Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([N:30]1[CH2:29][CH2:28][CH:27]([NH:26][C:24]([C:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([C:8]4[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:15]=3[NH:22][C:21]=2[CH3:23])=[O:25])[CH2:32][CH2:31]1)(=[O:35])[CH3:34]
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)NC1CCNCC1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f6) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23](OC)=[O:24])=[CH:18][C:17]=3[Cl:27])=[CH:12][CH:11]=2)[C:7]([CH3:28])=[N:6][C:5]=1[CH3:29])(=[O:3])[NH2:2].[NH3:30]>>[NH2:30][C:23](=[O:24])[CH2:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[CH:14]=[CH:15][C:10]([C:8]3[N:9]=[C:4]([C:1]([NH2:2])=[O:3])[C:5]([CH3:29])=[N:6][C:7]=3[CH3:28])=[CH:11][CH:12]=2)=[C:17]([Cl:27])[CH:18]=1
Reactant: COC(=O)Cc1ccc(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2)c(Cl)c1
Reactant: N
Product: Cc1nc(C)c(-c2ccc(-c3ccc(CC(N)=O)cc3Cl)cc2)nc1C(N)=O
Temperature: 140 °C
Yield: 27.4 %

Procedure:
Methyl 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetate (Intermediate 1-1; 60 mg, 0.15 mmol) and ammonia (7M in methanol) (2091 μL, 14.64 mmol) were sealed into a microwave tube. The reaction was heated to 140° C. for 1 hour in the microwave reactor and cooled to RT. Removal of the solvent under reduced pressure gave crude product. The crude product was purified by preparative HPLC (Waters—Xbridge Prep C18 5 μm), using decreasingly polar mixtures of water (containing 0.1% formic acid) and {MeOH(3):MeCN(1)} as eluents. Fractions containing the desired compound were evaporated to dryness to afford 6-(4′-(2-amino-2-oxoethyl)-2′-chlorobiphenyl-4-yl)-3,5-dimethylpyrazine-2-carboxamide (16.20 mg, 28.0%) as a colourless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([O:14][CH2:15][C@H:16]2[CH2:18][O:17]2)[C@H:11]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH3:38])=[CH:21][CH:20]=2)[C@@H:10]([O:39][CH2:40][C:41]2[CH:50]=[C:49]([O:51][CH3:52])[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH:42]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+]>COCCO>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@H:10]([O:39][CH2:40][C:41]2[CH:50]=[C:49]([O:51][CH3:52])[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH:42]=2)[C@@H:11]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH3:38])=[CH:21][CH:20]=2)[C@H:12]([O:14][CH2:15][C@H:16]([OH:17])[CH2:18][O:17][CH2:16][CH2:15][O:14][CH3:12])[CH2:13]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1ccccc1COCCCOc1ccc([C@@H]2[C@@H](OCc3cc(OC)c4ccccc4c3)CN(C(=O)OC(C)(C)C)C[C@H]2OC[C@H]2CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCO
Product: COCCOC[C@@H](O)CO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](OCc2cc(OC)c3ccccc3c2)[C@H]1c1ccc(OCCCOCc2ccccc2OC)cc1

Procedure:
In analogy to the procedure described in example 1 (k) the (3R,4R,5S)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-(4-methoxy-naphthalen-2-ylmethoxy)-5-[(2R)-oxiranylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester was treated with sodium 2-methoxy-ethylate (prepared from 2-methoxy-ethanol and sodium hydride) to give the (3S,4R,5R)-3-[(2R)-2-hydroxy-3-(2-methoxy-ethoxy)-propoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester as colorless oil; MS: 790.4 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=O)[NH:12]3)[CH2:10][CH:9]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[O:8][C:5]2=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=[S:32])[NH:12]3)[CH2:10][CH:9]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1NC(=O)C2(CC(c3cccs3)Oc3ccc(Br)cc32)N1
Solvent: C1COCCO1
Product: O=C1NC(=S)NC12CC(c1cccs1)Oc1ccc(Br)cc12
Yield: 70.9 %

Procedure:
A suspension of 6-bromo-2-(thiophen-2-yl)spiro[chroman-4,4′-imidazolidine]-2′,5′-dione (135 mg, 0.357 mmol) and Lawesson's Reagent (144.3 mg, 0.357 mmol) in anhydrous 1,4-dioxane (4 mL) was heated under reflux for 24 h. The mixture was concentrated in vacuo and the residue was purified by preparative TLC to give 6-bromo-2-(thiophen-2-yl)-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (100 mg, 80%). 1H-NMR (CDCl3): 2.41 (m, 1H), 2.55 (dd, 1H), 6.04 (dd, 1H), 6.80 (d, 1H), 6.94 (t, 1H), 7.12 (d, 1H), 7.33 (m, 3H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][N:6]([CH:8]2[CH2:11][O:10][CH2:9]2)[CH:5]([CH3:12])[CH2:4][N:3]1[C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]2[C:25](=[O:26])[N:24]([CH3:27])[CH:23]=[C:22]([C:28]3[C:33]([CH:34]=[O:35])=[C:32]([N:36]4[CH2:48][CH2:47][C:46]5[N:45]6[C:40]([CH2:41][CH2:42][CH2:43][CH2:44]6)=[CH:39][C:38]=5[C:37]4=[O:49])[N:31]=[CH:30][CH:29]=3)[CH:21]=2)=[N:17][CH:18]=1.[BH4-].[Na+]>CO>[CH3:1][C@H:2]1[CH2:7][N:6]([CH:8]2[CH2:11][O:10][CH2:9]2)[C@H:5]([CH3:12])[CH2:4][N:3]1[C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]2[C:25](=[O:26])[N:24]([CH3:27])[CH:23]=[C:22]([C:28]3[CH:29]=[CH:30][N:31]=[C:32]([N:36]4[CH2:48][CH2:47][C:46]5[N:45]6[C:40]([CH2:41][CH2:42][CH2:43][CH2:44]6)=[CH:39][C:38]=5[C:37]4=[O:49])[C:33]=3[CH2:34][OH:35])[CH:21]=2)=[N:17][CH:18]=1
Reactant: CC1CN(C2COC2)C(C)CN1c1ccc(Nc2cc(-c3ccnc(N4CCc5c(cc6n5CCCC6)C4=O)c3C=O)cn(C)c2=O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@@H]1CN(c2ccc(Nc3cc(-c4ccnc(N5CCc6c(cc7n6CCCC7)C5=O)c4CO)cn(C)c3=O)nc2)[C@@H](C)CN1C1COC1
Reaction time: 0.5 h
Yield: 40.1 %

Procedure:
To a solution of 155b (80 mg, 0.12 mmol) at 0° C. in methanol (5 mL) was added sodium borohydride (12 mg, 0.36 mmol). The reaction mixture was stirred for 30 minutes. It was then quenched with water (1 mL) and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 155 (32 mg, 40%). MS-ESI: [M+H]+665.3. 1H NMR (500 MHz, CDCl3) δ 8.68 (d, J=2.0 Hz, 1H), 8.50 (d, J=5.0 Hz, 1H), 8.04 (d, J=2.5 Hz, 1H), 7.88 (s, 1H), 7.86 (d, J=2.5 Hz, 1H), 7.37-7.33 (m, 2H), 6.82 (d, J=9.0 Hz, 1H), 6.32 (s, 1H), 5.02 (d, J=13.0 Hz, 1H), 4.78-4.71 (m, 2H), 4.67-4.61 (m, 3H), 4.44-4.39 (m, 1H), 4.31-4.29 (m, 1H), 3.96-3.91 (m, 1H), 3.86-3.80 (m, 2H), 3.78-3.75 (m, 1H), 3.72 (s, 3H), 3.21-3.19 (m, 1H), 3.01-2.93 (m, 3H), 2.85-2.83 (m, 2H), 2.72 (d, J=10.0 Hz, 2H), 2.49-2.47 (m, 1H), 2.05-2.03 (m, 2H), 1.98-1.97
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH:6]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C.[Pd]>[CH2:6]([C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][C:9]=1[C:8]([OH:12])=[O:7])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccc2c(c1)C(c1ccccc1)OC2=O
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C(=O)O)c(Cc2ccccc2)c1
Reaction time: 18 h
Yield: 91 %

Procedure:
To a solution of 9 (12.0 g, 50 mmol) in ethanol was added 10% palladium on carbon (1.5 g). The resulting suspension was hydrogenated at 60 psi for 18 h. Filtration through celite followed by removal of the solvent in vacuo gave 10 as a white solid (11.0 g, 45.5 mmol, 91.1%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:8].[CH:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)=[O:10].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1.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>[CH:9]([C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[Cl:8])=[CH:13][CH:12]=1)=[O:10]
Reactant: Clc1ccccc1Br
Reactant: O=Cc1ccc(B(O)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: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=Cc1ccc(-c2ccccc2Cl)cc1

Procedure:
To a solution of 2-bromochlorobenzene (0.24 mL, 2 mmol) and 4-formylbenzeneboronic acid (0.35 g, 2.2 mmol) in toluene (20 mL) were added 2M aq. sodium carbonate (2.6 mL) followed by (Ph3P)4Pd (0.34 g, 0.3 mmol). The resulting reaction mixture was refluxed for 3 h, cooled and diluted ethyl acetate. The organic phase was washed with water, saturated aq. sodium bicarbonate, brine and dried over sodium sulfate. The filtrate was concentrated in vacuo and the residue obtained was purified by chromatography (hexane:ethyl acetate; 4:1) to yield the title product.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([C:21](OC)=[O:22])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>C1COCC1.C(OCC)(=O)C.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>[Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([CH2:21][OH:22])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Temperature: -78 °C
Yield: 106.5 %

Procedure:
1-tert-Butyl 2-methyl (2S,4R)-4-{[tert-butyl(dimethyl)silyl]-oxy}pyrrolidine-1,2-dicarboxylate (5.00 g, 13.91 mmol) was dissolved in dry THF (50 mL) under nitrogen and cooled to −78° C. Diisobutylaluminum hydride solution (31.0 mL, 31.0 mmol, 1.0 M in toluene) was added dropwise over 30 minutes. After stirring for ten minutes, the mixture was slowly warmed to room temperature at which point TLC indicated complete conversion. The mixture was diluted with ethyl acetate (200 mL) and saturated aqueous sodium potassium tartrate (200 mL). The mixture was stirred vigorously for 30 minutes until two phases were apparent. The aqueous layer was then extracted twice with ethyl acetate and washed with brine. The organic layer was dried over MgSO4, filtered and concentrated to give 4.91 g of the crude alcohol as a pale yellow oil. LC/MS (M-Boc+H)+ m/z=232.2. 1H NMR (CDCl3) δ 4.88 (d, 1H), 4.27 (bs, 1H), 4.14 (m, 1H), 3.69 (t, 1H), 3.54 (m, 1H), 3.42 (d, 1H), 3.34 (dd, 1H), 1.96 (m, 1H), 1.58 (m, 1H), 1.47 (s, 9H), 0.87 (s, 9H), 0.06 (s, 6H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19](B4OC(C)(C)C(C)(C)O4)=[CH:18][CH:17]=3)[CH2:14][CH2:13][CH:12]2[C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:41]1[N:42]=[C:43]([C@@H:46]2[CH2:50][CH2:49][CH2:48][N:47]2[C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[NH:44][CH:45]=1.C(O)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH:12]([C:31]3[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=3)[CH2:13][CH2:14][CH:15]2[C:16]2[CH:21]=[CH:20][C:19]([C:45]3[N:44]=[C:43]([C@@H:46]4[CH2:50][CH2:49][CH2:48][N:47]4[C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[NH:42][CH:41]=3)=[CH:18][CH:17]=2)=[CH:9][CH:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(Br)c[nH]1
Reactant: CC(C)(C)c1ccc(N2C(c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)CCC2c2ccc([N+](=O)[O-])cc2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(C3CCC(c4ccc([N+](=O)[O-])cc4)N3c3ccc(C(C)(C)C)cc3)cc2)c[nH]1
Yield: 78.1 %

Procedure:
The product from Example 40B (0.7 g, 1.33 mmol), (S)-tert-butyl 2-(4-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (0.462 g, 1.463 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.109 g, 0.133 mmol) in a mixture of toluene (6 mL), ethanol (6 mL) and a 1N aq. sodium bicarbonate solution (1.6 mL, 1.6 mmol) was reacted according to the procedure in Example 39F to provide the title compound (0.66 g, 78%, yellow solid) as a mixture of stereoisomers.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:31](O)[CH2:32][OH:33]>C1(C)C=CC=CC=1.C(OC(=O)C)C>[CH3:1][C:2]1[CH:3]=[C:4]([O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]3[O:33][CH2:32][CH2:31][O:17]3)=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: OCCO
Reactant: Cc1cc(Oc2ccc(C=O)cc2)ccc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc(Oc2ccc(C3OCCO3)cc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 98 %

Procedure:
4-[(3-Methyl-4-nitrophenyl)oxy]benzaldehyde (1.72 g, 6.4 mmol), p-toluenesulfonic acid (120 mg, 0.64 mmol), and ethylene glycol (1.7 mL, 32 mmol) were heated to reflux in 70 mL toluene for 16 hours in a round bottom flask equipped with a Dean-Stark trap. The reaction mixture was cooled to room temperature, diluted with ethylacetate and extracted with 1N NaOH. The organic layer was dried over MgSO4, filtered and concentrated to afford 1.89 g crude 2-{4-[(3-methyl-4-nitrophenyl)oxy]phenyl}-1,3-dioxolane, which was used without further purification.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4](=[O:18])[CH:5]([NH:10][C:11](=[O:17])[CH:12]([NH3+:16])[CH2:13][C:14]#[CH:15])[CH2:6][CH:7]([CH3:9])[CH3:8].CCN(C(C)C)C(C)C.[CH2:28]([O:35][C:36](Cl)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[CH2:28]([O:35][C:36]([NH:16][CH:12]([CH2:13][C:14]#[CH:15])[C:11]([NH:10][CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([O:3][CH3:2])=[O:18])=[O:17])=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C#CCC([NH3+])C(=O)NC(CC(C)C)C(=O)OC
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C#CCC(NC(=O)OCc1ccccc1)C(=O)NC(CC(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
To a solution of compound 2 (8.5 g; 31 mmol) in dry THF (100 mL) was added DIEA (16.02 g; 124 mmol) and the reaction mixture was stirred for 30 min at room temperature. Benzylchloroformate (6.87 g; 40.3 mmol) was added and stirring was continued at room temperature for 16 h. The solvent was removed on the rotary evaporator and the residue was taken up in ethyl acetate (150 mL) and washed sequentially with water (50 mL), 5% HCl (2×50 mL), and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give 3 as a white solid (10.46 g: 90% yield). 1H NMR (CDCl3) δ 7.3 (m, 5H), 6.7 (s, 1H), 5.6 (s, 1H), 5.1 (s, 2H), 4.6 (m, 1H), 4.4 (m, 1H), 3.7 (s, 3H), 2.6 (m, 2H), 2.8 (s, 1H), 2.6 (m, 1H), 1.6 (m, 2H), 1.5 (m, 1H), 0.9 (d, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].[IH:10].C([O-])(O)=O.[Na+]>>[I:10][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[NH2:9]
Reactant: Nc1ncnc(Cl)c1N
Reactant: I
Agent: O=C([O-])O
Agent: [Na+]
Product: Nc1ncnc(I)c1N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
6-Chloropyrimidine-4,5-diamine (Intermediate 88) (90 mg) was added slowly to HI (57%, aq) (2 mL) at 0° C. The reaction mixture was allowed to stir at 0° C. for 30 minutes and then at ambient temperature for 24 hours. NaHCO3 (sat aq.) was added dropwise until the reaction mixture was pH 8. The product was extracted with EtOAc (3×15 mL). The combined organics were dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as a grey solid (144 mg, 98%);
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:4]=1.[N-:13]=[N+:14]=[N-:15].[Na+].O>CN(C=O)C>[N:13]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:4]=1)=[N+:14]=[N-:15]
Reactant: CC(C)(C)c1cccc(CBr)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cccc(CN=[N+]=[N-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dissolve 3-tert-butyltoluene (0.5 mL, 2.9 mmol) in carbon tetrachloride (20 mL). Add NBS (530 mg, 3 mmol) and irradiate the reaction mixture with a 250 watt sun-lamp with simultaneous heating to reflux for 1 h. Cool to ambient temperature, filter, and concentrate filtrate to dryness to give crude 1-bromomethyl-3-tert-butylbenzene. Dissolve crude 1-bromomethyl-3-tert-butylbenzene (600 mg) in anhydrous DMF. Add portion wise sodium azide (260 mg, 4 mmol) and stir at room temperature for 2 h. Pour the mixture into water (250 mL), extract with EtOAc (3×50 mL), wash combined organic extracts with brine, dry over MgSO4, filter and evaporate solvent to give crude 1-azidomethyl-3-tert-butylbenzene, that was used without further purification. Dissolve crude 1-azidomethyl-3-tert-butylbenzene in methanol containing 10% Pd/C (75 mg) at 5° C., and stir the resulting slurry under 1 atm H2 for 1 h. Filtrate, concentrate in vacuo and purify by chromatography on silica gel eluting sequentially with hexane/EtOAc (4:1 and 1:1), EtOAc, methanol and 2M ammonia in methanol to give the title compound (255 mg, 53% overall). MS (ES+) m/z: 164 (M+H)+.
Reaction SMILES: C([C:5]1[C:13]([CH2:14][N:15]([C:17](=[O:24])[CH:18](O)CC(C)C)C)=[C:12]([NH2:25])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(C)(C)C.[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27]>C(Cl)Cl>[F:29][C:28]([F:31])([F:30])[C:26]([OH:32])=[O:27].[NH2:25][C:12]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:13]=1[CH2:14][N:15]([O:27][CH2:26][CH3:28])[C:17]([CH3:18])=[O:24]
Reactant: CC(C)CC(O)C(=O)N(C)Cc1c(N)ccc(C(=O)O)c1C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCON(Cc1cc(C(=O)O)ccc1N)C(C)=O
Reaction time: 12 h

Procedure:
To a stirred solution of t-butyl-4-amino-3-[(2-hydroxy-4,N-dimethylpentanoylamino)methyl]benzoic acid (2.98 g, 9.67 mmole) in CH2Cl2 (20 mL) at RT was added TFA (20 mL). After 12 hr, the reaction contents were concentrated, washed with hexanes and dried under high vacuum overnight affording the title compound as an orange oil (3.51 g, 9.60 mmol). This product was used without further purification: MS (ES) m/e 253 (M+H-TFA)+.
Reaction SMILES: [N:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([O-])(O)=O.[Na+].Cl[CH2:22][C:23]#[N:24]>C(#N)C>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([N:1]2[CH2:6][CH2:5][N:4]([CH2:22][C:23]#[N:24])[CH2:3][CH2:2]2)=[N:8]1
Reactant: c1ccc2c(N3CCNCC3)n[nH]c2c1
Reactant: N#CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: N#CCN1CCN(c2n[nH]c3ccccc23)CC1
Temperature: 25 °C
Yield: 55.8 %

Procedure:
To a stirred suspension of 3-piperazin-1-yl-1H-indazole (6.0 g, 29.7 mmol) and NaHCO3 (2.7 g, 32.7 mmol) in dry acetonitrile (125 ml) was added chloroacetonitrile (2.1 ml, 31.2 mmol) at room temperature, under nitrogen. The suspension was warmed to reflux for 17.5 hours, cooled to room temperature, and subsequently filtered. The remaining solids were washed with dichloromethane and the combined filtrates were concentrated. The resulting brown oil was purified via flash column chromatography (silica gel, 0-50% EtOAc/DCM) to give 4.0 g of product as an off-white solid, m.p. 121-123° C.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=2[Cl:29])=[CH:14][C:5]=1[O:6][CH2:7][P:8](=[O:13])([O:11]C)[O:9]C)([O-:3])=[O:2].O>Cl>[N+:1]([C:4]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:21][C:20]=2[Cl:29])=[CH:14][C:5]=1[O:6][CH2:7][P:8](=[O:9])([OH:13])[OH:11])([O-:3])=[O:2]
Reactant: COP(=O)(COc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])OC
Agent: Cl
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1OCP(=O)(O)O

Procedure:
Dimethyl 2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxymethylphosphonate (1 g) in 20 ml of 6N hydrochloric acid is heated under reflux overnight. The solution is then poured into water and the mixture is extracted with methylene chloride. The combined solvent extracts are dried over magnesium sulfate and the solvent is then evaporated off to give 2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxymethylphosphonic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([S:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][C:16]([N:22]3[CH2:26][CH2:25][C@H:24]([N:27]([CH3:29])[CH3:28])[CH2:23]3)=[CH:15]4)=[N:9][N:10]=2)[CH:7]=1.N#N.C([Sn](CCCC)(CCCC)[C:37]([O:39][CH2:40][CH3:41])=[CH2:38])CCC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:40]([O:39][C:37]([C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([S:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][C:16]([N:22]3[CH2:26][CH2:25][C@H:24]([N:27]([CH3:28])[CH3:29])[CH2:23]3)=[CH:15]4)=[N:9][N:10]=2)[CH:7]=1)=[CH2:38])[CH3:41]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CN(C)[C@H]1CCN(c2cnc3ccc(Sc4nnc5ccc(Br)cn45)cc3c2)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N#N
Solvent: CN(C)C=O
Product: C=C(OCC)c1ccc2nnc(Sc3ccc4ncc(N5CC[C@H](N(C)C)C5)cc4c3)n2c1
Temperature: 85 °C
Reaction time: 16 h
Yield: 13.9 %

Procedure:
The solution of (81.1) (256.5 mg, 0.546 mmol) and PdCl2(PPh3)2 (38.4 mg, 0.055 mmol) in DMF (10 ml) was bubbled by N2 for 5 min. Tributyl(1-ethoxyvinyl)stannane (296 mg, 0.820 mmol) was added. The reaction tube was flushed by N2 for 5 min again and sealed. The sealed-tube was stirred at 85° C. for 16 h. The mixture was evaporated to dryness and the residue was purified by flash chromatography (CombiFlash, ISCO, eluent MeOH/DCM from 0 to 10%) to afford the title compound (35 mg, yield 13.91%). LCMS (method A): [M+H]+=461.2, tR=1.96 min.
Reaction SMILES: C(Br)C.[Mg].[C:5]1(=[O:11])[CH2:9][CH2:8][C:7](=[O:10])[CH2:6]1.[F:12][C:13]([F:34])([F:33])[C:14]1[CH:32]=[CH:31][C:17]([O:18][C:19]2[CH:30]=[CH:29][C:22]([O:23][CH:24]([CH3:28])[C:25](Cl)=[O:26])=[CH:21][CH:20]=2)=[CH:16][CH:15]=1>O1CCCC1.CCOCC.O>[F:12][C:13]([F:33])([F:34])[C:14]1[CH:32]=[CH:31][C:17]([O:18][C:19]2[CH:30]=[CH:29][C:22]([O:23][CH:24]([CH3:28])[C:25]([CH:6]3[C:7](=[O:10])[CH2:8][CH2:9][C:5]3=[O:11])=[O:26])=[CH:21][CH:20]=2)=[CH:16][CH:15]=1
Reactant: O=C1CCC(=O)C1
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Solvent: CCBr
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)C1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl bromide (6 g, 55 mmol) is added to magnesium turnings (1.34 g) in the presence of tetrahydrofuran (THF; 15 ml). After reaction is complete, the solution is diluted to 50 ml with THF cooled in an ice bath and cyclopentane-1,3-dione (50 mmol) is added rapidly with stirring. THF (250 ml) is added to this mixture and it is allowed to warm to RT. 2-[4-(4-Trifluoromethylphenoxy)phenoxy]propionic acid chloride (55 mmol) is added dropwise with stirring, and the mixture is allowed to stand at RT for 30 minutes. It is then poured into a mixture of ice, water and ether. The aqueous layer is extracted several times with ether. The combined ether extracts are washed with water, dried over sodium sulfate and the solvent is removed to give 2-[[2-[4-(4-trifluoromethylphenoxy)phenoxy]propionyl]]cyclopentane-1,3-dione (V; Y is H, Z is CF3, R1 is CH3 and n is one). ##STR5##