Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][C:7]([CH3:15])([CH3:14])[CH:6]2O.[NH:17]1[CH:21]=[C:20]([C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[N:19]=[CH:18]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC)=O)=NC(OC)=O>C1COCC1>[CH:25]([O:24][C:22]([C:20]1[N:19]([CH:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9](=[O:13])[CH2:8][C:7]2([CH3:15])[CH3:14])[CH:18]=[N:17][CH:21]=1)=[O:23])([CH3:27])[CH3:26]
Reactant: COc1ccc2c(c1)C(O)C(C)(C)CC2=O
Reactant: CC(C)OC(=O)c1c[nH]cn1
Agent: COC(=O)N=NC(=O)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(n1cncc1C(=O)OC(C)C)C(C)(C)CC2=O
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution of 6-methoxy-4-hydroxy-3,3-dimethyl-3,4-dihydro-2H-naphthalen-1-one (0.75 g, 3.28 mmol), isopropyl 4-imidazolecarboxylate (0.36 g, 2.30 mmol), which can be prepared as described in Example 1, in THF (20 mL) at 0° C. is added triphenylphosphine (0.87 g, 3.28 mmol), followed by dimethyl azodicarboxylate (40% in toluene, 1.2 mL, 3.28 mmol) and the cooling bath is removed. After 16 hours, the mixture is diluted with ethyl acetate and washed twice with half-saturated brine. The mixture is extracted five times with 1M aqueous HCl (20 mL portions). The acidic aqueous phases are then cooled to 0° C., the pH is adjusted to ca. 9 with 2M aqueous NaOH at 0° C. and the aqueous phase is extracted three times with dichloromethane. The combined organic phases are dried over MgSO4, filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (dichloromethane-methanol, 99:1 to 49:1) to give 3-(7-methoxy-2,2-dimethyl-4-oxo-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid isopropyl ester; MS: (ESI) m/z 357.1 (M+H)+ The HCl salt of the title compound can be prepared by dissolution in diethyl ether followed by treatment with an excess of 1N HCl in diethyl ether. The resulting heterogeneous solution is concentrated to furnish the HCl salt of 3-(7-methoxy-2,2-dimethyl-4-oxo-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid isopropyl ester 1H NMR (400 MHz, MeOD) δ ppm 1.00 (s, 3 H), 1.23 (s, 3 H), 1.48 (d, J=6.3 Hz, 3 H), 1.50 (d, J=6.3 Hz, 3 H), 2.61 (d, J=17.4 Hz, 1 H), 2.78 (d, J=17.4 Hz, 1 H), 3.89 (s, 3H), 5.34-5.47 (m, 1 H), 6.85 (d, J=2.3 Hz, 1 H), 6.95 (s, 1 H), 7.20 (dd, J=8.6, 2.3 Hz, 1 H), 8.16 (d, J=8.6 Hz, 1 H), 8.40 (s, 1 H), 8.94 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][C:7]2[NH:8][C:9]([C:12]3[C:21](O)=[C:20]4[C:15]([CH:16]=[CH:17][CH:18]=[N:19]4)=[C:14]([N:23]4[CH2:28][CH2:27][N:26]([CH2:29][C:30]([NH:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:25][CH2:24]4)[N:13]=3)=[N:10][N:11]=2)=[CH:4][CH:3]=1.C(O)=[O:39]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[NH:8][C:9]([C:12]3[CH:21]=[C:20]4[C:15]([CH:16]=[CH:17][C:18]([OH:39])=[N:19]4)=[C:14]([N:23]4[CH2:24][CH2:25][N:26]([CH2:29][C:30]([NH:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:28]4)[N:13]=3)=[N:10][N:11]=2)=[CH:36][CH:37]=1
Reactant: CC(C)NC(=O)CN1CCN(c2nc(-c3nnc(Cc4ccc(F)cc4)[nH]3)c(O)c3ncccc23)CC1
Reactant: O=CO
Product: CC(C)NC(=O)CN1CCN(c2nc(-c3nnc(Cc4ccc(F)cc4)[nH]3)cc3nc(O)ccc23)CC1

Procedure:
In a similar manner as described in example 17, 2-(4-{7-[5-(4-fluorobenzyl)-4H-1,2,4-triazol-3-yl]-8-hydroxy-1,6-naphthyridin-5-yl}piperazin-1-yl)-N-isopropylacetamide (31 mg, 38%) was prepared as the formic acid. 1H NMR (CDCl3): δ 9.13 (d, J=4.0 Hz, 1 H), 8.42 (d, J=8.4 Hz, 1 H), 7.56(dd, J=8.4, 4.0 Hz, 1 H), 7.36 (m, 2 H), 7.02 (m, 2 H), 4.19 (s, 2 H), 4.17-4.13 (m, 1 H), 3.37 (s, 4 H), 3.13 (s, 2 H), 2.82 (s, 4 H), 1.20 (d, J=6.4 Hz, 6 H); MS m/z 505 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3]N(C)C=O.[N:8]1([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[NH:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.CI>O>[CH3:3][N:24]([C:15]1[CH:16]=[C:17]([C:20]([F:23])([F:21])[F:22])[CH:18]=[CH:19][C:14]=1[N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[C:25](=[O:32])[C:26]1[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=1
Reactant: O=C(Nc1cc(C(F)(F)F)ccc1N1CCCCC1)c1ccncc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CN(C(=O)c1ccncc1)c1cc(C(F)(F)F)ccc1N1CCCCC1
Reaction time: 1 h
Yield: 51.5 %

Procedure:
Sodium hydride (60% (w/w) oil mixture) (200 mg, 0.500 mmol) was added at 0° C. to an N,N-dimethylformamide (DMF; 0.5 ml) solution of N-[2-(1-piperidinyl)-5-(trifluoromethyl)phenyl]isonicotinamide (SRPIN-1, GIF-0340) (121 mg, 0.496 mmol), obtained as described in Referential example 1-3. The resulting mixture was stirred for one hour, and an N,N-dimethylformamide (DMF) solution of methyl iodide (0.8 M, 0.62 ml, 0.496 mmol) was added thereto at 0° C. The resulting mixture was stirred for three hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (12 g, hexane/ethyl acetate=1/1). Thus, N-methyl-N-[2-(1-piperidinyl)-5-(trifluoromethyl)phenyl]isonicotinamide (GIF-0614) (65.9 mg, 51.5%) was yielded as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([CH2:18][OH:19])[C:10]21[CH2:12][CH2:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.Cl[Si:26]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[O:27][Si:28](Cl)([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30]>CN(C=O)C>[CH2:1]([O:8][C@H:9]1[C:10]2([CH2:12][CH2:11]2)[C@H:13]2[C@@H:14]([O:17][Si:26]([CH:36]([CH3:38])[CH3:37])([CH:39]([CH3:41])[CH3:40])[O:27][Si:28]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:30])[CH3:31])[O:19][CH2:18]2)[C@H:15]1[OH:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[Si](Cl)(O[Si](Cl)(C(C)C)C(C)C)C(C)C
Reactant: OC[C@@H]1[C@@H](O)[C@@H](O)[C@@H](OCc2ccccc2)C12CC2
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si]1(C(C)C)OC[C@@H]2[C@@H](O[Si](C(C)C)(C(C)C)O1)[C@@H](O)[C@@H](OCc1ccccc1)C21CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
To a stirred mixture of triol 24 (2.9 g, 10.9 mmol) and imidazole (5.2 g, 76.8 mmol) in DMF (80 mL) at 0° C. under argon was added dropwise 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (3.5 mL, 11.0 mmol). After the mixture was stirred at room temperature for 1 h, quenched with MeOH (15 mL) and water (100 mL) was added and the mixture was extracted with EtOAc (2×200 mL). The combined organic layers were washed with brine (40 mL) dried over Na2SO4. The solvent was removed and the residue was purified by silica gel column chromatography (EtOAc:Hexane 1:30 to 1:5) to give 25 (5.1 g, 92%) as an oil. [α]24D−105.94° (c 0.58, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.41-7.26 (m, 5H), 4.77 (d, J=12 Hz, 1H), 4.62 (d, J=12 Hz, 1H), 4.18-4.14 (m, 3H), 4.05 (dd, J=4.5, 12.0 Hz, 1H), 3.78 (dd, J=8, 12 Hz, 1H), 2.89 (m, 1H), 2.78 (d, J=2.0 Hz, 1H, OH) 1.08-0.97 (m, 28H), 0.61 (m, 1H), 0.43 (m, 1H), 0.32 (m, 1H), 0.24 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 154.0, 147.3, 138.1, 128.4, 80.2, 74.2, 71.2, 71.1, 64.9, 50.1, 29.24 23.83, 17.6, 17.5, 17.4, 17.3, 17.2, 17.1, 17.0, 16.9, 16.8, 13.4, 12.9, 12.7, 12.5. 7.20; HR-MS Calcd. For (C27H46O5Si2+H)+ 507.2884. found 507.2798.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:4]=1[C:5]([NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]([F:17])([F:16])[F:15])[CH2:10][CH2:9]1)=[O:6].CC1C(O)=C(C=O)C(COP(O)(O)=O)=CN=1.O>CO.[Pd].[H][H]>[NH2:22][C:19]1[CH:20]=[CH:21][C:3]([N:2]([CH3:25])[CH3:1])=[C:4]([CH:18]=1)[C:5]([NH:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([C:14]([F:16])([F:17])[F:15])[CH2:12][CH2:13]1)=[O:6]
Reactant: [H][H]
Reactant: CN(C)c1ccc([N+](=O)[O-])cc1C(=O)N[C@H]1CC[C@H](C(F)(F)F)CC1
Agent: [Pd]
Agent: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Solvent: O
Solvent: CO
Product: CN(C)c1ccc(N)cc1C(=O)N[C@H]1CC[C@H](C(F)(F)F)CC1

Procedure:
Prepared analogously to example 4b with 2-dimethylamino-5-nitro-N-(trans-4-trifluoromethylcyclohexyl)-benzamide (50 mg; 0.14 mmol) with Pd/C/H2 (15 mg/50 psi) in 10 mL MeOH. Yield: quantitative; MS: [m+H]+=330; HPLC: Rt=1.14 min (Method MC-1)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20](OCC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:26][C:27]([CH3:31])([CH3:30])[CH2:28][OH:29]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:26][C:27]([CH3:31])([CH3:30])[CH2:28][OH:29])=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Reactant: CC(C)(N)CO
Solvent: CN(C)C=O
Product: CC(C)(CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-amino-2-methyl-1-propanol employing methods similar to those described in Example 2 and using N,N-dimethylformamide as the reaction solvent. The product was obtained as an off-white solid: 1H NMR (d6-DMSO) tautomers are observed δ 11.95 (1H, br s), 10.95 (1H, br s), 10.01 (1H, br s), 8.17 (0.70H, s), 8.13 (0.30H, s), 7.34-7.25 (3H, m), 7.15-7.09 (2H, m), 4.86 (1H, br s), 3.98 (2H, s), 3.50-3.41 (2H, m), 1.29 (3H, s), 1.24 (3H, s); HRMS calcd for C20H20FN3O4+H+: 386.1516. Found 386.1521.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]=[O:10])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:20])([F:19])[F:18].S(=O)(=O)([OH:23])N.Cl([O-])=O.[Na+].CCCCCC>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([OH:23])=[O:10])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:18])([F:19])[F:20]
Reactant: COc1cc(C=O)ccc1-c1ccccc1C(F)(F)F
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(C(=O)O)ccc1-c1ccccc1C(F)(F)F
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
The 2-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-carboxaldehyde of Step B (0.95 g, 3.41 mmol) and sulfamic acid (0.43 g, 4.43 mmol) were dissolved in a mixture of tetrahydrofuran and water (1:1, v/v, 30 mL). Sodium chlorite (0.31 g, 4.43 mmol) was added under stirring, and the solution turned yellow. After 30 minutes, additional sodium chlorite (0.1 g) and sulfamic acid were added, and the solution stirred an additional hour. The solution was then concentrated, and the residue partitioned between ethyl acetate and water. The ethyl acetate layer was dried and concentrated to yield an oil, which solidified upon trituration with hexane to provide the title compound (0.84 g) as a yellow solid, which was used in the next step.
Reaction SMILES: [C:1]1(=[O:19])[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](Cl)=[O:12])[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12.[N+](=[CH:22][CH3:23])=[N-].[ClH:24]>C1(C)C=CC=CC=1.CC(C)=O>[Cl:24][CH:22]([CH3:23])[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]2[C:1]1=[O:19]
Reactant: O=C(Cl)CCCCCN1C(=O)c2ccccc2C1=O
Reactant: CC=[N+]=[N-]
Reactant: Cl
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: CC(Cl)C(=O)CCCCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 6-phthalimidohexanoyl chloride (2 g.) in dry toluene was added to an ethereal solution of diazoethane at -78° C. and the mixture was allowed to warm to room temperature and stand for 15 hours. On standing a solid crystallized out of solution. The reaction mixture was filtered and the filtrate evaporated to dryness giving 1.43 g. of yellow-green oil. This oil was then dissolved in acetone and concentrated hydrochloric acid added until effervescence ceased. The resulting yellow-brown solution was then evaporated to dryness and azeotroped three times with toluene to give N-(7-chloro-6-oxooctyl)phthalimide (1.4 g.) which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:16]2[CH:17]=[C:18]([CH:24]=[CH:25][C:26]([O:28]CC)=[O:27])[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[CH3:31][O:32][CH2:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39]Cl)=[CH:37][CH:36]=1>>[CH3:23][O:22][C:21]1[CH:20]=[CH:19][C:18]([CH:24]=[CH:25][C:26]([OH:28])=[O:27])=[CH:17][C:16]=1[C:3]1[C:2]([O:1][CH2:39][C:38]2[CH:41]=[CH:42][C:35]([O:34][CH2:33][O:32][CH3:31])=[CH:36][CH:37]=2)=[CH:11][C:10]2[C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=2[CH:4]=1
Reactant: CCOC(=O)C=Cc1ccc(OC)c(-c2cc3c(cc2O)C(C)(C)CCC3(C)C)c1
Reactant: COCOc1ccc(CCl)cc1
Product: COCOc1ccc(COc2cc3c(cc2-c2cc(C=CC(=O)O)ccc2OC)C(C)(C)CCC3(C)C)cc1
Yield: 92.4 %

Procedure:
In a manner similar to that of Example 1(a), by reaction of 2.5 g (6.12 mmol) of ethyl 3-[3-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyphenyl]acrylate obtained in Example 13(f) with 1.26 g (6.73 mmol) of 4-methoxymethoxybenzyl chloride obtained above, 3.0 g (87%) of the expected compound were obtained in the form of a white powder having a melting point of 106°-108° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([Cl:13])=[CH:6][C:5]=1[NH2:14].[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH2:21][C:22](Cl)=[O:23]>>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([Cl:13])=[CH:6][C:5]=1[NH:14][C:22](=[O:23])[CH2:21][C:17]1[S:16][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)Cc1cccs1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)cc1N
Product: COC(=O)c1cc([N+](=O)[O-])c(Cl)cc1NC(=O)Cc1cccs1
Reaction time: 18 h
Yield: 67.6 %

Procedure:
To a suspension of 2-amino-4-chloro-5-nitrobenzoic acid methyl ester (221 mg in 2.5 mL of dry 1,2-dichloroethane) was added a solution of thiophen-2-yl-acetyl chloride (169 mg in 3.0 mL dry 1,2-dichloroethane) and the mixture heated at reflux on an oil bath. After 18 hours, the reaction was cooled and the solvent removed in vacuo. Recrystallization of the crude product from methanol gave the title compound (230 mg).
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([N:10]2[C:14]([CH:15]([CH3:17])[CH3:16])=[N:13][N:12]=[N:11]2)[CH:7]=[C:6]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=2)[CH:5]=1.[Li+].[OH-].Cl>CO.O.C1COCC1>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:6]2[CH:5]=[C:4]([CH:9]=[C:8]([N:10]3[C:14]([CH:15]([CH3:17])[CH3:16])=[N:13][N:12]=[N:11]3)[CH:7]=2)[C:3]([OH:25])=[O:2])=[N:19][CH:20]=1
Reactant: COC(=O)c1cc(-c2ccc(Cl)cn2)cc(-n2nnnc2C(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1nnnn1-c1cc(C(=O)O)cc(-c2ccc(Cl)cn2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.2 %

Procedure:
3-(5-Chloro-pyridin-2-yl)-5-(5-isopropyl-tetrazol-1-yl)-benzoic acid methyl ester (1.84 g, 5.14 mmol) was dissolved in a mixture of MeOH (15 mL), water (2 mL) and THF (2 mL), and LiOH 308 mg, 12.86 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours, made pH neutral by addition of 1N HCl, and then extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure to give 1.70 g of 3-(5-chloro-pyridin-2-yl)-5-(5-isopropyl-tetrazol-1-yl)-benzoic acid, Mp=179.5-181.2° C., MS (M+H)=344.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:21][N:6]2[C:7]3[C:12]([C:13]([CH2:14][C:15]([O:17][CH2:18][CH2:19][CH3:20])=[O:16])=[C:5]2[CH2:4][CH2:3]1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[CH3:22]C(OC(OC(OC(C)(C)C)=O)=O)(C)C>CO>[CH3:22][NH:1][C@H:2]1[CH2:21][N:6]2[C:7]3[C:12]([C:13]([CH2:14][C:15]([O:17][CH2:18][CH2:19][CH3:20])=[O:16])=[C:5]2[CH2:4][CH2:3]1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](N)CC2
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CO
Product: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Reaction time: 2 h

Procedure:
Propyl [(7R)-7-amino-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate (2.5 g) and TEA (1.4 mL) were dissolved in 87 mL MeOH. Boc2O (2.1 g) was added in 10 mL MeOH, and the mixture was stirred for 2 h. The solvent was removed and propyl {(7R)-7-[(tert-butoxycarbonyl)amino]-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl}acetate was purified on silica gel (ethyl acetate/hexanes). Propyl {(7R)-7-[(tert-butoxycarbonyl)amino]-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl}acetate (3.15 g) was dissolved in DMF (81 mL). The mixture was cooled in an ice bath and MeI (3.47 g) was added followed by NaH (342 mg, 60% w/w in mineral oil). The ice bath was removed after 0.5 h, and the mixture was stirred for 1 h at RT. The reaction was quenched with ½ (sat.) aqueous ammonium chloride. Work up consisted of extraction of the aqueous layer with ether (2×). The combined organic fractions were washed with water and brine, then dried (MgSO4). The solvent was evaporated under reduced pressure and propyl {(7R)-7-[(tert-butoxycarbonyl)(methyl)amino]-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl}acetate was purified on silica gel (ethyl acetate/hexanes). {(7R)-7-[(tert-butoxycarbonyl)-(methyl)amino]-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl}acetate and anisole (2.2 g) were dissolved in 66 mL DCM. 66 mL of TFA was added and the mixture was stirred for 1 h. The mixture was then stripped several times with toluene. Work up consisted of extraction with dichloromethane (3×) from aqueous sodium carbonate. The combined organic fractions were washed with brine and dried (MgSO4). The solvent was evaporated under reduced pressure and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate was obtained after purification on silica gel. (MeOH/DCM).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[F:13][C:14]([F:27])([F:26])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22](=[O:25])[CH2:23]Cl.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:23][C:22]([NH:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14]([F:13])([F:26])[F:27])=[O:25])[CH2:11][CH2:12]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C(CCl)Nc1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CN1CCN(c2ccccn2)CC1)Nc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
A mixture of 1-pyridin-2-ylpiperazine (24 mg, 0.15 mmol, Aldrich), N-(2-trifluoromethylphenyl)-2-chloroacetamide (48 mg, 0.20 mmol, Maybridge) and sodium carbonate (50 mg) in N,N-dimethylformamide/water (2:1, 2 mL) was shaken at room temperature for 18 hours. The resulting mixture was decanted, concentrated under reduced pressure and the residue purified by preparative HPLC to provide 41 mg (75%) of the desired product. 1H NMR (500 MHz, DMSO-d6) δ 2.65 (t, J=4 Hz, 4H), 3.23 (s, 2H), 3.58 (t, J=4 Hz, 4H), 6.65 (t, J=5 Hz, 1H), 6.85 (d, J=6 Hz, 1H), 7.38 (t, J=6 Hz, 1H), 7.55 (t, J=6 Hz, 1H), 7.73 (m, 2H), 8.15 (d, J=5 Hz, 1H), 8.22 (d, J=6 Hz, 1H), 9.95 (s, 1H); MS (ESI/APCI+) m/e 365 (M+H)+.
Reaction SMILES: [C:1](=[O:38])([O:3][C:4]([CH3:37])([CH3:36])[CH2:5][C@@H:6]([CH2:17][C:18]([N:21]1[CH2:25][CH2:24][C@H:23]2[CH2:26][N:27]([C:29]([C:31]3([C:34]#[N:35])[CH2:33][CH2:32]3)=[O:30])[CH2:28][C@@H:22]12)=[C:19]=[O:20])[CH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[F:16])[NH2:2].OO.C(=O)([O-])[O-:42].[K+].[K+].O>CS(C)=O>[C:1](=[O:38])([O:3][C:4]([CH3:36])([CH3:37])[CH2:5][C@@H:6]([CH2:17][C:18]([N:21]1[CH2:25][CH2:24][C@H:23]2[CH2:26][N:27]([C:29]([C:31]3([C:34]([NH2:35])=[O:42])[CH2:32][CH2:33]3)=[O:30])[CH2:28][C@@H:22]12)=[C:19]=[O:20])[CH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[F:16])[NH2:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C[C@@H](CC(=C=O)N1CC[C@H]2CN(C(=O)C3(C#N)CC3)C[C@H]21)Cc1cc(F)c(F)cc1F)OC(N)=O
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C[C@@H](CC(=C=O)N1CC[C@H]2CN(C(=O)C3(C(N)=O)CC3)C[C@H]21)Cc1cc(F)c(F)cc1F)OC(N)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 83 %

Procedure:
(R)-4-((3aS,6aS)-5-(1-cyanocyclopropylcarbonyl)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-4-carbonyl-1-(2,4,5-trifluorophenyl)butan-2-yltertbutyl carbamate 17a (300 mg, 0.58 mmol) was dissolved in DMSO (5 mL), added 30% of hydrogen peroxide (0.5 mL) and potassium carbonate (160 mg, 1.16 mmol) at 0° C., the temperature of reaction solution was raised to room temperature and stirred for 5 minutes, added water (20 mL), extracted by dichloromethane, dried by anhydrous sodium sulfate, concentrated, residues was purified by column chromatography to give (R)-4-((3aS,6aS)-5-(1-aminocarbonylcyclopropylcarbonyl)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-4-carbonyl-1-(2,4,5-trifluorophenyl)butan-2-yltertbutyl carbamate 28a (265 mg, 85%) as white foamy solid. MS m/z (ESI): 539.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])=[C:6]([OH:8])[CH:7]=1.[CH3:13][O:14][CH2:15][CH2:16][CH2:17]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[C:9]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][C:6]=1[O:8][CH2:17][CH2:16][CH2:15][O:14][CH3:13])([CH3:12])([CH3:11])[CH3:10]
Reactant: COCCCBr
Reactant: CC(C)(C)c1ccc(Br)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COCCCOc1cc(Br)ccc1C(C)(C)C
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A suspension of 2.60 g of 5-bromo-2-tert-butyl-phenol, 4.34 g of 3-methoxypropyl bromide and 5.55 g of caesium carbonate in 40 ml of acetone is stirred at 60° C. overnight After cooling to room temperature, the mixture is filtered and the crude product obtained after concentration of the filtrate is purified by means of FC (80 g of silica gel, hexane/ethyl acetate=98:2). The title compound is obtained in the form of an oil: Rf (hexane/ethyl acetate=9:1)=0.56.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:10]([CH2:11][CH:12]=O)=[C:4]2[CH:3]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:10]([CH2:11][CH2:12][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[C:4]2[CH:3]=1
Reactant: COc1ccc(-c2nn3ccc(Br)cc3c2CC=O)cc1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc(-c2nn3ccc(Br)cc3c2CCN2CCCCC2)cc1
Temperature: 20 °C
Reaction time: 17 h

Procedure:
To a solution of 2-(5-bromo-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl)acetaldehyde (40 mg, 0.12 mmol) and piperidine (23 μl, 0.23 mmol) in 1,2-dichloroethane (3.5 ml) was added sodium triacetoxyborohydride (49 m, 0.23 mmol). The reaction mixture was stirred at 20° C. for 17 h. The reaction mixture was diluted with dichloromethane (10 mL) and washed with a 5% sodium bicarbonate solution (6 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give a residue that was purified by automated ISCO chromatography (methanol/dichloromethane; 5/95). The title compound was obtained as a white solid (28 mg, 58%). LCMS m/z 414.1, 416.1 (M+H)+, ret. time=1.76 min.