Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][NH2:22])=[CH:15][CH:14]=3)[CH:10]=[CH:9][C:8]2=[O:23])=[C:4]([F:26])[CH:3]=1.CCN(CC)CC.[C:34](Cl)(=[O:36])[CH3:35]>C(Cl)Cl>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:8](=[O:23])[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][NH:22][C:34](=[O:36])[CH3:35])=[CH:17][CH:18]=3)=[CH:12]2)=[C:4]([F:26])[CH:3]=1
Reactant: CC(=O)Cl
Reactant: NCCOc1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3F)c2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCOc1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3F)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.4 %

Procedure:
According to Scheme 19 Step 3: To a solution of 1-(4-chloro-2-fluorobenzyl)-5-(4-(2-aminoethoxy)phenyl)pyridin-2(1H)-one (1 eq, 0.18 mmol, 0.07 g) in CH2Cl2 (5 mL) at 0° C. were added Et3N (6 eq, 1.10 mmol, 0.15 mL) and 30 min. later acetyl chloride (1.5 eq, 0.27 mmol, 19 μL) and. The reaction mixture was stirred 1 hour at room temperature. The reaction mixture was quenched with water and extracted with CH2Cl2. The organic phase was dried over Na2SO4, filtered and evaporated. The crude product was purified by silica gel chromatography (AIT Flashsmart prepacked column 25 g SiO2, CH2Cl2/AcOEt 70/30) to afford N-(2-(4-(1-(4-chloro-2-fluorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)phenoxy)ethyl)acetamide (0.08 mmol, 0.04 g, 47%) as a white solid.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]2[C:7](/[C:8](=[CH:14]/[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)/[C:9](=[O:13])[NH:10]2)=[CH:6][CH:5]=1.CS(C)=O.O>CO>[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)[C:9](=[O:13])[NH:10]2)=[CH:6][CH:5]=1
Reactant: O=C1Nc2cc(Cl)ccc2/C1=C/c1cccc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CO
Product: O=C1Nc2cc(Cl)ccc2C1Cc1cccc(Cl)c1
Temperature: 25 °C
Yield: 93.3 %

Procedure:
Sodium borohydride (3.0 g, 79 mmol) (Aldrich) was added in small portions to a suspension of E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one (19 g, 66 mmol) (from example 1a supra) in methanol (200 mL) and DMSO (50 mL) at such a rate that gas evolution was not too vigorous. When the addition was complete, mixture was stirred at room temperature for 0.5 hr-1 hr. After adding to water (200 mL), the resulting precipitate was collected and dried to give 18 g of rac-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one as a light yellow solid. MS: 293 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:32])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[C:28]([F:29])=[CH:27][CH:26]=[C:25]([F:30])[C:24]=3[F:31])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.[CH3:34][OH:35]>>[CH3:34][O:35][C:1](=[NH:2])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](=[O:19])(=[O:20])[NH:21][CH2:22][C:23]3[C:28]([F:29])=[CH:27][CH:26]=[C:25]([F:30])[C:24]=3[F:31])=[CH:14][CH:13]=2)=[O:32])[CH:4]=1
Reactant: CO
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3c(F)ccc(F)c3F)cc2)c1
Agent: Cl
Product: COC(=N)c1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3c(F)ccc(F)c3F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
4-[3-(3-Cyanophenyl)-ureido]-N-(2,3,6-trifluorobenzyl)-benzenesulfonamide (230 mg, 0.5 mmol) was dissolved in HCl/MeOH (25 ml, 7 M) at 0° C. under inert atmosphere and stirred overnight at rt. The solution was concentrated and dried in vacuo to yield 99% of 3-{3-[4-(2,3,6-trifluorobenzyl-sulfamoyl)-phenyl]-ureido}-benzimidic acid methyl ester.
Reaction SMILES: O[CH:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:3]1[N:12]([C:13]([O:15]C(C)(C)C)=[O:14])[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4]1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[C:20]1([CH:2]2[CH:3]3[CH2:4][C:5]4([O:9][CH2:8][CH2:7][O:6]4)[CH2:10][CH2:11][N:12]3[C:13](=[O:15])[O:14]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1C(O)c1ccccc1)OCCO2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1OC(c2ccccc2)C2CC3(CCN12)OCCO3
Yield: 88.1 %

Procedure:
A mixture of (±)-1,1-dimethylethyl 7-(hydroxyphenylmethyl)-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate (183.6 g) and potassium tert-butoxide (6 g) in toluene (900 ml) was stirred and refluxed for 2 hours. The solvent was evaporated and the residue was stirred in petrol ether and water. The mixture was decanted and the residue was stirred up in DIPE. The precipitate was filtered off and dried, yielding 127.4 g (92%) of (±)-tetrahydro-1'-phenylspiro(1,3-dioxolan-2,7'(8'H)-3H-oxazolo[3,4-a]pyridin)-3'-one (interm. 2).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.[C:28](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:29].[Na+].OCC(=O)C.C(O)(=O)C.C(=O)(O)[O-].[Na+]>CN1CCCC1=O.C(Cl)Cl>[CH2:28]([N:25]1[CH2:24][CH2:23][N:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15]/[CH:14]=[C:5]3\[C:6](=[O:13])[NH:7][C:8](=[O:12])[C:9]4[C:4]\3=[CH:3][C:2]([I:1])=[CH:11][CH:10]=4)=[CH:21][CH:20]=2)[CH2:27][CH2:26]1)[CH3:29]
Reactant: O=C1NC(=O)c2ccc(I)cc2/C1=C/Nc1ccc(N2CCNCC2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCN1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(I)cc43)cc2)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 75.6 %

Procedure:
(4Z)-6-Iodo-4-{[(4-piperazin-1-ylphenyl)amino]methylene}isoquinoline-1,3(2H,4H)-dione (47.4 mg, 0.1 mmol) is dissolved in N-methylpyrrolidinone (1 mL) and methylene chloride (0.3 mL), followed by addition of sodium triacetoxyborohydride (244 mg, 1.15 mmol), 1-hydroxy-propan-2-one (0.177 mL, 2.58 mmol) and acetic acid (0.15 mL, 2.6 mmol). After stirring at room temperature for 40 min, methylene chloride and saturated sodium bicarbonate solution were added. The organic layer is separated and dried to give 38 mg (71%) of the title compound as a yellow solid. MS (ESI) m/z 533.4 (M+H)+1.
Reaction SMILES: [NH2:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4](Cl)[CH:3]=1.[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1>CN1C(=O)CCC1.O>[NH2:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4]([N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)[CH:3]=1
Reactant: c1c[nH]cn1
Reactant: Nc1cc(Cl)c(C(=O)Nc2ccc3cn[nH]c3c2)cc1[N+](=O)[O-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Nc1cc(-n2ccnc2)c(C(=O)Nc2ccc3cn[nH]c3c2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a solution of 4-amino-2-chloro-N-(1H-indazol-6-yl)-5-nitrobenzamide (1 mmol; see Example 154) in NMP (2 mL) was added with imidazole (5 mmol). The resulting mixture was subjected to microwave irradiation at 120° C. for 2 h. The reaction mixture was cooled to room temperature and diluted with water (30 mL). The solid formed was collected by filtration, washed with water, and dried in vacuo. The product, 4-amino-2-imidazol-1-yl-N-(1H-indazol-6-yl)-5-nitro-benzamide, obtained as a yellow solid was used without any purification.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[N:13]1([C:19]2[S:20][C:21]3[C:27](=[O:28])[CH2:26][CH2:25][CH2:24][C:22]=3[N:23]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.CI>C1COCC1>[CH3:1][CH:26]1[CH2:25][CH2:24][C:22]2[N:23]=[C:19]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[S:20][C:21]=2[C:27]1=[O:28]
Reactant: O=C1CCCc2nc(N3CCOCC3)sc21
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CC1CCc2nc(N3CCOCC3)sc2C1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 13.4 %

Procedure:
A solution of N,N-diisopropylamine (0.60 g, 0.83 mL, 5.9 mmol) in dry THF (5 mL) was cooled to −78° C. and n-butyllithium (2.36 mL, 2.5M in hexane, 5.9 mmol) was added dropwise. The reaction mixture was allowed to warm to 0° C., stirred for 15 minutes and cooled to −78° C. A suspension of Example 6 (1.4 g, 5.9 mmol) in THF (5 mL) was added slowly. The reaction mixture was warmed to 0° C. and stirred for 10 min at 0° C. before dropwise addition of methyl iodide (0.84 g, 0.37 mL, 5.9 mmol). A solid formed immediately. The reaction mixture was allowed to warm slowly to r.t. The solid was filtered, washed with THF and then purified by column chromatography (SiO2, 1:3 EtOAc/hexane) to give the title compound (0.20 g, 13%) as a white solid. δH (DMSO-d6) 3.70 (4H, t, J 4.9 Hz), 3.54 (4H, t, J 4.9 Hz), 2.80-2.72 (2H, m), 2.55-2.45 (1H, m), 2.15-2.09 (1H, m), 1.82-1.72 (1H, m), 1.10 (3H, d, J 6.9 Hz). LCMS (ES+) 253.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[C:11]([O:19]C)[CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[C:11]([OH:19])[CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: COc1cccc2c(=O)[nH]c(-c3ccc(F)cc3)nc12
Agent: BrB(Br)Br
Product: O=c1[nH]c(-c2ccc(F)cc2)nc2c(O)cccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.9 %

Procedure:
2-(4-Fluorophenyl)-8-methoxyquinazolin-4(3H)-one (460 mg, 1.70 mmol) was dissolved under argon in boron tribromide solution (1M solution in tetrahydrofuran; 5.11 ml, 5.11 mmol) and stirred under reflux conditions for 4 h. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was taken up in aqueous sodium hydroxide solution (10 ml) and stirred at room temperature for a further 3 h. Subsequently, the reaction solution was neutralized with dilute aqueous hydrochloric acid (1M). Filtration with suction and thorough drying gave 2-(4-fluorophenyl)-8-hydroxyquinazolin-4(3H)-one (370 mg, 85% of theory) as a colorless solid. 1H NMR (400 MHz, d6-DMSO δ, ppm) 12.49 (br. s, 1H, NH), 9.65 (br. s, 1H, OH), 8.49 (m, 2H), 7.67 (dd, 1H), 7.38 (m 2H), 7.34 (d, 1H), 7.23 (dd, 1H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C@@H:12]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C@@H:12]1[CH2:16][CH2:15][NH:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CCCOCc2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(COCCC[C@@H]2CCNC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.9 %

Procedure:
To a solution of tert-butyl 3(R)-[3-(benzyloxy)propyl]pyrrolidine-1-carboxylate (170 mg, 0.53 mmol) in 2 mL of CH2Cl2 was added CF3COOH (0.5 mL) at room temperature under N2. The solution was stirred for 3 h at room temperature and then concentrated under vacuum. To the residue was added 20 mL of water, and the solution was washed with 30 mL of petroleum ether. The aqueous layer was adjusted to pH 8.0 with 2M aqueous NaHCO3 solution. The product was extracted into CH2Cl2 (3×40 mL), and the combined organic layers were dried over Na2SO4 and concentrated in vacuo to give the free amine (115 mg, 99%) as a yellowish oil. LC-MS (ESI) m/z 220 (M+H+).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:32][C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=1)[CH:9]=[CH:10][CH:11]([CH2:23][O:24][Si](C(C)(C)C)(C)C)[CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)(C)(C)C.F.C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[NH2:7][C@H:8]([CH2:32][C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=1)/[CH:9]=[CH:10]/[CH:11]([CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)[CH2:23][OH:24]
Reactant: CC(C)(C)OC(=O)N[C@@H](C=CC(CO[Si](C)(C)C(C)(C)C)Cc1ccc2ccccc2c1)Cc1ccc2ccccc2c1
Agent: F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N[C@@H](/C=C/C(CO)Cc1ccc2ccccc2c1)Cc1ccc2ccccc2c1
Reaction time: 3 h

Procedure:
((1R)-4-(tert-Butyldimethylsilanyloxymethyl)-1-((2-naphthyl)methyl)-5-(2-naphthyl)pent-2-enyl)carbamic acid tert-butylester (2.20 g; 3.60 mmol) was dissolved in a mixture of acetonitrile (100 ml) and an aqueous solution of hydrogen fluoride (48%, 4.5 ml). After stirring for 3 h a mixture of ethyl acetate (200 ml) and aqueous sodium carbonate (10%, 200 ml) was added. The phases were separated and the organic phase was dried (Magnesium sulfate) and evaporated in vacuo. The residue was chromatographed on silica (4×38 cm) using a mixture of ethyl acetate (85%), ethanol (14%) and conc. aqueous ammonia (1%) as eluent. Two close spots were separated this way. The one that eluted first was clean on HPLC whereas the following contained several isomers. The first fraction had E-geometry and 220 mg of (3E,5R)-5-amino-6-((2-naphthyl)-2-(2-naphthyl)methyl)hex-3-en-1-ol were taken to the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:20]([C:22]1[NH:26][C:25]([C:27]([OH:29])=[O:28])=[CH:24][C:23]=1[CH3:30])=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:20][C:22]4[NH:26][C:25]([C:27]([OH:29])=[O:28])=[CH:24][C:23]=4[CH3:30])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1cc(C(=O)O)[nH]c1C=O
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)O)[nH]c1C=C1C(=O)Nc2ncnc(Nc3ccc(F)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 96 h
Yield: 85.8 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (45.9 mg, 0.3 mmol) and piperidine (3 drops) in ethanol (2 mL) was stirred at room temperature for 4 days.The precipitate was collected by vacuum filtration, washed with ethanol and dried, then washed with 1N HCl (3×), water (5×) and dried to give 88.8 mg (86%) of the title compound. 1H NMR (360 MHz, DMSO-d6) δ 13.55 (br s, 1H, NH), 11.84 (br s, 1H, NH), 9.28 (s, 1H), 8.34 (s, 1H), 7.74 (m, 1H), 7.43 (m, 1H), 7.41 (s, 1H), 7.38 (t, J=9.1 Hz, 1H), 6.74 (d, J=2.15 Hz, 1H), 2.22 (s, 3H, CH3). MS 414 [M++1].
Reaction SMILES: CO[C:3](=[O:21])[C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=O.[C:22]1([CH2:34][C:35]([NH2:37])=[O:36])[C:32]2=[C:33]3[C:28](=[CH:29][CH:30]=[CH:31]2)[CH2:27][CH2:26][CH2:25][N:24]3[CH:23]=1>>[C:22]1([C:34]2[C:35](=[O:36])[NH:37][C:3](=[O:21])[C:4]=2[C:6]2[C:14]3[C:9](=[CH:10][C:11]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=4)=[CH:12][CH:13]=3)[NH:8][CH:7]=2)[C:32]2=[C:33]3[C:28](=[CH:29][CH:30]=[CH:31]2)[CH2:27][CH2:26][CH2:25][N:24]3[CH:23]=1
Reactant: COC(=O)C(=O)c1c[nH]c2cc(-c3cccnc3)ccc12
Reactant: NC(=O)Cc1cn2c3c(cccc13)CCC2
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1c[nH]c2cc(-c3cccnc3)ccc12

Procedure:
Beginning with (6-(pyridin-3-yl)indol-3-yl)oxoacetic acid methyl ester and 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)acetamide, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]1[CH2:17][CH2:16][N:15]([C:18]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])[CH2:14]1)[C:5]([O:7]C)=[O:6].[Li+].[OH-].C1COCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.CO>[I:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]1[CH2:17][CH2:16][N:15]([C:18]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])[CH2:14]1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(OC2CCN(C(=O)N3CCCC3)C2)c(I)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(OC2CCN(C(=O)N3CCCC3)C2)c(I)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.1 %

Procedure:
A mixture of compound 34d (180 mg, 0.41 mmol), LiOH (39 mg, 1.62 mmol), THF (3 mL), MeOH (3 mL), and H2O (3 mL) was stirred at room temperature for 4 h. The mixture was acidified with 15% aqueous citric acid and extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resultant residue was dried under reduced pressure for 2 h to give compound 34e (166 mg).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:35])([CH3:34])[CH:14]([O:26]CC1C=CC=CC=1)[C:15]([O:17][CH2:18][CH2:19][O:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2]>[Pd].CO>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:34])([CH3:35])[CH:14]([OH:26])[C:15]([O:17][CH2:18][CH2:19][O:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:16])(=[O:9])=[O:10])(=[O:3])[CH3:2]
Reactant: CCOC(=O)OCCOC(=O)C(OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCNC(C)=O
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)OCCOC(=O)C(O)C(C)(C)COS(=O)(=O)CCCNC(C)=O
Reaction time: 8 h
Yield: 35.4 %

Procedure:
Following the general procedure for the hydrogenolysis of benzyl ethers of Description 18, a mixture of (ethoxycarbonyloxy)ethyl (2R/S)-4-{[3-(acetylamino)propyl]sulfonyloxy}-3,3-dimethyl-2-(phenylmethoxy)butanoate (37c) (1.7 g, 3.3 mmol) and 1.4 g of 10 wt.-% of palladium on activated carbon in 30 mL of methanol (MeOH) was stirred overnight under a hydrogen atmosphere. After purification by mass-guided preparative HPLC, 500 mg (35% yield) of the title compound (37) was obtained as a yellow viscous oil after lyophilization of the solvents. The analytical data was consistent with the data obtained for (ethoxycarbonyloxy)ethyl (2R)-4-{[3-(acetylamino)propyl]sulfonyloxy}-2-hydroxy-3,3-dimethylbutanoate (32).
Reaction SMILES: OO.[Br:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([F:12])[CH:5]=1.Cl([O-])=[O:14].[Na+].OS([O-])(=O)=O.[K+]>C(#N)C.O>[Br:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]([OH:14])=[O:9])=[C:6]([F:12])[CH:5]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: [O-][Cl+][O-]
Agent: O=S(=O)([O-])O
Agent: OO
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
To a mixture of water (3 ml) and acetonitrile (5 ml) were added Na2HPO4.12H2O (0.11 g), 31% aqueous hydrogen peroxide (0.34 g, 3.1 mmol), 4-bromo-2-fluorobenzaldehyde (0.41 g, 2.0 mmol) and sodium chlorite (0.27 g, 3.0 mmol), successively, and stirred at room temperature for 1 hour. The reaction solution was poured into 5% KHSO4, extracted three times with ethyl acetate and the combined extracts were dried over MgSO4. The solvent was evaporated under a reduced pressure to give the title compound (0.42 g; 96%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[C:8]3([C:14]4[CH:15]=[C:16]([C:21]5[C:22]([F:27])=[N:23][CH:24]=[CH:25][CH:26]=5)[CH:17]=[CH:18][C:19]=4[O:20][C:5]2=[C:4]([F:28])[CH:3]=1)[CH2:12][O:11][C:10]([NH2:13])=[N:9]3.[O:29]1[CH2:34][CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH2:31][CH2:30]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.O>[O:29]1[CH2:30][CH:31]=[C:32]([C:2]2[N:7]=[C:6]3[C:8]4([C:14]5[CH:15]=[C:16]([C:21]6[C:22]([F:27])=[N:23][CH:24]=[CH:25][CH:26]=6)[CH:17]=[CH:18][C:19]=5[O:20][C:5]3=[C:4]([F:28])[CH:3]=2)[CH2:12][O:11][C:10]([NH2:13])=[N:9]4)[CH2:33][CH2:34]1
Reactant: NC1=NC2(CO1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(Cl)nc12
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: NC1=NC2(CO1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(C3=CCOCC3)nc12
Temperature: 135 °C

Procedure:
A mixture of 2-chloro-4-fluoro-8-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[3,2-b]pyridine-10,4′-oxazol]-2′-amine (19.00 mg, 0.047 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (24.90 mg, 0.119 mmol), bis-(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(ii) (1.678 mg, 2.370 μmol) and potassium phosphate (22.14 mg, 0.104 mmol) in a 2:1 mixture of dioxane and water (1.5 mL was heated at 135° C. in the microwave for 25 minutes. The reaction mixture was purified by column chromatography (SiO2, CH2Cl2 to CH2Cl2/EA=3:1 to 2:1 to 1:1 to pure EA to EA/MeOH=100:5) to give 2-(3,6-dihydro-2H-pyran-4-yl)-4-fluoro-8-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[3,2-b]pyridine-10,4′-oxazol]-2′-amine as a off white solid.
Reaction SMILES: C([S:4][CH:5]1[CH2:8][N:7]([C:9]2[S:10][CH:11]=[C:12]([CH2:14][NH:15][C:16]([C:18]3[O:19][CH:20]=[CH:21][CH:22]=3)=[O:17])[N:13]=2)[CH2:6]1)(=O)C.C(O)(=O)C.NN.C1(P(O[C:44]2[C@H:45]([CH3:68])[C@H:46]3[C@@H:63]([C@H:64]([OH:66])[CH3:65])[C:62](=[O:67])[N:47]3[C:48]=2[C:49]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=2)=[O:50])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(#N)C.C(OCC)(=O)C>[O:19]1[CH:20]=[CH:21][CH:22]=[C:18]1[C:16]([NH:15][CH2:14][C:12]1[N:13]=[C:9]([N:7]2[CH2:6][CH:5]([S:4][C:44]3[C@H:45]([CH3:68])[C@@H:46]4[C@@H:63]([C@H:64]([OH:66])[CH3:65])[C:62](=[O:67])[N:47]4[C:48]=3[C:49]([O:51][CH2:52][C:53]3[CH:54]=[CH:55][C:56]([N+:59]([O-:61])=[O:60])=[CH:57][CH:58]=3)=[O:50])[CH2:8]2)[S:10][CH:11]=1)=[O:17]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@@H]12
Reactant: CC(=O)SC1CN(c2nc(CNC(=O)c3ccco3)cs2)C1
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(CNC(=O)c5ccco5)cs4)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To a solution of 3-acetylthio-1-{4-[(furan-2-carbonylamino)methyl]-1,3-thiazol-2-yl}azetidine (341 mg, 1.12 mmol) (obtained as described in Reference Example 67) in dimethylformamide (10 ml) was added hydrazine acetate (123 mg, 1.34 mmol) at room temperature under an atmosphere of nitrogen and the mixture was stirred for 1 hour. After checking the completion of the reaction, a solution of p-nitrobenzyl (1R,5S,6S)-2-(diphenylphosphoryloxy)-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (797 mg, 1.34 mmol) in acetonitrile (20 ml) was added dropwise into the resulting mixture in an ice bath under an atmosphere of nitrogen, followed by the addition of diisopropylethylamine (0.78 ml, 4.48 mmol). The mixture was stirred for 3 hours while gradually raising the temperature to room temperature. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with 0.5 M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluant: ethyl acetate) to afford p-nitrobenzyl (1R,5S,6S)-2-(1-{4-[(furan-2-carbonylamino)methyl]-1,3-thiazol-2-yl}azetidin-3-yl)thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (641 mg, yield 89%) as a pale yellow solid.