Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:5]=[CH:6][C:7]2[C:16](=[O:17])[N:15]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[CH:23]=3)[CH2:14][C@H:13]3[N:9]([CH2:10][CH2:11][CH2:12]3)[C:8]=2[N:30]=1)[CH3:2].C=O.[C:33](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[CH2:1]([NH:3][C:4]1[N:5]=[CH:6][C:7]2[C:16](=[O:17])[N:15]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([N:24]4[CH2:29][CH2:28][N:27]([CH3:33])[CH2:26][CH2:25]4)[CH:23]=3)[CH2:14][C@H:13]3[N:9]([CH2:10][CH2:11][CH2:12]3)[C:8]=2[N:30]=1)[CH3:2]
Reactant: CCNc1ncc2c(n1)N1CCC[C@H]1CN(c1cncc(N3CCNCC3)c1)C2=O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CCNc1ncc2c(n1)N1CCC[C@H]1CN(c1cncc(N3CCN(C)CC3)c1)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
(S)-9-Ethylamino-5-[5-(piperazine-1-yl)pyridin-3-yl]-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (56.1 mg, 0.137 mmol) obtained in Step 2 was dissolved in 1,2-dichloroethane (4 mL), and the mixture was stirred at room temperature for 1 hour after adding 37% formalin solution (0.0310 mL, 0.411 mmol) and sodium triacetoxyborohydride (87.0 mg, 0.411 mmol). Thereafter, a saturated aqueous sodium bicarbonate solution was added to the mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (Compound 42) (43.0 mg, 74%).
Reaction SMILES: ClC1C=[CH:6][CH:5]=[C:4]([C:8]([O:10]O)=O)C=1.[CH3:12][O:13][CH2:14][O:15]CCC=C>C(Cl)Cl>[CH3:12][O:13][CH2:14][O:15][CH2:6][CH2:5][CH:4]1[CH2:8][O:10]1
Reactant: C=CCCOCOC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COCOCCC1CO1
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.5 %

Procedure:
m-Chloroperbenzoic acid (20.6 g, 95.6 mmol) was gradually added to a solution of 4-methoxymethoxy-1-butene (10.46 g, 90.1 mmol) in methylene chloride (250 ml) while cooling in an ice-bath, the mixture was stirred at room temperature for 6 hours. The reaction mixture was filtered, and the filtrate was washed with a 10% sodium sulfide aqueous solution and sodium hydrogencarbonate aqueous solution, dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford 2-(2-methoxymethoxyethyl)oxirane (10.3 g, 86%) as a colorless oil.
Reaction SMILES: C(OC([NH:8][C:9]1([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]3[CH:34]=[C:33]([C:35]4[CH:40]=[CH:39][C:38]([C:41]5[C:42]6[N:46]([C:47]([F:56])([F:55])[N:48]7[C:52]=5[C:51]([CH3:53])=[CH:50][CH:49]7[CH3:54])[C:45]([CH3:57])=[CH:44][C:43]=6[CH3:58])=[CH:37][CH:36]=4)[N:32]=[N:31]3)=[CH:21][CH:20]=2)[CH2:14][O:13]C(C)(C)[O:11][CH2:10]1)=O)(C)(C)C.B(F)(F)F.CCOCC>C(Cl)Cl>[NH2:8][C:9]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]2[CH:34]=[C:33]([C:35]3[CH:40]=[CH:39][C:38]([C:41]4[C:42]5[N:46]([C:47]([F:56])([F:55])[N:48]6[C:52]=4[C:51]([CH3:53])=[CH:50][CH:49]6[CH3:54])[C:45]([CH3:57])=[CH:44][C:43]=5[CH3:58])=[CH:37][CH:36]=3)[N:32]=[N:31]2)=[CH:21][CH:20]=1)([CH2:10][OH:11])[CH2:14][OH:13]
Reactant: CC1=CC(C)N2C1=C(c1ccc(-c3cn(CCCCCc4ccc(CCC5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)cc4)nn3)cc1)c1c(C)cc(C)n1C2(F)F
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CC1=CC(C)N2C1=C(c1ccc(-c3cn(CCCCCc4ccc(CCC(N)(CO)CO)cc4)nn3)cc1)c1c(C)cc(C)n1C2(F)F
Temperature: 0 °C
Yield: 60.8 %

Procedure:
To a cold solution (0° C.) of 21 (40 mg, 50.3 μmol) in dry CH2Cl2 (10 mL) were added 4 Å molecular sieves (0.40 g) and BF3.OEt2 (0.18 g, 1.27 mmol) with vigorous stirring. The mixture was stirred at 0° C., and the reaction was monitored by TLC (hexanes/EtOAc 2:1). On the disappearance of 21 (˜5 h), the reaction was quenched by adding saturated aqueous NaHCO3 solution (10 mL). After the mixture was stirred for 30 min, CH2Cl2 (30 mL) was added. The organic layer was separated and washed with saturated aqueous NaHCO3 solution (20 mL), water (2×20 mL), and brine (2×20 mL). The solution was dried (Na2SO4) and concentrated under vacuum. The residue was purified by chromatography (CH2Cl2/MeOH 9:1) to give 3 (20.1 mg, 61%). 1HNMR δ 7.96 (d, 2H, J=8.4 Hz), 7.84 (s, 1H), 7.34 (d, 2H, J=8.4 Hz), 7.11-7.01 (m, 4H), 5.98 (s, 2H), 4.39 (t, 2H, J=7.2 Hz), 3.85-3.57 (m, 4H), 3.56-3.01 (br s, 4H), 2.61-2.51 (m, 4H), 2.55 (s, 6H), 2.00-1.92 (m, 2H), 1.70-1.56 (m, 2H), 1.43 (s, 6H), 1.46-1.05 (m, 4H); 13C NMR δ 155.6, 147.0, 143.0, 141.2, 139.8, 138.6, 134.7, 131.4, 128.6, 128.5, 128.3, 126.3, 122.5, 121.3, 119.9, 50.4, 35.1, 30.8, 30.3, 29.7, 29.4, 26.0, 14.6, 14.1; 19F NMR δ-146.1 (m). HRMS m/z: calcd for C37H46BF2N6O2 (MH+), 655.3737; found, 655.3746.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].Br[CH:14]([CH2:20][CH2:21][Br:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[O:12][CH:14]([CH2:20][CH2:21][Br:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Reactant: CCOC(=O)C(Br)CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCBr)Oc1cc([N+](=O)[O-])c(F)cc1Cl

Procedure:
To a solution containing 2-chloro-4-fluoro-5-nitrophenol (1 equivalent) and ethyl 2,4-dibromobutanoate (1 equivalent) in DMF is added potassium carbonate (1 equivalent) at room temperature and the mixture is stirred. After completion of the reaction, to the reaction mixture is added aqueous diluted hydrochloric acid and the mixture is extracted with ethyl acetate. After concentrating the organic layer, the residue is subjected to chromatography to give ethyl 2-(2-chloro-4-fluoro-5-nitrophenoxy)-4-bromobutanoate.
Reaction SMILES: [CH:1]([C:3]1[CH:30]=[CH:29][C:6]([O:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[C:9]=2[CH3:28])=[CH:5][CH:4]=1)=O.[S:31]1[CH2:35][C:34](=[O:36])[NH:33][C:32]1=[O:37].C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[O:37]=[C:32]1[NH:33][C:34](=[O:36])/[C:35](=[CH:1]/[C:3]2[CH:4]=[CH:5][C:6]([O:7][C:8]3[N:13]=[CH:12][N:11]=[C:10]([O:14][CH:15]4[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:17][CH2:16]4)[C:9]=3[CH3:28])=[CH:29][CH:30]=2)/[S:31]1
Reactant: O=C1CSC(=O)N1
Reactant: Cc1c(Oc2ccc(C=O)cc2)ncnc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: Cc1c(Oc2ccc(/C=C3\SC(=O)NC3=O)cc2)ncnc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 30 °C
Yield: 66.3 %

Procedure:
To a solution of tert-butyl 4-((6-(4-formylphenoxy)-5-methylpyrimidin-4-yl)oxy)piperidine-1-carboxylate (950 mg, 0.002298 mole), thiazolidine-2,4-dione (241 mg, 0.00206 mole) and benzoic acid (0.0364 mg, 0.000298 mole) in toluene (30 ml), piperidine (0.033 ml, 0.00344 mole) was added and reaction mixture was refluxed for 7 hours using Dean-Stark apparatus. Then reaction mixture was cooled to 30° C. and solid product was filtered, washed with ice cold toluene and dried to yield 700 mg white solid product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:22]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[N:24]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([NH:16][CH:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:35]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36]1>>[CH:17]1([NH:16][C:15]2[N:10]3[N:9]=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([C:37]5[CH:38]=[CH:39][S:35][CH:36]=5)[CH:3]=4)[C:22]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]5[CH2:31][CH2:32][CH2:33][CH2:34]5)[N:24]=4)=[C:11]3[CH:12]=[CH:13][CH:14]=2)[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: OB(O)c1ccsc1
Reactant: Brc1cccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Product: c1cc(-c2ccsc2)cc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Yield: 47 %

Procedure:
In a similar manner as described in Example 29 from 2-(3-bromophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine (200 mg, 0.39mmol) and thiophene-3-boronic acid, N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[3-(3-thienyl)phenyl]pyrazolo[1,5-a]pyridin-7-amine (94 mg, 47%) was obtained as a yellow foam. 1H NMR (CDCl3): δ 8.00 (d, 1H), 7.92 (s. 1H), 7.81 (d, 1H), 7.67 (d, 1H), 7.57 (d, 1H), 7.49–7.42 (m, 2H), 7.40–7.34 (m, 2H), 7.32–7.27 (m, 1H), 6.38 (d, 1H), 6.09–6.03 (m, 2H), 5.22 (d, 1H), 4.36 (m, 1H), 4.00 (m, 1H), 2.15–2.05 (m, 4H), 1.82–1.56 (m, 12H); MS m/z 521 (M+1).
Reaction SMILES: O.[OH:2][CH:3]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[C:4]([OH:6])=[O:5].C([O-])([O-])=O.[K+].[K+].[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24]Br.O>CN(C=O)C>[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24][O:5][C:4](=[O:6])[CH:3]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:24][C:23]2[CH:26]=[CH:27][C:28]([Cl:29])=[C:21]([Cl:20])[CH:22]=2)=[CH:9][CH:8]=1)[OH:2]
Reactant: O=C(O)C(O)c1ccc(O)cc1
Reactant: Clc1ccc(CBr)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccc(Cl)c(Cl)c1)C(O)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of hydroxy-(4-hydroxy-phenyl)-acetic acid monohydrate (10 g) in DMF (50 mL) was added K2CO3 (29.7 g,) followed by 3,4-dichlorobenzyl bromide (16.1 mL). The mixture was stirred at room temperature for 3 h. The mixture was poured into water (250 mL) and extracted with EtOAc. The organic layer was washed with water 1N HCl, brine, dried over Na2SO4, and concentrated. The resulting solid was triturated with diethyl ether and filtered to provide [4-(3,4-dichloro-benzyloxy)-phenyl]-hydroxy-acetic acid 3,4-dichloro-benzyl ester as a white solid (9.4 g). 1H NMR (400 MHz, DMSO d6): 7.69 (d, 1H), 7.63 (d, 1H), 7.55 (d, 1H), 7.41 (m, 1H), 7.37 (d, 1H), 7.31 (m, 2H), 7.20 (m, 1H), 6.97 (m, 2H), 6.06 (d, 1H), 5.16 (d, 1H), 5.1 (m, 4H).
Reaction SMILES: [C:1]([C:11]1[CH:31]=[CH:30][C:14]([CH2:15][NH:16][C:17]2[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:32]1([CH2:38][CH2:39][C:40](Cl)=[O:41])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:1]([C:11]1[CH:31]=[CH:30][C:14]([CH2:15][N:16]([C:40](=[O:41])[CH2:39][CH2:38][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:17]2[CH:18]=[CH:19][C:20](/[CH:23]=[CH:24]/[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][CH:22]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCC#Cc1ccc(CNc2ccc(/C=C/C(=O)OCC)cc2)cc1
Reactant: O=C(Cl)CCc1ccccc1
Product: CCCCCCCCC#Cc1ccc(CN(C(=O)CCc2ccccc2)c2ccc(/C=C/C(=O)OCC)cc2)cc1

Procedure:
The title compound was prepared following the procedure E using of ethyl (2E)-3-{4-[(4-dec-1-ynylbenzyl)amino]phenyl}acrylate and 3-phenylpropanoyl chloride (58%). M+ (ESI): 560.6. HPLC, Rt: 6.4 min (purity: 98.7%).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](B(O)O)=[CH:14][N:13]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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.O1CCOCC1>[Cl:8][C:6]1[CH:7]=[C:2]([C:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=[N:13][CH:14]=2)[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=1
Reactant: Clc1cc(Br)c2nccn2n1
Reactant: OB(O)c1cncc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Clc1cc(-c2cncc3ccccc23)c2nccn2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 55.5 %

Procedure:
A microwave vial was charged with a mixture of 8-bromo-6-chloroimidazo[1,2-b]pyridazine (0.8 g, 3.44 mmol), isoquinolin-4-ylboronic acid (0.6 g, 1.734 mmol), dioxane (16 mL), tetrakis(triphenylphosphine)palladium(0) (0.100 g, 0.087 mmol), and K3PO4 (2.60 mL, 5.20 mmol) (2.0 M water solution) was stirred at room temperature for 5 min. under nitrogen. The resulting mixture was heated to 100° C. for 4 h in microwave. The reaction mixture was cooled to room temperature, quenched with water, and diluted with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by BIOTAGE® (30-100% EtOAc/EtOAc/CH2Cl2, 1.2 L, then 50-100% B/EtOAc/CH2Cl2, B: 10% MeOH/EtOAc/CH2Cl2, 800 mL) to give the product (0.27 g, 55%). 1H NMR (400 MHz, CDCl3) δ ppm 9.41 (1H, s), 8.72 (1H, s), 8.66 (1H, d, J=4.53 Hz), 8.03-8.17 (1H, m), 7.90 (1H, s), 7.71 (3H, d, J=3.02 Hz), 7.26 (1H, d, J=4.53 Hz); LC/MS: Rt=1.35 min. LC/MS (Condition A): 281.13/283.13.
Reaction SMILES: [C:1]1([C:7]2([CH2:20][O:21][CH2:22][C:23]3[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([NH:33][C:34](=O)[C:35]([F:38])([F:37])[F:36])[CH:24]=3)[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N-:59]=[N+:60]=[N-:61].[Na+]>C(Cl)(Cl)(Cl)Cl>[C:1]1([C:7]2([CH2:20][O:21][CH2:22][C:23]3[CH:24]=[C:25]([N:33]4[C:34]([C:35]([F:37])([F:38])[F:36])=[N:61][N:60]=[N:59]4)[CH:26]=[C:27]([C:29]([F:31])([F:30])[F:32])[CH:28]=3)[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(NC(=O)C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(-n3nnnc3C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
tert-Butyl 4-phenyl-4-((3-(2,2,2-trifluoroacetamido)-5-(trifluoromethyl)benzyloxy)methyl)piperidine-1-carboxylate (100 mg, 0.18 mmol) in carbon tetrachloride (3 mL) was treated with triphenylphosphine (117 mg, 0.45 mmol) and heated at reflux overnight. After cooling to room temperature, the reaction was concentrated and the residue dissolved in dimethylformamide (2 mL). The mixture was treated with sodium azide (25 mg, 0.37 mmol) and stirred at room temperature for 5 h. The solvents were evaporated and the crude product purified by flash chromatography on silica gel (30% ethyl acetate/hexanes) to afford 46 mg (45%). 1H-NMR (CDCl3, 500 MHz) δ 7.61 (s, 1H), 7.59 (s, 1H), 7.30-7.32 (m, 2H), 7.23-7.26 (m, 2H), 7.12 (s, 1H), 7.05-7.08 (m, 1H), 4.51 (s, 2H), 3.74 (m, 2H), 3.46 (s, 2H), 2.99-3.03 (m, 2H), 2.21-2.24 (m, 2H), 1.79-1.84 (m, 2H), 1.42 (s, 9H). Mass spec.: 608.16 (MNa)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[Cl:43][C:44]1[CH:53]=[CH:52][C:51]2[C:46](=[CH:47][C:48]([N:54]3[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]3)=[CH:49][N:50]=2)[N:45]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:14])([CH3:13])[C:10]([N:57]1[CH2:58][CH2:59][N:54]([C:48]2[CH:49]=[N:50][C:51]3[C:46]([CH:47]=2)=[N:45][C:44]([Cl:43])=[CH:53][CH:52]=3)[CH2:55][CH2:56]1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: Clc1ccc2ncc(N3CCNCC3)cc2n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N1CCN(c2cnc3ccc(Cl)nc3c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
To a stirred mixture of 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (180 mg, 0.89 mmol, 1.5 eq), triethylamine (209 mg, 2.07 mmol, 3.5 eq) and HOBt (120 mg, 0.89 mmol, 1.5 eq) in anhydrous CH2Cl2 (10 mL), EDCI (170 mg, 0.89 mmol, 1.5 eq) was added. The resulting mixture was stirred at RT for 30 min, and then 2-chloro-7-(piperazin-1-yl)-1,5-naphthyridine (D-19) (0.59 mmol, 1.0 eq) was added. The reaction mixture was stirred at RT for 20 h, and then quenched with water (30 mL) and CH2Cl2 (15 mL), and the organic layer was separated. The organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo. The resultant residue was purified by silica gel column chromatography (2% MeOH—CH2Cl2) to afford the desired product, tert-butyl(1-(4-(6-chloro-1,5-naphthyridin-3-yl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate (D-20) (193 mg, 75.4% yield, 2 steps). ESI-MS m/z: 434.18[M+H]+.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[NH2:10][C:11]1[CH:20]=[CH:19][C:18]([C:21]([C:23]2[N:31]3[C:26]([C:27]([OH:32])=[CH:28][CH:29]=[CH:30]3)=[C:25]([O:33][CH3:34])[C:24]=2[CH3:35])=[O:22])=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14].S([O-])(O)(=O)=O.[K+]>O1CCCC1>[NH2:10][C:11]1[CH:20]=[CH:19][C:18]([C:21]([C:23]2[N:31]3[C:26]([C:27]([O:32][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[CH:28][CH:29]=[CH:30]3)=[C:25]([O:33][CH3:34])[C:24]=2[CH3:35])=[O:22])=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1cc(C(=O)c2c(C)c(OC)c3c(O)cccn23)ccc1N
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(=O)c2c(C)c(OC)c3c(OCC(=O)OC(C)(C)C)cccn23)ccc1N
Reaction time: 2 h
Yield: 63.6 %

Procedure:
5.4 ml (9.31 mmol) of potassium hexamethyldisilylamide (0.5 M solution in toluene) and then 0.69 ml (4.66 mmol) of tert-butyl 2-bromoacetate are added, dropwise, to the solution of 1.50 g (4.23 mmol) of methyl 2-amino-5-[(8-hydroxy-1-methoxy-2-methylindolizin-3-yl)carbonyl]benzoate (Stage F of Example 1) in 15 ml of tetrahydrofuran at −20° C. under argon. The mixture is stirred for 2 hours, allowing it to return to ambient temperature. The reaction medium is poured into a saturated aqueous solution of potassium hydrogen sulphate and the mixture is extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate, and concentrated under reduced pressure. The oil obtained is purified by flash chromatography on silica gel (dichloromethane/methanol gradient=100/0 to 90/10). 1.26 g (64%) of a yellow powder are obtained.
Reaction SMILES: [C:1](=[O:15])([O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[O:2][CH2:3]Cl.[I-:16].[Na+]>CC(C)=O>[C:1](=[O:15])([O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[O:2][CH2:3][I:16]
Reactant: [I-]
Reactant: O=C(OCCl)Oc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(OCI)Oc1ccc([N+](=O)[O-])cc1
Temperature: 40 °C
Reaction time: 5 h
Yield: 89 %

Procedure:
Chloromethyl p-nitrophenyl carbonate (52) (100 g, 0.43 moles), sodium iodide (228 g, 1.30 moles) and 50 g of dried molecular sieves (4 Å) were added to 2 L of acetone under nitrogen with mechanical stirring. The resulting mixture was stirred at 40° C. for 5 hours (monitored by 1H NMR). Upon completion, the solid materials were removed by filtration and the solvent was removed under reduced pressure. The residue was redissolved in dichloromethane (1 L) and washed twice with saturated aqueous sodium carbonate (300 mL) followed by water (300 mL). The organic layer was separated and dried over anhydrous sodium sulfate. Removal of solvent gave 123.6 g (89%) of the title compound (53) as a solid upon standing. The compound was found to be unstable to LC-MS. 1H NMR (CDCl3, 400 MHz): 6.06 (s, 2H), 7.42 (d, J=9 Hz, 2H), 8.30 (d, J=9 Hz, 2H). 13C NMR (CDCl3, 100 MHz): 155.1, 151.0, 146.0, 125.8, 125.7, 121.9, 33.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[C:14]1([C:20]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:28]3[CH:24]([CH2:25][NH:26][CH2:27]3)[S:23][CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[C:29]1([C:20]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:28]3[CH:24]([CH2:25][N:26]([C:10](=[O:12])[CH2:9][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[CH2:27]3)[S:23][CH2:22][CH2:21]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: c1ccc(C2(c3ccccc3)CCSC3CNCC32)cc1
Reactant: COc1ccccc1CC(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1CC(=O)N1CC2SCCC(c3ccccc3)(c3ccccc3)C2C1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 92.6 %

Procedure:
1.13 g of N,N'-carbonyldiimidazole are added to a solution, cooled to 0° C., of 1.16 g of 2-methoxyphenylacetic acid in 20 cm3 of dry dichloromethane. The mixture is stirred for 40 minutes at 0° C. and then a solution of 2.15 g of (4aRS,7aRS)4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole hydrochloride and 0.9 cm3 of triethylamine in 20 cm3 of dichloromethane is added. The reaction mixture is stirred for one hour at 0° C. and is then washed with a saturated aqueous solution of sodium hydrogen carbonate. The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is washed with 30 cm3 of ethyl ether and 30 cm3 of diisopropyl oxide and it is then dried under reduced pressure (2.7 kPa). 2.66 g of (4aRS,7aRS)-4,4-diphenyl-6-[(2-methoxyphenyl)acetyl]perhydrothiopyrano[2,3 -c]pyrrole are obtained in the form of a white solid; melting point 172° C.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:42])[CH2:14][O:15][C:16]1[C:25]2[C:20](=[C:21]([O:26][CH2:27][C:28]([N:30]3[CH2:34][CH2:33][CH2:32][C@@H:31]3[C:35]([O:37]C(C)(C)C)=[O:36])=[O:29])[CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:35]([C@H:31]1[CH2:32][CH2:33][CH2:34][N:30]1[C:28](=[O:29])[CH2:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:20]=1[CH:19]=[CH:18][CH:17]=[C:16]2[O:15][CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([OH:7])=[O:5])=[O:42])([OH:37])=[O:36]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)COc1cccc2c(OCC(=O)N3CCC[C@@H]3C(=O)OC(C)(C)C)cccc12
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@H]1CCCN1C(=O)COc1cccc2c(OCC(=O)N3CCC[C@@H]3C(=O)O)cccc12
Reaction time: 8 h
Yield: 97.8 %

Procedure:
A solution of 290 mg (0.5 mmol) (R)-1-[[5-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-naphthalen-1-yloxy]-acetyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 5 ml trifluoroacetic acid was stirred for 18 h at room temperature. The solvent was removed in vacuo and the residue suspended in 10 ml ether. The resulting suspension was stirred overnight. Filtration and drying gave 230 mg (98%) of the title compound as a white powder.
Reaction SMILES: [CH:1]1([C@@H:4]2[O:15][CH2:14][C@:7]3([C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=4[F:23])[NH:8][O:9][C@@H:10]([CH2:11][O:12][CH3:13])[C@@H:6]3[CH2:5]2)[CH2:3][CH2:2]1>C(O)(=O)C.[Zn]>[NH2:8][C@@:7]1([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[CH2:14][O:15][C@@H:4]([CH:1]2[CH2:3][CH2:2]2)[CH2:5][C@H:6]1[C@@H:10]([OH:9])[CH2:11][O:12][CH3:13]
Reactant: COC[C@@H]1ON[C@@]2(c3ccc(F)cc3F)CO[C@@H](C3CC3)C[C@@H]12
Agent: [Zn]
Solvent: CC(=O)O
Product: COC[C@H](O)[C@@H]1C[C@H](C2CC2)OC[C@@]1(N)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Zinc powder (2.22 g, 34.0 mmol) was added to a solution of rel-(3R,3aR,5R,7aS)-5-cyclopropyl-7a-(2,4-difluorophenyl)-3-(methoxymethyl)hexahydro-1H-pyrano[3,4-c][1,2]oxazole (C39) (850 mg, 2.61 mmol) in acetic acid (9 mL), and the resulting mixture was allowed to cool to room temperature and stir for 5 hours. The mixture was filtered through Celite, and the filtrate was concentrated in vacuo to afford the product as an oil. Yield: 845 mg, 2.58 mmol, 99%. LCMS m/z 328.2 [M+H+].