Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1.[CH3:13][C:14](C)([O-])[CH3:15].[K+].C(Br)(C)C>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[CH:4]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)[CH:14]([CH3:15])[CH3:13]
Reactant: COC(=O)Cc1ccc(Br)cc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)Br
Product: COC(=O)C(c1ccc(Br)cc1)C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The (4-bromophenyl)acetic acid methyl ester in the Step 1 and potassium t-butoxide (4.8 g, 1 eq) were dissolved in 200 ml DMF at 0° C. Isopropyl bromide (4 ml. 1 eq) was added into the mixture and stirred at room temperature for 3 hours. When the reaction was completed, the mixture was extracted 3 times with ethyl acetate and water, and washed with saline solution. After the organic layer was dried with anhydrous and the solvent was removed at low pressures, the target compound 2-(4-bromophenyl)3-methylbutyric acid methyl ester was obtained by separation and purification of the mixture using a column chromatography (ethyl acetate:n-hexane=1:10) (6.60 g, 57%).
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][O:16][C:15]2[CH:19]=[C:20]([NH:23][C:24]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[NH:25])[CH:21]=[CH:22][C:14]1=2)C(=O)OC(C)(C)C)[CH3:2].[OH-].[Na+].C(Cl)Cl>CO.Cl>[CH2:1]([NH:3][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][O:16][C:15]2[CH:19]=[C:20]([NH:23][C:24]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[NH:25])[CH:21]=[CH:22][C:14]1=2)[CH3:2]
Reactant: CCN(CCN1CCOc2cc(NC(=N)c3cccs3)ccc21)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCNCCN1CCOc2cc(NC(=N)c3cccs3)ccc21
Temperature: 25 °C

Procedure:
Under positive argon pressure, an orange suspension of tert-butyl ethyl(2-(7-(thiophene-2-carboximidamido)-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethyl)carbamate (4 g, 9.29 mmol) in MeOH (30 mL) and 1N HCl (30 mL) was refluxed for 1 hour. The mixture was then cooled to room temperature, transferred to an ice bath, and 1N NaOH (75 mL) was then added. The solution turned a milky green colour with a black suspension. The mixture was then treated with CH2Cl2 (50 mL) and stirred for half an hour. After this time, the mixture was transferred to a separatory funnel and the product was extracted into CH2Cl2 (2×50 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was subjected to flash chromatography on silica gel using the following sequence of eluents: EtOAc; 1:99 (2M NH3 in MeOH):CH2Cl2; 2.5:97.5 (2M NH3 in MeOH):CH2Cl2; and 5:95 (2M NH3 in MeOH):CH2Cl2. A brown solid was obtained (2 g, 65.1%). 1H-NMR (CDCl3) δ 7.40-7.37 (m, 2H), 7.07-7.04 (m, 1H), 6.75-6.72 (m, 1H), 6.52-6.50 (m, 2H), 4.82 (brs, 2H), 4.24 (t, J=4.5 Hz, 2H), 3.39-3.31 (m, 4H), 2.86 (t, J=6.3 Hz, 2H), 2.71 (q, J=6.9 Hz, 2H), 1.13 (t, J=7.2 Hz, 3H); ESI-MS (m/z, %): 331 (MH+, 100), 260 (95); HPLC purity: 94.1% by area.
Reaction SMILES: [F:1][CH:2]([F:25])[O:3][C:4]1[CH:24]=[CH:23][C:7]([CH2:8][C:9]2[C:10]([CH3:22])=[C:11]([CH3:21])[C:12]([CH:19]=C)=[C:13]([CH:18]=2)[C:14]([O:16][CH3:17])=[O:15])=[CH:6][CH:5]=1.CC(C)=[O:28].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[F:25][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[C:10]([CH3:22])=[C:11]([CH3:21])[C:12]([CH:19]=[O:28])=[C:13]([CH:18]=2)[C:14]([O:16][CH3:17])=[O:15])=[CH:23][CH:24]=1
Reactant: CC(C)=O
Reactant: C=Cc1c(C(=O)OC)cc(Cc2ccc(OC(F)F)cc2)c(C)c1C
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cc(Cc2ccc(OC(F)F)cc2)c(C)c(C)c1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-(4-(difluoromethoxy)benzyl)-3,4-dimethyl-2-vinylbenzoate (0.16 g) in a mixed solvent of acetone (3.00 mL)-acetonitrile (3.00 mL)-water (3.00 mL) were added osmium oxide (fixed catalyst I) (0.06 g) and sodium periodate (0.49 g), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.04 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH2:17][CH:18]=[CH2:19])[C:9](=[O:16])[N:10]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:5]2=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([OH:36])([CH3:35])[CH3:34])=[CH:29][C:28]=1B1OC(C)(C)C(C)(C)O1>C(P([Pd]P(C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C)(C)C.CN1C(=O)CCC1>[CH3:13][C:12]([CH3:15])([CH3:14])[CH2:11][N:10]1[C:5]2[C:6](=[N:7][C:2]([C:32]3[CH:31]=[C:30]([C:33]([OH:36])([CH3:34])[CH3:35])[CH:29]=[CH:28][C:27]=3[CH3:26])=[CH:3][CH:4]=2)[N:8]([CH2:17][CH:18]=[CH2:19])[C:9]1=[O:16]
Reactant: C=CCn1c(=O)n(CC(C)(C)C)c2ccc(Cl)nc21
Reactant: Cc1ccc(C(C)(C)O)cc1B1OC(C)(C)C(C)(C)O1
Agent: CC(C)(C)[PH]([Pd][PH](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: C=CCn1c(=O)n(CC(C)(C)C)c2ccc(-c3cc(C(C)(C)O)ccc3C)nc21
Temperature: 100 °C

Procedure:
5-Chloro-1-(2,2-dimethylpropyl)-3-(prop-2-en-1-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (71-5, 100 mg, 0.36 mmol, 1.0 equiv), Cs2CO3 (1.17 g, 3.57 mmol, 10.0 equiv), 2-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propan-2-ol (225 mg, 0.82 mmol, 2.3 equiv), and bis(tri-t-butyl-phosphino)palladium (18.3 mg, 0.04 mmol, 0.1 equiv) were added to anhydrous NMP (4 mL). The resulting suspension was warmed to 100° C. for 20 min in a microwave emitter. Following this duration, the reaction contents were filtered through Celite® and washed with EtOAc (5 mL). The filtrate was then diluted with saturated aqueous NaHCO3 (5 mL). The layers were separated and the aqueous layer was back-extracted with 3×5 mL EtOAc. The combined organics were dried over Na2SO4, filtered and concentrated to give a brown semi-solid. Purification by reverse-phase HPLC afforded 1-(2,2-dimethylpropyl)-5-[5-(1-hydroxy-1-methylethyl)-2-methylphenyl]-3-prop-2-en-1-yl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (71-6) as a white solid. HRMS (M+H)+: observed=394.2490, calculated=394.2489.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([N:29]1[C:33]([CH3:34])=[N:32][N:31]=[N:30]1)[CH2:11][S:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:7])=[O:6].C(SCC(OC)CNS(CCC[I:62])(=O)=O)CCCCCCCCCCCCCCC>>[CH2:13]([S:12][CH2:11][CH:10]([N:29]1[C:33]([CH3:34])=[N:32][N:31]=[N:30]1)[CH2:9][NH:8][S:5]([CH2:4][CH2:3][CH2:2][I:62])(=[O:7])=[O:6])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)n1nnnc1C
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)n1nnnc1C

Procedure:
3-(3-Chloropropylsulfonylamino)-1-hexadecylthio-2-(5-methyl-1H-tetrazol-1-yl)propane IIIi1 is allowed to react and worked up by the same procedure as described in (5). m.p. 63.5°-65.5° C. The summary of the experimental condition and the physical data of the product are listed in Table 8.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][NH:14][C:15]1C=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].COC(=O)C[N:26]1C2C=CC=CC=2NC[C@H](NC(OC(C)(C)C)=O)C1=O>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][NH:14][C:15]1[C:16]([NH2:21])=[CH:17][CH:18]=[CH:19][N:26]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CNc1ccccc1N)C(=O)O
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Product: CC(C)(C)OC(=O)N[C@@H](CNc1ncccc1N)C(=O)O

Procedure:
(2S)2-tert-Butoxycarbonylamino-3-(3-aminopyridin-2-ylamino)propionic acid was prepared by a similar method to (2S)2-tert-Butoxycarbonylamino-3-(2-aminophenylamino)-propionic acid in Step B of the synthesis of 600a to give 3.68 g (quant.) as a dark solid.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:33]=[CH:34][CH:35]=1)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19]([C:21]2[S:31][C:24]3=[N:25][C:26]([NH:29][CH3:30])=[CH:27][N:28]=[C:23]3[CH:22]=2)=[O:20])[CH:17]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].Cl[C:37]1N=C2SC(C(NC3C=C(NC(=O)C4C=CC=C(C(C#N)(C)C)C=4)C=CC=3C)=O)=CC2=NC=1.CNC.C1COCC1>>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:33]=[CH:34][CH:35]=1)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19]([C:21]2[S:31][C:24]3=[N:25][C:26]([N:29]([CH3:37])[CH3:30])=[CH:27][N:28]=[C:23]3[CH:22]=2)=[O:20])[CH:17]=1)=[O:10])([CH3:5])[CH3:4])#[N:2]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2ncc(Cl)nc2s1
Reactant: CNc1cnc2cc(C(=O)Nc3cc(NC(=O)c4cccc(C(C)(C)C#N)c4)ccc3C)sc2n1
Agent: CNC
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2ncc(N(C)C)nc2s1
Yield: 9 %

Procedure:
Preparation analogous to 96a (step 11) by using 3-chloro-N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide 95 (0.061 mmol, 30 mg) and dimethylamine 2M in THF (1.531 mmol, 765 μL) to give N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-3-(dimethylamino)thieno[2,3-b]pyrazine-6-carboxamide 96b (3 mg, 9%). NMR (400 MHz, DMSO-d6) 1.76 (s, 6H), 2.25 (s, 3H), 3.20 (s, 6H), 7.28 (d, J=8.6 Hz, 1H), 7.61 (m, 2H), 7.76 (d, J=7.8 Hz, 1H), 7.84 (d, J=2.0 Hz, 1H), 7.95 (d, J=7.8 Hz, 1H), 8.05 (s, 1H), 8.30 (s, 1H), 8.43 (s, 1H), 10.13 (s, 1H), 10.35 (s, 1H). (m/z)=499 (M+H)+.
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:18]([OH:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.[CH2:21](O)[CH3:22]>P([O-])([O-])([O-])=O>[CH3:1][C@@:2]12[C@:18]([OH:19])([C:21]#[CH:22])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2
Reactant: CCO
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Agent: O=P([O-])([O-])[O-]
Product: C#C[C@]1(O)CC[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@@]21C
Temperature: 37 °C
Reaction time: 216 h

Procedure:
Estradiol conjugate (33.5 mg, 0.039 mmol), prepared from Conjugate 1 as described in Example 16, was dissolved in 58 mL of a 9:4 ethanol/0.05 M aqueous phosphate buffer (pH 7.4) mixture, and the solution was shaken in a 37° C. incubator for 9 days. Six 8 mL aliquots were collected at 1-, 2-, 3-, 5-, 7-, and 9-day intervals. Estradiol release was quantified by adding 33 μL of a 0.09 M solution of butylated hydroxytoluene (BHT) in deuterochloroform as an internal standard, then comparing integrals of 1H NMR signals corresponding to the steroid and the internal standard. Results are shown in Table 4 below.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]=[CH:14][CH:13]=2)[CH:10]=1)[C:6]#[N:7].Cl.Cl[CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C([O-])([O-])=O.[K+].[K+].CCN(C(C)C)C(C)C>C(#N)C>[NH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([N:11]=[C:12]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:14]=[CH:13]2)[CH:10]=1)[C:6]#[N:7]
Reactant: ClCCN1CCCCC1
Reactant: N#Cc1cc(N)cc(Nc2ccnc3cc(Cl)ccc23)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(N)cc(N=c2ccn(CCN3CCCCC3)c3cc(Cl)ccc23)c1
Yield: 2.9 %

Procedure:
3-Amino-5-[(7-chloroquinolin-4-yl)amino]benzonitrile hydrochloride prepared from step B of example 19 (200 mg, 0.68 mmol), 1-(2-chloroethyl)piperidine hydrochloride (125 mg, 1 eq), K2CO3 (468 mg, 5 eq) and DIEA (0.11 mL, 1 eq) were refluxed in 30 mL of acetonitrile for 72 h. The reaction mixture was then filtered. The filtrate was evaporated and the residue was purified by flash chromatography on silica gel (AcOEt/MeOH//100/0 to 95/5) to yield expected compound as a yellow powder (8 mg, 3% yield). m/z (ESI) 406.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].Br[CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[K].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH:12]([O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [K]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccccc1OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 39.5 %

Procedure:
A mixture of o-nitrophenol (2.08 g, 15.0 mmol), 1-[bromo(phenyl)methyl]benzene (3.70 g, 15.0 mmol) and potassium carbonated (K2CO3) (4.14 g, 30.0 mmol) in acetone (60 mL) was kept at reflux temperature for 5 h. The reaction mixture was cooled to room temperature, concentrated in vacuo. The residue was partitioned between dichloromethane (CH2Cl2) and water (H2O), organic layer dried over sodium sulphate (Na2SO4), filtered, concentrated. The residue was purified by silica gel flash chromatography to give subtitled compound (1.81 g).
Reaction SMILES: O.[OH:2][C:3]1([CH2:16][CH:17]([OH:20])CO)[CH2:15][CH2:14][C:6]2([O:11][CH2:10][C:9]([CH3:13])([CH3:12])[CH2:8][O:7]2)[CH2:5][CH2:4]1>ClCCl>[OH:2][C:3]1([CH2:16][CH:17]=[O:20])[CH2:15][CH2:14][C:6]2([O:7][CH2:8][C:9]([CH3:12])([CH3:13])[CH2:10][O:11]2)[CH2:5][CH2:4]1
Reactant: CC1(C)COC2(CCC(O)(CC(O)CO)CC2)OC1
Solvent: ClCCl
Solvent: O
Product: CC1(C)COC2(CCC(O)(CC=O)CC2)OC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Water (7 mL) and NalO4 (5.41 g) are added to a solution of 3-(9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-propane-1,2-diol (4.63 g) in dichloromethane (70 mL) chilled in an ice bath. The cooling bath is removed and the resulting mixture is vigorously stirred at room temperature overnight. The mixture is then filtered and the filtrate is dried (Na2SO4) and concentrated to give the crude title compound that is directly subjected to the next reaction step. Yield: 4.28 g (crude); Mass spectrum (ESI+): m/z=243 [M+H]+.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[CH2:9]([O:16][CH2:17][C:18](Cl)=[O:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][C:18](=[O:19])[CH2:17][O:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:3]
Reactant: O=C(Cl)COCc1ccccc1
Reactant: CCOC(=O)CN
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
In 50 ml of methylene chloride was added 15.0 g (35.8 mmol)of glycine ethyl ester hydrochloric acid, followed by addition of 9.2 g (75.3 mmol)of 4-dimethylaminopyridine under ice-cooling. After stirring for 10 minutes, 6.5 ml (39.4 mmol)of benzyloxyacetylchloride was added dropwise under ice-cooling over 30 minutes. The temperature was raised up to room temperature, and the mixture was stirred for 12 hours. To the mixture, 20 ml of methylene chloride was added, and filtered. To the filtrate, 5% hydrochloric acid was added, and the mixture was extracted with methylene chloride. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and 9.0 g of N-benzyloxyacetylglycine ethyl ester was obtained (yield 100%).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:5][C@H:4]([C:6](=[CH2:11])[CH2:7][CH2:8][CH:9]=[O:10])[C@H:3]1[CH2:12][CH2:13][C:14](=[O:16])[CH3:15]>C1(C)C=CC=CC=1>[OH:10][CH2:9][CH2:8][CH2:7][C:6]([C@@H:4]1[C@@H:3]([CH2:12][CH2:13][C:14](=[O:16])[CH3:15])[C:2]([CH3:17])([CH3:1])[CH2:5]1)=[CH2:11]
Reactant: C=C(CCC=O)[C@H]1CC(C)(C)[C@@H]1CCC(C)=O
Solvent: Cc1ccccc1
Product: C=C(CCCO)[C@H]1CC(C)(C)[C@@H]1CCC(C)=O
Temperature: 90 °C

Procedure:
4-((1S,2R)-3,3-dimethyl-2-(3-oxobutyl)cyclobutyl)pent-4-enal (11.8 g, 0.05 mol.), toluene (70.8 g, 600 wt. %) and (ethylenediamine) [1,2-bis(diphenylphosphino) ethane]ruthenium(bispivalate) (4.8 mg, 0.00625 mmol, 0.0125 mol.%) were loaded altogether in a 200 ml autoclave equipped with a mechanical stirring device. Sealed autoclave was then purged under stirring with nitrogen (3 times 5 bars) and hydrogen (3 times 5 bars) before being pressurized to 20 bars hydrogen. It was then heated to 90° C. and hydrogen pressure was maintained to 20 bars during all the reaction to afford desired product with 95% selectivity. Upon reaction completion (checked by both hydrogen consumption and GC), to autoclave was then cooled down to 25° C. It was then depressurized and purged with nitrogen (3 times 5 bars) and reaction mixture was then transferred to a round-bottomed flask and solvent was removed under vacuum. After flash chromatography, 4-((1R,4S)-4-(5-hydroxypent-1-en-2-yl)-2,2-dimethylcyclobutyl)butan-2-one was obtained in 90% yield.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[C:9](/[CH:11]=[CH:12]/[C:13]3[N:17]([CH3:18])[N:16]=[C:15]([N:19]4[CH2:23][CH2:22][CH2:21][CH:20]4[CH3:24])[N:14]=3)[N:10]=[C:6]2[C:5]([CH3:25])=[N:4][CH:3]=1>[Pd].CO>[CH3:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][CH2:12][C:13]3[N:17]([CH3:18])[N:16]=[C:15]([N:19]4[CH2:23][CH2:22][CH2:21][CH:20]4[CH3:24])[N:14]=3)[N:10]=[C:6]2[C:5]([CH3:25])=[N:4][CH:3]=1
Reactant: Cc1ncc(C)n2nc(/C=C/c3nc(N4CCCC4C)nn3C)nc12
Agent: [Pd]
Solvent: CO
Product: Cc1ncc(C)n2nc(CCc3nc(N4CCCC4C)nn3C)nc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.3 %

Procedure:
A mixture of (E)-5,8-dimethyl-2-(2-(1-methyl-3-(2-methylpyrrolidin-1-yl)-1H-1,2,4-triazol-5-yl)vinyl)-[1,2,4]triazolo[1,5-a]pyrazine (50 mg, 148 μmol, Eq: 1.00) and palladium on carbon 10% (31.4 mg, 29.5 μmol, Eq: 0.2) in methanol (20 ml) was stirred for 5 hours at 25° C. under hydrogen atmosphere. The catalyst was filtered off, the filtrate was evaporated affording 5,8-dimethyl-2-{2-[2-methyl-5-(2-methyl-pyrrolidin-1-yl)-2H-[1,2,4]triazol-3-yl]-ethyl}-[1,2,4]triazolo[1,5-a]pyrazine (49 mg, 97.4%) as a colorless viscous oil. MS: m/z=341.5
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=O)[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=O.[CH2:14]([NH2:18])[CH2:15][CH2:16][CH3:17].C(O)C.O>C(OCC)(=O)C.C1C=CC=CC=1>[OH:1][C:2]1[CH:3]=[C:4]2[C:11](=[O:13])[N:18]([CH2:14][CH2:15][CH2:16][CH3:17])[C:6](=[O:8])[C:5]2=[CH:9][CH:10]=1
Reactant: CCCCN
Reactant: O=C(O)c1ccc(O)cc1C(=O)O
Solvent: CCO
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCCCN1C(=O)c2ccc(O)cc2C1=O

Procedure:
In a 250-ml round bottom flask were placed 20.5 g (112.6 mmols) of 4-hydroxyphthalic acid, 8.2 g (112.6 mmols) of n-butylamine and 100 ml of absolute ethanol. After mixing, the resulting mixture generated heat gently. The mixture was sufficiently stirred until the solids were completely dissolved. The alcohol was distilled off under reduced pressure, after which the viscous liquid thus obtained was heated at 180° C. for about 3 hours with continuous extraction of water. After cooling, the residue was solidified. The solidified residue was dissolved in an ethyl acetate-benzene (1:1 by volume) mixed solvent, and the resulting solution was washed with water, an aqueous sodium carbonate solution and then water. The organic layer was dried over anhydrous magnesium sulfate, concentrated, and then cooled to obtain powder crystals having a slightly yellowish white color. The crystals were collected by suction filtration and dried. Yield: 18.5 g (75%), m.p. 126°-127° C. The product was determined to be 4-hydroxy-N-n-butylphthalimide by investigation of its structure by NMR and infrared absorption spectrum.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:15])=O>>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(Cl)nc(Cl)c1C(=O)O
Product: Cc1cc(Cl)nc(Cl)c1C(=O)Cl

Procedure:
A solution of 2,6-dichloro-4-methyl-nicotinic acid (3.94 g, 19.1 mmol) in thionyl chloride (18 mL) was heated to 80° C. for 2 h. After cooling, the solution was concentrated in vacuo to give 2,6-dichloro-4-methyl-nicotinoyl chloride as yellow oil. It was carried on to the next step without further purification. This transformation can also be accomplished using oxalyl chloride with catalytic DMF in place of thionyl chloride.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:28])[C:7]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:8][N:9]2[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])=[C:4]([CH3:29])[C:3]=1[F:30].[NH:31]1[CH2:34][CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[N:31]1([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:28])[C:7]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:8][N:9]3[CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[O:21][CH3:22])=[C:4]([CH3:29])[C:3]=2[F:30])[CH2:34][CH2:33][CH2:32]1
Reactant: C1CNC1
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(Cl)c(F)c(C)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(N3CCC3)c(F)c(C)c2c1=O
Reaction time: 72 h

Procedure:
A mixture of ethyl 7-chloro-1-(2,4-dimethoxybenzyl)-6-fluoro-5-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (254 mg), azetidine (0.085 mL), and potassium carbonate (160 mg) in dichloromethane (5 mL) was stirred for 3 days, diluted with dichloromethane, washed with water and 10% citric acid, filtered through a cotton plug, and concentrated.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[N:12]([CH2:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[C@H:11]([C:19]([F:22])([F:21])[F:20])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.Cl.[C@H:24]12[CH2:30][C@H:27]([NH:28][CH2:29]1)[CH2:26][O:25]2.C(N(CC)CC)C>C(OCC)(=O)C>[CH3:16][CH:15]([CH3:17])[C:14](=[O:18])[CH2:13][N:12]1[C:4]2=[N:3][C:2]([N:28]3[CH2:29][C@@H:24]4[CH2:30][C@H:27]3[CH2:26][O:25]4)=[CH:7][C:6](=[O:8])[N:5]2[CH2:9][CH2:10][C@H:11]1[C:19]([F:22])([F:21])[F:20]
Reactant: C1O[C@@H]2CN[C@H]1C2
Reactant: CC(C)C(=O)CN1c2nc(Cl)cc(=O)n2CC[C@H]1C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)C(=O)CN1c2nc(N3C[C@@H]4C[C@H]3CO4)cc(=O)n2CC[C@H]1C(F)(F)F
Temperature: 130 °C
Yield: 49 %

Procedure:
220 mg (0.51 mmol) of (8S)-2-chloro-9-(3-methyl-2-oxobutyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 105.99 mg (0.78 mmol) of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride are mixed together. The powder obtained is placed in a tube and 227 μl (1.63 mmol) of triethylamine are added. The tube is sealed and heated at 130° C. in an oil bath for 3 hours. The crude product obtained is taken up in ethyl acetate and the organic phase is washed with water, dried over magnesium sulfate and then evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH) to give 100 mg of (8S)-9-(3-methyl-2-oxobutyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are as follows: