Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1)[CH3:2].C[N:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=C([N+]([O-])=O)C1=O.N>>[CH2:1]([N:3]1[CH2:8][CH2:7][C:6]2[N:11]=[CH:16][C:15]([N+:17]([O-:19])=[O:18])=[CH:14][C:5]=2[CH2:4]1)[CH3:2]
Reactant: Cn1cc([N+](=O)[O-])cc([N+](=O)[O-])c1=O
Reactant: CCN1CCC(=O)CC1
Agent: N
Product: CCN1CCc2ncc([N+](=O)[O-])cc2C1
Yield: 92.9 %

Procedure:
1-Ethyl-4-piperidone (500 mg, 3.93 mmol) was mixed with 1-methyl-3,5-dinitro-2-pyridone (392 mg, 1.97 miol) in 1M methanolic ammonia (40 mL, 40 mmol) and heated at reflux for 3 h. The solvent was evaporated off and the residue was suspended in CHCl3 and flash chromatographed over silica gel (32 g) eluting with EtOAc to afford an orange solid (379 mg, 93% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH:14]3[CH2:15][CH2:16][CH:11]([CH2:12][CH2:13]3)[CH:10]2[C:17]([O:19][CH3:20])=[O:18])[C:5]([Cl:21])=[CH:4][N:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[F:30][C:31]1[CH:32]=[C:33]2[C:39](B3OC(C)(C)C(C)(C)O3)=[N:38][N:37]([C:49]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:34]2=[N:35][CH:36]=1.B([O-])[O-]>O.C1COCC1.CCOC(C)=O.C(Cl)Cl.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>[Cl:21][C:5]1[C:6]([NH:8][CH:9]2[CH:14]3[CH2:15][CH2:16][CH:11]([CH2:12][CH2:13]3)[CH:10]2[C:17]([O:19][CH3:20])=[O:18])=[N:7][C:2]([C:39]2[C:33]3[C:34](=[N:35][CH:36]=[C:31]([F:30])[CH:32]=3)[N:37]([C:49]([C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)([C:56]3[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=3)[C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)[N:38]=2)=[N:3][CH:4]=1
Reactant: CC1(C)OB(c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ncc(F)cc23)OC1(C)C
Reactant: COC(=O)C1C2CCC(CC2)C1Nc1nc(Cl)ncc1Cl
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: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C1C2CCC(CC2)C1Nc1nc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ncc(F)cc23)ncc1Cl
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 83 %

Procedure:
A solution of (+/−)-trans-(2,3)-methyl 3-((2,5-dichloropyrimidin-4-yl)amino)-bicyclo-[2.2.2]octane-2-carboxylate, 37, (0.50 g, 1.51 mmol) and K3PO4 (0.96 g, 4.54 mmol) in water (2.5 mL) and THF (10.00 mL) was degassed for 15 min with a stream of nitrogen. Then, 5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-pyrazolo[3,4-b]pyridine, 6, (0.84 g, 1.67 mmol) was added and the mixture was degassed for an additional 15 min. Then, Pd(PPh3)4 (0.09 g, 0.08 mmol) was added to the mixture. The vessel was sealed and heated to 90° C. After 2.5 hr., an additional 0.1 equivalent of boronate, 6, was added and the mixture was heated for an additional 30 min. The cooled solution was diluted with EtOAc, washed with water, dried over Na2SO4, filtered and concentrated in vacuo. Flash chromatography (SiO2, 0-35% EtOAc in DCM) gave the desired product (0.85 g, 83% yield) which was sufficiently pure for use in the next reaction: LC/MS Gradient 10-90%, 0.1% formic 5 min, C18/ACN, RT=3.85 min, (M+H) 673.27.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C@:9]2([CH3:28])[C:13](=[O:14])[N:12]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=3)[C:11](=[O:27])[NH:10]2)=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+]>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C@:9]2([CH3:28])[C:13](=[O:14])[N:12]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=3)[C:11](=[O:27])[NH:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc([C@@]2(C)NC(=O)N(c3ccc(C#N)c(C(F)(F)F)c3)C2=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@]1(c2ccc(O)cc2)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Reaction time: 8 h

Procedure:
5 g of (R)-4-[4-(4-methoxyphenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl]-2-trifluoromethylbenzonitrile are dissolved in 50 mL of dichloromethane. 14 mL of boron trifluoride/dimethylsulphide complex are added and the mixture is stirred overnight at AT. It is then poured in an aqueous solution of sodium bicarbonate and the product is extracted with dichloromethane. After drying over magnesium sulphate then evaporation of the solvent, the crude product is purified over a silica gel column (eluent 50/50 heptane/ethyl acetate) to provide 3.5 g of a slightly brown solid.
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH2:15]([O:17][C:18](=[O:26])[CH:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH3:16]>>[CH2:15]([O:17][C:18](=[O:26])[CH:19]([O:14][C:11]1[CH:10]=[CH:9][C:8]([C:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)=[CH:13][CH:12]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH3:16]
Reactant: Oc1ccc(C2=CCCCCC2)cc1
Reactant: CCCCCC(Br)C(=O)OCC
Product: CCCCCC(Oc1ccc(C2=CCCCCC2)cc1)C(=O)OCC

Procedure:
Analogously to the process described in Example 1, 13.2 g of p-(1-cycloheptenyl)-phenol and 28 g of 2-bromoheptanoic acid ethyl ester give α-[p-(1-cycloheptenyl)-phenoxy]-heptanoic acid ethyl ester, of boiling point 160°-164° C, as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([C:21](O)=[O:22])[O:12]1.[CH3:24][C:25]([CH3:31])([CH3:30])[C:26]([NH:28][NH2:29])=[O:27].C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C>C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH3:24][C:25]([CH3:31])([CH3:30])[C:26]([NH:28][NH:29][C:21]([C@@H:13]1[C@@H:14]2[C@@H:15]([O:16][C:17]([CH3:19])([CH3:20])[O:18]2)[C@H:11]([N:6]2[CH:5]=[N:4][C:3]3[C:7]2=[N:8][CH:9]=[N:10][C:2]=3[Cl:1])[O:12]1)=[O:22])=[O:27]
Reactant: CC(C)(C)C(=O)NN
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](C(=O)O)O[C@H]2n1cnc2c(Cl)ncnc21
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](C(=O)NNC(=O)C(C)(C)C)O[C@H]2n1cnc2c(Cl)ncnc21
Yield: 59.6 %

Procedure:
(3aS,4S,6R,6aR)-6-(6-Chloro-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxole-4-carboxylic acid (2.5 g) suspended in 1,2-dimethoxymethane (100 ml) was treated with 2,2-dimethyl-propionic acid hydrazide (1.1 g) and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), and the mixture heated under reflux for 16 h. The mixture was poured into aqueous citric acid (250 ml) and extracted with ethyl acetate; the organic layers were washed with citric acid and brine, dried (MgSO4) and evaporated in vacuo to give the crude product. Purification by flash chromatography on silica gel (Biotage cartridge), eluting with ethyl acetate:cyclohexane 65:35, gave the title compound as a white solid (1.92 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:9](Cl)=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH3:17])[C:12](=[O:18])[CH2:11]3)[CH:5]=[N:6][CH:7]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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>[N:6]1[CH:5]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH3:17])[C:12](=[O:18])[CH2:11]3)[CH:3]=[C:2]([C:22]2[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=2)[CH:7]=1
Reactant: OB(O)c1cccnc1
Reactant: CN1C(=O)Cc2c1ccc(-c1cncc(Br)c1)c2Cl
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: ClCCl
Solvent: COCCOC
Product: CN1C(=O)Cc2cc(-c3cncc(-c4cccnc4)c3)ccc21
Temperature: 120 °C

Procedure:
To 5-(5-bromo-pyridin-3-yl)-4-chloro-1-methyl-1,3-dihydro-indol-2-one prepared as described in Example 28, (100 mg, 0.30 mmol) was added 3-pyridine boronic acid (CAS#1692-25-7, 47.3 mg, 0.385 mmol), 1,2-dimethoxyethane (3 mL), and 2 M aqueous sodium carbonate (0.385 mL, 0.770 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.11 mmol/g loading, (135 mg, 0.015 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 120° C. for 2.5 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethanol-dichloromethane, 1 to 8%) to furnish 5-[3,3′]bipyridinyl-5-yl-1-methyl-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 336.0905 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 3.18 (s, 3H), 3.68 (s, 2H), 7.15 (d, J=8.1 Hz, 1H), 7.50-7.60 (m, 2H), 8.20 (t, J=2.1 Hz, 1H), 8.21-8.27 (m, 1H), 8.65 (dd, J=4.7, 1.6 Hz, 1H), 8.68 (d, J=2.0 Hz, 1H), 8.97 (d, J=2.1 Hz, 1H), 9.03 (d, J=2.4 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([S:20][CH2:21][C@@H:22]([C:24]([OH:26])=[O:25])[NH2:23])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][C:36]=1[S:45](Cl)(=[O:47])=[O:46].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1>[CH:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][C:36]=1[S:45]([NH:23][C@H:22]([C:24]([OH:26])=[O:25])[CH2:21][S:20][C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:28][CH:27]=1)(=[O:46])=[O:47]
Reactant: COc1ccc(C(SC[C@H](N)C(=O)O)(c2ccccc2)c2ccccc2)cc1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(C(SC[C@H](NS(=O)(=O)c2ccc3ccccc3c2)C(=O)O)(c2ccccc2)c2ccccc2)cc1
Reaction time: 1 h
Yield: 75.4 %

Procedure:
To a stirred mixture of commercially available S-4-monomethoxytrityl-(L)-cysteine (11) (0.34 g, 1 mmol), dioxane (5 mL) and 10% aqueous sodium carbonate (5 mL) was added 2-naphtalenesulfonyl chloride (0.25 g, 1.1 mmol). After stirring for 1 h, the reaction mixture was acidified by addition of 5% aqueous citric acid (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were dried (magnesium sulfate) and concentrated under reduced pressure. The crude product was chromatographed on silica gel (methanol/dichloromethane/triethylamine, 0/99/1 to 4/95/1, v/v/v) to yield 12 (76% yield, 0.44 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][CH:13]([CH3:18])[C:14]([F:17])([F:16])[F:15])=[N:7][N:6]=[CH:5]2.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:21]=1B1OC(C)(C)C(C)(C)O1>>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:21]=1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][CH:13]([CH3:18])[C:14]([F:17])([F:16])[F:15])=[N:7][N:6]=[CH:5]2
Reactant: CC(Oc1nncc2cc(Cl)ccc12)C(F)(F)F
Reactant: Cc1ccc(N)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(N)cc1-c1ccc2c(OC(C)C(F)(F)F)nncc2c1

Procedure:
The title compound was prepared according to a procedure similar to that described in Example 225, using 6-chloro-1-(1,1,1-trifluoropropan-2-yloxy)phthalazine and 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenamine as starting materials. MS (ESI, pos. ion) m/z: 348.1 (M+1). The racemic material was subjected to Preparative SFC separation using a chiral column to afford its (R)- and (S)-enantiomers.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].Cl.[NH:16]1[CH2:19][CH2:18][CH2:17]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:16]2[CH2:19][CH2:18][CH2:17]2)=[O:8])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12]
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1
Reactant: C1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(F)c(C(F)(F)F)c1)N1CCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.6 %

Procedure:
Commercially available 4-fluoro-3-(trifluoromethyl)benzoic acid (230 mg, 1.10 mmol) was dissolved in dichloromethane (50 mL), and azetidine hydrochloride (120 mg, 1.28 mmol), HATU (550 mg, 1.45 mmol) and N,N-diisopropylethylamine (0.50 mL, 2.87 mmol) were added, followed by stirring at room temperature for 4 hours under nitrogen atmosphere. 0.5N hydrochloric acid (100 mL) was added, and extraction was carried out with dichloromethane (100 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=60%-80%) to afford the desired compound (211 mg, yield 78%) as a colorless liquid.
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]([C:37]1[N:38]=[C:39]([NH:42]C(=O)C(F)(F)F)[S:40][CH:41]=1)[C:7]([NH:9][CH:10]1[C:35](=[O:36])[N:12]2[C:13]([C:32]([OH:34])=[O:33])=[C:14]([CH2:17][S:18][C:19]3[N:23]([CH2:24][C:25]([C:29]([OH:31])=[O:30])=[N:26][O:27][CH3:28])[N:22]=[N:21][N:20]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[C:2]#[CH:3].C([O-])(=O)C.[Na+].Cl>O>[CH2:1]([O:4][N:5]=[C:6]([C:37]1[N:38]=[C:39]([NH2:42])[S:40][CH:41]=1)[C:7]([NH:9][CH:10]1[C:35](=[O:36])[N:12]2[C:13]([C:32]([OH:34])=[O:33])=[C:14]([CH2:17][S:18][C:19]3[N:23]([CH2:24][C:25]([C:29]([OH:31])=[O:30])=[N:26][O:27][CH3:28])[N:22]=[N:21][N:20]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[C:2]#[CH:3]
Reactant: C#CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC(=NOC)C(=O)O)CS[C@H]12)c1csc(NC(=O)C(F)(F)F)n1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: C#CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC(=NOC)C(=O)O)CS[C@H]12)c1csc(N)n1

Procedure:
A mixture of 7-[2-(2-propynyloxyimino)-2-{2-(2,2,2-trifluoroacetamido)thiazol-4-yl}acetamido]-3-[1-(2-carboxy-2-methoxyiminoethyl)-1H-tetrazol-5yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer: in the 7-position) (2.0 g) and sodium acetate.trihydrate (3.71 g) in water (15 ml) was stirred overnight at room temperature. The solution was adjusted to pH 2.5 with 10% hydrochloric acid under ice-cooling and the resultant precipitates were filtered and washed with water to give 7-[2-(2-propynyloxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-[1-(2-carboxy-2-methoxyiminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer: in the 7-position).(1.12 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]#[C:11][C@@H:12]2[NH:16][C:15](=[O:17])[CH2:14][CH2:13]2)=[N:6][C:7]=1[O:8][CH3:9].[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:10]=[CH:11]\[C@@H:12]2[NH:16][C:15](=[O:17])[CH2:14][CH2:13]2)=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1nc(C#C[C@H]2CCC(=O)N2)ccc1Cl
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Product: COc1nc(/C=C\[C@H]2CCC(=O)N2)ccc1Cl
Yield: 71 %

Procedure:
Lindlar catalyst (50 mg) was added to a solution of (5R)-5-[(5-chloro-6-methoxypyridin-2-yl)ethynyl]pyrrolidin-2-one (232 mg) in methanol (5 mL), and the mixture was stirred at room temperature for eight hours in a hydrogen atmosphere. The reaction solution was filtered through celite, and then the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→0:1) to give the title compound as a colorless oil (166 mg, 71%).
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:10]([OH:38])=[C:11]2[C:16](=[C:17]([C:19]3[N:20]=[CH:21][S:22][CH:23]=3)[N:18]=1)[N:15]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:14](=[O:31])[C:13]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[CH:12]2)=[O:8].[OH-].[Na+].CO.C1COCC1>C([O-])(O)=O.[Na+]>[CH2:24]([N:15]1[C:16]2[C:11](=[C:10]([OH:38])[C:9]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:39])=[O:2])=[O:8])=[N:18][C:17]=2[C:19]2[N:20]=[CH:21][S:22][CH:23]=2)[CH:12]=[C:13]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:14]1=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)CCNC(=O)c1nc(-c2cscn2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCNC(=O)c1nc(-c2cscn2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.1 %

Procedure:
A mixture of 3-[(1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-thiazol-4-yl-1,2-dihydro-[1,7]naphthyridine-6-carbonyl)-amino]-propionic acid methyl ester (24 mg, 0.044 mmol), 2 M NaOH (3 mL), MeOH (3 mL) and THF (3 mL) was stirred at r.t. for 16 h, then concentrated to approximately one-third of its original volume. 1 M HCl was added until pH was about 3-4, and the resulting suspension was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (10-100% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration to give 13 mg of the title compound. MS: (+) m/z 527.33 (M+1).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13](=O)[CH3:14])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:16]([NH2:21])(=[O:20])[C:17]([CH3:19])=[CH2:18].CC(C)([O-])C.[K+]>O1CCOCC1>[CH3:18][CH:17]1[CH2:19][C:12]([C:9]2[CH:10]=[CH:11][C:6]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[CH:7][CH:8]=2)=[C:13]([CH3:14])[NH:21][C:16]1=[O:20]
Reactant: C=C(C)C(N)=O
Reactant: CC(=O)Cc1ccc(-n2ccnc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC1=C(c2ccc(-n3ccnc3)cc2)CC(C)C(=O)N1

Procedure:
Similar to example 1, the reaction is carried out with 3 g 1-[4-(1-imidazolyl)-phenyl]-2-propanone, 30 ml 1,4-dioxane, 1.45 g methacrylic acid amide and 1.74 g potassium tert-butoxide.
Reaction SMILES: [CH:1]1([C:5]2[N:6]=[C:7]([CH2:10][CH2:11][C:12]3[CH:36]=[CH:35][N:15]4[C:16](=[O:34])[C:17](/[CH:26]=[C:27](\[CH3:33])/[C:28]([O:30]CC)=[O:29])=[C:18]([N:20]5[CH2:25][CH2:24][O:23][CH2:22][CH2:21]5)[N:19]=[C:14]4[CH:13]=3)[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([C:5]2[N:6]=[C:7]([CH2:10][CH2:11][C:12]3[CH:36]=[CH:35][N:15]4[C:16](=[O:34])[C:17](/[CH:26]=[C:27](\[CH3:33])/[C:28]([OH:30])=[O:29])=[C:18]([N:20]5[CH2:25][CH2:24][O:23][CH2:22][CH2:21]5)[N:19]=[C:14]4[CH:13]=3)[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)/C(C)=C/c1c(N2CCOCC2)nc2cc(CCc3nc(C4CCC4)cs3)ccn2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C/C(=C\c1c(N2CCOCC2)nc2cc(CCc3nc(C4CCC4)cs3)ccn2c1=O)C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.1 %

Procedure:
Ethyl (E)-3-{8-[2-(4-cyclobutyl-1,3-thiazol-2-yl)ethyl]-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl}-2-methyl-2-propenoate (120 mg, 0.236 mmol) dissolved in methanol (5 ml) was added dropwise with 1 N aqueous sodium hydroxide (2 ml) under ice cooling. The reaction solution was stirred for 10 minutes and then warmed to room temperature because the reaction did not progress. The reaction solution was stirred for 45 minutes, then further added with 1 N aqueous sodium hydroxide (2 ml), and after 1 hour, further added with 1 N aqueous sodium hydroxide (2 ml). The solvent was evaporated under reduced pressure, and the resulting sodium salt of the title compound was dissolved in 1,4-dioxane, added with 4 N hydrochloric acid (6 ml) and stirred. Then the reaction solution was concentrated under reduced pressure, and the residue was neutralized with saturated aqueous sodium hydrogencarbonate and extracted with chloroform and methanol. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by thin layer silica gel chromatography (chloroform:methanol=30:1) to obtain 75 mg (66%) of the title compound as yellow crystals.
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.Cl[CH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1.[K+].[Br-]>>[OH:1][CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[N:15]([CH2:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1
Reactant: CC(C)(C)[Si](C)(C)OCCC1Oc2ccccc2NC1=O
Reactant: ClCc1cccc2ccccc12
Agent: [Br-]
Agent: [K+]
Product: O=C1C(CCO)Oc2ccccc2N1Cc1cccc2ccccc12

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine by Methods F and G, alkylating with 1-chloromethylnaphthalene, in 42% overall yield. the crude product was crystallized from ether/EtOAc/hexane to afford a white solid, mp 100°-104° C.; IR (KBr) 3435, 2896, 1668, 1504, 1414, 1253, 1132, 1068, 768, 758 cm-1 ; 1H NMR (CDCl3) δ1.92 (br s, 1H plus HDO), 2.26-2.44 (m, 2H), 3.96 (t, J=5.6 Hz, 2H), 4.94 (dd, J=7.5, 5.6 Hz, 1H), 5.62 (ABq, JAB =16.9 Hz, 2H), 6.72 (dd, J=8.0, 1.1 Hz, 1H), 6.84 (td, J=8.1, 1.5 Hz, 1H), 6.96-7.11 (m, 3H), 7.36 (t, J=7.4 Hz, 1H), 7.54-7.64 (m, 2H), 7.78 (d, J=8.2 Hz, 1H), 7.92 (d, J=7.8 Hz, 1H), 8.04 (d, J=8.1 Hz, 1H); MH+ at m/z=334; Anal. Calc'd for C21H19NO3 : C, 75.66; H, 5.74; N. 4.20. Found: C, 75.56; H, 5.80; N, 4.14.
Reaction SMILES: P(Br)(Br)Br.[C:5]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH:18](O)[CH3:19])=[CH:15][CH:16]=2)[C:11]([CH3:22])([CH3:21])[CH2:10][CH2:9]1)(=[O:7])[CH3:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[PH4+].[CH:43]([C:45]1[CH:54]=[CH:53][C:48]([C:49]([O:51][CH3:52])=[O:50])=[CH:47][CH:46]=1)=O.O1C(CC)C1>N1C=CC=CC=1.CCOCC>[C:5]([N:8]1[C:17]2[C:12](=[CH:13][C:14](/[C:18](/[CH3:19])=[CH:43]/[C:45]3[CH:54]=[CH:53][C:48]([C:49]([O:51][CH3:52])=[O:50])=[CH:47][CH:46]=3)=[CH:15][CH:16]=2)[C:11]([CH3:21])([CH3:22])[CH2:10][CH2:9]1)(=[O:7])[CH3:6]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC(=O)N1CCC(C)(C)c2cc(C(C)O)ccc21
Agent: BrP(Br)Br
Agent: CCC1CO1
Agent: [PH4+]
Solvent: CCOCC
Solvent: c1ccncc1
Product: COC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CCN3C(C)=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Two drops of pyridine, followed by 3.28 g (0.012 mol) of phosphorus tribromide in 20 ml of ether, were added to 6.0 g (0.024 mol) of N-acetyl-4,4-dimethyl-6-(1-hydroxyethyl)-1,2,3,4-tetrahydroquinoline in 75 ml of ether, at 0° C., with stirring. Stirring was continued for 1 hour at 0° C., and then the reaction mixture was poured onto 100 g of ice. The resulting mixture was extracted with ether and the combined extracts were dried (MgSO4) and then evaporated in vacuo. This gave 7.0 g of a white solid which was dissolved in 100 ml of toluene. To the resulting solution ws added 12.6 g (0.048 mol) triphenylphosphine, and then the mixture was refluxed for 18 hours, during which time the phosphonium salt precipitated as a viscous oil. The solvent was decanted from the oil, and then the latter was triturated under hot toluene. The toluene was removed by decantation, the residue was dissolved in dichloromethane, the dichloromethane was dried, and then the dichloromethane was removed by evaporation in vacuo. The residue (7.5 g, 0.013 mol), 2.15 g of methyl 4-formylbenzoate and 75 ml of 1,2-epoxybutane were heated under reflux for 48 hours. The reaction mixture was then evaporated in vacuo to give the title compound in admixture with the corresponding (Z)-isomer. The isomers were separated by column chromatography on silicic acid, eluting with etherhexane (1:1 by volume). The (E)-isomer (2.8 g) was further purified by recrystallization from etherhexane to give 2.3 g (25% yield) of the title compound, mp 141°-142° C.