Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([C:21]2[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[CH:22]=2)=[C:4]2[C:9]3=[C:10]([C:12](=[O:19])[C:13]([C:15]([O:17]C)=[O:16])=[CH:14][N:8]3[N:7]([CH3:20])[CH2:6][CH2:5]2)[CH:11]=1.O1CCCC1.Cl>O>[F:1][C:2]1[C:3]([C:21]2[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[CH:22]=2)=[C:4]2[C:9]3=[C:10]([C:12](=[O:19])[C:13]([C:15]([OH:17])=[O:16])=[CH:14][N:8]3[N:7]([CH3:20])[CH2:6][CH2:5]2)[CH:11]=1
Reactant: COC(=O)c1cn2c3c(c(C4=CC(=O)CCC4)c(F)cc3c1=O)CCN2C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CN1CCc2c(C3=CC(=O)CCC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Temperature: 25 °C
Reaction time: 96 h
Yield: 38.1 %

Procedure:
120 mg of the compound (171) obtained in Example 48 was added to a mixture solution of 3 ml of tetrahydrofuran, 1 ml of 6N hydrochloric acid and 1 ml of water, and the solution was stirred for four days at room temperature. The deposited solid matter was filtered off and washed with water and ethanol in this order to obtain 44 mg of the subject compound (172).
Reaction SMILES: C([C:9]([CH2:21][CH2:22]CCCCCC)([C:18]([O-:20])=O)C(S(O)(=O)=O)C([O-])=O)CCCCCCC.[Na+].[Na+].S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+]>O>[C:18]([O:20][CH2:18][CH2:9][CH2:21][CH3:22])(=[O:20])[CH:9]=[CH2:21]
Reactant: CCCCCCCCC(CCCCCCCC)(C(=O)[O-])C(C(=O)[O-])S(=O)(=O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: C=CC(=O)OCCCC
Temperature: 65 °C
Reaction time: 3 h

Procedure:
98 Parts of butyl acrylate and 2 parts of tricyclodecenyl acrylate are polymerized in 154 parts of water containing 2 parts of sodium dioctylsulfosuccinate (70% strength) as emulsifier and 0.5 part of potassium persulfate by stirring for 3 hours at 65° C. A 40% strength dispersion is obtained, the mean particle size of the latex being about 0.1 μm.
Reaction SMILES: [CH3:1][C:2]1[N:24]=[C:5]2[N:6]=[C:7]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.Cl.[NH:26]1[CH2:31][CH2:30][CH:29]([C:32]2[NH:36][C:35]3[CH:37]=[C:38]([C:41]([F:44])([F:43])[F:42])[CH:39]=[CH:40][C:34]=3[N:33]=2)[CH2:28][CH2:27]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:1][C:2]1[N:24]=[C:5]2[N:6]=[C:7]([C:16]3[CH:23]=[CH:22][C:19]([CH2:20][N:26]4[CH2:31][CH2:30][CH:29]([C:32]5[NH:36][C:35]6[CH:37]=[C:38]([C:41]([F:44])([F:43])[F:42])[CH:39]=[CH:40][C:34]=6[N:33]=5)[CH2:28][CH2:27]4)=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1
Reactant: Cc1nc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn2n1
Reactant: FC(F)(F)c1ccc2nc(C3CCNCC3)[nH]c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: Cc1nc2nc(-c3ccc(CN4CCC(c5nc6ccc(C(F)(F)F)cc6[nH]5)CC4)cc3)c(-c3ccccc3)cn2n1
Temperature: 25 °C
Reaction time: 120 h
Yield: 30 %

Procedure:
200 mg (0.64 mmol) 4-(2-methyl-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)benzaldehyde and 232 mg (0.64 mmol) 2-piperidine-4-yl-6-trifluoromethyl-1H-benzimidazole hydrochloride salt were treated as described in example 2.0. Additional NaBH(OAc)3 has been added after 24 and 26 hours (two equivalents each). After five days stirring at room temperature the solvents have been evaporated and the residue was purified via chromatography. 109 mg of the desired compound were obtained.
Reaction SMILES: [OH:1]O.[CH2:3]([C:5]1[S:6][C:7]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:9]=1)[CH3:4]>ClCCl.C[Re](=O)(=O)=O>[CH2:3]([C:5]1[S:6][C:7]([C:17]2[CH:22]=[CH:21][N+:20]([O-:1])=[CH:19][CH:18]=2)=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)[N:9]=1)[CH3:4]
Reactant: OO
Reactant: CCc1nc(-c2ccc(F)cc2)c(-c2ccncc2)s1
Agent: C[Re](=O)(=O)=O
Solvent: ClCCl
Product: CCc1nc(-c2ccc(F)cc2)c(-c2cc[n+]([O-])cc2)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
3.9 ml (44 mmol) of a 30% strength hydrogen peroxide solution are added dropwise with cooling to a solution of 2.18 g (7.24 mmol) of 4-[2-ethyl-4-(4-fluorophenyl)-1,3-thiazol-5-yl]pyridine and 46.2 mg (0.19 mmol) of methyltrioxorhenium (VII) in 10 ml dichloromethane such that the temperature of the reaction mixture does not exceed 15° C., and the mixture is stirred at room temperature for 16 h. The reaction mixture is then diluted with 100 ml of dichloromethane, and the organic phase is washed successively with 30 ml of a saturated aqueous NaHCO3 solution, 30 ml of a saturated Na2SO3 solution and 30 ml of water and dried over MgSO4. Under reduced pressure, the product is freed from the solvent, giving 1.98 g (85%) of the desired product; 1H-NMR(DMSO-d6) δ: 8.12 (d, 2H), 7.53 (m, 2H), 7.25 (d, 2H), 7.21 (m, 2H), 3.03 (q, 2H), 1.36 (t, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18](Br)[CH:17]=1)[C:10]([CH3:25])([CH3:24])[CH2:9]2)=[O:5])[CH3:2].[Br-].[CH:27]1([Zn+])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.O1CCCC1.[Cl-].[NH4+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:17]=1)[C:10]([CH3:25])([CH3:24])[CH2:9]2)=[O:5])[CH3:2]
Reactant: [Zn+]C1CCCCC1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(F)cc(Br)c1)N2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(F)cc(C3CCCCC3)c1)N2
Temperature: 70 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
A mixture of 2-(3-bromo-5-fluoro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.41 g, 1.0 mmol), cyclohexylzinc bromide solution 0.5 M in tetrahydrofuran (3.0 mL, 1.5 mmol), 1,1′-bis(diphenylphosphino) ferrocenedichloropalladium (II) (41 mg, 0.05 mmol), and DMF (0.5 mL) in dioxane (3 mL) was stirred at 70° C. for 2 hours. Then treated with saturated ammonium chloride (20 mL), extracted with ether (100 mL). After removal of solvent, the residue was purified on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company)(10% ethyl acetate/hexanes) to afford 2-(3-cyclohexyl-5-fluoro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.21 g, 51%) as a white solid: LC/MS m/e calcd for C26H32FNO2 M+: 410.6, observed: 410.1.
Reaction SMILES: [CH:1](=[O:4])[CH2:2][CH3:3].[OH:5][CH2:6][CH:7]([CH2:9]O)[OH:8]>>[CH2:2]([CH:1]1[O:5][CH2:6][CH:7]([OH:8])[CH2:9][O:4]1)[CH3:3]
Reactant: CCC=O
Reactant: OCC(O)CO
Product: CCC1OCC(O)CO1

Procedure:
By the method of Example 27 propionaldehyde was condensed with glycerol, and the resulting intermediate was purified by the formation of the benzoate, 5-benzoyloxy-2-ethyl-1,3-dioxane, m.p. 62°-68.5° C. The benzoate was hydrolyzed by the method of Example 27 to yield 2-ethyl-5-hydroxy-1,3-dioxane, b.p. 94°-97° C/23-25 mm Hg. By the method of Example 27 the intermediate 5-hydroxy compound was converted to 5-benzyloxy-2-ethyl-1,3-dioxane, b.p. 85°-91° C/0.025-0.03 mm Hg, nD25 1.5050. The ir and nmr spectra of the product were consistent with the assigned structure and showed the product to consist of 90% cis isomer.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]([CH3:13])([CH3:12])[CH:10]=O)=[CH:4][CH:3]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH:32]1[CH2:35][CH2:34][CH2:33]1>ClCCl.C([O-])(O)=O.[Na+]>[N:32]1([CH2:10][C:9]([CH3:13])([CH3:12])[O:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[N:7][CH:6]=2)[CH2:35][CH2:34][CH2:33]1
Reactant: C1CNC1
Reactant: CC(C)(C=O)Oc1ccc(Cl)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(CN1CCC1)Oc1ccc(Cl)nc1
Temperature: 0 °C

Procedure:
In a 100 pressure flask 2-(6-chloropyridin-3-yloxy)-2-methylpropanal (10 g, 50.1 mmol, Eq: 1.00), acetic acid (5.7 mL, 100 mmol) and sodium triacetoxyborohydride (22.3 g, 105 mmol, Eq: 2.1) were dissolved in dichloromethane (58 mL) and cooled to 0° C. To this solution was added azetidine (11.8 mL, 175 mmol, 3.5 equiv) via dropwise addition. The reaction was heated overnight at 55° C., then cooled to ambient temperature. The reaction mixture was diluted with 120 ml saturated NaHCO3 and 80 ml dichloromethane. Mixture was shaken and the dichloromethane layer collected. The organic layer was washed again with 100 ml of 5% NaHCO3 (aq) solution and with an equal volume of 50% diluted brine. The aqueous phase was back-extracted 2×70 ml dichlormethane. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by Analogix MPLC (SF25-60 gram column) eluted with 100% DCM to 5% MeOH/DCM gradient to afford a 70:30 mixture of the desired product: 2-(6-chloro-pyridin-3-yloxy)-2-methyl-propan-1-ol (7.5 g) as a pale yellow oil. Used as is in the next step.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[N:11]1[S:12][CH:13]=[C:14]2[C:19]([CH2:20][OH:21])=[CH:18][CH:17]=[CH:16][C:15]=12.C(N(CC)CC)C>ClCCl>[N:11]1[S:12][CH:13]=[C:14]2[C:19]([CH:20]=[O:21])=[CH:18][CH:17]=[CH:16][C:15]=12
Reactant: OCc1cccc2nscc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=Cc1cccc2nscc12
Reaction time: 0.5 h
Yield: 95 %

Procedure:
Under nitrogen atmosphere, dimethyl sulfoxide (10.8 mL, 153 mmol) was added to a solution of oxalyl chloride (6.68 mL, 76.0 mmol) in dichloromethane (200 mL) at −78° C., and the mixture was stirred for 30 min. To the reaction mixture was added a solution of 2,1-benzisothiazol-4-ylmethanol (4.20 g, 25.4 mmol) in dichloromethane (54 mL), and the mixture was stirred for 2 hr. To the reaction mixture was added triethylamine (32.2 mL, 229 mmol) at −78° C., and the mixture was stirred for 1 hr. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80) to give the title compound (3.94 g, yield 95%).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[S:10]([CH2:12][C:13]([OH:15])=O)=[O:11].[NH2:16][CH:17]1[C:35](=[O:36])[N:19]2[C:20]([C:32]([OH:34])=[O:33])=[C:21]([CH2:24][S:25][C:26]3[S:30][C:29]([CH3:31])=[N:28][N:27]=3)[CH2:22][S:23][C@H:18]12>>[N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[NH:1][C:2]=1[S:10]([CH2:12][C:13]([NH:16][CH:17]1[C:35](=[O:36])[N:19]2[C:20]([C:32]([OH:34])=[O:33])=[C:21]([CH2:24][S:25][C:26]3[S:30][C:29]([CH3:31])=[N:28][N:27]=3)[CH2:22][S:23][C@H:18]12)=[O:15])=[O:11]
Reactant: O=C(O)CS(=O)c1nc2ccccc2[nH]1
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)CS(=O)c4nc5ccccc5[nH]4)[C@H]3SC2)s1

Procedure:
448 mg. of benzimidazol-2-ylsulfinylacetic acid and 7-amino-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid were reacted in the same manner as described in Example 28 and 161 mg. of 7-(benzimidazol-2-ylsulfinylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid were obtained.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]([CH3:20])([CH2:15][C:16]#[C:17][CH2:18][CH3:19])[CH2:13][OH:14]>C(Cl)Cl.O>[CH3:11][C:12]([CH3:20])([CH2:15][C:16]#[C:17][CH2:18][CH3:19])[CH:13]=[O:14]
Reactant: CCC#CCC(C)(C)CO
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCC#CCC(C)(C)C=O
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 84.1 %

Procedure:
To a solution of oxalyl chloride (27 g, 214 mmol) in anhydrous DCM (300 ml) at −78° C. under nitrogen was added anhydrous DMSO (33.4 g, 428 mmol) and the mixture was stirred at −78° C. for 20 min. A solution of 2,2-dimethylhept-4-yn-1-ol (20 g, 142 mmol) in anydrous DCM (50 ml) was added slowly over a period of 25 min. The reaction mixture was stirred at −78° C. for 2 hours and quenched by the addition of TEA (165 ml, 1.14 mol) and diluted with water (700 ml). The organic layer was separated and washed with a 1.5M aqueous solution of HCl (200 ml), water and brine. The organic layer was dried (MgSO4) and the solvent was removed under reduced pressure to afford the titled compound as a pale brown liquid (16.5 g, 87%). TLC: Pet. ether/EtOAc (8/2): Rf=0.75.
Reaction SMILES: C1(N2C3C(=CC=CC=3)C(CCCN3CCC(C4C=C(NC(=O)C(C)C)C=CC=4)CC3)=C2C2C=CC=CC=2)C=CC=CC=1.[CH3:43][CH:44]([CH3:73])[C:45]([NH:47][C:48]1[CH:53]=[CH:52][CH:51]=[C:50]([CH:54]2[CH2:59][CH2:58][N:57]([CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][C:65](=O)[C:66]3[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=3)[CH2:56][CH2:55]2)[CH:49]=1)=[O:46].Cl.[CH3:75][O:76][C:77]1[CH:82]=[CH:81][C:80]([NH:83]N)=[CH:79][CH:78]=1>>[CH3:75][O:76][C:77]1[CH:82]=[C:81]2[C:80](=[CH:79][CH:78]=1)[NH:83][C:65]([C:66]1[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=1)=[C:64]2[CH2:63][CH2:62][CH2:61][CH2:60][N:57]1[CH2:58][CH2:59][CH:54]([C:50]2[CH:49]=[C:48]([NH:47][C:45](=[O:46])[CH:44]([CH3:43])[CH3:73])[CH:53]=[CH:52][CH:51]=2)[CH2:55][CH2:56]1
Reactant: COc1ccc(NN)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(=O)c3ccccc3)CC2)c1
Agent: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4)n(-c4ccccc4)c4ccccc34)CC2)c1
Agent: Cl
Product: COc1ccc2[nH]c(-c3ccccc3)c(CCCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1
Yield: 32.7 %

Procedure:
According to the procedure used for the synthesis of N-(3-{1-[3-(1,2-diphenyl-1H-indol-3-yl)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide, 2-methyl-N-{3-[1-(6-oxo-6-phenylhexyl)-4-piperidinyl]phenyl}propanamide (14.3 mg, 0.0339 mmol) and 1-(4-methoxyphenyl)hydrazine hydrochloride (7.10 mg, 0.0407 mmol) provided N-(3-{1-[4-(5-methoxy-2-phenyl-1H-indol-3-yl)butyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.8 mg, 33%). 1H NMR (400 MHz, CDCl3) δ 7.95 (d, 2H, J=7.8 Hz), 7.61–7.15 (m, 11H), 6.97 (d, 1H, J=7.0 Hz), 3.88 (s, 3H), 3.09 (d, 2H, J=11.3 Hz), 2.99 (t, 2H, J=7.0 Hz), 2.55–2.35 (m, 4H), 2.12–1.70 (m, 6H), 1.68–1.52 (m, 2H), 1.48–1.34 (m, 2H), 1.25 (d, 6H, J=6.7 Hz); ESMS m/e: 524.3 (M+H)+.
Reaction SMILES: [C:1]([NH:3][C:4]([NH:9][CH2:10][C:11]#[CH:12])=[N:5][CH2:6][CH2:7][SH:8])#[N:2].[Na].[CH3:14][C:15]1[N:16]=[CH:17][NH:18][C:19]=1[CH2:20]Cl.Cl>C(O)C>[C:1]([NH:3][C:4]([NH:5][CH2:6][CH2:7][S:8][CH2:20][C:19]1[NH:18][CH:17]=[N:16][C:15]=1[CH3:14])=[N:9][CH2:10][C:11]#[CH:12])#[N:2]
Reactant: Cc1nc[nH]c1CCl
Reactant: C#CCNC(=NCCS)NC#N
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: C#CCN=C(NC#N)NCCSCc1[nH]cnc1C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
The ethanol solution of the product of step B, above, (about 10 m moles) was added to a solution of 0.46 sodium (0.02 g-atoms) in 10 ml ethanol at 4° C. under nitrogen. After 5 minutes, a solution of 1.67 g (10 m moles) of 4-methyl-5-chloromethylimidazole.HCl in 14 ml ethanol was added and the mixture was stirred at room temperature under nitrogen for 70 minutes. The reaction mixture was filtered through a bed of celite filter aid to remove the inorganic salts and the celite was washed with ethanol. The filtrate was evaporated to dryness and the product was purified by chromatography on a silica gel column (20 g silica, 3.2×4.5 cm bed) with ethanol-chloroform mixtures as the solvent. The ethanol content was gradually increased from 2 to 15%. The eluant was evaporated to dryness to give 1.906 g of crystalline product. Recrystallization from 2-propanol gave 1.49 g (54%) of the title product, m.p. 144°-145° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:10]=[C:11]=[S:12])[CH:8]=2)[CH:3]=[N:2]1.Cl.[CH2:14]([O:16][C:17](=[O:21])[CH2:18][CH2:19][NH2:20])[CH3:15].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:14]([O:16][C:17](=[O:21])[CH2:18][CH2:19][NH:20][C:11](=[S:12])[NH:10][C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[N:2][NH:1]2)=[CH:5][CH:6]=1)[CH3:15]
Reactant: S=C=Nc1ccc2cn[nH]c2c1
Reactant: CCOC(=O)CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCNC(=S)Nc1ccc2cn[nH]c2c1
Yield: 37.1 %

Procedure:
A solution of 5 g (28.6 mmol) of lH-indazol-6-yl isothiocyanate, 5.3 g (34.3 mmol) of beta-alanine ethyl ester hydrochloride and 4.8 ml (34.3 mmol) of triethylamine in 50 ml of chloroform is left at room temperature under agitation for one hour. The chloroform phase is washed with water (2 × 10 ml) and with a 1 N hydrochloric acid solution (2 × 10 ml). It is dried and concentrated to dryness. The residue (8 g) is triturated in ethyl ether (3 × 20 ml). There is obtained 3.1 g of (lH-indazol-6-yl)thiocarbamoyl-beta-alanine ethyl ester (yield 28%, melting point 145° C.).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:16])[C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)[CH3:2].[NH:21]1[CH2:26][CH2:25][S:24][CH2:23][CH2:22]1.CCOCC>CN1CCCC1=O>[CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:16])[C:9]([F:15])=[C:10]([N:21]3[CH2:26][CH2:25][S:24][CH2:23][CH2:22]3)[C:11]=2[F:13])[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2c(F)c(F)c(F)c(F)c21
Reactant: C1CSCCN1
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: CCn1cc(C(=O)O)c(=O)c2c(F)c(F)c(N3CCSCC3)c(F)c21
Reaction time: 2 h

Procedure:
A 289 mg portion of 1-ethyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was dissolved in 3 ml of 1-methyl-2-pyrrolidone. A 350 mg portion of thiomorpholine was added and the mixture was stirred for 2 hours. Ether was added, the solid collected and recrystallized from acetone, giving 250 mg of the desired product as a white solid, mp 308°-310° C.
Reaction SMILES: [CH3:1][C:2]([CH3:31])=[C:3]([N:8]1[C@H:11](SC)[C@@H:10]([C@H:14]([O:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[CH3:15])[C:9]1=[O:30])[C:4]([O:6][CH3:7])=[O:5].[Cl:32]Cl>ClCCl.C(Cl)(Cl)(Cl)Cl>[Cl:32][CH:11]1[N:8]([C:3](=[C:2]([CH3:31])[CH3:1])[C:4]([O:6][CH3:7])=[O:5])[C:9](=[O:30])[C@@H:10]1[C@H:14]([O:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:18])[CH3:15]
Reactant: COC(=O)C(=C(C)C)N1C(=O)[C@H]([C@@H](C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)[C@H]1SC
Reactant: ClCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C(=C(C)C)N1C(=O)[C@H]([C@@H](C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)C1Cl
Temperature: 0 °C

Procedure:
To a solution of methyl 3-methyl-2-[(3S,4R)-4-methylthio-3-{(1R)-1-(p-nitrobenzyloxycarbonyloxy)ethyl}-2-oxoazetidin-1-yl]but-2-enoate (481 mg) in dichloromethane (5 ml) was added a solution of chlorine (83 mg) in carbon tetrachloride (0.65 ml) at -78° C. The solution was allowed to warm to 0° C. during 45 minutes and evaporated in vacuo. The residue was chromatographed on silica gel (12 g) eluting with 10-33% ethyl acetate in hexane to give methyl 2-[(3S)-4-chloro-3-{(1R)-1-(p-nitrobenzyloxycarbonyloxy)ethyl}-2-oxoazetidin-1-yl]-3-methylbut-2-enoate [a mixture (55:45) of (4R) isomer and (4S) isomer] (394 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]([CH2:20][CH2:21][O:22][CH3:23])[CH3:19])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.ClC1C=C(NC2C=CC(CN3CCN(C)CC3)=CN=2)C(=O)N(C)N=1.C([O:51][CH2:52][C:53]1[C:58]([N:59]2[N:68]=[CH:67][C:66]3[C:61](=[C:62]([F:73])[CH:63]=[C:64]([C:69]([CH3:72])([CH3:71])[CH3:70])[CH:65]=3)[C:60]2=[O:74])=[CH:57][CH:56]=[CH:55][C:54]=1[B-](F)(F)F)(=O)C.[K+]>>[C:69]([C:64]1[CH:65]=[C:66]2[C:61](=[C:62]([F:73])[CH:63]=1)[C:60](=[O:74])[N:59]([C:58]1[CH:57]=[CH:56][CH:55]=[C:54]([C:2]3[CH:3]=[C:4]([NH:10][C:11]4[CH:16]=[CH:15][C:14]([CH2:17][N:18]([CH2:20][CH2:21][O:22][CH3:23])[CH3:19])=[CH:13][N:12]=4)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=3)[C:53]=1[CH2:52][OH:51])[N:68]=[CH:67]2)([CH3:72])([CH3:70])[CH3:71]
Reactant: COCCN(C)Cc1ccc(Nc2cc(Cl)nn(C)c2=O)nc1
Reactant: CC(=O)OCc1c(-n2ncc3cc(C(C)(C)C)cc(F)c3c2=O)cccc1[B-](F)(F)F
Agent: CN1CCN(Cc2ccc(Nc3cc(Cl)nn(C)c3=O)nc2)CC1
Agent: [K+]
Product: COCCN(C)Cc1ccc(Nc2cc(-c3cccc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)nn(C)c2=O)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[5-(5-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-one was prepared using the general procedure described in example 41 substituting 6-Chloro-4-(5-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-pyridin-2-ylamino)-2-methyl-2H-pyridazin-3-one for 6-chloro-2-methyl-4-(5-((4-methylpiperazin-1-yl)methyl)pyridin-2-ylamino)pyridazin-3(2H)-one in step 3. For the Suzuki reaction, potassium (2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)trifluoroborate (Eq: 1.2) was used in place of 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate. After removal of the acetate protecting group using potassium carbonate in methanol, water was added dropwise and the reaction was stirred at room temperature overnight. The solid that formed was filtered, washed with water then ether and dried in a vacuum oven to give 52 mgs of a crystalline white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.38 (s, 9H) 2.13 (s, 3H) 2.47 (s, 2H) 3.22 (s, 3H) 3.39-3.49 (m, 4H) 3.79 (s, 3H) 4.43 (br. s., 2H) 4.58 (br. s., 1H) 7.41-7.65 (m, 5H) 7.75 (d, J=13.22 Hz, 1H) 7.87 (s, 1H) 8.17 (s, 1H) 8.46-8.59 (m, 2H) 9.40 (s, 1H). MS: (M+H)+=628.
Reaction SMILES: [C:1]([C@H:5]1[NH:8][C:7](=[O:9])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:10]1([C@H:16]([N:19]=[C:20]=[O:21])[CH2:17][CH3:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([C@H:16]([NH:19][C:20]([N:8]2[C@H:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:6][C:7]2=[O:9])=[O:21])[CH2:17][CH3:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)[C@@H]1CC(=O)N1
Reactant: CC[C@@H](N=C=O)c1ccccc1
Product: CC[C@@H](NC(=O)N1C(=O)C[C@H]1C(C)(C)C)c1ccccc1

Procedure:
Following the same procedure as in example 1, step F, but using 4(S)-tert-butylazetidine-2-one as starting material and 1(R)-phenylpropyl isocyanate as reactant, 4(S)-tert-butyl-2-oxoazetidine-1-carboxylic acid (1(R)-phenylpropyl)amide was obtained as a waxy solid.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:19]1[C:27]2[C:22]3[C:23](=[CH:28][CH:29]=[CH:30][C:21]=3[C:20]1=[O:31])[CH:24]=[CH:25][CH:26]=2.C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:8][NH:9][C:10](=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:19]1[C:27]2[C:22]3[C:23](=[CH:28][CH:29]=[CH:30][C:21]=3[C:20]1=[O:31])[CH:24]=[CH:25][CH:26]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCCCCCBr)NOCc1ccccc1
Reactant: O=C1Nc2cccc3cccc1c23
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(CCCCCCN1C(=O)c2cccc3cccc1c23)NOCc1ccccc1

Procedure:
In a manner analogous to that of example 2(b), 7-bromo-heptanoic acid benzyloxy-amide 0.46 g, 1.5 mmol) was reacted with benzo[cd]indol-2(1H)-one (0.25 g, 1.5 mmol) in the presence of potassium carbonate (0.2 g, 1.4 mmol) to give 7-(2-oxo-2H-benzo[cd]indol-1-yl)-heptanoic acid benzyloxyamide as an amorphous solid (yield 0.08 g, 13%; purified by column chromatography using silica gel and ethyl acetate:heptane=1:1 as an eluent). MS (M+H+)=403.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[N:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:16][C:17]1[NH:21][N:20]=[N:19][N:18]=1>O1CCCC1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>[N:1]1([C:7]2[N:12]=[C:11]([C:13]([NH:16][C:17]3[NH:21][N:20]=[N:19][N:18]=3)=[O:15])[CH:10]=[N:9][CH:8]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1cncc(N2CCOCC2)n1
Agent: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1nnn[nH]1)c1cncc(N2CCOCC2)n1

Procedure:
To a suspension of 2.50 g of 6-(4-morpholinyl) pyrazine-2-carboxylic acid in 50 ml of tetrahydrofuran, 3.60 ml of triethylamine and 1.60 ml of pivaloyl chloride were added dropwise successively at 0° C. under stirring. After stirring for 1 hour at 0° C., 1.12 g of 5-amino-1H-tetrazole was added to the mixture, and the reaction mixture was stirred for 1 hour at room temperature, and then refluxed for 12 hours. The reaction mixture was evaporated, and water was added to the residue. The precipitate was collected by filtration, and recrystalized from a mixture of dimethylsulfoxide and methanol affording 1.74 g of the desired compound as yellow needles. The obtained crystal was consistent with that of (a).