Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([NH2:13])=[O:12].[O-:14]CC.[Na+].[C:18]([OH:21])(=[O:20])[CH3:19].Cl>[Na].O.C(O)C>[NH2:13][C:11]([C:3]1[C:4]2[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=2[S:6][C:2]=1[NH:1][C:19](=[O:14])[C:18]([OH:21])=[O:20])=[O:12]
Reactant: NC(=O)c1c(N)sc2c1CCCC2
Reactant: CC[O-]
Reactant: CC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: NC(=O)c1c(NC(=O)C(=O)O)sc2c1CCCC2

Procedure:
A suspension of 392 g. (2.0 mole) of 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide and 321.2 g. (2.2 mole) of diethyl oxylate in 5 l. of absolute ethanol is added to a solution of sodium ethoxide, prepared from 50.6 g. (2.2 g. atoms) of sodium, in 2 l. of absolute ethanol under nitrogen. The mixture is stirred with heating at the reflux temperature for 6 hrs. and then refrigerated overnight. It is then diluted with stirring to 15 l. with cool water. A finely divided precipitate forms which is removed by filtration. The filtrate is carefully acidified with 150 g. (2.5 mole) of acetic acid dissolved in 350 ml. of water. The resulting product which precipitates is collected on a filter, washed with water and air dried to yield 194.6 g. (0.7 mole) of the product of Procedure 2. The filtrate is acidified to pH 2 with concentrated hydrochloric acid and the resulting precipitate is collected on a filter, washed with water and air dried to give 264.8 g. (0.99 mole) of the desired product. A portion thereof weighing 25 g. is recrystallized from 1.4 l. of dioxane, yield 18.2 g., m.p. 223.5°-224.5° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14]Br)=[N:10][N:9]([C:16]3[CH:17]=[C:18]([NH:22][C:23](=[O:25])[CH3:24])[CH:19]=[CH:20][CH:21]=3)[C:8]2=[O:26])=[CH:4][CH:3]=1.[I-:29].[Na+]>CC(C)=O.O>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14][I:29])=[N:10][N:9]([C:16]3[CH:17]=[C:18]([NH:22][C:23](=[O:25])[CH3:24])[CH:19]=[CH:20][CH:21]=3)[C:8]2=[O:26])=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: CC(=O)Nc1cccc(-n2nc(CBr)c(=O)n(Cc3ccc(Cl)cc3)c2=O)c1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)Nc1cccc(-n2nc(CI)c(=O)n(Cc3ccc(Cl)cc3)c2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
According to Scheme 7 Step 6: A mixture of N-(3-(4-(4-chlorobenzyl)-6-(bromomethyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide (200 mg, 0.43 mmol) and sodium iodide (97 mg, 0.65 mmol) in acetone (10 mL) was stirred overnight at room temperature. The mixture was diluted with water (100 mL) and the aqueous layer was extracted twice with 100 mL of DCM. The organic layer were combined and successively dried over MgSO4, filtered and concentrated under reduced pressure to afford N-(3-(4-(4-chlorobenzyl)-6-(iodomethyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide 14(A) (220 mg) as a white solid. The tittle product was used in the next reaction without any further purification.
Reaction SMILES: Cl[C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[N:17][N:18]([CH3:21])[C:19]=3[CH3:20])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[OH:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C.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>[CH3:21][N:18]1[C:19]([CH3:20])=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:3]3[C:2]([C:26]4[CH:27]=[CH:28][C:23]([OH:22])=[CH:24][CH:25]=4)=[N:7][CH:6]=[CH:5][N:4]=3)[CH2:9][CH2:10]2)[CH:16]=[N:17]1
Reactant: Cc1c(CN2CCN(c3nccnc3Cl)CC2)cnn1C
Reactant: OB(O)c1ccc(O)cc1
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: CC(=O)N(C)C
Solvent: O
Product: Cc1c(CN2CCN(c3nccnc3-c3ccc(O)cc3)CC2)cnn1C
Temperature: 25 °C
Yield: 85.6 %

Procedure:
Stir together 3′-chloro-4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (920 mg, 3.00 mmol), 4-(hydroxy)benzene boronic acid (497 mg, 3.6 mmol), potassium carbonate (996 mg, 7.2 mmol), tetrakis(triphenylphosphine)palladium(0) (0.018 g, 0.015 mmol) and water (6 mL) in N,N-dimethylacetamide (12 mL) at 120° C. for 5 hr. Cool to room temperature, add water (20 mL), extract with DCM (3×30 mL) and pass through an IST Phase Separator Frit®. Purify using SCX chromatography, eluting with 2.5 M ammonia in methanol and further purify using silica gel chromatography (eluting with 5:95 to 15:85 methanol:DCM). Concentrate and dry in a vacuum oven over night to give 4-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-phenol as a light yellow powder (936 mg, 86%). MS (ES): m/z=365 [M+H].
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Br.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:22]3[C:21](=[O:23])[NH:20][C:19]4[CH:24]=[C:25]([N:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)[CH:26]=[CH:27][C:18]=4[C:17]=3[C:16]3[C:34]([CH3:37])=[N:35][NH:36][C:15]=3[N:14]=2)=[CH:9][CH:8]=1>C1COCC1>[C:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:22]3[C:21](=[O:23])[NH:20][C:19]4[CH:24]=[C:25]([N:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)[CH:26]=[CH:27][C:18]=4[C:17]=3[C:16]3[C:34]([CH3:37])=[N:35][NH:36][C:15]=3[N:14]=2)=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Cc1n[nH]c2nc(-c3ccc(O)cc3)c3c(=O)[nH]c4cc(N5CCNCC5)ccc4c3c12
Agent: Br
Solvent: C1CCOC1
Product: CC(=O)Oc1ccc(-c2nc3[nH]nc(C)c3c3c2c(=O)[nH]c2cc(N4CCNCC4)ccc23)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 9.2 %

Procedure:
132 μl (1.84 mmol, 145 mg) of acetyl chloride is added in several portions to a suspension of 602 mg (1.18 mmol) of 5-(4-hydroxyphenyl)-1-methyl-9-(piperazin-1-yl)-3H-benzo[f]pyrazolo[3,4-c][2,7]naphthyridin-6(7H)-one hydrobromide in 120 ml of THF at 0° C. The mixture is then stirred for 48 hours at room temperature and then concentrated under reduced pressure. The residue is purified by reverse-phase preparative HPLC to yield 51 mg (8%) of 4-(1-methyl-6-oxo-9-(piperazin-1-yl)-6,7-dihydro-3H-benzo[f]pyrazolo[3,4-c][2,7]naphthyridin-5-yl)phenyl acetate in the form of a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C([O-])(O)=O.[Na+].Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1)=[O:26]>CC#N.C1COCC1>[N+:34]([C:31]1[CH:32]=[CH:33][C:28]([O:27][C:25]([NH:1][CH2:2][C@@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[CH2:4][CH:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[O:26])=[CH:29][CH:30]=1)([O-:36])=[O:35]
Reactant: CC(C)(C)OC(=O)N[C@H](CN)CC1CCCCC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@H](CNC(=O)Oc1ccc([N+](=O)[O-])cc1)CC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
To a stirred solution of (S)-tert-butyl 1-amino-3-cyclohexylpropan-2-ylcarbamate (0.65 g, 2.54 mmol) in MeCN (20 mL) and THF (5 mL) was added powdered NaHCO3 (0.43 g, 5.08 mmol) followed by a solution of p-nitrophenyl chloroformate (0.51 g, 5.08 mmol) in MeCN (20 mL) dropwise over 10 min. The mixture was stirred at rt for 2 h, filtered through a pad of Celite and concentrated to leave a white solid. This material was purified by chromatography on a 40-g silica cartridge eluted with a gradient from 0-100% EtOAc in hexanes to afford (S)-tert-butyl 1-(p-nitrophenoxycarbonylamino)-3-cyclohexylpropan-2-ylcarbamate (0.67 g, 67%) as an off-white solid.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:57][N:58]1[CH2:63][CH2:62][CH:61]([NH2:64])[CH2:60][CH2:59]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:64][CH:61]5[CH2:62][CH2:63][N:58]([CH3:57])[CH2:59][CH2:60]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-methylpiperidin-4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46-1.78 (m, 10H) 1.98 (m, 4H) 2.18 (s, 3H) 2.79 (d, J=11.4 Hz, 2H) 3.33 (s, 3H) 3.74 (m, 1H) 3.94 (s, 3H) 4.04 (t, J=14.0 Hz, 2H) 4.75 (q, J=7.9 Hz, 1H) 7.50 (s, 1H) 7.47 (d, J=1.5 Hz, 1H) 7.94 (s, 1H) 8.09 (d, J=7.8 Hz, 1H) 8.27 (d, J=8.1 Hz, 1H) 8.26 (s, 1H). [M+H] calc'd for C27H35F2N7O3, 544. found 544.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C@H:23]([OH:25])[CH3:24])[C:20](O)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[F:27][CH:28]1[CH2:31][NH:30][CH2:29]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.CN1CCOCC1>C(#N)C>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16](=[O:17])[NH:18][C@@H:19]([C:20]([N:30]3[CH2:31][CH:28]([F:27])[CH2:29]3)=[O:21])[C@H:23]([OH:25])[CH3:24])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: FC1CNC1
Reactant: C[C@@H](O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H](O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N1CC(F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.1 %

Procedure:
A 25 mL round-bottomed flask was charged with (2R,3R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-hydroxybutanoic acid (184 mg, 0.54 mmol), 3-fluoroazetidine hydrochloride (66 mg, 0.59 mmol), and HATU (242 mg, 0.64 mmol). Then added acetonitrile (1.1 mL) followed by N,N-diisopropylethylamine (0.20 mL, 1.1 mmol) and N-methylmorpholine (0.05 mL, 0.45 mmol). The reaction mixture was stirred at room temperature overnight then concentrated. The crude solid was purified by chromatography over SiO2 with EtOAc/heptane (gradient: 10-80% EtOAc) to afford 112 mg (52%) of [(1R,2R)-1-(3-fluoro-azetidine-1-carbonyl)-2-hydroxy-propyl]-carbamic acid 9H-fluoren-9-ylmethyl ester as a white solid. MS: [M+H]+=399.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:15]([O:17][C:18]([CH:20]1[NH:25][C:24](=[O:26])[CH:23]([CH2:27][CH:28]([CH3:30])[CH3:29])[N:22]([OH:31])[C:21]1=[O:32])=[O:19])[CH3:16]>CN(C)C=O.C(OCC)(=O)C>[CH2:7]([C:20]1([C:18]([O:17][CH2:15][CH3:16])=[O:19])[NH:25][C:24](=[O:26])[CH:23]([CH2:27][CH:28]([CH3:29])[CH3:30])[N:22]([O:31][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:21]1=[O:32])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)C1NC(=O)C(CC(C)C)N(O)C1=O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(Cc2ccccc2)NC(=O)C(CC(C)C)N(OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
7.60 g of potassium carbonate and 6.3 ml of benzyl chloride were added to 100 ml of a solution of 9.57 g of 3-ethoxycarbonyl-1-hydroxy-6-isobutylpiperazine-2,5-dione in anhydrous N,N-dimethylformamide, on ice-cooling. The mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with 450 ml of ethyl acetate, then washed three times with an aqueous solution saturated with sodium chloride, and dried with anhydrous magnesium sulfate. The resulting solution was subjected to distillation to remove the solvent. The residue was allowed to stand. The resulting crystals were collected by filtration and washed with methanol to obtain 4.51 g of (3RS,6SR)-3-benzyl-1-benzyloxy-3-ethoxycarbonyl-6-isobutylpiperazine-2,5-dione as colorless columnar crystals.
Reaction SMILES: [Na].[CH:2]1([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[C:15]([F:17])[CH:16]=[C:11]3[C:10]([C:18]#[N:19])=[N:9]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[C:20]([OH:23])(=[O:22])[CH3:21].[Cl-].[NH4+:25]>CO>[C:20]([OH:23])(=[O:22])[CH3:21].[CH:2]1([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[C:15]([F:17])[CH:16]=[C:11]3[C:10]([C:18](=[NH:25])[NH2:19])=[N:9]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [NH4+]
Reactant: N#Cc1nn(CC2CCCC2)c2ncc(F)cc12
Agent: [Cl-]
Agent: [Na]
Solvent: CC(=O)O
Solvent: CO
Product: N=C(N)c1nn(CC2CCCC2)c2ncc(F)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under an atmosphere of argon, 296 mg (12.861 mmol) of sodium were, a little at a time, stirred into methanol. After the sodium had been consumed, 3.670 g (purity 86%, about 12.861 mmol) of 1-(cyclopentylmethyl)-5-fluoro-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile were added a little at a time, and the mixture was stirred at RT for 2 h. 3.004 g (50.021 mmol) of acetic acid and 825 mg (15.433 mmol) of ammonium chloride were then added, and the mixture was boiled under reflux overnight. The reaction mixture was concentrated, the residue was triturated with 1N sodium hydroxide solution and the precipitate was filtered off with suction and dried under high vacuum. This gave 2.840 g (purity 98%, 83% of theory) of the target compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[N:3]=1.[CH:12]1([C:15]2[C:16]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[N:17][CH:18]=[C:19]([CH:21]3[CH2:23][CH2:22]3)[CH:20]=2)[CH2:14][CH2:13]1>>[Br:1][C:2]1[N:3]=[C:4]([CH3:11])[C:5]([C:6]([N:27]2[CH2:28][CH2:29][N:24]([C:16]3[C:15]([CH:12]4[CH2:13][CH2:14]4)=[CH:20][C:19]([CH:21]4[CH2:23][CH2:22]4)=[CH:18][N:17]=3)[CH2:25][CH2:26]2)=[O:8])=[CH:9][CH:10]=1
Reactant: Cc1nc(Br)ccc1C(=O)O
Reactant: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Product: Cc1nc(Br)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 56.3 %

Procedure:
Using 6-bromo-2-methylnicotinic acid (604 mg) and 1-(3,5-dicyclopropylpyridin-2-yl)piperazine (816 mg) described in Preparation Example 88 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (695 mg) was obtained.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13](=[O:24])[NH:14][CH:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH3:16])[CH:12]=1)[C:7](O)=[O:8])(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:58][O:59][C:60]1[CH:61]=[C:62]([CH:86]=[CH:87][CH:88]=1)[CH2:63][N:64]([CH2:72][C@@H:73]([OH:85])[C@@H:74]([NH2:84])[CH2:75][C:76]1[CH:81]=[C:80]([F:82])[CH:79]=[C:78]([F:83])[CH:77]=1)[C:65](=[O:71])[O:66][C:67]([CH3:70])([CH3:69])[CH3:68]>CN(C=O)C.C(OCC)(=O)C>[C:67]([O:66][C:65](=[O:71])[N:64]([CH2:72][C@@H:73]([OH:85])[C@@H:74]([NH:84][C:7](=[O:8])[C:6]1[CH:10]=[C:11]([C:13](=[O:24])[NH:14][CH:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH3:16])[CH:12]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=1)[CH2:75][C:76]1[CH:77]=[C:78]([F:83])[CH:79]=[C:80]([F:82])[CH:81]=1)[CH2:63][C:62]1[CH:86]=[CH:87][CH:88]=[C:60]([O:59][CH3:58])[CH:61]=1)([CH3:70])([CH3:68])[CH3:69]
Reactant: COc1cccc(CN(C[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)C(=O)OC(C)(C)C)c1
Reactant: CC(=O)c1cc(C(=O)O)cc(C(=O)NC(C)c2ccc(F)cc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(CN(C[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C(C)=O)cc(C(=O)NC(C)c3ccc(F)cc3)c2)C(=O)OC(C)(C)C)c1
Reaction time: 0.17 h
Yield: 78.1 %

Procedure:
A mixture of 3-acetyl-5-((1-(4-fluorophenyl)ethyl)carbamoyl)benzoic acid (from step 3, 85.0 mg, 0.257 mmol), HATU (117 mg, 0.309 mmol) and Hunig's base (133 mg, 0.2 mL, 1.029 mmol) in DMF (2.0 mL) was stirred for 10 min and then tert-butyl 3-methoxybenzyl((2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl)-carbamate (112 mg, 0.257 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with H2O (3 times). The organic layer was dried over sodium sulfate and concentrated under vacuum. The crude product was purified by reverse phase prep HPLC to give the title compound (150 mg): HPLC retention time: 2.265 min (method A). MS (ESI) (M+H)+ 748.47.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH3:4].CCN(C(C)C)C(C)C.[N:14]([C:17]([CH3:23])([CH3:22])[CH2:18][C:19](Cl)=[O:20])=[N+:15]=[N-:16]>C(Cl)Cl>[N:14]([C:17]([CH3:23])([CH3:22])[CH2:18][C:19]([N:2]([CH2:3][CH3:4])[CH3:1])=[O:20])=[N+:15]=[N-:16]
Reactant: CC(C)(CC(=O)Cl)N=[N+]=[N-]
Reactant: CCNC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(C)C(=O)CC(C)(C)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 89.4 %

Procedure:
To a stirred ice cold solution of N-methylethanamine (2.65 mL, 1 equiv, 30.9 mmol) and DIEA (7.0 mL, 1.3 equiv, 40.2 mmol) in anhydrous DCM (150 mL) was added 3-azido-3-methylbutanoyl chloride (5.0 g, 30.9 mmol) in small portions. The ice bath was removed and the reaction was stirred and left at room temperature for 3 h. The contents of the reaction were poured into a separatory funnel. The organic layer was washed with 1 M HCl (3×100 mL) and saturated NaHCO3 (2×100 mL). It was dried over anhydrous MgSO4, filtered, concentrated and dried under high vacuum to give a crude oil (7.14 g, 96.1%). This material was purified on an ISCO flash chromatography system with ethyl acetate and hexanes as eluent. The desired fractions were collected and concentrated to give a pale yellow oil (5.09 g, 89.4%). 1H NMR (CDCl3, 400 MHz): δ 1.42 (s, 6H), 2.40 (s, 2H), (dq, J=2.4 & 8.8, 2H). LRMS (ESI+) for C8H16N4O (184.1); Found: 185 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][CH:9]([OH:12])[C:8]2[CH:7]=[C:6]([N:13]=[N: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)[CH:5]=[CH:4][C:3]1=2.C(NCC)(C)C.[CH3:33][O:34][CH2:35]Cl>C(Cl)Cl>[CH3:26][C:2]1([CH3:1])[CH2:11][CH2:10][CH:9]([O:12][CH2:33][O:34][CH3:35])[C:8]2[CH:7]=[C:6]([N:13]=[N:14][C:15]3[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(N=Nc2ccc3c(c2)C(O)CCC3(C)C)cc1
Reactant: COCCl
Agent: CCNC(C)C
Solvent: ClCCl
Product: CCOC(=O)c1ccc(N=Nc2ccc3c(c2)C(OCOC)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (±) ethyl 4-[(5,5-dimethyl-8-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)azo]benzoate (Compound D5, 49.7 mg, 0.141 mmol) in 4 ml of dry CH2Cl2 at 0° C. was added isopropyl ethyl amine (0.152 ml, 0.847 mmol) followed by chloromethyl methyl ether (0.0323 ml, 0.423 mmol). The reaction mixture was stirred at room temperature for 12 h. Solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate and the solution was washed with NaHCO3 (sat.), and brine. The organic layer was dried (MgSO4). The solvent was removed under reduced pressure, the residue was purified by flash chromatography (silica, ethyl acetate:hexane, 1:3) to afford the title compound as a red oil.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1C[O:14]CC1.[CH2:16]([O:18][C:19](=[O:37])[CH2:20][C:21]1[C:22]([CH3:36])=[N:23][C:24]2[N:25]([N:28]=[C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:30]=2)[C:26]=1[I:27])[CH3:17].C1(C2ON2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>C1COCC1>[CH2:16]([O:18][C:19](=[O:37])[CH:20]([C:21]1[C:22]([CH3:36])=[N:23][C:24]2[N:25]([N:28]=[C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:30]=2)[C:26]=1[I:27])[OH:14])[CH3:17]
Reactant: C1CCOC1
Reactant: CCOC(=O)Cc1c(C)nc2cc(C(=O)OCC)nn2c1I
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Agent: [K+]
Product: CCOC(=O)c1cc2nc(C)c(C(O)C(=O)OCC)c(I)n2n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
To a stirred solution of 0.9M KHMDS/THF (39.1 mL, 35.2 mmol) in THF (100 mL) at −78° C. was added a THF (50 mL) solution of ethyl 6-(2-ethoxy-2-oxoethyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (11.3 g, 27.1 mmol) over 5 min. After 30 min, a THF (50 mL) solution of 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (9.20 g, 35.2 mmol) was added to the red reaction mixture and stirred for additional 30 min at −78° C. Then, the resulting orange reaction mixture was quenched with sat. NH4Cl (50 mL), diluted with EtOAc (200 mL), washed with water (100 mL), brine (100 mL), dried (Na2SO4), filtered and concentrated to give solid. This solid was triturated with small amount of ethyl acetate and solids were filtered, washed with hexanes and dried under high vac to afford ethyl 6-(2-ethoxy-1-hydroxy-2-oxoethyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (7.3 g, 16.85 mmol, 62.2% yield) as light yellow solid. 1H NMR (500 MHz, CDCl3) δ: 7.33 (s, 1H), 5.75 (d, J=2.1 Hz, 1H), 4.52 (qd, J=7.1, 1.2 Hz, 2H), 4.37-4.30 (m, 2H), 3.57 (d, J=2.4 Hz, 1H), 2.63 (s, 3H), 1.48 (t, J=7.2 Hz, 3H), 1.27 (t, J=7.0 Hz, 3H). LCMS (M+H)=434.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][N:6]([CH3:15])[C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)=[O:20].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH:19]([C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:18]=[CH:17][CH:16]=[C:4]([CH2:5][N:6]([CH3:15])[C:7](=[O:14])[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:3]=2)=[CH:23][CH:22]=1)=[O:20]
Reactant: CN(Cc1cccc(Br)c1)C(=O)c1ccccc1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CN(Cc1cccc(-c2ccc(C=O)cc2)c1)C(=O)c1ccccc1
Temperature: 90 °C

Procedure:
8.8 g (29 mmol) of N-(3-bromo benzyl)-N-methylbenzamide, 8.7 g (58 mmol) of 4-formylbenzene-boronic acid and 125 ml of toluene are introduced into a three-necked flask under argon. 36 ml (72 mmol) of aqueous potassium carbonate solution (2M) are added dropwise, the reaction medium is degassed with argon and 1 g of tetrakis(triphenylphosphine)palladium(0) chloride is added with heating at 90° C. for 24 hours. The reaction medium is poured into water and extracted with dichloromethane, and the organic phase is separated out after settling of the phases has taken place, dried over magnesium sulfate and evaporated. The residue obtained is purified by chromatography on a column of silica eluded with a mixture of heptane and ethyl acetate (50/50). After evaporation of the solvents, 7.2 g (75%) of the expected product are collected.
Reaction SMILES: C(OC(=O)C)(=O)C.[C:8]1(/[CH:14]=[C:15](\[CH2:19][C:20]([OH:22])=[O:21])/[C:16]([OH:18])=O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[C:8]1([CH:14]=[C:15]2[CH2:19][C:20](=[O:21])[O:22][C:16]2=[O:18])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)C/C(=C\c1ccccc1)C(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: O=C1CC(=Cc2ccccc2)C(=O)O1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2.3 l (approx. 2.49 kg, approx. 24.4 mol) of acetic anhydride are added at 20° C. to a solution of 2.28 kg (11.1 mol) of (E)-phenylitaconic acid in 5.7 l of THF. The mixture is stirred for 5 hours at room temperature. After 1 hour there is a clear light yellow solution; after 3 hours the product begins to crystallize out. The THF is removed under vacuum, 5.0 l of methyl tert-butyl ether are added to the residue in order to complete the crystallization, and the product is filtered off with suction. It is washed with MTB ether, dried with suction and dried under vacuum at 40° C. Yield: 1.68 kg (8.94 mol, 81% of theory), m.p. 167°-170° C.