([CH:20]=[CH:19][C:18]=1[F:21])[C:13]([NH:12][O:11][CH2:10][CH2:9][NH:7][CH3:6])=[O:14]
Reactant: CN(CCONC(=O)c1ccc(F)c(F)c1Nc1ccc(I)cc1F)C(=O)OC(C)(C)C
Agent: Cl
Product: CNCCONC(=O)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reaction time: 0.33 h
Yield: 85 %

Procedure:
[2-({1-[3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-phenyl]-methanoyl}-aminooxy)-ethyl]-methyl-carbamic acid tert-butyl ester (3.28 g, 5.80 mmol) was dissolved in ethereal hydrogen chloride solution (20 mL, 1.0 M in diethyl ether). The resultant solution was stirred at ambient temperature for 48 h, during which precipitation of a white solid ensued. Hexanes (20 mL) was added and the reaction mixture was stirred vigorously for an additional 20 min. The reaction mixture was filtered, and the filter cake was broken up with a spatuala. The solid was washed with hexanes (50 mL) and ether (20 mL) and was dried in vacuo to afford a free-flowing, tan-colored powder (2.46 g, 85% yield). Recrystallization from acetonitrile afforded colorless needles: m.p. 173-176° C.; 1H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H), 8.76 (br s, 2H), 8.64 (s, 1H), 7.55 (dd, J=11.0, 1.9 Hz, 1H), 7.47 (dd, J=7.1, 6.3 Hz, 1H), 7.33 (d, J=8.3 Hz, 1H), 7.23 (dt, J=7.6, 9.2 Hz, 1H), 6.64 (td, J=8.8, 4.2 Hz, 1H), 4.05 (t, 4.9 Hz, 2H), 3.11 (br s, 2H), 2.56 (t, J=4.6 Hz, 3H); 19F NMR (376 MHz, DMSO-d6) δ −128.2 (t, J=10.1 Hz), −132.5 (d, J=20.2 Hz), −144.0 (d, 20.2 Hz). Anal Calcd./Found for C16H16F3IN3O2Cl: C, 38.31/38.20; H, 3.21/3.10; N, 8.38/8.34; F, 11.36/11.21; Cl, 7.07/7.05.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]1[CH:9]=[C:10]([CH:17]=[C:18]([F:20])[CH:19]=1)[O:11][CH2:12][CH2:13][C:14]([OH:16])=O.[Cl-].[Cl-].[Cl-].[Al+3].Cl>ClCCl.CN(C=O)C>[F:20][C:18]1[CH:19]=[C:8]([F:7])[CH:9]=[C:10]2[C:17]=1[C:14](=[O:16])[CH2:13][CH2:12][O:11]2
Reactant: O=C(O)CCOc1cc(F)cc(F)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1CCOc2cc(F)cc(F)c21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.5 ml of DMF and 7.35 ml (84.29 mmol) of oxalyl chloride were slowly added dropwise to a solution of 11.36 g (42.15 mmol) of the compound from Example 169A in 400 ml of dichloromethane at RT. After stirring at RT for 3 h, the solvents were removed in a rotary evaporator, and the residue was again taken up in 200 ml of dichloromethane. 6.74 g (50.57 mmol) of aluminum trichloride were added in portions to the reaction mixture, and the mixture was stirred for 1 h. 150 ml of 2N hydrochloric acid and 200 ml of dichloromethane were added, the phases were separated, and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate and filtered, and the solvents were removed in vacuo. The crude product was purified by flash chromatography on silica gel (mobile phase: dichloromethane). 6.46 g (80% of theory) of the title compound were obtained.
Reaction SMILES: [N:1]1[CH2:2][CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[NH2:8].Cl.C1(=O)NCCCCC1.C(=O)([O-])[O-].[K+].[K+].[N:24]1[CH:29]=[CH:28][C:27]([C:30](=O)[CH2:31][C:32](OCC)=[O:33])=[N:26][CH:25]=1>C(O)C>[N:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:8]=[C:7]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:1]3[C:32](=[O:33])[CH:31]=2)=[N:26][CH:25]=1
Reactant: NC1=NCC=CC=C1
Reactant: CCOC(=O)CC(=O)c1ccncn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=C1CCCCCN1
Solvent: CCO
Product: O=c1cc(-c2ccncn2)nc2n1CCCCC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 28.7 %

Procedure:
To a suspension of 77.9 g (524.1 mmol) of 2H-azepin-7-amine, 3,4,5,6-tetrahydro, monohydrochloride (synthesis as described in WO96/14844 or Journal of Medicinal Chemistry (1998), 41(9), 1361-1366 or by analogy with the method described in example 1, step 1.1. and 1.2 using ε-caprolactam instead of (+/−)-3-phthalimidopiperidin-2-one) in 390 mL of ethanol was added 72.4 g (524.1 mmol) of potassium carbonate. The reaction mixture was stirred at room temperature for 10 min, 101.7 g (524.1 mmol) of ethyl 3-(4-pyrimidinyl)-3-oxopropionate was added and the resulting mixture was stirred under reflux for 16 h. The cooled solution was evaporated to remove solvent. The mixture was dissolved in dichloromethane, washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated to dryness. The residue was filtrate through a pad of silica, rinsing with dichloromethane and then ethyl acetate. After evaporation, the resulting solid was triturated with diethyl ether to afford 36.4 g (28%) of pure product as a white-brown powder.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1([C:22]2[C:26]([C:27]([O:29]CC)=[O:28])=[CH:25][NH:24][N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H-].[Na+].[Cl-].[Na+].[OH-].[K+]>CN(C)C=O.C(O)C>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][N:24]1[CH:25]=[C:26]([C:27]([OH:29])=[O:28])[C:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:23]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1cccc(Oc2ccccc2)c1
Reactant: CCOC(=O)c1c[nH]nc1-c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C(O)c1cn(Cc2cccc(Oc3ccccc3)c2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 77.3 %

Procedure:
3-Phenoxybenzyl chloride (11.32 g) and ethyl 3-phenyl-1H-pyrazole-4-carboxylate (11.30 g) were dissolved in N,N-dimethylformamide (100 ml). Sodium hydride (60%, oily, 2.49 g) was added to the solution at 0° C., and the solution was stirred at room temperature for 20 hours. The reaction mixture was poured into saturated aqueous sodium chloride solution, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatograpy, and an oily substance was obtained from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). A mixture of the oily substance obtained, potassium hydroxide (8.53 g) and ethanol (150 ml) was refluxed for 5 hours. After the reaction solvent was removed under reduced pressure, water was added to the mixture, then the mixture was acidified using 1N hydrochloric acid. The colorless crystals obtained were collected by filtration to yield 1-(3-phenoxybenzyl)-3-phenyl-1H-pyrazole-4-carboxylic acid (14.83 g, yield: 77%). This was recrystallized from acetone-hexane. Melting point: 148–149° C.
Reaction SMILES: C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH2:50][F:51])[CH2:11][O:12]2)C1C=CC=CC=1.C(OCC)(=O)C>C(O)C.O1CCCC1.[Pd]>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@@:10]([CH2:50][F:51])([CH2:11][O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH3:49])=[CH:45][CH:46]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](CF)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](CF)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59.2 %

Procedure:
To a suspension of (1S,2S,3S,4R,5S)-2,3,4-tris-benzyloxy-5-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-1-fluoromethyl-6,8-dioxa-bicyclo[3.2.1]octane (40 mg, 0.06 mmol) and palladium black (40 mg, 0.38 mmol, Aldrich® high surface area) in ethanol (0.5 mL) and tetrahydrofuran (0.1 mL) was added fomic acid (0.085 mL, 2.24 mmol) and the resulting mixture was stirred at room temperature for 1.5 hours. Ethyl acetate was added and the mixture was filtered through a short pad of Celite® and concentrated in vacuo. The crude material was purified by flash chromatography over silica gel using a 4 g redisep silica cartridge (eluting with a gradient of 50 to 100% ethyl acetate in heptane) to afford the title compound as a solid (15.6 mg, 63% yield). (LCMS) 483.0 (M+HCOO−: negative mode). 1H NMR (500 MHz, METHANOL-d4) delta ppm 7.44 (s, 1 H), 7.38 (s, 1 H), 7.37 (s, 1 H), 7.09-7.12 (m, 2 H), 6.80-6.83 (m, 2 H), 4.71 (dd, J=46.59, 10.49 Hz, 1 H), 4.50 (dd, J=48.30, 10.73 Hz, 1 H), 4.19 (dd, J=7.56, 0.98 Hz, 1 H), 4.04 (d, J=0.98 Hz, 2 H), 4.00 (q, J=6.99 Hz, 2 H), 3.80 (dd, J=8.29, 0.98 Hz, 1 H), 3.67 (t, J=8.17 Hz, 1 H), 3.54-3.57 (m, 2 H), 1.37 (t, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:26]C)=[C:6]2[C:10]=1[N:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17]CC3C=CC=CC=3)=[C:13]([F:25])[CH:12]=1)[N:8]=[CH:7]2.B(Br)(Br)Br>Br.C(OCC)(=O)C.C([O-])(O)=O.[Na+].O>[Cl:1][C:2]1[C:10]2[N:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:25])[CH:12]=3)[N:8]=[CH:7][C:6]=2[C:5]([OH:26])=[CH:4][CH:3]=1
Reactant: COc1ccc(Cl)c2c1cnn2-c1ccc(OCc2ccccc2)c(F)c1
Agent: Br
Agent: BrB(Br)Br
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: O
Product: Oc1ccc(-n2ncc3c(O)ccc(Cl)c32)cc1F
Temperature: -78 °C
Reaction time: 2 h
Yield: 23.1 %

Procedure:
A mixture of 7-chloro-1-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}-4-(methyloxy)-1H-indazole (D29) (2.41 g, 6.30 mmol) in 48% hydrobromic acid (120 mL) was heated to reflux and reaction was followed by LC-MS. After 2 hrs, the mixture was concentrated to ˜30 mL on the rotary evaporator and then solid NaHCO3 was added to pH 6. The product was extracted into ethyl acetate and the extracts were dried (Na2SO4) and concentrated. This product was dissolved in dichloromethane (60 mL) and cooled to −78° C. under argon and boron tribromide (2.381 mL, 25.2 mmol) was added dropwise via syringe. After 10 mins at −78° C., the mixture was allowed to reach room temperature and stirring was continued for 24 hrs. The mixture was diluted with ethyl acetate and NaHCO3/water and the pH adjusted to 6 and the product was extracted into ethyl acetate. The extracts were dried (Na2SO4), concentrated and chromatographed (silica, 10% methanol in dichloromethane to crude product that was recolumned by 0-100% ethyl acetate in hexane) to give the title compound as an off-white powder (405 mg) (E14).
Reaction SMILES: Cl[CH2:2][C@H:3]([OH:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7](/[CH:11]=[CH:12]/[C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])[CH:6]=1.[Na+].[I-].[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C=O)C>[N:24]([CH2:2][C@H:3]([OH:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7](/[CH:11]=[CH:12]/[C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])[CH:6]=1)=[N+:25]=[N-:26]
Reactant: O[C@@H](CCl)Cc1cccc(/C=C/c2c(Cl)cccc2Cl)c1
Reactant: [N-]=[N+]=[N-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@H](O)Cc1cccc(/C=C/c2c(Cl)cccc2Cl)c1
Temperature: 75 °C

Procedure:
To a solution of (R,E)-1-chloro-3-(3-(2,6-dichlorostyryl)phenyl)propan-2-ol (0.67 g, 1.96 mmol) in DMF (20 mL) was added NaI (˜25 mg, 0.16 mmol) and NaN3 (0.64 g, 9.8 mmol) and the reaction mixture was heated at 75° C. overnight. After cooling to room temperature, the mixture was partitioned between EtOAc and water. The combined organics were washed with water, 5% aqueous LiCl and brine, filtered through Na2SO4 and concentrated under reduced pressure to give (R,E)-1-azido-3-(3-(2,6-dichlorostyryl)phenyl)propan-2-ol. This material was used in the next synthetic step without purification.
Reaction SMILES: [CH:1]12[C:10](=[O:11])O[C:7](=[O:8])[CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[NH3:12]>>[CH:1]12[C:10](=[O:11])[NH:12][C:7](=[O:8])[CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2
Reactant: O=C1OC(=O)C2CCCCC12
Reactant: N
Product: O=C1NC(=O)C2CCCCC12
Reaction time: 2 h

Procedure:
A mixture of cyclohexane-1,2-dicarboxylic anhydride (3 g; 19.5 mmol) and 29% aqueous ammonia (3.4 g) was heated to and kept at an inner temperature of 180 to 190° C. for 2 hours to give the objective compound quantitatively. M.P., 132°-136° C.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH:30]([CH3:32])[CH3:31])[N:5]([C:24](=[O:29])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]2[NH:23][N:22]=[N:21][N:20]=2)=[CH:9][CH:8]=1.[BH4-].[Li+]>>[NH:23]1[C:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:10]2[CH:11]=[CH:12][C:7]([CH2:6][N:5]([C:24](=[O:29])[CH2:25][CH2:26][CH2:27][CH3:28])[C@H:4]([CH2:3][OH:2])[CH:30]([CH3:31])[CH3:32])=[CH:8][CH:9]=2)=[N:20][N:21]=[N:22]1
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)OC)C(C)C
Agent: [BH4-]
Agent: [Li+]
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](CO)C(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.8 g of N-valeryl-N-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-(L)-valine methyl ester is dissolved in 30 ml of ThF, treated at 5° C. with 83 mg of lithium borohydride and stirred at room temperature for 24 h. The reaction mixture is then concentrated, treated with water and adjusted to pH 2 with hydrochloric acid, a white precipitate forming. The mixture is extracted with ethyl acetate, washed with water and brine, dried and finally separated by means of flash chromatography (CH2Cl2 --MeOH 5:1). FAB-MS: m/e=422 (M+H)+.