Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[CH:24])=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[O:30]1[CH2:35][CH2:34][C:33](=[O:36])[CH2:32][CH2:31]1.[Cl-].[NH4+]>O1CCCC1>[CH2:16]([O:15][C:14]1[CH:13]=[C:12]([C:23]#[C:24][C:33]2([OH:36])[CH2:34][CH2:35][O:30][CH2:31][CH2:32]2)[N:11]=[N:10][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1CCOCC1
Reactant: C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.6 %

Procedure:
3,4-bis(Benzyloxy)-6-ethynylpyridazine (Intermediate 5; 3.0 g, 9.49 mmol) was dissolved in tetrahydrofuran (24 ml) under nitrogen atmosphere and the resulting solution was cooled to −78° C. n-Butyl lithium (23% solution in hexane; 7.92 ml, 28.48 mmol, 3.0 eq) was added slowly at −78° C., and the resulting mixture was allowed to stir for 30 minutes. Dihydro-2H-pyran-4(3H)-one (1.0 g, 10.44 mmol, 1.1 equiv.) was added slowly to reaction mass and the whole was allowed to warm to room temperature. The crude mixture was then poured into a saturated solution of aqueous ammonium chloride (300 ml) and product was extracted into ethyl acetate (100 ml×2). The organic layer was separated, washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (eluting with 0-30% ethyl acetate in hexane) to yield the desired material (2.0 g, 501% yield).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[I-:16].[Na+].CC1C=CC(S([N-]Cl)(=O)=O)=CC=1.O.O.O.[Na+].Cl>CN(C=O)C.O>[CH2:6]([O:5][P:4]([C:9]1[CH:14]=[C:13]([I:16])[CH:12]=[CH:11][C:10]=1[OH:15])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(OCC)c1ccccc1O
Reactant: [I-]
Agent: Cc1ccc(S(=O)(=O)[N-]Cl)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)c1cc(I)ccc1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.5 %

Procedure:
To a cooled (0° C.) mixture of (2-hydroxy-phenyl)-phosphonic acid diethyl ester (13.1 g, 56.9 mmol) and sodium iodide (10.2 g, 68.3 mmol) in DMF (200 mL) was added chloramine-T trihydrate (19.2 g, 68.3 mmol) over 5 min. After 10 min, the reaction was allowed to warm to rt and the mixture was allowed to stir at rt for 2 h. The mixture was diluted with H2O (50 mL), acidified using 0.5 N HCl and extracted twice with EtOAc. The organic extracts were pooled and washed sequentially with satd. Na2S2O3/brine (1/1) and then brine. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was chromatographed over silica gel (elution with a stepwise gradient 5-15% EtOAc-hexanes) to give 14.9 g (73%) of a colorless solid after recrystallization (EtOAc-hexanes). Rf 0.30 (20% EtOAc-hexanes). Electrospray Mass Spectrum (50/50 acetonitrile/water) m/z 357 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][C@H:18]([C:35]#[N:36])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28]([F:34])[CH:27]=2)=[CH:22][CH:21]=1.C(N(CC)CC)C.O>CN(C=O)C.[Cl-].[Na+].O>[C:35]([C@@H:18]([NH:17][C:14]([C@@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28]([F:34])[CH:27]=2)=[CH:22][CH:21]=1)#[N:36]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)O
Reactant: N#Cc1ccc(-c2ccc(C[C@H](N)C#N)cc2)cc1F
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@H](C#N)Cc1ccc(-c2ccc(C#N)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.6 %

Procedure:
A 50% solution of propane phosphonic acid anhydride (0.964 g) (T3P) in DMF was added to a stirred solution of (S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (0.290 g), (S)-4′-(2-amino-2-cyanoethyl)-3-fluorobiphenyl-4-carbonitrile (0.335 g) and triethylamine (0.880 mL) in DMF (3 mL) at 0° C. The resulting solution was allowed to warm to RT and stirred for 18 h. The mixture was poured into water and brine and the mixture extracted with ethyl acetate. The organics were washed with saturated brine, dried and evaporated. The crude product was purified by flash silica chromatography, eluting with 30% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to afford (S)-tert-butyl 2-((S)-1-cyano-2-(4′-cyano-3′-fluorobiphenyl-4-yl)ethylcarbamoyl)piperidine-1-carboxylate as a colourless solid (0.443 g).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2([OH:12])[CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[CH2:24]([Sn:28](Cl)([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH3:27].[Cl-].[NH4+]>O1CCCC1>[CH2:33]([Sn:28]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:29][CH2:30][CH2:31][CH3:32])[C:2]1[N:7]=[C:6]([C:8]2([OH:12])[CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1)[CH2:34][CH2:35][CH3:36]
Reactant: OC1(c2cccc(Br)n2)CCC1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cccc(C2(O)CCC2)n1
Reaction time: 0.5 h

Procedure:
Tetrahydrofuran (10 mL) solution of 293.1 mg of 1-(6-bromo-2-pyridinyl)cyclobutanol obtained in Example 69-1 was cooled to −78° C. in an acetone/dry ice bath in a nitrogen atmosphere, and 1.8 mL of 1.58 M n-butyllithium/hexane solution was gradually added thereto, and stirred for 30 minutes. Subsequently, tetrahydrofuran (2.0 mL) solution of 0.36 mL of tri-n-butyltin chloride was added thereto at −78° C., and the reaction solution was stirred for 30 minutes. This was processed with aqueous saturated ammonium chloride solution, extracted with ethyl acetate, and the organic layer was washed with saturated saline water, and purified through silica gel column chromatography (hexane/ethyl acetate) to obtain 48.7 mg of the entitled compound as a pale yellow oily substance.
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[CH:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=[CH:6][C:5]=2[N:4]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:3]12.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:36])=[C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH2:34][NH2:35])[CH2:28][CH2:27]2)[CH:25]=1.CCN(C(C)C)C(C)C.C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:36])=[C:24]([N:26]2[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][CH2:34][NH:35][C:12]([C:8]3[CH:7]=[CH:6][C:5]4[N:4]5[CH2:15][CH2:16][CH2:17][CH2:18][CH:3]5[C:2](=[O:1])[NH:11][C:10]=4[CH:9]=3)=[O:14])[CH2:30][CH2:31]2)[CH:25]=1
Reactant: O=C(O)c1ccc2c(c1)NC(=O)C1CCCCN21
Reactant: Cc1ccc(Cl)cc1N1CCN(CCCN)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1ccc(Cl)cc1N1CCN(CCCNC(=O)c2ccc3c(c2)NC(=O)C2CCCCN32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 1582.5 %

Procedure:
To a solution of 6,6a,7,8,9,10-hexahydro-6-oxo-5H-pyrido[1,2-a]quinoxaline-3-carboxylic acid (200 mg, 0.80 mmole), 3-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)propan-1-amine (1.0 mmol), DMAP (10 mg) and DIPEA (0.30 mL) in DMF (5 mL) was added EDC (0.377 g, 2.0 mmole). The reaction solution was stirred at room temperature overnight. The solvent removed and EtOAc (60 mL) was added. The organic layer was washed with saturated sodium bicarbonate (10 mL), water (10 mL) and dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified by column chromatography with 0-10% methanol in dichloromethane to provide the N-(3-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)propyl)-6,6a,7,8,9,10-hexahydro-6-oxo-5H-pyrido[1,2-a]quinoxaline-3-carboxamide as white solid (6.28 g,78%). 1HNMR (300 MHz, dmso-d6), ppm: 10.48 (s, 1H), 8.27 (t, 1H), 7.41 (dd, 1H), 7.29 (d, 1H), 7.15 (d, 1H), 6.97 (d, 1H), 6.96 (s, 1H), 6.83 (d. 1H), 3.83 (d, 1H), 3.57 (dd, 1H), 3.26 (q, 2H), 2.84 (m, 4H), 2.73 (dt, 1H), 2.40 (t, 2H), 2.20 (s, 3H), 2.00 (m, 1H), 1.83 (m, 1H), 1.69 (m, 3H), 1.52-1.33 (m, 3H). MS (ESI+) M/z: 496, 498 (M+H).
Reaction SMILES: [C:1]([C@H:5]1[C:9](=[O:10])OC(=O)[NH:6]1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH:13]1[CH2:16][CH2:15][CH2:14]1>C(O)C>[NH2:6][C@@H:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:9]([N:13]1[CH2:16][CH2:15][CH2:14]1)=[O:10]
Reactant: C1CNC1
Reactant: CC(C)(C)[C@@H]1NC(=O)OC1=O
Agent: Cl
Solvent: CCO
Product: CC(C)(C)[C@H](N)C(=O)N1CCC1
Yield: 98.7 %

Procedure:
(S)-4-tert-butyloxazolidine-2,5-dione (1.59 g, 10.12 mmol) and azetidine hydrochloride (0.946 g, 10.12 mmol) were combined in ethanol (5 mL) in a 2 mL microwave vial. The vial was capped and subjected to microwave irradiation at 150° C. for 10 min. The reaction was concentrated under reduced pressure and azeotroped with twice with toluene (5 mL) to provide the desired (S)-2-amino-1-(azetidin-1-yl)-3,3-dimethylbutan-1-one as a brown oil (1.7 g, 99%) that was used without further purification. LCMS (+ESI) m/z: 171.1 [M+H]+.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:22]O>>[N:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([O:14][CH3:22])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(-c2ccncc2)cc1

Procedure:
4-(4-Pyridyl)benzoic acid hydrochloride (12.4 g) was dissolved in methanol (200 ml), concentrated sulfuric acid (5 ml) was added at room temperature, and the mixture was heated under reflux for 3 hours. After completion of the reaction, the solvent was distilled off, and a saturated aqueous solution of sodium hydrogencarbonate was added to the residue to extract it with ethyl acetate. The extract was dried over anhydrous sodium sulfate, the solvent was distilled off, and hexane was added to the residue to solidify it, thereby obtaining the title compound (9.86 g) as colorless powder.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[OH:14][CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]2[CH:21]3[CH2:30][CH2:29][CH2:28][CH:22]3[C:23](=[O:27])[NH:24][C:25]=2[CH:26]=1>CN(C=O)C.CCOCC>[Si:1]([O:14][CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]2[CH:21]3[CH2:30][CH2:29][CH2:28][CH:22]3[C:23](=[O:27])[NH:24][C:25]=2[CH:26]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1Nc2cc(CCO)ccc2C2CCCC12
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCCc1ccc2c(c1)NC(=O)C1CCCC21
Reaction time: 4 h
Yield: 84.7 %

Procedure:
At 0° C., 0.62 g (5.4 mmol) of tert-butyldimethylsilyl chloride and 0.72 g (10.7 mol) of imidazole are added to a solution of 0.62 g (2.7 mmol) of 7-(2-hydroxyethyl)-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one in 10 ml of DMF. After 4 hours at room temperature, the batch is diluted with ether, washed with water, 10% citric acid and saturated NaHCO3, dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography with hexane-ethyl acetate on silica gel yields 0.79 g of product.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].O>CN(C)C=O>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:23][CH:24]=3)[N:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCN(c2nc(-c3ccc(O)cc3)cc3ccccc23)CC1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(-c2cc3ccccc3c(N3CCN(CC)CC3)n2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The resulting 1-(4-ethylpiperazin-1-yl)-3-(4-hydroxyphenyl)isoquinoline (0.57 g) was dissolved in N,N-dimethylformamide (5 ml), to which were added potassium carbonate (0.24 g) and ethyl bromoacetate (210 ml), and the mixture was stirred at room temperature for 2 days. Water was added to the reaction solution, followed by the extraction with ethyl acetate. The extract was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give obtain 1-(4-ethylpiperazin-1-yl)-3-[4-(ethoxycarbonylmethoxy)phenyl]isoquinoline (0.57 g) as a pale yellow viscous oil.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[N:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][N:10]=1.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[CH:30]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(Cl)Cl>[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[CH2:30][N:7]1[CH2:6][CH:5]2[CH2:1][N:2]([C:9]3[N:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][N:10]=3)[CH2:3][CH:4]2[CH2:8]1
Reactant: CCOC(=O)c1cnc(N2CC3CNCC3C2)nc1
Reactant: O=Cc1ccc2ccccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(=O)c1cnc(N2CC3CN(Cc4ccc5ccccc5c4)CC3C2)nc1
Reaction time: 3 h
Yield: 93.1 %

Procedure:
To a solution of ethyl 2-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-ylpyrimidine-5-carboxylate (0.187 g, 0.71 mmol) in DCE (2 ml) was added 2-naphthaldehyde (0.205 g, 1.31 mmol) and sodium triacetoxyborohydride (0.274 g, 1.25 mmol). The mixture was stirred for 3 h, then poured into DCM (100 ml). Sat. NaHCO3 (100 ml) was added, and extracted with further DCM (100 ml). The combined organic extracts were dried (MgSO4), concentrated and purified by flash column chromatography to yield the title compound (0.266 g, 99%). 1H NMR (300 MHz, CDCl3) δ: 1.39 (3H, t, J=6.9 Hz), 2.59 (2H, d, J=6.9 Hz), 2.73-2.90 (2H, m), 2.94-3.10 (2H, m), 3.67 (2H, d, J=11.7 Hz), 3.82 (2H, s), 3.90 (2H, dd, J=8.1, 12 Hz), 4.37 (2H, q, J=7.2 Hz), 7.41-7.43 (3H, m), 7.74 (1H, s), 7.76-7.89 (3H, m), 8.88 (2H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:19][C@H:20]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)[CH3:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:6]([CH:10]=1)[C:7]([NH:19][C@H:20]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)[CH3:21])=[O:9]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)c1cc(Cl)ccc1COC1CCCC1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2COC2CCCC2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 1 from 5-chloro-2-[(cyclopentyloxy)methyl]benzoic acid (step 1) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 5 of Example 1):
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](Cl)=[N:11][CH:12]=[N:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][C:26]=1[F:32])#[N:24].[H-].[Na+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10]([NH:29][C:28]2[CH:30]=[CH:31][C:25]([C:23]#[N:24])=[C:26]([F:32])[CH:27]=2)=[N:11][CH:12]=[N:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(N)cc1F
Reactant: Cc1ccc(-c2ncnc(Cl)c2OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ncnc(Nc3ccc(C#N)c(F)c3)c2OCc2ccccc2)cc1
Reaction time: 1 h
Yield: 76.1 %

Procedure:
The compound from step 4 (0.3 g, 0.96 mmol) was dissolved in DMF (4.83 ml), 4-cyano-3-fluoroaniline (0.131 g, 1 eq) and NaH (0.155 g of 60% dispersion in mineral oil, 4 eq) were added. After 1 hour LCMS showed complete conversion, the reaction was quenched with NH4Cl(sat) and extracted with EtOAc. The extracts were dried concentrated and the residue purified by silica gel chromatography (0-20% EtOAc in hexane) to give 0.3 g of the title compound.
Reaction SMILES: [Na].[CH3:2][C:3]1[C:8]([CH3:9])=[C:7]([N+]([O-])=O)[C:6]([CH3:13])=[CH:5][N+:4]=1[O-:14].Cl.[CH3:16][OH:17]>C(OCC)(=O)C>[CH3:16][O:17][C:7]1[C:6]([CH3:13])=[CH:5][N+:4]([O-:14])=[C:3]([CH3:2])[C:8]=1[CH3:9]
Reactant: Cc1c[n+]([O-])c(C)c(C)c1[N+](=O)[O-]
Reactant: CO
Agent: Cl
Agent: [Na]
Solvent: CCOC(C)=O
Product: COc1c(C)c[n+]([O-])c(C)c1C

Procedure:
22.6 g of sodium were dissolved in 4 1 of methanol under argon. 120 g of 2,3,5-trimethyl-4-nitropyridine 1-oxide were then added portionwise thereto and the solution was left to boil under reflux overnight. The pH was adjusted to 7 by means of 5N hydrogen chloride in ethyl acetate while cooling and the mixture was then evaporated in vacuo. The residue was taken up in 1.5 1 of methylene chloride, the solution was filtered through silica gel, which was rinsed with 0.5 1 of methylene chloride, the combined filtrates were evaporated in vacuo and the residue was crystallized from petroleum ether. There was obtained 4-methoxy-2,3,5-trimethylpyridine 1-oxide of melting point 48-50° .
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][O:12][C:13]3[CH:34]=[CH:33][C:16]([CH2:17][N:18]4[CH:22]=[C:21]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20]([O:30][CH2:31][CH3:32])=[N:19]4)=[CH:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C1(C)C=CC=CC=1>[CH2:31]([O:30][C:20]1[C:21]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][N:18]([CH2:17][C:16]2[CH:33]=[CH:34][C:13]([O:12][CH2:11][C:9]3[N:10]=[C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[N:7]4[CH:8]=3)=[CH:14][CH:15]=2)[N:19]=1)[CH3:32]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3cn4c(Cl)cccc4n3)cc2)nc1OCC
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: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3cn4c(-c5ccccc5)cccc4n3)cc2)nc1OCC
Yield: 96.3 %

Procedure:
A mixture of ethyl 3-[1-[4-(5-chloroimidazo[1,2-a]pyridin-2-ylmethoxy)benzyl]-3-ethoxy-1H-pyrazol-4-yl]propionate (676 mg), phenylboronic acid (195 mg), tetrakis(triphenylphosphine)palladium (40.4 mg), sodium carbonate (339 mg), ethanol (3 ml), water (3 ml) and toluene (15 ml) was refluxed overnight under an argon atmosphere. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-ethoxy-1-[4-(5-phenylimidazo[1,2-a]pyridin-2-ylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (707 mg, yield: 96%) as colorless crystals from the fraction eluted with ethyl acetate. This was recrystallized from ethyl acetate-hexane. Melting point: 104–105° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[C:12]([O:14][CH3:15])=[O:13])[CH2:3][CH2:2]1.[O:16]=[C:17]1[N:23]([CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C@@H:33]([C:46](O)=[O:47])[CH2:34][C:35]3[CH:44]=[C:43]([CH3:45])[C:38]4[NH:39][C:40](=[O:42])[O:41][C:37]=4[CH:36]=3)=[O:31])[CH2:26][CH2:25]2)[CH2:22][CH2:21][C:20]2[CH:49]=[CH:50][CH:51]=[CH:52][C:19]=2[NH:18]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[O:16]=[C:17]1[N:23]([CH:24]2[CH2:25][CH2:26][N:27]([C:30]([O:32][C@H:33]([CH2:34][C:35]3[CH:44]=[C:43]([CH3:45])[C:38]4[NH:39][C:40](=[O:42])[O:41][C:37]=4[CH:36]=3)[C:46]([N:1]3[CH2:2][CH2:3][CH:4]([N:7]4[CH2:11][CH2:10][CH2:9][C@H:8]4[C:12]([O:14][CH3:15])=[O:13])[CH2:5][CH2:6]3)=[O:47])=[O:31])[CH2:28][CH2:29]2)[CH2:22][CH2:21][C:20]2[CH:49]=[CH:50][CH:51]=[CH:52][C:19]=2[NH:18]1
Reactant: COC(=O)[C@@H]1CCCN1C1CCNCC1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc2oc(=O)[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CCCN1C1CCN(C(=O)[C@@H](Cc2cc(C)c3[nH]c(=O)oc3c2)OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
93 mg (0.44 mmol) methyl (S)-1-piperidin-4-yl-pyrrolidine-2-carboxylate were added to a solution of 200 mg (0.39 mmol) (R)-1-carboxy-2-(4-methyl-2-oxo-2,3-dihydrobenzoxazol-6-yl)-ethyl 4-(2-oxo-1,2,4,5,-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 140 mg (0.44 mmol) TBTU and 61 μL (0.44 mmol) triethylamine in 2 mL DMF and the reaction mixture was shaken overnight at RT. The reaction solution was purified by HPLC without working up; the fractions containing the product were concentrated by evaporation and lyophilised.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([CH3:31])[O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:24]=[N:25][C:26]([CH3:29])=[CH:27][CH:28]=3)=[C:18]([CH3:30])[CH:17]=1)=[N:8][CH:9]=[N:10]2.[OH:32][C@H:33]1[CH2:38][CH2:37][O:36][C:34]1=[O:35]>>[OH:32][C@@H:33]([CH2:38][CH2:37][OH:36])[C:34]([NH:1][CH2:2][C@H:3]([O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:24]=[N:25][C:26]([CH3:29])=[CH:27][CH:28]=3)=[C:18]([CH3:30])[CH:17]=1)=[N:8][CH:9]=[N:10]2)[CH3:31])=[O:35]
Reactant: O=C1OCC[C@@H]1O
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4cccc(O[C@H](C)CN)c34)cc2C)cn1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4cccc(O[C@H](C)CNC(=O)[C@@H](O)CCO)c34)cc2C)cn1
Yield: 53 %

Procedure:
The procedure described in Example 63 was repeated using 5-[(1R)-2-amino-1-methylethoxy]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine and (S)-α-hydroxybutyrolactone to give the title compound in 53% yield as a solid; NMR Spectrum: (CDCl3) 1.55 (d, 3H), 1.79 (m, 1H), 2.05 (m, 1H), 2.26 (s, 3H), 2.49 (s, 3H), 3.90-3.65 (m, 4H), 4.21 (dd, 1H), 4.94 (m, 1H), 6.96 (m, 2H), 7.11 (d, 1H), 7.23 (dd, 1H), 7.39 (d, 1H), 7.43 (m, 1H), 7.60-7.52 (m, 2H), 7.69 (s, 1H), 8.00 (s, 1H), 8.55 (s, 1H); Mass spectrum: MH+ 518.