Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:27])[C:8]2[CH:9]=[C:10]3[CH:23]=[C:22]([F:24])[C:21](F)=[C:20]([F:26])[C:11]3=[N:12][C:13]=2[N:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:15]=1)=[O:5])[CH3:2].[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:27])[C:8]2[CH:9]=[C:10]3[CH:23]=[C:22]([F:24])[C:21]([N:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[C:20]([F:26])[C:11]3=[N:12][C:13]=2[N:14]([C:16]([CH3:18])([CH3:17])[CH3:19])[CH:15]=1)=[O:5])[CH3:2]
Reactant: C1CNCCN1
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Product: CCOC(=O)c1cn(C(C)(C)C)c2nc3c(F)c(N4CCNCC4)c(F)cc3cc2c1=O

Procedure:
The 3-ethoxycarbonyl-7,9-difluoro-4-oxo-8-(1-piperazinyl)-1-tert.-butyl-1,4-dihydro-benzo[b][1,8]naphthyridine was prepared under the conditions of Example 35, but starting from 1.9 g of 3-ethoxycarbonyl-7,8,9-trifluoro-4-oxo-1-tert.-butyl-1,4-dihydro-benzo[b][1,8]naphthyridine and 4.3 g of piperazine. After recrystallizing once from 50 cm3 of diisopropyl ether and 10 cm3 of propan-2-ol, 2 g of 3-ethoxycarbonyl-7,9-difluoro-4-oxo-8-(1-piperazinyl)-1-tert.-butyl-1,4-dihydro-benzo[b][1,8]naphthyridine are obtained in the form of a yellow solid melting at 186° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([OH:12])[C:4]=2[N:3]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:20][S:21]([O:12][CH:5]1[C:4]2[N:3]=[C:2]([Br:1])[CH:11]=[CH:10][C:9]=2[CH2:8][CH2:7][CH2:6]1)(=[O:23])=[O:22]
Reactant: OC1CCCc2ccc(Br)nc21
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCCc2ccc(Br)nc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
To a cold (0° C.) stirred solution of 2-bromo-5,6,7,8-tetrahydroquinolin-8-ol (500 mg, 2.36 mmol) in dry CH2Cl2 (10 mL) was added triethylamine (0.72 mL, 5.2 mmol) followed by methanesulfonyl chloride (0.35 mL, 3.6 mmol). The resulting mixture was stirred at 0° C. for 1 h, then warmed slowly to room temperature and stirred a further 1 h. Saturated aqueous NaHCO3 (30 mL) was added and the phases were separated. The aqueous layer was extracted with CH2Cl2 (3×30 mL) and the combined organic extracts were dried (MgSO4) and concentrated to give 605 mg (88%) of 2-bromo-5,6,7,8-tetrahydroquinolin-8-yl methanesulfonate as an orange solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH:7]=[CH:6]2)#[CH:2].[N:19]([Si](C)(C)C)=[N+:20]=[N-:21].[OH-].[Na+].Cl>ClCCl>[F:18][C:15]1[CH:16]=[CH:17][C:12]([N:8]2[C:9]3[C:5](=[CH:4][C:3]([C:1]4[N:19]=[N:20][NH:21][CH:2]=4)=[CH:11][CH:10]=3)[CH:6]=[CH:7]2)=[CH:13][CH:14]=1
Reactant: C#Cc1ccc2c(ccn2-c2ccc(F)cc2)c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Fc1ccc(-n2ccc3cc(-c4c[nH]nn4)ccc32)cc1
Temperature: 170 °C
Reaction time: 2 h
Yield: 103.9 %

Procedure:
A mixture of 5-ethynyl-1-(4-fluorophenyl)-1H-indole (9.6 g) and neat azidotrimethylsilane (21.7 g) was heated in a sealed tube at 170° C. for 24 h. The reaction mixture was cooled to 0° C. and a mixture of dichloromethan (150 mL) and 2 N aqueous sodium hydroxide was added. After stirring at room temperature for 2 h, the mixture was acidified with concentrated hydrochloric acid. The phases were separated and the aqueous phase was extracted with dichloromethane (2×200 mL). The combined organic phases were washed with brine (200 mL), dried (MgSO4) and the volatile solvents evaporated in vacuo affording pure title compound 19a as an oil (11.8 g): 1H NMR (CDCl3) δ 6.80 (d, 1H), 7.25 (t, 2H), 7.40 (d, 1H), 7.55 (dd, 2H), 7.60 (d, 1H), 7.75 (broad d, 1H), 8.05 (s, 1H), 8.20 (broad s, 1H).
Reaction SMILES: [CH3:1][N:2]1[S:7][C:6]2[CH2:8][CH2:9][CH2:10][C:5]=2[C:3]1=[O:4].[C:11]([SH:15])([CH3:14])([CH3:13])[CH3:12].[Na]>CO>[C:11]([S:15][S:7][C:6]1[CH2:8][CH2:9][CH2:10][C:5]=1[C:3]([NH:2][CH3:1])=[O:4])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)S
Reactant: Cn1sc2c(c1=O)CCC2
Agent: [Na]
Solvent: CO
Product: CNC(=O)C1=C(SSC(C)(C)C)CCC1

Procedure:
2-methyl-4,5-trimethylene-4-isothiazolin-3-one (0.78 parts) and sodium tertiary butyl mercaptan (0.56 parts) were stirred together in methanol (10 parts by volume) at 20° to 25° C. for 1 hour. The reactants were then drowned out into distilled water (100 parts by volume) and the disulphide reaction product (1 part) which separated was filtered and dried. The disulphide melted at 153°-5° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH2:21][CH2:20][N:19]([S:23]([C:26]4[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=4[CH3:33])(=[O:25])=[O:24])[C:18]=3[CH:34]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].F[C:36]1C=CC(C)=C(S(Cl)(=O)=O)[CH:41]=1>>[CH2:36]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH2:21][CH2:20][N:19]([S:23]([C:26]4[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=4[CH3:33])(=[O:25])=[O:24])[C:18]=3[CH:34]=2)=[O:13])=[CH:10][C:2]=1[F:1])[CH3:41]
Reactant: Cc1ccc(F)cc1S(=O)(=O)N1CCOc2ccc(C(=O)Nc3ccc(C(=O)O)c(F)c3)cc21
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(F)ccc2C)CCO3)cc1F

Procedure:
2-Fluoro-4-{[4-(5-fluoro-2-methyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid, MS (ISP): m/e=487.1 (M−H), was prepared as described for example 21, steps 1 to 8. Step 7 was performed using 5-fluoro-2-methyl-benzenesulfonyl chloride and yielded 2-fluoro-4-{[4-(5-fluoro-2-methyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 8.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([NH2:12])=[O:11].C(=O)([O-])[O-].[K+].[K+].Br[C:20]([CH3:29])([CH3:28])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].O>C(#N)C>[NH2:12][C:10]([CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][C:20]([CH3:29])([CH3:28])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:11]
Reactant: NC(=O)CCc1ccccc1O
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccccc1CCC(N)=O
Temperature: 80 °C

Procedure:
3-(2-Hydroxyphenyl)propionamide (5.6 g, 33.9 mmol) was dissolved in acetonitrile (15 mL), and potassium carbonate (18.7 g, 135 mmol) was added thereto. Subsequently, tert-butyl 2-bromoisobutyrate (30.3 g, 135 mmol) was added, and the mixture was stirred at 80° C. After completion of reaction, water was added thereto, and the resultant mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, followed by drying over sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (chloroform/methanol=40/1), whereby the target compound was obtained (2.67 g, 26%).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([O:10][C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[C:17]([NH2:21])=[CH:16][CH:15]=[CH:14]4)=[C:4]2[CH:3]=[N:2]1.[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:21][C:17]2[C:18]3[C:13](=[CH:12][C:11]([O:10][C:9]4[CH:8]=[CH:7][N:6]=[C:5]5[NH:1][N:2]=[CH:3][C:4]=45)=[CH:20][CH:19]=3)[CH:14]=[CH:15][CH:16]=2)=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: Nc1cccc2cc(Oc3ccnc4[nH]ncc34)ccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc2cc(Oc3ccnc4[nH]ncc34)ccc12)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-(1H-Pyrazolo[3,4-b]pyridin-4-yloxy)naphthalen-1-amine (25 mg, 0.09 mmol), 4-chlorobenzoic acid (16 mg, 0.10 mmol) and TBTU (35 mg, 0.108 mmol) were dissolved in DMF (0.75 mL). Hunig's base (18 mg, 0.14 mmol) was then added and the reaction mixture was stirred at RT for 16 h. Additional 4-chlorobenzoic acid (6 mg, 0.036 mmol) and TBTU (12 mg, 0.036 mmol) were added to the reaction and stirring was continued for 3 days. The reaction mixture was concentrated in vacuo. The remaining dark brown residue was purified by silica gel chromatography (0% to 2% MeOH in DCM) to yield 4-chloro-N-(6-(1H-pyrazolo[3,4-b]pyridin-4-yloxy)-1-naphthalenyl)benzamide as an off-white solid. MS (ESI, pos. ion) m/z: 415.0 (M+1). MS (ESI pos. ion) m/z: 415.0 (M+H). Calc'd for C23H15ClN4O2−414.85.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].N1C=CN=C1.[CH3:16][C:17]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])[CH3:18]>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[Si:20]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7])([C:17]([CH3:19])([CH3:18])[CH3:16])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N#Cc1cccc(CO)c1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cccc(C#N)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 99 %

Procedure:
To an ice-cold solution of 3-hydroxymethyl benzonitrile (4.95 g, 37 mmol) in CH2Cl2 (47 mL) was added imidazole (5.1 g, 74 mmol), DMAP (0.45 g, 3.7 mmol), and TBSCl (6.2 g, 41 mmol), and the reaction mixture was stirred for 12 h. The reaction mixture was diluted with water, and the aqueous layer was extracted with CH2Cl2 (3×150 mL). The combined organics were washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure to provide 3-(tert-butyldimethylsilyloxymethyl)-benzonitrile (9-1 g, 99%) as a clear oil: 1H NMR (300 MHz, CDCl3) δ 7.51 (s, 1H), 7.42 (d, J=6 Hz, 1H), 7.35-7.28 (m, 1H), 4.75 (s, 2H), 0.94 (s, 9H), 0.11 (s, 6H).
Reaction SMILES: CC(O[CH2:5][C:6]1[C:11]2=[CH:12][CH:13]=[C:14](C=O)[C:10]2=[CH:9]OC=1)=O.C([NH2:21])(CC)C>>[CH:9]1[NH:21][CH:5]=[CH:6][C:11]2[C:10]=1[CH:14]=[CH:13][CH:12]=2
Reactant: CCC(C)N
Reactant: CC(=O)OCc1cocc2c(C=O)ccc1-2
Product: c1cc2cc[nH]cc-2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Baldrinal (2) (1.1 g) was reacted with 2.5 g of sec-butylamine. After stirring for 10 minutes at room temperature, color changes from yellow to orange. When all the baldrinal was reacted, the excess amine was removed by rotary evaporation. After column chromatography with 8:3 hexanes:ethyl acetate as solvent, 15.7 mg of cyclopenta[c]pyridine (3) was collected.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)=[CH:14][N:13]=2)=[O:10])=[CH:4][C:3]=1[CH3:25].C([Sn](CCCC)(CCCC)[C:31]1[CH:36]=[CH:35][N:34]=[N:33][CH:32]=1)CCC>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.CN(C=O)C>[F:24][C:20]1[CH:19]=[C:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]3[CH:6]=[N:7][C:2]([C:31]4[CH:36]=[CH:35][N:34]=[N:33][CH:32]=4)=[C:3]([CH3:25])[CH:4]=3)=[N:13][CH:14]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: Cc1cc(CC(=O)Nc2ccc(-c3cccc(F)c3)cn2)cnc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1cc(CC(=O)Nc2ccc(-c3cccc(F)c3)cn2)cnc1-c1ccnnc1
Temperature: 120 °C
Reaction time: 10 h

Procedure:
To a reaction tube containing 2-(6-chloro-5-methylpyridin-3-yl)-N-(5-(3-fluorophenyl)pyridin-2-yl)acetamide 74-5 (54 mg, 0.15 mmol), 4-(tributylstannyl)pyridazine (55 mg, 0.15 mmol) and Pd(PPh3)4 (16 mg, 0.015 mmol) under Argon was added DMF (0.8 mL). The mixture was stirred at 120° C. for 10 hours. The crude product was purified by reverse phase HPLC to give N-(5-(3-fluorophenyl)pyridin-2-yl)-2-(5-methyl-6-(pyridazin-4-yl)pyridin-3-yl)acetamide 74 as white solid. MS m/z 400.1 (M+1); 1H NMR 400 MHz (CDCl3) δ 9.42 (dd, 1H, J1=4.8 Hz, J2=1.2 Hz), 9.29 (dd, 1H, J1=10.4 Hz, J2=1.2 Hz), 8.56 (d, 1H, J=1.6 Hz), 8.46 (d, 1H, J=1.6 Hz), 8.28 (d, 1H, J=8.8 Hz), 7.90 (dd, 1H, J1=17.6 Hz, J2=2.4 Hz), 7.72 (d, 1H, J=1.6 Hz), 7.70 (dd, 1H, J1=10.8 Hz, J2=2.0 Hz), 7.44-7.39 (m, 1H), 7.32-7.30 (m, 1H), 7.25-7.21 (m, 1H), 7.09-7.04 (m, 1H), 3.82 (s, 2H), 2.44 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[N+:9]([CH3:12])([O-:11])=[O:10]>>[CH3:1][C:2]1[S:6][C:5]([CH:7]=[CH:12][N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=O)s1
Reactant: C[N+](=O)[O-]
Product: Cc1ccc(C=C[N+](=O)[O-])s1
Yield: 76 %

Procedure:
In close analogy to the procedure described above, 5-Methyl-thiophene-2-carbaldehyde is reacted with nitromethane to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[NH2:21][C@@H:22]([CH2:26][OH:27])[CH2:23][CH2:24][CH3:25]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][C@H:22]([CH2:23][CH2:24][CH3:25])[CH2:26][OH:27])[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: CCC[C@@H](N)CO
Reactant: Clc1nc(Cl)c2c(n1)CCS2
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCC[C@H](CO)Nc1nc(Cl)nc2c1SCC2
Temperature: 120 °C

Procedure:
1.4 g 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (II) are placed in 9 ml dioxane, then first 3.5 ml diisopropylethylamine, then 0.9 g D-norvalinol are added. The reaction mixture is heated in the microwave at 120° C., until there is no further reaction, and cooled, then evaporated down. The residue is treated with petroleum ether/ethyl acetate 9:1 in the ultrasound bath, the solid is suction filtered and dried. 1.5 g (III-3) are obtained as a solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[F:13])[S:9][C:8]([CH3:15])([CH3:14])[CH2:7][C:6]2=[O:16].B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[F:13])[S:9][C:8]([CH3:14])([CH3:15])[CH2:7][C:6]2=[O:16]
Reactant: COc1cc2c(cc1F)SC(C)(C)CC2=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1(C)CC(=O)c2cc(O)c(F)cc2S1
Temperature: -230 °C
Reaction time: 23 h
Yield: 67.9 %

Procedure:
To a solution of 6-methoxy-7-fluoro-2,2-dimethyl-thiochroman-4-one (Compound 203, 1.75 g, 7.29 mmol) in 25 mL CH2Cl2 cooled to -23° C. was added BBr3 (5.46 g, 21.8 mmol; 21.8 mL of a 1M solution in CH2Cl2) over a 10 minute period. After stirring for 23 hours at -230° C. the solution was warmed to 0° C. for 3 hours, and then cooled to -78° C. and quenched by the slow addition of 25 mL of H2O. Upon warming to room temperature the aqueous layer was extracted with CH2Cl2 and the combined organic layers were washed with saturated aqueous NaHCO3, H2O, and saturated aqueous NaCl before being dried over MgSO4. Removal of the solvents under reduced pressure, followed by column chromatography (10 to 20% EtOAc/hexanes) afforded 1.12 g (68%) of the title compound as a colorless solid. 1H NMR (300 MHz, CDCl3)δ: 7.82 (1H, d J=9.3 Hz), 6.97 (1H, d, J=10.4 Hz), 5.54 (1H, s), 2.86 (2H,s), 1.46 (6H, s).
Reaction SMILES: Cl.[C:2]1([CH:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][C@@H:19]4[CH2:24][CH2:23][C@H:22]([CH2:25][NH2:26])[CH2:21][CH2:20]4)[CH:14]=3)[O:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1.O>[C:2]1([CH:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][C@@H:19]4[CH2:24][CH2:23][C@H:22]([CH2:25][NH:26][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:21][CH2:20]4)[CH:14]=3)[O:9]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC[C@H]1CC[C@@H](Oc2ccc3c(c2)CCC(c2ccccc2)O3)CC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)NC[C@H]1CC[C@@H](Oc2ccc3c(c2)CCC(c2ccccc2)O3)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.4 %

Procedure:
To a solution of 150 mg [cis-4-(2-phenyl-chroman-6-yloxy)-cyclohexylmethyl]amine hydrochloride (0.40 mmol) at room temperature in 4 ml of pyridine 47 μl of methanesulfonyl chloride (0.60 mmol) were added and stirring at room temperature was continued for 16 h. The reaction mixture was diluted with water and extracted with dichloromethane The combined organic layers were washed with diluted aqueous hydrochloric acid, dried with sodium sulfate and filtered, and the solvent removed under reduced pressure. The crude product was purified by reversed phase HPLC. 97 mg of the title compound were isolated as a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=O)[CH3:11].O.[NH2:14][NH2:15]>C(O)CO>[CH3:9][O:8][C:6]1[CH:7]=[C:2]2[C:3]([C:10]([CH3:11])=[N:14][NH:15]2)=[CH:4][CH:5]=1
Reactant: COc1ccc(C(C)=O)c(F)c1
Reactant: NN
Solvent: OCCO
Solvent: O
Product: COc1ccc2c(C)n[nH]c2c1
Temperature: 165 °C
Reaction time: 24 h
Yield: 51.4 %

Procedure:
To a stirred solution of 2′-fluoro-4′-methoxyacetophenone (0.5 g, 3.0 mmol) in ethylene glycol (10 mL) was added dropwise hydrazine hydrate (0.1 g, 3.1 mmol). The mixture was stirred for 24 h and partitioned between dichloromethane (20 mL) and water (3×20 mL). The organic layer was dried (magnesium sulfate), concentrated in vacuo and purified by column chromatography [SiO2; ethyl acetate-heptane (1:1)] to give an orange oil. The oil was dissolved in ethylene glycol (10 mL) and heated at 165° C. for 24 h. The solution was cooled to room temperature and partitioned between dichloromethane (20 mL) and water (3×20 mL). The organic extract was dried (magnesium sulfate), concentrated in vacuo and purified by column chromatography [SiO2; ethyl acetate-heptane (1:5)] to give the product (0.25 g, 51%) as a colourless solid: IR νmax (Nujol/cm−1) 1624, 1519, 1458, 1295, 1208, 1170, 1024 and 821; NMR δH (400 MHz, CDCl3) 2.54 (3H, s), 3.86 (3H, s), 6.78-6.81 (2H, m) and 7.52 (1H, d, J 9 Hz).
Reaction SMILES: [CH2:1]([C@@H:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=1)[C@@H:4]([CH3:7])[CH2:5]O)[CH3:2].[BrH:22].O>ClCCl>[Br:22][CH2:5][C@H:4]([CH3:7])[C@H:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=1)[CH2:1][CH3:2]
Reactant: CC[C@@H](c1cccc(OCc2ccccc2)c1)[C@@H](C)CO
Reactant: Br
Solvent: ClCCl
Solvent: O
Product: CC[C@@H](c1cccc(OCc2ccccc2)c1)[C@@H](C)CBr
Yield: 86.4 %

Procedure:
The product of Example 32 (2.6 g, 9 mmol) was dissolved in dichloromethane, and the mixture was cooled in an ice-water bath, then 48% hydrobromic acid (0.54 mL, 10 mmol) was added dropwise, after the addition was complete, it was reacted at room temperature for 16 hours. After that, water was added therein for separating, the aqueous phase was extracted with dichloromethane three times, then the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the target compound 2.7 g, yield: 87%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:32][C:8]([CH2:9][C:10]2[CH:15]([C:16]([OH:18])=[O:17])[N:14]3[C:19](=[O:30])[C@@H:20]([C:21](=[O:29])[CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C@H:13]3[S:12][C:11]=2[NH2:31])=[CH:7][CH:6]=1)=[O:4].C(O[CH2:37][CH3:38])(=O)C>CO>[C:23]1([CH:22]([O:17][C:16]([CH:15]2[N:14]3[C:19](=[O:30])[C@@H:20]([C:21](=[O:29])[CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C@H:13]3[S:12][C:11]([NH2:31])=[C:10]2[CH2:9][C:8]2[O:32][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)=[O:18])[C:38]2[CH:37]=[CH:3][CH:5]=[CH:6][CH:7]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccc(CC2=C(N)S[C@@H]3[C@H](C(=O)Cc4ccccc4)C(=O)N3C2C(=O)O)o1
Reactant: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(CC2=C(N)S[C@@H]3[C@H](C(=O)Cc4ccccc4)C(=O)N3C2C(=O)OC(c2ccccc2)c2ccccc2)o1

Procedure:
A solution of 6.85 g of crystallised 3-(5-methoxycarbonyl-furfuryl)-7β-phenylacetyl-amino-ceph-2-em-4ξ-carboxylic acid in 50 ml of methanol is treated with 100 ml of ethyl acetate and the methanol is almost completely removed under reduced pressure. A total of 6.0 g of crude diphenyldiazomethane is then added in small amounts. The reaction mixture is freed from solvent after a total reaction period of 60 minutes at room temperature. The residual oil is triturated with 500 ml of petroleum ether, the undissolved material is filtered off and crystallised from 100 ml of hot ethyl acetate. The first crystalline fraction is recrystallised twice from a mixture of methylene chloride and cyclohexane to yield the 3-(5-methoxycarbonyl-furfuryl)-7β-phenylacetyl-amino-ceph-2-em-4ξ-carboxylic acid diphenylmethyl ester in the form of colourless felted needles, m.p. 164°-166°; [α]D20 = + 267° ± 1° (c = 1.134 in chloroform): thin-layer chromatogram (silica gel): Rf = 0.71 (system: toluene/ethyl acetate 1:1), Rf = 0.60 (system: toluene/ethyl acetate 2:1), Rf = 0.70 (system: toluene/acetone 2:1), Rf = 0.49 (system: toluene/acetone 4:1) and Rf = 0.30 (system toluene/acetone 9:1); ultraviolet absorption spectrum (in 95% ethanol): λmax = 268 mμ (ε = 21000) and λmin = 234 mμ (ε = 11000); infrared absorption spectrum (in mineral oil): characteristic bands at 2,98μ, 5,61μ, 5,74μ, 6,03μ, 6,53μ, 7,59μ, 8,26μ, 8,54μ, 8,72μ, 9,81μ, 10,14μ, 13,13μ and 14,42μ.
Reaction SMILES: [CH2:1]([NH2:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.[CH3:12][O:13][C:14]1[N:23]=[C:22](OC)[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:26][CH3:27])[CH:20]=2)[N:15]=1>>[CH3:12][O:13][C:14]1[N:23]=[C:22]([NH:11][CH2:1][C:2]2[CH:10]=[CH:9][C:8]3[O:7][CH2:6][O:5][C:4]=3[CH:3]=2)[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:26][CH3:27])[CH:20]=2)[N:15]=1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: COc1ccc2nc(OC)nc(OC)c2c1
Product: COc1ccc2nc(OC)nc(NCc3ccc4c(c3)OCO4)c2c1
Temperature: 155 °C
Reaction time: 1 h
Yield: 17.8 %

Procedure:
3.75 g (24.8 mmol) of piperonylamine was added to a solution of 2.00 g (8.26 mmol) of the 2,4,6-trimethoxyquinazoline prepared in Example 88 in dimethyl sulfox (15 ml). The obtained mixture was stirred under heating at 150 to 160° C. After one hour, the reaction mixture was purified by silica gel column chromatography (ethyl acetate/n-hexane) and recrystallized from ethyl acetate/n-hexane to give 0.50 g of the title compounds as a pale-yellow crystal.
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[C:5]([CH3:12])[CH:6]=[CH:7][C:8]=2[CH3:11])[CH:3]1O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH2:10][C:9]2[C:4]([CH:3]=1)=[C:5]([CH3:12])[CH:6]=[CH:7][C:8]=2[CH3:11]
Reactant: Cc1ccc(C)c2c1CC(C)C2O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1=Cc2c(C)ccc(C)c2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
9.06 g of 2,4,7 trimethylindanol (51.4 mmol) were dissolved in 100 ml of toluene in a 250 ml, 2-neck flask equipped with magnetic stirring bar, Dean-Stark separator and bubble condenser. 0.15 g of p-toluenesulphonic acid monohydrate (0.78 mmol, 0.015 eq) were added, and the solution was heated to reflux, distilling the toluene-H2O azeotrope. After about 2 h, the temperature increased toward the boiling point of toluene, and after a few drops of pure toluene distillate, the reaction was stopped by cooling to room temperature and treating the solution with 100 ml of saturated NaHCO3 aqueous solution. The organic phase was extracted with Et2O with the standard procedure, the combined organic phases were washed with H2O and then dried with Na2SO4. After filtration, the solvents were evaporated under reduced pressure to give 7.24 g of an off-white waxy product (yield: 89%).