Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([O:12]CC)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].O.[OH-].[Li+:17]>O1CCCC1>[CH:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]([O-:12])=[O:11])[CH2:8][CH2:9]1)([CH3:3])[CH3:2].[Li+:17]
Reactant: CCOC(=O)C1CCN(C(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N1CCC(C(=O)[O-])CC1
Reaction time: 8 h
Yield: 100 %

Procedure:
Ethyl 1-isopropylpiperidine-4-carboxylate (Farmaco., 1993, Vol. 48, p. 1439) (3.43 g) was dissolved in tetrahydrofuran (60 ml), and water (15 ml) and lithium hydroxide (421 mg) were added at room temperature to stir the mixture overnight. The reaction mixture was concentrated under reduced pressure to obtain the title compound (3.05 g) as a white solid.
Reaction SMILES: [CH:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:10]([CH:12]1[CH2:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[C:19]([F:29])[CH:18]=3)(O)[CH2:13]1)=[O:11])[CH2:2]2.[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>ClCCCl>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[CH:5]12[CH2:8][CH2:9][CH:1]([CH2:7][CH2:6]1)[CH2:2][N:3]([C:10]([CH:12]1[CH2:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]4[CH2:25][CH2:26][CH2:27][CH2:28]4)=[C:19]([F:29])[CH:18]=3)=[CH:13]1)=[O:11])[CH2:4]2
Reactant: O=C(C1CC(O)(c2ccc(CN3CCCC3)c(F)c2)C1)N1CC2CCC(CC2)C1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(C1C=C(c2ccc(CN3CCCC3)c(F)c2)C1)N1CC2CCC(CC2)C1

Procedure:
A solution of example 26, 3-aza-bicyclo[3.2.2]nonan-3-yl(3-(3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl)-3-hydroxycyclobutyl)methanone (0.59 g, 1.48 mmol) in trifluoroacetic acid (2.5 mL) and 1,2-dichloroethane (16 mL) was refluxed for 20 h and concentrated to give crude 3-aza-bicyclo[3.2.2]nonan-3-yl(3-(3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl)cyclobut-2-enyl)methanone trifluoroacetate salt as a dark purplish-brown oil, with residual TFA. This material was dissolved in EtOH (40 mL) and added to a hydrogenation bottle containing 10% palladium on carbon (93 mg) slurried in EtOH (˜3 mL). The mixture was shaken at room temperature under 48 psi of hydrogen for 2 h, filtered through diatomaceous earth with an EtOH rinse and concentrated to yield an orange oil. This was dissolved in EtOAc and washed with aqueous K2CO3 and brine, dried over MgSO4 and concentrated to afford 0.38 g of light orange oil. Flash chromatography on a 2″×3.5″ silica gel column flushing with 2% MeOH/EtOAc (500 mL) and then eluting with 500 ml each 5% and 10% MeOH/EtOAc afforded 0.256 g (45%) of the title compound as a light orange oil: Rf=0.21 (20% MeOH/EtOAc).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]([OH:11])[C:9]#[CH:10])[CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[C:9]#[CH:10])[CH:5]=[CH:4][CH:3]=1
Reactant: C#CC(O)c1cccc(Br)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: C#CC(=O)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(6-bromopyridin-2-yl)prop-2-yn-1-ol (Example 512 Step 1) (1.00 g, 4.72 mmol) in CH2Cl2 (30 mL) was added Dess-Martin periodinane (4.00 g, 9.43 mmol). The reaction was stirred at room temperature for 2 h. It was subsequently diluted with CH2Cl2 and washed with 20% Na2S2O3. The combined organic layers were dried (MgSO4), filtered, and evaporated. Flash chromatography (0-25% EtOAc/hexanes) afforded the title compound as a colorless solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].IC.[C:16](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:11]([O:10][C:8](=[O:9])[CH:7]([CH3:16])[C:6]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)=[O:13])[CH3:12]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CC(=O)c1ccco1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCOC(=O)C(C)C(=O)c1ccco1

Procedure:
In a flask were placed ethyl 3-(2-furyl)-3-oxopropanoate (0.5 g), iodomethane (0.14 ml), finely ground potassium carbonate (0.75 g) and acetone (5 ml). The mixture was stirred at reflux for 2 h. A further portion of iodomethane (0.9 mmol, 0.056 ml) and potassium carbonate (0.9 mmol, 0.12 g) were added and the mixture stirred at reflux for 1 h. The reaction mixture was filtered and concentrated under vacuum. Yield (0.5 g, 93%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:13]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([Si](C(C)C)(C(C)C)C(C)C)[CH:19]=[CH:18]2)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N+](C)(C)C.[F-]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:13]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[CH:18]2)=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(C(=O)C3(Cc4ccccc4)CCCN3C(=O)OC(C)(C)C)ccc21
Agent: C[N+](C)(C)C
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1(Cc1ccccc1)C(=O)c1ccc2[nH]ccc2c1
Reaction time: 1 h
Yield: 42.9 %

Procedure:
To a stirred solution of 2-benzyl-2-(1-triisopropylsilanyl-1H-indole-5-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.145 g, 0.259 mmol) in THF (5 mL) at ambient temperature under nitrogen was added TMAF (0.026 g, 0.285 mmol). After one hour, the reaction mixture was concentrated in vacuo. Purification of the residue by chromatography (silica, 25-50% EtOAc in hexanes) gave 2-benzyl-2-(1H-indole-5-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.045 g, 0.111 mmol, 43%) as a colourless foam.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1B(O)O>>[CH3:11][O:10][C:5]1[CH:4]=[CH:3][C:2]([C:13]2[S:12][CH:16]=[CH:15][CH:14]=2)=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: OB(O)c1cccs1
Reactant: COc1ccc(Br)cc1C=O
Product: COc1ccc(-c2cccs2)cc1C=O

Procedure:
Ex-45A: 2-Methoxy-5-(thiophen-2-yl)-benzaldehyde was prepared from 5-bromo-2-methoxybenzaldehyde and thiophene-2-boronic acid in a similar manner as described in Ex-3A. 1H NMR (CDCl3) δ 10.49 (s, 1H), 8.07 (d, J=3 Hz, 1H), 7.79 (dd, J=3, 9.0 Hz, 1H), 7.28–7.26 (m, 2H), 7.09–7.06 (m, 1H), 7.02 (d, J=9 Hz, 1H), 3.97 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH2:26][C:27]([O:29]CC)=[O:28])[CH:21]=[CH:20]3)[CH:10]=1.CO.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.O1CCCC1>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH2:26][C:27]([OH:29])=[O:28])[CH:21]=[CH:20]3)[CH:10]=1
Reactant: CCOC(=O)Cn1ccc2cc(OCc3cccc(-c4c(C)cccc4C)c3)ccc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cccc(C)c1-c1cccc(COc2ccc3c(ccn3CC(=O)O)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.8 %

Procedure:
To a solution of ethyl {5-[(2′,6′-dimethylbiphenyl-3-yl)methoxy]-1H-indol-1-yl}acetate (0.27 g, 0.65 mmol) in a mixed solvent of methanol (10 mL) and tetrahydrofuran (10 mL) was added 85% aqueous solution (5 mL) of potassium hydroxide (0.13 g, 1.97 mmol), and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was made weak acidic with 10% aqueous citric acid solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2-2:1) to give the title compound (0.19 g, yield 76%) as a pale-yellow amorphous solid.
Reaction SMILES: [NH2:1][C:2]1([CH2:8][C:9]([O:11]CC)=[O:10])[CH2:7][CH2:6][CH2:5][O:4][CH2:3]1.Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C(N(CC)C(C)C)(C)C.[OH-].[Na+]>C(#N)C.CO>[CH2:18]([O:17][C:15]([NH:1][C:2]1([CH2:8][C:9]([OH:11])=[O:10])[CH2:7][CH2:6][CH2:5][O:4][CH2:3]1)=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)CC1(N)CCCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CC#N
Product: O=C(O)CC1(NC(=O)OCc2ccccc2)CCCOC1
Yield: 28.8 %

Procedure:
Ethyl (3-aminotetrahydro-2H-pyran-3-yl)acetate (Preparation 32, 1.33 g, 7.109 mmol), benzyl chloroformate (1.53 g, 8.53 mmol) and N,N-diisopropylethylamine (3.72 mL, 21.3 mmol) were stirred in anhydrous acetonitrile (30 mL) for 18 hours at room temperature. The reaction was concentrated in vacuo then partitioned between ethyl acetate and water. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with heptane:ethyl acetate:methanol (100:0:0-0:90:10). The oil isolated was then dissolved in methanol (10 mL) and a 1M aqueous solution of sodium hydroxide (10 mL) and heated to 75° C. for 18 hours. The methanol was removed in vacuo and the mixture partitioned between dichloromethane (10 mL) and water. The aqueous layer was acidified with 2M aqueous hydrogen chloride and extracted with dichloromethane (4×10 mL). The organic layer was dried over MgSO4 to afford the title compound as a oil (0.6 g, 29% yield over 2 steps).
Reaction SMILES: [OH-].[Li+].[CH2:3]([O:5]/[C:6](=[CH:12]\[C:13]1[CH:14]=[N:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N:25]([CH3:36])[C:26]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:27])[CH:20]=2)=[CH:17][CH:18]=1)/[C:7]([O:9]CC)=[O:8])[CH3:4].C(O)(=O)C.O>O1CCCC1.C(OCC)(=O)C>[CH2:3]([O:5]/[C:6](=[CH:12]\[C:13]1[CH:14]=[N:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N:25]([CH3:36])[C:26]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:27])[CH:20]=2)=[CH:17][CH:18]=1)/[C:7]([OH:9])=[O:8])[CH3:4]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OCC)C(=O)OCC)cn2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OCC)C(=O)O)cn2)c1
Temperature: 68 °C
Reaction time: 24 h
Yield: 45.5 %

Procedure:
0.4 mL (0.45 mmol) of aqueous 1 M lithium hydroxide solution is added to a solution of 0.14 g (0.3 mmol) of ethyl (Z)-2-ethoxy-3-{6-[3-(3-heptyl-1-methylureido)phenyl]pyrid-3-yl}acrylate in 6 mL of tetrahydrofuran. The reaction mixture is stirred at 68° C. for 24 hours. After cooling, the reaction is worked up by addition of 0.45 mL (0.45 mmol) of aqueous 1 M acetic acid solution and 10 mL of water and extraction with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution and then dried over magnesium sulfate. The solvents are evaporated off. The crude product obtained is purified by chromatography on a column of silica eluted with a 90/10 dichloromethane/methanol mixture to give 60 mg (46%) of (Z)-2-ethoxy-3-{6-[3-(3-heptyl-1-methylureido)phenyl]pyrid-3-yl}acrylic acid in the form of a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:18])[CH:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH3:11].O1CCC[CH2:20]1>O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH3:11])[CH2:20][O:18]1
Reactant: C1CCOC1
Reactant: CC(C(=O)c1ccc(F)cc1F)c1cccnc1
Solvent: O
Product: CC(c1cccnc1)C1(c2ccc(F)cc2F)CO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of dimethylsulphoxonium methylide (36.5 ml of a 0.6M solution in tetrahydrofuran) was added dropwise to a stirred solution of the product of part (ii) (4.36 g) in tetrahydrofuran (35 ml) at -20°. The solution was allowed to warm to room temperature and stirring was continued for 18 hours and then diluted with water. The mixture was extracted with ethyl acetate and the combined extracts were dried (Na2SO4). Evaporation of the solvent gave the title compound as an oil (4.50 g) which was used directly in the next stage.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12](O)=[O:13])[CH2:6][CH2:5]2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([CH2:12][OH:13])[CH2:6][CH2:5]2
Reactant: Nc1ccc2c(c1)CCC(C(=O)O)O2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)CCC(CO)O2
Yield: 83.9 %

Procedure:
To a stirred solution of 11.4 grams (61.7 mmol) of 6-aminochroman-2-carboxylic acid in 100 mL of THF was slowly added 6.64 g (122 mmol) of lithium aluminum hydride. The mixture was refluxed for 30 min, then quenched with ethyl acetate and 150 mL of 1 N HCl. Sufficient 12 N HCl was added to completely dissolve all of the inorganic precipitates. The aqueous phase was extracted twice with ethyl acetate, and the organic fractions combined, washed twice with brine, and concentrated in vacuo to an oil. This oil was distilled to afford 9.28 g of 6-amino-2-hydroxymethylchromane as a clear oil that crystallizes on cooling (87.6% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25](O)=[O:26])=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:28][C:29]1[CH:30]=[C:31]([S:35]([NH:38][CH:39]2[CH2:41][CH2:40]2)(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1>>[CH:39]1([NH:38][S:35]([C:31]2[CH:30]=[C:29]([NH:28][C:25]([C:24]3[CH:23]=[N:22][N:15]4[C:16]([C:18]([F:21])([F:20])[F:19])=[CH:17][C:12]([C:4]5[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:9])[F:10])=[C:2]([CH3:1])[CH:3]=5)=[N:13][C:14]=34)=[O:26])[CH:34]=[CH:33][CH:32]=2)(=[O:37])=[O:36])[CH2:41][CH2:40]1
Reactant: Nc1cccc(S(=O)(=O)NC2CC2)c1
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)Nc4cccc(S(=O)(=O)NC5CC5)c4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.8) and 3-amino-N-cyclopropyl-benzenesulfonamide [CAS 459434-39-0] according to general procedure II. Yellow solid. MS (ISP) 582.0 [(M−H)−]; mp 201° C.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[O:18][CH2:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[F:21][CH:22]([F:32])[O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>>[F:21][CH:22]([F:32])[O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:1]2[CH:2]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=3[O:18][CH2:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]2=[O:7])=[CH:26][CH:25]=1
Reactant: O=Cc1ccc(OC(F)F)cc1
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OCC
Product: CCOc1cccc(F)c1C1CC(C)C(=O)N1Cc1ccc(OC(F)F)cc1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-ethoxy-6-fluorophenyl)-2-methylbutanoate with commercially available 4-(difluoromethoxy)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.90 min.; [M+H]+: 394.01 g/mol.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]([CH3:8])[CH3:7])C.Cl.[OH-].[K+].[Cl:15][C:16]1[CH:17]=[C:18]([NH:23][C:24]2[C:25]3[CH:33]=[C:32]([NH:34][C:35](=[O:45])[CH2:36]P(=O)(OCC)OCC)[N:31]=[CH:30][C:26]=3[N:27]=[CH:28][N:29]=2)[CH:19]=[CH:20][C:21]=1[Cl:22].[Li+].[Cl-]>O.C(Cl)Cl.CO.CC(N(C)C)=O.C1COCC1>[Cl:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][C:21]=1[Cl:22])[NH:23][C:24]1[C:25]2[CH:33]=[C:32]([NH:34][C:35](=[O:45])/[CH:36]=[CH:4]/[CH2:5][N:6]([CH3:7])[CH3:8])[N:31]=[CH:30][C:26]=2[N:27]=[CH:28][N:29]=1
Reactant: CCOC(CN(C)C)OCC
Reactant: CCOP(=O)(CC(=O)Nc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cn1)OCC
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CN(C)C/C=C/C(=O)Nc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cn1
Temperature: 40 °C
Reaction time: 20 h
Yield: 94.6 %

Procedure:
To a stirred mixture of 2,2-diethoxy-N,N-dimethylethanamine (2.08 g, 12.9 mmol) and water (2.2 mL) at room temperature and under a nitrogen atmosphere was added an aq. 37% HCl (2.16 mL, 25.7 mmol). After addition the mixture was stirred at 40° C. (bath) for 20 h. It was cooled to 0° C. (bath). This is called solution A. KOH (1.84 g, 32.9 mmol) was dissolved in water (10 mL) at room temperature under a nitrogen atmosphere. It was cooled to 0° C. (bath). This is called solution B. To a stirred heterogeneous mixture of compound 231 (2.49 g, 5.14 mmol) and THF (10 mL) at room temperature and under a nitrogen atmosphere was added minimum amount of DMA (5.5 mL) to give a homogeneous solution. LiCl (218 mg, 5.14 mmol) was added and stirred at 0° C. (bath) for 15 min. The cold solution B was added and stirred at 0° C. for 2 min. Then the cold solution A was added and the final reaction mixture was continued to stir at 0° C. under a nitrogen atmosphere. The reaction was monitored by TLC (DCM-MeOH=10:1). After 15 min it was found ca. 20% of compound 231 left. More KOH (0.40 g, 7.14 mmol) was added as a solid. After stirred further for 15 min. it was poured into water (300 mL). Petroleum ether (300 mL) was added and stirred at room temperature for 15 min. Petroleum ether layer was decanted. More petroleum ether (300 mL) was added and stirred for 15 min. The solid was collected by suction filtration; washed with water (4×30 mL); dried under reduced pressure over silica gel/KOH to give (2E)-N-[4-(3,4-dichloroanilino)pyrido[3,4-d]-pyrimidin-6-yl]-4-(dimethylamino)-2-butenamide (4) (2.03 g, 95%) as a beige solid, mp 161-164° C.; HPLC: 98.6% pure; 1N NMR δ [(CD3)2SO] 10.92 (s, 1H), 10.36 (s, 1H), 9.09-8.95 (m, 2H), 8.67 (br s, 1 H), 8.27 (br s, 1 H), 7.92 (br d, J=7.8 Hz, 1H), 7.65 (d, J=8.8, 1H), 6.88 (dt, J=15.4, 6.0 Hz, 1H), 6.52 (br d, J=15.4 Hz, 1H), 3.09 (dd, J=6.0, 1.2 Hz, 2H), 2.19 (s, 6H). Anal. Calcd for C19H18Cl2N6O.1.2H2O: C, 51.99; H, 4.69; N, 19.15. Found C, 51.93; H, 4.59; N, 19.15.
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:25])[CH2:24][C@H:21]3[S:20][C:19](NC(=O)/C=N\OC(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)(C3N=C(NC(OC(C)(C)C)=O)SC=3)[C:18]=2[CH2:64][S:65][C:66]2[N:67]([CH3:71])[N:68]=[N:69][CH:70]=2)=[S:16])C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1(OC)C=CC=CC=1.[N+](C)([O-])=O.Cl.O>[CH3:71][N:67]1[C:66]([S:65][CH2:64][C:18]2[CH2:19][S:20][C@@H:21]3[CH2:24][C:23](=[O:25])[N:22]3[C:17]=2[C:15]([OH:14])=[S:16])=[CH:70][N:69]=[N:68]1
Reactant: Cn1nncc1SCC1=C(C(=S)OC(c2ccccc2)c2ccccc2)N2C(=O)C[C@H]2SC1(NC(=O)/C=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(=O)OC(C)(C)C)n1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: COc1ccccc1
Solvent: O
Product: Cn1nncc1SCC1=C(C(O)=S)N2C(=O)C[C@H]2SC1
Reaction time: 1 h
Yield: 128.2 %

Procedure:
To a solution of 7μ-[(Z)-2-(2-t-butoxycarbonylaminothiazol -4-yl)- 2-trityloxyiminoacetamido-3-(3-methyl-1,2,3-triazol-4-yl)thiomethylthio-3-cephem-4-carboxylic acid diphenylmethyl ester (900 mg: 0.869 mMol.) in a mixture of anisole (4 ml) and nitromethane (16 ml) is added a solution of aluminum chloride (924 mg: 6.95 mMol.) in anisole (2 ml) at -40° C., and the mixture is stirred for 1 hour at -40°-30° C. The reaction mixture is diluted with 1N-hydrochloric acid (7 ml) and water and washed with ethyl acetate. The aqueous layer is concentrated under reduced pressure to remove organic solvent and passed through a column of styrene-divinylbenzene copolymer adsorbent. The product is eluted with methanol-water (4:1) to give 7μ-(Z)-2-(2-aminothiazol -4-yl)-2-hydroxyiminoacetamido]-3-(3-methyl-1,2,3-triazol-4-yl)thiomethylthio-3-cephem-4-carboxylic acid as pale yellow powder (366 mg). Yield: 80%.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:25])=[C:16]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH:17]=1)[N:5]=2.[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:25][C:15]1[CH:14]=[CH:13][C:12]([O:11][C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:1][C:29]([CH:26]4[CH2:28][CH2:27]4)=[O:30])=[N:10][C:9]3=[CH:8][CH:7]=2)=[CH:17][C:16]=1[NH:18][C:19](=[O:24])[C:20]([F:22])([F:21])[F:23]
Reactant: Nc1nc2ccc(Oc3ccc(Cl)c(NC(=O)C(F)(F)F)c3)nc2s1
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(Nc1nc2ccc(Oc3ccc(Cl)c(NC(=O)C(F)(F)F)c3)nc2s1)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
N-{5-[(2-Amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-2-chlorophenyl}-2,2,2-trifluoroacetamide (5.0 g, 12.9 mmol) was dissolved in pyridine (25 mL), cyclopropanecarbonyl chloride (1.28 ml, 14.2 mmol) was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was treated with aqueous sodium hydrogen carbonate solution (100 mL), and diluted with ethyl acetate (100 mL). The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residual solid was crystallized from ethyl acetate (30 mL), collected by filtration, and dried to give the title compound (3.46 g, 59%) as a colorless powder.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[C:18]([O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[CH:17][C:16]([Br:27])=[CH:15][N:14]=1)=[S:11])(=O)C1C=CC=CC=1.Br[CH2:29][C:30]([CH:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]1)=O>C(O)C>[Br:27][C:16]1[CH:17]=[C:18]([O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:13]([NH:12][C:10]2[S:11][CH:29]=[C:30]([CH:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)[N:9]=2)=[N:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)CBr)CC1
Reactant: O=C(NC(=S)Nc1ncc(Br)cc1Oc1ccc(F)cc1)c1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2csc(Nc3ncc(Br)cc3Oc3ccc(F)cc3)n2)CC1
Temperature: 25 °C
Yield: 74.7 %

Procedure:
1-(5-bromo-3-(4-fluorophenoxy)pyridin-2-yl)thiourea (3.00 g, 8.77 mmol; prepared according to Example 179, Step D), TEA (2.08 mL, 14.9 mmol) and tert-butyl 4-(2-bromoacetyl)piperidine-1-carboxylate (3.49 g, 11.4 mmol) were refluxed in ethanol (75 mL) for 2 hours. The reaction was cooled to room temperature and filtered to afford the title compound (3.6 g, 74.7% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:12][CH2:13][CH2:14][NH2:15])[CH:6]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH2:5]2.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:12][CH2:13][CH2:14][NH:15][C:33]([NH:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([O:25][CH3:24])[CH:27]=1)=[O:34])[CH:6]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)[CH2:5]2
Reactant: NCCCN1Cc2ccc(F)cc2CC1Cc1ccc(F)cc1
Reactant: COc1cccc(N=C=O)c1
Product: COc1cccc(NC(=O)NCCCN2Cc3ccc(F)cc3CC2Cc2ccc(F)cc2)c1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 3-[6-fluoro-3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 238-b) as a starting material, and using 3-methoxyphenyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.