Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:20][C:21]1[NH:25][N:24]=[CH:23][C:22]=1[C:26]#[N:27])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:29]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[N:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[C:42]([C:47]([CH3:50])([CH3:49])[CH3:48])[CH:43]=3)[C:38]2=[O:51])[C:30]=1[CH:31]=[O:32].C(=O)([O-])[O-].[K+].[K+]>[Cu]I>[C:47]([C:42]1[CH:43]=[C:44]2[C:39](=[CH:40][CH:41]=1)[C:38](=[O:51])[N:37]([C:33]1[C:30]([CH:31]=[O:32])=[C:29]([N:24]3[CH:23]=[C:22]([C:26]#[N:27])[C:21]([NH:20][C:1]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)=[N:25]3)[CH:36]=[CH:35][CH:34]=1)[N:46]=[CH:45]2)([CH3:50])([CH3:48])[CH3:49]
Reactant: CC(C)(C)c1ccc2c(=O)n(-c3cccc(Br)c3C=O)ncc2c1
Reactant: N#Cc1cn[nH]c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)c1ccc2c(=O)n(-c3cccc(-n4cc(C#N)c(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)c3C=O)ncc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
To degassed DMF (1.5 mL) were added 5-(tritylamino)-1H-pyrazole-4-carbonitrile (1.36 g, 3.89 mmol), 2-bromo-6-(6-tert-butyl-1-oxophthalazin-2(1H)-yl)benzaldehyde (1.0 g, 2.6 mmol), copper (I) iodide (494 mg, 2.6 mmol) and potassium carbonate (717 mg, 5.19 mmol). The reaction was inerted five times by alternating vacuum and a nitrogen purge and then heat to 100° C. (external); for 8 hr. TLC the following morning showed trace amounts of starting materials. The reaction was diluted with EtOAc (50 mL) and through a pad of diatomaceous earth. The pad was rinsed with additional EtOAc (50 mL) and concentrated in vacuo. The crude material was bound to silica column and purified over a 40 g silica gel cartridge, eluting the column with a 20-40% EtOAc/hexanes, isocratic hold for 5 minutes, then 40-100% EtOAc/hexanes gradient over 20 minutes. The product containing fractions were combined and concentrated to give 1-[3-(6-tert-Butyl-1-oxo-1H-phthalazin-2-yl)-2-formyl-phenyl]-3-(trityl-amino)-1H-pyrazole-4-carbonitril (632 mg, 37%).
Reaction SMILES: F[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]2[S:13][C:12]([NH:14][C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=[CH:17][CH:16]=3)=[N:11][C:10]=2[C:25]([NH2:27])=[O:26])=[O:7])=[CH:4][CH:3]=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>CN1C(=O)CCC1>[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:2]2[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]3[S:13][C:12]([NH:14][C:15]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[N:18]=[CH:17][CH:16]=4)=[N:11][C:10]=3[C:25]([NH2:27])=[O:26])=[O:7])=[CH:4][CH:3]=2)[CH2:33][CH2:32]1
Reactant: CN1CCNCC1
Reactant: NC(=O)c1nc(Nc2ccnc3ccccc23)sc1NC(=O)c1ccc(F)cc1
Solvent: CN1CCCC1=O
Product: CN1CCN(c2ccc(C(=O)Nc3sc(Nc4ccnc5ccccc45)nc3C(N)=O)cc2)CC1
Temperature: 150 °C
Yield: 69 %

Procedure:
A mixture of 5-(4-fluorobenzamido)-2-(quinolin-4-ylamino)thiazole-4-carboxamide (110 mg, 0.27 mmol) and 1-methyl-piperazine (1.5 mL) in NMP (1.5 mL) was heated at 150° C. for 4 hrs. The reaction mixture was diluted with ice water (1 mL). The resulting solids were collected by filtration and washed successively with water and ether, and dried to give 0.090 g (69% yield) of the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6](Br)=[CH:5][N:4]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:12]=[CH:11][C:10]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][N:4]=1
Reactant: COc1ncc(Br)cn1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1cnc(OC)nc1
Temperature: 135 °C
Reaction time: 12 h

Procedure:
A mixture of 2-methoxy-5-bromopyrimidine (75.43 g, 0.399 mol), ethyl acrylate (47.5 ml, 0.439 mol), palladium (II) acetate (1.07 g, 0.0048 mol), tri-o-tolylphosphine (2.92 g, 0.0096 mol) and triethylamine (84 ml) were heated at 135° C. with stirring under argon for 12 h. After allowing to cool the solid mass was dissolved in water and ethyl acetate, filtered, and the aqueous phase separated and further extracted with ethyl acetate. The combined extracts were washed with saturated aqueous ammonium chloride, dried (MgSO4) and evaporated. The solid thus obtained was triturated with ether/light petrol (1:3, 350 ml), filtered, washed and dried, yield 52.41 g (63%). 1H-NMR (CDCl3) δ 1.33 (3H, t), 4.06 (3H, s), 4.28 (2H, q), 6.45 (1H, d), 7.58 (1H, d), 8.67 (2H, s); MS (APCI+) found (M+H)=209; C10H12N2O3 requires 208.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:8]=1[C:9]([OH:11])=[O:10]>O>[CH3:6][C:7]1[C:15]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:14][CH:13]=[C:12]([CH3:16])[C:8]=1[C:9]([OH:11])=[O:10]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1cccc(C)c1C(=O)O
Solvent: O
Product: Cc1ccc(S(=O)(=O)Cl)c(C)c1C(=O)O
Temperature: 55 °C
Reaction time: 1 h

Procedure:
4 ml of chlorosulfonic acid are added slowly to 1 g (0.067 mol) of 2,6-dimethylbenzoic acid and the reaction mixture is stirred for 1 hour at 55° C. After cooling, the mixture is poured into 100 ml of iced water. The precipitate formed is filtered off, washed with cold water and then dried in a desiccator under vacuum to give 1.22 g of the expected product in the form of a white solid (yield=73%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[CH2:7][NH:8][CH2:9][CH2:10][O:11][CH3:12])([CH3:4])(C)C.C(O)[C:15]1[CH:20]=[CH:19]C=[CH:17][CH:16]=1.O.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29]([OH:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1.O>C1C=CC=CC=1>[C:23]1([CH3:33])[CH:24]=[CH:25][C:26]([S:29]([OH:32])(=[O:30])=[O:31])=[CH:27][CH:28]=1.[CH2:1]([O:5][C:6](=[O:13])[CH2:7][NH:8][CH2:9][CH2:10][O:11][CH3:12])[C:4]1[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=1
Reactant: COCCNCC(=O)OC(C)(C)C
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COCCNCC(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 85.1 %

Procedure:
To a solution of 55.8 g of N-(2-methoxyethyl)glycine tert-butyl ester in 200 ml of benzene was added 63.8 g of benzyl alcohol and 72.9 g of p-toluenesulfonic acid monohydrate. The mixture was heated at reflux for 10 hours with the continuous removal of water through a Dean-Stark water trap. At the end of this period, the solution was concentrated in vacuo, and to the residue was added 300 ml of dry ethyl ether. After 2 hours at room temperature, the formed precipitate was filtered, washed with dry ethyl ether and then recrystallized from ethyl acetate to yield 99.2 g (85 percent) of N-(2-methoxyethyl)glycine benzyl ester p-toluenesulfonate, M.P. 95°-6° C. The following amino acid benzyl ester p-toluenesulfonate not previously reported in the chemical literature were synthesized by the aforementioned procedure.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1Cl)=[O:13])[CH2:8]2.[CH3:26][NH:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1[N:27]([CH3:26])[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:13])[CH2:8]2
Reactant: CNCCc1ccccc1
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1Cl
Product: CN(CCc1ccccc1)c1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1-c1ccccc1

Procedure:
5-(Methyl-phenethyl-amino)-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide was prepared using Procedure A from 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Intermediate 3) and N-methylphenethylamine. Mass spectrum (ES) MH+=455.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][Cl:28]>CC(C)=O>[Cl:28][CH2:27][CH2:26][CH2:25][N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[CH2:13][CH2:14]1
Reactant: ClCCCBr
Reactant: c1ccc2nc(CN3CCNCC3)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: ClCCCN1CCN(Cc2ccc3ccccc3n2)CC1
Reaction time: 20 h
Yield: 65.7 %

Procedure:
A mixture consisting of 1-(2-quinolylmethyl)piperazine (21.75 g, 95.7 mmol), potassium carbonate (19.90 g, 144 mmol), 1-bromo-3-chloropropane (16.57 g, 105 mmol) and acetone (250 ml) was heated under reflux and stirring for 20 hours, insoluble matter was removed and the solvent was distilled off. The oil residue was dissolved in chloroform and the resulting solution was then subjected to chromatography on a silica gel column (developer: chloroform/methanol=100/1), whereby 19.10 g of the title compound were obtained as a yellow oil (yield: 65.7%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.[NH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28]>>[OH:28][CH2:27][C:26]([NH:25][C:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:24])=[CH:20][N:19]=1)=[O:23])([CH3:30])[CH3:29]
Reactant: Cc1onc(-c2ccc(F)cn2)c1COc1ccc(C(=O)O)nc1
Reactant: CC(C)(N)CO
Product: Cc1onc(-c2ccc(F)cn2)c1COc1ccc(C(=O)NC(C)(C)CO)nc1
Yield: 66 %

Procedure:
As described for example 23f, 5-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyridine-2-carboxylic acid (75 mg, 0.23 mmol) was converted, using 2-amino-2-methyl-1-propanol instead of isopropylamine, to the title compound (60 mg, 66%), which was obtained as a light-bluish solid. MS: m/e=401.4 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:7]=1.[C:33]([N:36]1[CH2:40][CH2:39][CH2:38][C@H:37]1[C:41](O)=[O:42])(=[O:35])[CH3:34].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN1C(=O)CCC1>[C:33]([N:36]1[CH2:40][CH2:39][CH2:38][C@H:37]1[C:41]([N:25]1[CH2:24][CH2:23][CH:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:8]3[CH:7]=[C:6]([NH:5][CH2:4][C:3]4[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:2]=4[F:1])[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=3)=[CH:21][CH:20]=2)[CH2:27][CH2:26]1)=[O:42])(=[O:35])[CH3:34]
Reactant: CC(=O)N1CCC[C@H]1C(=O)O
Reactant: NC(=O)c1cnc(Nc2ccc(C3CCNCC3)cc2)cc1NCc1cccc(F)c1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(=O)N1CCC[C@H]1C(=O)N1CCC(c2ccc(Nc3cc(NCc4cccc(F)c4F)c(C(N)=O)cn3)cc2)CC1
Temperature: 25 °C
Yield: 100.9 %

Procedure:
The mixture of compound 4-(2,3-difluorobenzylamino)-6-(4-(piperidin-4-yl)phenylamino)nicotinamide (Example 209) (50 mg, 0.11 mmol), (S)-acetyl-pyrrolidine-2-carboxylic acid (35 mg, 0.22 mmol), DIEA (180 μL, 1.1 mmol) in 4 mL NMP was stirred at RT. To it was added BOP (210 mg, 0.55 mmol). The mixture was stirred for overnight, quenched with TFA, and subjected to reverse phase preparative HPLC to isolate the title compound (64 mg). MS found for C31H34F2N6O3 as (M+H)+ 577.5. UV: λ=259 nm. 1H NMR (a pair of rotomers): (CD3OD) δ 8.13 (with 8.15, 1H, s), 7.36 (with 7.32, 2H, d, J=8.8 Hz), 7.25 (1H, m), 7.16 (1H, m), 7.13-7.07 (3H, m), 5.83 (with 5.79, 1H, s), 4.95 (1H, m), 4.65 (1H, m), 4.56 (with 4.55, 2H, s), 4.20 (1H, m), 3.66 (2H, m), 3.30 (1H, m), 2.92 (1H, m), 2.79 (1H, m), 2.27 (1H, m), 2.12 (with 2.10, 3H, s), 2.07-1.85 (5H, m), 1.68 (2H, m) ppm.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:27])[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C@@H:23]([CH3:26])[CH2:24][OH:25])[CH:17]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH3:30][C@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][N:32]1[C:37]1[N:41]2[CH:42]=[C:43]([O:46][C@H:47]3[C:56]4[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=4)[C@@H:50]([NH2:57])[CH2:49][CH2:48]3)[CH:44]=[CH:45][C:40]2=[N:39][N:38]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:57][C@@H:50]2[C:51]3[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=3)[C@H:47]([O:46][C:43]3[CH:44]=[CH:45][C:40]4[N:41]([C:37]([N:32]5[CH2:33][CH2:34][CH2:35][CH2:36][C@@H:31]5[CH3:30])=[N:38][N:39]=4)[CH:42]=3)[CH2:48][CH2:49]2)=[O:27])[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C@@H:23]([CH3:26])[CH2:24][OH:25])[CH:17]=2)[N:9]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: C[C@@H](CO)Oc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@@H](CO)Oc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC[C@@H]5C)n4c3)c3ccccc32)c1
Temperature: 70 °C
Reaction time: 6.75 h
Yield: 58.9 %

Procedure:
A solution of Intermediate 152c (59 mg, 0.13 mmol) in 1,4-dioxane (1.3 mL) was treated with Intermediate 81d (44 mg, 0.12 mmol) and DIPEA (0.025 mL, 0.14 mmol) and the mixture was stirred at 70° C. for 6.75 h then at 50° C. for 64 h. The cooled solution was concentrated in vacuo, and the residue was partitioned between DCM and water. The phases were separated and the aqueous layer was extracted with DCM (×2). The combined organic phase was washed with brine, dried (Na2SO4) and concentrated in vacuo to a brown gum. The gum was purified by FCC, using 0-10% MeOH in DCM to give the title compound as a pale yellow glass (49 mg, 61%). LCMS (Method 3): Rt 3.74 min, m/z 693.5 [MH+].
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1([C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH:28]=O)[CH:24]=[CH:23][N:22]=[N:21]1>>[N:20]1([C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH2:28][N:1]2[CH:2]([C:10]3[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=3[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]2=[O:8])[CH:24]=[CH:23][N:22]=[N:21]1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(-n2ccnn2)c1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(-n2ccnn2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with 3-(1H-1,2,3-triazol-1-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.71 min.; [M+H]+: 393.08 g/mol.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N+:8]([O-])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.[CH3:17][O+:18](C)C.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>ClCCl.O>[C:1]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:17][OH:18])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[O+](C)C
Reactant: CC(C)(C)c1cc[n+]([O-])cc1
Agent: F[B-](F)(F)F
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1ccnc(CO)c1
Yield: 73 %

Procedure:
4-t-Butyl-pyridine N-oxide (11.0 g, 72.9 mmole) is dissolved in 200 ml dichloromethane in a 500 ml one neck round bottom flask under nitrogen. The solution is treated with trimethyloxonium tetrafluoroborate (10.8 g, 72.9 mmole), is stirred 1h at room temperature, and the volatiles are removed in vacuo. The solid residue is dissolved in 200 ml methanol in a 500 ml one neck round bottom flask. The solution is heated to reflux, is treated with ammonium persulfate (3.3 g, 14.5 mmole) in 15 ml water, and the reaction mixture is vigorously refluxed for 30 min. The reaction is treated with a second lot of ammonium persulfate (1.65 g, 7.2 mmole) in 7 ml water and is refluxed for an additional 1 h. The reaction is cooled and the bulk of the methanol is removed in vacuo. The residue is diluted with 300 ml conc ammonium hydroxide and the mixture is extracted with 4×100 ml dichloromethane. The combined organics are dried over potassium carbonate and are concentrated in vacuo to a yellow oil. The crude material is chromatographed over 400 g silica gel (230-400 mesh), eluting with 40% acetone/hexane, while collecting 50 ml fractions. Fractions 26-52 are combined and concentrated to afford 8.79 g (73%) of 4-t-Butyl-2-hydroxymethyl-pyridine as a yellow oil.
Reaction SMILES: O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3].[CH:19]([O:24][CH3:25])([O:22][CH3:23])OC.O=[C:27]1C[CH2:30][CH:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:28]1>CCCCC>[CH3:25][O:24][C:19]1([O:22][CH3:23])[CH2:27][CH2:28][CH:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:30]1
Reactant: COC(=O)CC1CCC(=O)C1
Reactant: COC(OC)OC
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: O
Solvent: CCCCC
Product: COC(=O)CC1CCC(OC)(OC)C1
Reaction time: 2 h
Yield: 90.9 %

Procedure:
Tetrahedron, 57 (2001), 5183. A mixture of Montmorillonite K10 (188 g, 571 mmol) in trimethyl orthoformate (316 mL, 2856 mmol) was stirred for 2 hrs under nitrogen. To the mixture was slowly added methyl 2-(3-oxocyclopentyl)acetate (89.2 g, 571 mmol), as a suspension in pentane (500 mL). The mixture was stirred for 16 hrs, then filtered through a CELITE® pad rinsing with pentane. The filtrate was concentrated under reduced pressure to afford the title compound (104.9 g, 519 mmol, 91% yield) as an amber oil. 1H NMR (400 MHz, CDCl3) δ ppm 3.67 (3 H, s) 3.20 (6 H, s) 2.35-2.46 (3 H, m) 2.11 (1 H, dd, J=13.18, 7.40 Hz) 1.86-1.96 (2 H, m) 1.74-1.83 (1 H, m) 1.44 (1 H, dd, J=13.05, 8.53 Hz) 1.34 (1 H, dd, J=12.55, 8.78 Hz). 13C NMR (101 MHz, CDCl3) δ ppm 172.73, 110.91, 50.93, 48.80, 48.61, 40.27, 39.66, 33.51, 33.25, 29.37.
Reaction SMILES: [H-].[Na+].[C:3]12([C:13]3[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=3[OH:20])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26]Cl.O>CN(C=O)C>[C:3]12([C:13]3[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=3[O:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])[CH2:4][CH:5]3[CH2:11][CH:9]([CH2:8][CH:7]([CH2:6]3)[CH2:12]1)[CH2:10]2
Reactant: Oc1ccc(Br)cc1C12CC3CC(CC(C3)C1)C2
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOCOc1ccc(Br)cc1C12CC3CC(CC(C3)C1)C2

Procedure:
3.8 g (0.13 mol) of sodium hydride (80% in oil) and 50 ml of DMF were introduced into a three-necked flask under a stream of nitrogen and a solution of 40 g (0.13 mol) of 2-(1-adamantyl)-4-bromophenol in 100 ml of DMF was added dropwise. The mixture was stirred until the evolution of gas had ceased. A solution of 18 ml (0.15 mol) of 2-methoxyethoxymethyl chloride in 20 ml of DMF was then added dropwise and the mixture was stirred for four hours at room temperature. The reaction medium was poured into water and extracted with ethyl ether. The organic phase was separated out after settling had taken place, washed with water, dried over magnesium sulfate and evaporated. The residue was purified by chromatography on a column of silica, eluted with a mixture of dichloromethane and hexane (50/50). After evaporation of the solvents, 40.1 g (78%) of the expected compound, having a melting point of 69°-70° C., were recovered.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.[NH2:13][CH:14]1[CH2:20][N:19]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][CH:17]([CH3:28])[N:16]([CH3:29])[CH2:15]1>CN(C)C=O>[CH2:21]([N:19]1[CH2:20][CH:14]([NH:13][C:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)=[O:12])[CH2:15][N:16]([CH3:29])[CH:17]([CH3:28])[CH2:18]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC1CN(Cc2ccccc2)CC(N)CN1C
Reactant: O=C(O)c1n[nH]c2ccccc12
Solvent: CN(C)C=O
Product: CC1CN(Cc2ccccc2)CC(NC(=O)c2n[nH]c3ccccc23)CN1C
Temperature: 60 °C
Reaction time: 2 h
Yield: 18.5 %

Procedure:
To a solution of 1H-indazole-3-carboxylic acid (2.2 g) in N,N-dimethylformamide (40 ml), N,N'-carbonyldiimidazole (2.2 g) is added, and the mixture is heated at 60° C. for 3.5 hours. A solution of 6-amino-1-benzyl-3,4-dimethylhexahydro-1H-1,4-diazepine (3.0 g) in N,N-dimethylformamide (10 ml) is added to the mixture, and the mixture is stirred at 25° C. for 2 hours. The solvent is evaporated under reduced pressure, and the residue is diluted with water and extracted with chloroform. The organic layer is washed successively with 10% aqueous sodium hydroxide solution, water and saturated aqueous sodium chloride solution, and dried over sodium sulfate. The solvent is evaporated under reduced pressure, and the residue is chromatographed on silica gel with elution 10% methanol-acetone. Fractions containing the title compound are pooled and evaporated under reduced pressure to give the title compound (0.9 g) which is one isomer with lower polarity in two isomers produced in the above reaction, m.p. 203°-205° C. (recrystallized from isopropyl alcohol).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]=[C:6]1[CH2:11][CH2:10][CH:9]([CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][CH2:7]1)C.[OH-].[Na+]>CO.C1COCC1>[C:17]([O:16][C:14]([NH:13][CH2:12][CH:9]1[CH2:8][CH2:7][C:6](=[CH:5][C:4]([OH:21])=[O:3])[CH2:11][CH2:10]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CCOC(=O)C=C1CCC(CNC(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1CCC(=CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 64 %

Procedure:
To a solution of [4-(tert-Butoxycarbonylamino-methyl)-cyclohexylidene]-acetic acid ethyl ester (0.518 g, 1.74 mmol) in MeOH (16 mL) and THF (4 mL) was added sodium hydroxide (9.0 mL, 1N, 9.0 mmol) and the reaction stirred at RT for 23 hr. The reaction was quenched with H2O and extracted with EtOAc (2×). The aqueous layer was acidified to pH 1 with 1N HCl and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to provide 0.300 g (64%) of product. ESI-MS m/z 270 (MH)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:27])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:26])[N:16]([CH2:24][CH3:25])[C:17](=[O:23])[N:18]([CH2:21][CH3:22])[C:19]=2[CH3:20])=[CH:10][CH:9]=1)[NH2:6].[Cl:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:30]=1[C:31](Cl)=[O:32].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:2][O:3][C:4](=[O:27])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:26])[N:16]([CH2:24][CH3:25])[C:17](=[O:23])[N:18]([CH2:21][CH3:22])[C:19]=2[CH3:20])=[CH:12][CH:13]=1)[NH:6][C:31]([C:30]1[C:29]([Cl:28])=[CH:37][CH:36]=[CH:35][C:34]=1[Cl:38])=[O:32]
Reactant: CCn1c(C)c(-c2ccc(C[C@H](N)C(=O)OC)cc2)c(=O)n(CC)c1=O
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c(C)c(-c2ccc(C[C@H](NC(=O)c3c(Cl)cccc3Cl)C(=O)OC)cc2)c(=O)n(CC)c1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98.9 %

Procedure:
To a suspension of 4-(1,3-diethyl-6-methyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester hydrochloride salt (0.76 mmol, 0.3 g) and 2,6-dichlorobenzoyl chloride (0.84 mmol, 0.175 g) in dichloromethane (2 mL) was added diisopropylethylamine (3.03 mmol, 0.53 mL) at room temperature. After 5 min, everything went into solution and the clear yellow solution was stirred for 15 h at room temperature. The resulting brown solution was diluted with dichloromethane (25 mL). The dichloromethane layer was washed successively with 1N hydrochloric acid (2×25 mL), saturated sodium bicarbonate solution (25 mL), and brine solution (25 mL) and was dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent gave the crude product which was purified by silica gel chromatography using a Biotage (40s) column to afford 0.40 g (99% yield) of N-[(2,6-dichlorophenyl)carbonyl]-4-(1,3-diethyl-6-methyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester as an amorphous white solid. ES-HRMS m/e calcd for C26H27Cl2N3O5 (M+Na) 554.1221, found 554.1229.