Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH2:13][CH2:14][CH2:15][C@@H:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][S:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[CH2:18][C@@H:17]1[C:32]([O:34]C)=[O:33].[OH-].[Na+].[ClH:38]>CO.O>[ClH:38].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH2:13][CH2:14][CH2:15][C@@H:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][S:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[CH2:18][C@@H:17]1[C:32]([OH:34])=[O:33]
Reactant: COC(=O)[C@H]1CN(CCSc2ccccc2F)CC[C@H]1CCCc1ccnc2ccc(OC)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2nccc(CCC[C@@H]3CCN(CCSc4ccccc4F)C[C@@H]3C(=O)O)c2c1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
A mixture of 0.12 g of methyl (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(2-fluorophenylthio)ethyl]piperidine-3-carboxylate and 0.6 cm3 of N aqueous sodium hydroxide in 1.8 cm3 of methanol was stirred for 20 hours at a temperature in the region of 60° C. The reaction mixture was evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was taken up in 5 cm3 of water and acidified with 1 cm3 of 2N aqueous hydrochloric acid. The mixture was again evaporated under the same conditions as above and then the new residue was triturated in 5 cm3 of a dichloromethane/methanol (90/10 by volume) mixture. After filtering and evaporating the filtrate under reduced pressure (5 kPa) at a temperature in the region of 40° C., the residue obtained was triturated in 3 cm3 of diisopropyl ether. The insoluble material was filtered off, washed with 2 times 1 cm3 of diisopropyl ether, and dried in the air. 0.14 g of (3R,4R)-4-(3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(2-fluorophenylthio)ethyl]piperidine-3-carboxylic acid hydrochloride was obtained in the form of a solid with a beige color which melts with softening at approximately 148° C.
Reaction SMILES: [C:1]([N:4]1[C:8]([NH2:9])=[N:7][C:6]([S:10](Cl)(=[O:12])=[O:11])=[N:5]1)(=[O:3])[CH3:2].[Cl:14][C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:16]=1[NH2:17]>N1C=CC=CC=1>[NH+:17]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:16]=1.[C:1]([N:4]1[C:8]([NH2:9])=[N:7][C:6]([S:10]([NH:17][C:16]2[C:15]([Cl:14])=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:22])(=[O:12])=[O:11])=[N:5]1)(=[O:3])[CH3:2]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: CC(=O)n1nc(S(=O)(=O)Cl)nc1N
Solvent: c1ccncc1
Product: CC(=O)n1nc(S(=O)(=O)Nc2c(Cl)cccc2Cl)nc1N
Product: c1cc[nH+]cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 94.7 %

Procedure:
The product of stage (c) (54 g) was treated with 2,6-dichloroaniline (42.63 g) in pyridine (350 ml), and the mixture was stirred at 60° C. for 12 hours. After cooling, the product was filtered off, washed with a little pyridine and ether, and dried in vacuo to give 53.6 g of the desired product, mp 213°-215° C.
Reaction SMILES: [NH2:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:21]([OH:23])=[O:22])=[C:6]([CH:9]([S:15][C:16]3[NH:20][N:19]=[N:18][N:17]=3)[CH2:10][CH2:11][C:12](=[O:14])[NH2:13])[CH2:7][S:8][C@H:3]12.C(=O)(O)[O-].[Na+].[CH3:31][S:32][CH2:33][C:34](Cl)=[O:35].[OH-].[Na+]>CC(C)=O>[CH3:31][S:32][CH2:33][C:34]([NH:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:21]([OH:23])=[O:22])=[C:6]([CH:9]([S:15][C:16]3[NH:17][N:18]=[N:19][N:20]=3)[CH2:10][CH2:11][C:12](=[O:14])[NH2:13])[CH2:7][S:8][C@H:3]12)=[O:35]
Reactant: NC(=O)CCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CSCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CSCC(=O)NC1C(=O)N2C(C(=O)O)=C(C(CCC(N)=O)Sc3nnn[nH]3)CS[C@H]12
Reaction time: 0.33 h

Procedure:
To a stirred, cooled (-20°) solution of 10.2 g. (0.026 mol.) of 7-amino-3-[1-(2-carbamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid in 220 ml. of 3% sodium bicarbonate and 220 ml. of acetone is dropwise added a solution of 3.66 g. (0.029 mol.) of methylmercaptoacetyl chloride in 52 ml. of acetone, during which time the pH of the reaction mixture is maintained at 8.0 by addition of 10% sodium hydroxide. After addition the reaction mixture is stirred an additional 20 minutes at -15°, then is warmed to 25° and extracted with ether. The remaining aqueous phase is cooled, 250 ml. of ethyl acetate is added and the slurry is acidified with 3N hydrochloric acid. The layers are separated and the aqueous phase is extracted twice more with ethyl acetate. The combined extracts are dried (MgSO4) and evaporated to dryness to yield the title compound.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[CH:8][C:7]([C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[CH2:16][NH:15][CH2:14][CH2:13]4)=[CH:6][N:5]=2)[CH2:3][CH2:2]1.[CH:20]1([C@@:23]2([CH2:30][S:31](Cl)(=[O:33])=[O:32])[C:27](=[O:28])[NH:26][C:25](=[O:29])[NH:24]2)[CH2:22][CH2:21]1>>[CH:20]1([C@:23]2([CH2:30][S:31]([N:15]3[CH2:14][CH2:13][C:12]4[C:17](=[CH:18][CH:19]=[C:10]([C:7]5[CH:8]=[N:9][C:4]([CH:1]6[CH2:3][CH2:2]6)=[N:5][CH:6]=5)[CH:11]=4)[CH2:16]3)(=[O:32])=[O:33])[NH:24][C:25](=[O:29])[NH:26][C:27]2=[O:28])[CH2:21][CH2:22]1
Reactant: O=C1NC(=O)[C@](CS(=O)(=O)Cl)(C2CC2)N1
Reactant: c1cc2c(cc1-c1cnc(C3CC3)nc1)CCNC2
Product: O=C1NC(=O)[C@](CS(=O)(=O)N2CCc3cc(-c4cnc(C5CC5)nc4)ccc3C2)(C2CC2)N1

Procedure:
The title compound was prepared from 6-[2-(cyclopropyl)pyrimidin-5-yl]-1,2,3,4-tetrahydroisoquinoline and (4S)-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)methanesulfonyl chloride using the general method described in Example 1.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:15]([CH2:16][CH2:17][CH3:18])=[C:14]2[C:9]([CH2:10][CH2:11][CH:12]([C:19]([O:21][CH3:22])=[O:20])[O:13]2)=[CH:8][CH:7]=1.[C:23](=[O:26])([O-])[O-].[K+].[K+].CN([CH:32]=[O:33])C>>[C:6]([C:7]1[CH:8]=[CH:9][C:32]([O:33][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[CH2:10][CH2:11][CH:12]([C:19]([O:21][CH3:22])=[O:20])[O:13][C:14]=3[C:15]=2[CH2:16][CH2:17][CH3:18])=[C:19]([CH2:12][CH:11]=[CH2:10])[C:23]=1[OH:26])(=[O:5])[CH3:15]
Reactant: CN(C)C=O
Reactant: CCCc1c(OCCCI)ccc2c1OC(C(=O)OC)CC2
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: C=CCc1c(OCCCOc2ccc3c(c2CCC)OC(C(=O)OC)CC3)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,4-Dihydroxy-3-(2-propenyl) acetophenone (Aldrich, 12.5 g, 65 mMol) and methyl 7-(3-iodopropoxy)-8-propylchroman-2-carboxylate (29.9 g, 71.5 mMol) were dissolved in DMF (300 ml) containing powdered potassium carbonate (26.91 g, 195 mMol). The mixture was allowed to stir at room temperature under nitrogen for 8 hours and then partitioned between water and toluene. The organic layer was separated and washed with water and brine and then dried over sodium sulfate. Evaporation of the volatiles in vacuo afforded 36 g of crude product which was chromatographed on Merck 60 silica gel using 5:95 ethyl acetate/toluene as eluant. 25 g of pure methyl 7-[3-[4-acetyl-3-hydroxy-2-(2-propenyl)phenoxy]propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylate were obtained in this manner.
Reaction SMILES: O[CH2:2][CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[CH:37][N:38]=[C:12]23)[CH2:7][CH2:6]1.C1(C)C=C[C:42]([S:45](Cl)(=O)=O)=CC=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(#N)C>[CH3:42][S:45][CH2:2][CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[CH:37][N:38]=[C:12]23)[CH2:7][CH2:6]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCCO)CC2)c2ncnn12
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCCSC)CC2)c2ncnn12
Reaction time: 4 h

Procedure:
A mixture of 4′-({4-[trans-4-(2-hydroxyethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.2 g), p-toluenesulfonyl chloride (0.089 g), triethylamine (0.066 mL), 4-dimethylaminopyridine (0.005 g) and acetonitrile (10 mL) was stirred for 4 hr. The reaction mixture was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in acetonitrile (15 mL), sodium thiomethylate (15% aqueous solution, 1.8 g) was added, and the mixture was stirred at 50° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.2 g, 94%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][N:5]=1.Br[CH:12]([CH3:14])[CH3:13].O>CN(C)C=O>[Br:3][C:4]1[C:9]([O:10][CH:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: CC(C)Br
Reactant: Oc1cccnc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1cccnc1Br
Yield: 48 %

Procedure:
Sodium hydride (160 mg) was dissolved in dimethylformamide (5 ml) and 2-bromo-3-pyridinol (500 mg) dissolved in dimethylformamide is slowly added dropwise. Then, 2-bromopropane (0.53 ml) was added to the solution and reacted for 5 hours at room temperature. Water was added to the suspension to dilute and extracted with ethyl acetate to separate an organic layer. The separated organic layer was dried with anhydrous magnesium sulfate and distilled under reduced pressure. As a result, 2-bromo-3-isopropyloxy pyridine (300 mg, yield: 48%) was obtained as an oil phase.
Reaction SMILES: CO[C:3]([C:5]1[CH:9]=[C:8]([Br:10])[N:7]([CH:11]([CH3:13])[CH3:12])[C:6]=1[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[C:18]([F:24])[CH:17]=1)O)=[O:4].[NH2:25][C:26]1[CH:27]=[C:28]([Cl:34])[C:29](=[O:33])[N:30]([CH3:32])[CH:31]=1.COC(C1C=C(Br)N(C(C)C)C=1C(C1C=CC(C#N)=CC=1)O)=O.CN1C(N)=CC(C)=N1.ClC(N(C)C)=C(C)C>CCOC(C)=O.CCN(CC)CC>[Br:10][C:8]1[N:7]([CH:11]([CH3:13])[CH3:12])[C:6]2[CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[C:18]([F:24])[CH:17]=3)[N:25]([C:26]3[CH:27]=[C:28]([Cl:34])[C:29](=[O:33])[N:30]([CH3:32])[CH:31]=3)[C:3](=[O:4])[C:5]=2[CH:9]=1
Reactant: Cn1cc(N)cc(Cl)c1=O
Reactant: COC(=O)c1cc(Br)n(C(C)C)c1C(O)c1ccc(C#N)c(F)c1
Agent: CC(C)=C(Cl)N(C)C
Agent: COC(=O)c1cc(Br)n(C(C)C)c1C(O)c1ccc(C#N)cc1
Agent: Cc1cc(N)n(C)n1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)n1c(Br)cc2c1C(c1ccc(C#N)c(F)c1)N(c1cc(Cl)c(=O)n(C)c1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described for Intermediate AX but in the step corresponding to Step AX1, 5-bromo-2-[(4-cyano-3-fluoro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester (Step BC1) and 5-amino-3-chloro-1-methyl-1H-pyridin-2-one (Step E5) were used instead of 5-bromo-2-[(4-cyano-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester and 2,5-dimethyl-2H-pyrazol-3-ylamine respectively. Moreover, in this step, the procedures described for Steps H3 and H2 using 1-chloro-N,N,2-trimethylpropenylamine and Et3N were used. The title compound (containing some of the corresponding 2-chloro analog) was obtained as a yellow solid. tR: 1.08 min (HPLC 3); ESI-MS: tR=0.99 min, [M+H]+ 503/505/507 (LC-MS 1); TLC: Rf=0.18 (EtOAc).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31]Cl)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1.[NH2:33][C@@H:34]([CH3:37])[CH2:35][OH:36]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][NH:33][C@@H:34]([CH3:37])[CH2:35][OH:36])(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Reactant: C[C@H](N)CO
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCN[C@@H](C)CO)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (Example 242) and (S)-2-amino-1-propanol (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C23H34N6O5SF [(M+H)+] 525.2290, observed 525.2294.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:13])[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=[O:9])([O-:3])=[O:2].[F:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:16]=1[C:17](Cl)=O.C(N(CC)CC)C.C1(C)C=CC=CC=1.C(NC1C=CC2N=C(C3C(F)=CC=CC=3F)OC(=O)C=2C=1)(=O)C>C1COCC1>[F:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:16]=1[C:17]1[O:9][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[N:13]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Agent: CC(=O)Nc1ccc2nc(-c3c(F)cccc3F)oc(=O)c2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1oc(-c2c(F)cccc2F)nc2cc([N+](=O)[O-])ccc12

Procedure:
4-Nitroanthranilic acid (0.6 g), 2,6-difluorobenzoyl chloride (0.93 mL) and triethyl amine/toluene (1/1) (18 mL) were reacted as described under (10). reaction time 2 days. Extraction between ethyl acetate (100 mL) and HCl (2N, 100 mL), followed by separation of the organic layer, drylng over MgSO4, filtering and evaporation gave a crude product which was dissolved in warm THF (20 mL) and precipitated with hexane twice to get the pure product 2-(2,6-difluoro-phenyl)-7-nitro-benzo[d][1,3]oxazin-4-one (0.417 g), mp. 187 C, MS m/e: 304 M+.
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[C:14]([C:17]1[CH:28]=[CH:27][C:20]2[O:21][CH:22]([CH2:25][OH:26])[CH2:23][O:24][C:19]=2[CH:18]=1)(=[O:16])[CH3:15]>CC(C)=O.C(O)(C)C.O.C(Cl)(Cl)Cl>[C:14]([C:17]1[CH:28]=[CH:27][C:20]2[O:21][CH:22]([C:25]([OH:3])=[O:26])[CH2:23][O:24][C:19]=2[CH:18]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)c1ccc2c(c1)OCC(CO)O2
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(=O)c1ccc2c(c1)OCC(C(=O)O)O2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Jones' reagent (11.6 ml.) was added dropwise to a stirred solution of 6-acetyl-2-hydroxymethyl-1,4-benzodioxan (4.0 g.) in acetone (70 ml.) at 10°-15° C. The reaction was stirred at room temperature for 18 hours then diluted with isopropanol/water/chloroform, the organic layer separated and evaporated in vacuo. The residue was redissolved in chloroform, extracted with saturated sodium carbonate solution (2×30 ml.) then the basic phase washed with chloroform, cooled and acidified to pH 1 with concentrated hydrochloric acid. The acidic solution was extracted with chloroform, the combined extracts washed with saturated brine, dried (Na2SO4) and evaporated in vacuo to give 6-acetyl-1,4-benzodioxan-2-carboxylic acid (1.56 g.), m.p. 159°-162° C. A sample was recrystallized from ethanol/ethyl acetate, m.p. 174°-175° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33](OCC)=[O:34])[C:15]1=[O:38].[O:39]1[CH2:43][CH2:42][CH2:41][CH:40]1[CH2:44][NH2:45]>CCO>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33]([NH:45][CH2:44][CH:40]2[CH2:41][CH2:42][CH2:43][O:39]2)=[O:34])[C:15]1=[O:38]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Reactant: NCC1CCCO1
Solvent: CCO
Product: O=C(NCC1CCCO1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Temperature: 25 °C

Procedure:
A solution of ethyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.025 g, 0.049 mmol) in EtOH (2.5 mL) under nitrogen was treated with 1-(tetrahydro-2-furanyl)methanamine (0.025 mL, 0.24 mmol) for 40 min. (130° C. in a microwave vessel. The reaction was then cooled to ambient temperature and the resulting suspension was filtered, washed with EtOH and Et2O then thoroughly dried under high vacuum to provide the title compound as a white solid: 1H NMR (300 MHz, DMSO-D6) δ ppm 1.7 (m, 4 H), 3.2 (m, 2 H), 3.6 (m, 2 H), 3.8 (m, 1 H), 3.9 (t, J=5.7 Hz, 2 H), 4.1 (s, 2 H), 4.6 (m, 1 H), 7.1 (m, 2 H), 7.3 (m, 2 H), 7.8 (s, 4 H), 8.2 (s, 1 H), 8.5 (d, J=1.4 Hz, 1 H), 10.0 (t, J=5.8 Hz, 1 H); ES+ MS: 571 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[C:10]([OH:12])=[O:11].C(=O)([O-])[O-].[K+].[K+].[CH3:19][C:20]1([CH3:34])[CH2:25][CH2:24][C:23]2[CH:26]=[C:27]([S:30](Cl)(=[O:32])=[O:31])[CH:28]=[CH:29][C:22]=2[O:21]1>O.C(#N)C>[CH3:19][C:20]1([CH3:34])[CH2:25][CH2:24][C:23]2[CH:26]=[C:27]([S:30]([N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][C@H:2]3[C:10]([OH:12])=[O:11])(=[O:32])=[O:31])[CH:28]=[CH:29][C:22]=2[O:21]1
Reactant: O=C(O)[C@@H]1Cc2ccccc2N1
Reactant: CC1(C)CCc2cc(S(=O)(=O)Cl)ccc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC1(C)CCc2cc(S(=O)(=O)N3c4ccccc4C[C@H]3C(=O)O)ccc2O1
Yield: 73 %

Procedure:
1 g (6.13 mmol) of 2,3-dihydro-(2S)-1H-indole-2-carboxylic acid, and 0.97 g (7.05 mmol) of potassium carbonate are solubilised in 2 ml of water. 1.6 g (6.13 mmol) of 3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-sulfonyl chloride solubilised in 12 ml of acetonitrile and 2 ml of water are added. Agitation is allowed to take place for 5 hours at ambient temperature. Water is added to the reaction medium, washing is performed with ethyl acetate, the acidity of the aqueous phase is raised to pH 3 by a solution of hydrochloric acid 1 N, and then extraction is performed using ethyl acetate. The organic phases are collected, dried on magnesium sulfate, filtered and concentrated under reduced pressure. The evaporation residue is purified by silica column chromatography eluting with the help of a dichloromethane/methanol (9/1; v/v) mixture. The expected product is obtained in the form of a beige foam with a yield of 73%.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:10][CH2:11][C:12]([NH:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[CH:18]2)=[O:13].CCCCCC>CN(C)C=O>[CH2:1]([NH:8][CH2:10][CH2:11][C:12]([NH:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[CH:18]2)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCCl)Nc1ccc2[nH]ncc2c1
Reactant: NCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=C(CCNCc1ccccc1)Nc1ccc2[nH]ncc2c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 44.7 %

Procedure:
N-benzylamine (4.0 ml, 36.5 mmol) was added to a solution of 3-chloro-N-(1H-indazol-5-yl)propanamide (1.70 g, 7.60 mmol) in N,N-dimethylformamide (2 ml), and the resulting mixture was stirred at 80° C. for 1 hour. Then, the reaction solution was cooled to 0° C. and hexane was added thereto to effect suspension. The solid precipitated was collected by filtration and purified by a silica gel column chromatography (eluent: chloroform/methanol=20/1) to obtain N3-benzyl-N1-(1H-indazol-5-yl)-β-alaninamide (1.00 g, 45%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[Cl:7][C:8]1[C:9]([CH3:25])=[C:10]([CH3:24])[C:11]2[N:12]([CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[N:16]=2)[N:13]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1>ClCCl>[Cl:7][C:8]1[C:9]([CH3:25])=[C:10]([CH3:24])[C:11]2[N:12]([C:14]([CH:30]3[CH:29]=[CH:28][N:27]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[N:26]=[CH:31]3)=[C:15]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[N:16]=2)[N:13]=1
Reactant: Cc1c(Cl)nn2cc(-c3ccc(F)cc3)nc2c1C
Reactant: CCOC(=O)Cl
Reactant: c1ccnnc1
Solvent: ClCCl
Product: CCOC(=O)N1C=CC(c2c(-c3ccc(F)cc3)nc3c(C)c(C)c(Cl)nn23)C=N1
Temperature: 10 °C
Yield: 82.4 %

Procedure:
7.8 ml (82 mmol) of ethyl chloroformate are added, dropwise, to a suspension of 9.00 g (32.6 mmol) of 6-chloro-2-(4-fluorophenyl)-7,8-dimethylimidazo[1,2-b]pyridazine and 11.9 ml (163 mmol) of pyridazine in 160 ml of dichloromethane at 10° C. The medium is stirred at 10° C. for a further hour and then left to stir for 3 hours. It is then poured into ice-cold water and the product is extracted with ethyl acetate. After several washes with water, the organic phase is dried over sodium sulfate and the solvent is concentrated under reduced pressure. The black residue is then solubilized in dichloromethane and stirred in the presence of animal charcoal, to give a dark-brown solid after filtration through a Büchner funnel and evaporation of the solvent under reduced pressure. The product is chromatographed on a neutral alumina column, elution being carried out with a mixture of dichloromethane and petroleum ether (80/20), to give 11.5 g of a beige powder after crystallization from diethyl ether and drying.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH:11]=[N:10][C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8][C:7]2=1)([O-:3])=[O:2].[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Cl>>[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][N:13]1[C:12]2[CH:11]=[N:10][C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8][C:7]=2[C:6]2[C:14]1=[CH:15][CH:16]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccc([N+](=O)[O-])cc12
Reactant: ClCc1cccc(Cl)c1
Product: CCOC(=O)c1cc2c3cc([N+](=O)[O-])ccc3n(Cc3cccc(Cl)c3)c2cn1

Procedure:
The title compound was prepared by alkylation of ethyl 6-nitro-9H-β-carboline-3-carboxylate (prepared according to Settimj, et. al., J. Heterocycl. Chem., 25, 1391–1397 (1988)) with 3-chlorobenzyl chloride in a manner similar to step (a) of example 7. LCMS (APCI, M+H+): 410.1/412.1=3/1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH:13]=O)[N:9]1[CH2:15][CH2:16][N:17]=[C:8]1[CH2:7][CH2:6]2.[NH2:18][C@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:20]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(OC(N1CCC[C@H](NCC2C=C3C(CCC4N3N=NN=4)=CC=2OC)[C@@H]1C1C=CC=CC=1)=O)(C)(C)C>>[C:28]([O:27][C:25]([N:21]1[CH2:22][CH2:23][CH2:24][C@H:19]([NH:18][CH2:13][C:12]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][C:8]4[N:9]3[CH2:15][CH2:16][N:17]=4)=[CH:4][C:3]=2[O:2][CH3:1])[C@@H:20]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: COc1cc2c(cc1C=O)N1CCN=C1CC2
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)[C@@H]1c1ccccc1
Agent: COc1cc2c(cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1)-n1nnnc1CC2
Product: COc1cc2c(cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1)N1CCN=C1CC2

Procedure:
This compound was prepared from Compound 15 and Compound 5 in the same manner of Compound 7.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][CH3:11])[CH:5]=[N:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]=1[OH:35]>>[CH3:18][O:19][C:20]1[CH:25]=[C:24]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([NH:8][C@H:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:10][CH3:11])[N:7]=2)[CH:23]=[CH:22][C:21]=1[OH:35]
Reactant: CC[C@H](Nc1cncc(Cl)n1)c1ccccc1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Product: CC[C@H](Nc1cncc(-c2ccc(O)c(OC)c2)n1)c1ccccc1
Yield: 45.5 %

Procedure:
In a procedure analogous to Example 2, reaction of 6-chloro-N-[(1S)-1-phenylpropyl]pyrazin-2-amine (135 mg, 0.57 mmol) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (158 mg, 0.63 mmol) furnished the product (87 mg, 45%).