Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH2:21][CH2:22][CH3:23])[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([C:16]2[NH:17][CH:18]=[CH:19][N:20]=2)[CH:15]=1)[C:10]([OH:12])=O)=[O:6])[CH2:2][CH3:3].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:57][C@@H:58]([CH2:72][C:73]1[CH:78]=[C:77]([F:79])[CH:76]=[C:75]([F:80])[CH:74]=1)[C@H:59]([OH:71])[CH2:60][NH:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([CH2:69][CH3:70])[CH:64]=1>C(Cl)Cl>[F:79][C:77]1[CH:78]=[C:73]([CH:74]=[C:75]([F:80])[CH:76]=1)[CH2:72][C@H:58]([NH:57][C:10](=[O:12])[C:9]1[CH:13]=[C:14]([C:16]2[NH:17][CH:18]=[CH:19][N:20]=2)[CH:15]=[C:7]([C:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:21][CH2:22][CH3:23])=[O:6])[CH:8]=1)[C@H:59]([OH:71])[CH2:60][NH:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([CH2:69][CH3:70])[CH:64]=1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)O)cc(-c2ncc[nH]2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCN(CCC)C(=O)c1cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(CC)c2)cc(-c2ncc[nH]2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 3-[(dipropylamino)carbonyl]-5-(1H-imidazol-2-yl)benzoic acid (250 mg, 0.79 mmol), diisopropylethylamine (103 mg, 0.8 mmol), and HBTU (330 mg, 0.87 mmol) in methylene chloride (5 mL) is added a mixture of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol prepared by the method of Example SP-272 (322 mg, 0.79 mmol) and diisopropylethylamine (206 mg, 1.6 mmol) in methylene chloride (5 mL). The reaction mixture is stirred at room temperature for 4 h and concentrated under reduced pressure. The residue is diluted with ethyl acetate (20 mL), washed with saturated sodium bicarbonate, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 5:95 methanol/methylene chloride) provides the title compound in pure form. APCI MS m/z 632.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH2:6][O:5][C:4]([C:7]2[CH:29]=[CH:28][C:10]([O:11][CH2:12][CH2:13][CH2:14][CH:15]3[CH2:20][CH2:19][N:18](CC4C=CC=CC=4)[CH2:17][CH2:16]3)=[CH:9][CH:8]=2)=[N:3]1.[H][H]>[Pd].CO>[CH3:1][C:2]1([CH3:30])[CH2:6][O:5][C:4]([C:7]2[CH:29]=[CH:28][C:10]([O:11][CH2:12][CH2:13][CH2:14][CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)=[N:3]1
Reactant: CC1(C)COC(c2ccc(OCCCC3CCN(Cc4ccccc4)CC3)cc2)=N1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC1(C)COC(c2ccc(OCCCC3CCNCC3)cc2)=N1
Yield: 90.9 %

Procedure:
A mixture of 13.5 parts of 4-[3-[4-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)phenoxy]propyl]-1-(phenylmethyl)piperidine and 200 parts of methanol was hydrogenated at normal pressure and at 50° C. with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 9.5 parts (90.9%) of 4-[3-[4-(4,5-dihydro -4,4-dimethyl-2-oxazolyl)phenoxy]propyl]piperidine as a residue (int. 74).
Reaction SMILES: Br[C:2]1[C:3]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[K+].[K+].O.[CH3:28][O:29][C:30]1[C:35](B(O)O)=[CH:34][CH:33]=[CH:32][N:31]=1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C:3]2[C:2]([C:35]3[C:30]([O:29][CH3:28])=[N:31][CH:32]=[CH:33][CH:34]=3)=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:12])[CH:4]=2)=[CH:15][CH:16]=1
Reactant: COC(=O)c1cc(Br)c(Oc2ccc(Cl)cc2)cc1F
Reactant: COc1ncccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(-c2cccnc2OC)c(Oc2ccc(Cl)cc2)cc1F
Temperature: 50 °C
Yield: 179.6 %

Procedure:
To a stirred solution of methyl 5-bromo-4-(4-chlorophenoxy)-2-fluorobenzoate (Preparation 32, 199 mg, 0.55 mmol) in dioxane (10 mL) and water (0.5 mL) was added potassium carbonate (158 mg, 1.14 mmol) and 2-methoxypyridin-3-ylboronic acid mono hydrate (147 mg, 0.86 mmol). The reaction was degassed three times followed by the addition of tetrakis(triphenylphosphine)palladium(0) (13.2 mg, 0.012 mmol). The reaction was degassed three times and heated at 50° C. overnight under a nitrogen atmosphere. The reaction was cooled to room temperature, concentrated in vacuo to afford a brown residue. The residue was partitioned between EtOAc (25 mL) and water (25 mL). The aqueous phase was extracted with EtOAc (2×25 mL). The combined organic extracts were washed with water (25 mL), brine (25 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford brown oil (383 mg). The oil was then purified by flash column chromatography using the Biotage System™ (50 g silica column, eluting with DCM). Fractions containing product were combined and concentrated in vacuo to afford the title compound as a grey oil (194 mg, 91%).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:35](=[O:36])[N:13]3[C:14]([C:19]([O:21][CH:22]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])=[C:15]([CH3:18])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClN1[C:42](=[O:43])CCC1=O>CO.C(Cl)Cl>[C:1]1([CH2:7][C:8]([NH:10][C@H:11]2[C:35](=[O:36])[N:13]3[C:14]([C:19]([O:21][CH:22]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[O:20])=[C:15]([CH3:18])[C@@H:16]([O:43][CH3:42])[S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CO
Solvent: ClCCl
Product: CO[C@H]1S[C@@H]2[C@@H](NC(=O)Cc3ccccc3)C(=O)N2C(C(=O)OC(c2ccccc2)c2ccccc2)=C1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 21 %

Procedure:
To a solution of diphenylmethyl 7α-phenyl-acetamido-3-methyl-3-cephem-4-carboxylate (2.88 g, 5.8 mmole) in 40 ml of methanol and 60 ml of methylene chloride, was added N-chlorosuccinimide (882 mg, 6.6 mmol) and the mixture was stirred for 90 minutes at room temperature. The reaction solution was then washed with brine (2X) and dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure. The resultant yellow foam (2.84 g) was chromatographed over 100 grams of silica gel employing 10-15% of ethyl acetate in toluene as the eluting solvent. The first fraction to elute from the column was the desired 2α-methoxy cephem compound which was subsequently recrystallized from a mixture of ethyl acetate and cyclohexane to give pure diphenylmethyl 7α-phenylacetamido-2α-methoxy-3-methyl-3-cephem-4-carboxylate. (638 mg, 21% yield) (m.p. 144°-145° C.) i.r. (CHCl3) 1780, 1725 and 1680 cm-1 ; n.m.r. (CDCl 3) δ1.95 (s, 3, CH3) 3.35 (s, 3, OCH3), 3.45 (s, 2, CH2Ph), 4.60 (s, 1, C2 --H), 4.70 (d, J=2 and 8 Hz, 1, C7 --H), 4.85 (d, J=2 Hz, 1, C6 --H), 6.95 (s, 1, CH2Ph), 7.3 (m, 16, aromatic H and N-H); u.v. (CHCl3) λmax 264 nm (ε=9726).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH2:6][O:7]2.C1C=C(Cl)C=C(C(OO)=[O:21])C=1.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl.O>[F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[CH:4]1[O:21][CH:5]1[CH2:6][O:7]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1ccc(F)c2c1C=CCO2
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Fc1ccc(F)c2c1OCC1OC21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.9 %

Procedure:
5,8-Difluoro-2H-chromene (35 g, 0.21 mole) was dissolved in 500 ml DCM and MCPBA (77%, 93 g, 0.42 mole) was added. The reaction was stirred at room temperature for 30 minutes. 50 g Na2S2O3 in 500 ml water was added to quench the reaction. The organic layer was washed with 2N NaOH solution (2×500 ml), brine (200 ml), dried over Na2SO4 and concentrated. The residue was recrystallized from EtOAc/Hexane solution to give rise to 21.6 g pure product. The residue from mother liquor was purified by column chromatography (EtOAc/hexane from 0/100 to 25/75 in 55 minute, additional 1.4 g obtained). Total Yield: 23 g, 60%. 1H NMR (CDCl3 400 MHz δ 7.00 (m, 1H), 6.63 (m, 1H), 4.67 (d, J=12.4 Hz, 1H), 4.27 (m, 2H), 3.84 (d, J=4.4 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][N:13]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>C1(C)C=CC=CC=1.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>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)=[N:13][CH:14]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: Brc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Oc1ccc(-c2ccc(Br)cn2)cc1
Yield: 23.7 %

Procedure:
4-(5-Bromo-2-pyridinyl)phenol (0.25 g, 24%) was prepared as a white solid from (4-hydroxyphenyl)boronic acid (0.60 g, 4.22 mmol), 2,5-dibromopyridine (1.0 g, 4.22 mmol), 2M Na2CO3 (6 mL), EtOH (2 mL) and Pd(PPh3)4 (0.15 g, 0.13 mmol) in toluene (4 mL) in a manner similar to Example 1, Step 1, except the reaction was heated overnight. 1H NMR (400 MHz, CDCl3): δ 8.68 (d, 1H, J=2.2 Hz), 7.90-7.80 (m, 3H), 7.56 (d, 1H, J=8.5 Hz), 6.92 (d, 2H, J=8.5 Hz), 5.18 (bs, 1H); LRMS (ESI), m/z 250/252 (M+H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH3:33])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:34][C@H:35]1[N:40]([CH3:41])[CH2:39][CH2:38][N:37]([CH2:42][CH2:43][OH:44])[CH2:36]1.CC(C)([O-])C.[K+]>C(O)(C)(C)C.O>[CH3:34][C@H:35]1[N:40]([CH3:41])[CH2:39][CH2:38][N:37]([CH2:42][CH2:43][O:44][C:2]2[CH:7]=[CH:6][N:5]3[C:8]([C:11]([NH:13][C:14]4[CH:22]=[CH:21][CH:20]=[C:19]5[C:15]=4[C:16]([CH3:33])=[N:17][N:18]5[CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[N:25]=4)=[O:12])=[CH:9][N:10]=[C:4]3[CH:3]=2)[CH2:36]1
Reactant: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(NC(=O)c3cnc4cc(F)ccn34)c12
Reactant: C[C@@H]1CN(CCO)CCN1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(NC(=O)c3cnc4cc(OCCN5CCN(C)[C@H](C)C5)ccn34)c12
Temperature: 95 °C
Yield: 33 %

Procedure:
7-Fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (Example 1, Step A), 0.300 g, 0.678 mmol), (R)-2-(3,4-dimethylpiperazin-1-yl)ethanol (0.536 g, 3.39 mmol), and potassium t-butoxide (0.456 g, 4.07 mmol) were combined in t-butanol in a pressure tube. The tube was sealed and warmed to 95° C. for 16 hours, then allowed to cool to ambient temperature. The mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with 10% aqueous potassium carbonate, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography (10% MeOH/DCM/0.5% NH4OH) of the crude material followed by trituration with ether gave 136 mg (33%) of the title compound. MS (APCI), positive scan, m/z=581.1 (M+H). [α]D=−5.3° (c=1.0, CHCl3).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S@@:25]([CH:33]2[CH2:35][CH2:34]2)(=[N:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:26])=[CH:21][CH:20]=1>>[CH2:31]([O:30][C:28]([N:27]=[S@@:25]([C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:2]2[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:4][N:3]=2)=[CH:24][CH:23]=1)([CH:33]1[CH2:34][CH2:35]1)=[O:26])=[O:29])[CH3:32]
Reactant: CCOC(=O)N=[S@@](=O)(c1ccc(N)cc1)C1CC1
Reactant: C[C@H](CO)Nc1nc(Cl)ncc1-c1cccs1
Product: CCOC(=O)N=[S@@](=O)(c1ccc(Nc2ncc(-c3cccs3)c(N[C@H](C)CO)n2)cc1)C1CC1
Yield: 50 %

Procedure:
In the reaction of (R)-2-(2-chloro-5-(2-thienyl)pyrimidine-4-ylamino)propan-1-ol (267 mg, 1.0 mmol) with (S)—S-(4-aminophenyl)-N-(ethoxycarbonyl)-S-cyclo-propyl-sulfoximide (241 mg, 0.9 mmol) according to procedure 5c, the desired product is obtained in 50% yield (250 mg) after chromatographic purification (silica gel, dichloromethane/ethanol (0%-20% ethanol)).
Reaction SMILES: [CH:1]1([CH2:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14](Cl)=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[N:17]2)=[CH:12][CH:11]=1>ClCCl>[Br:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:8][CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[N:17]2)=[CH:12][CH:11]=1
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Reactant: NCC1CCCCC1
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2cc(Br)ccc2c1NCC1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.8 %

Procedure:
Under a nitrogen atmosphere, cyclohexylmethylamine (40.9 mL, 315 mmol) was added dropwise to a solution of 7-bromo-4-chloro-3-nitroquinoline (30.0 g, 105 mmol) in dichloromethane (524 mL). The reaction was stirred for 18 hours at ambient temperature and then concentrated under reduced pressure. Water (200 mL) was added to the residue, and the mixture was stirred for three hours. Acetonitrile was added; a precipitate formed. The solid was isolated by filtration, dried under a flow of air for two hours, and recrystallized from acetonitrile to provide 24.0 g of (7-bromo-3-nitroquinolin-4-yl)cyclohexylmethylamine as a yellow solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[N:2]1.[N+](C1C=CC=CC=1S([N:20]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=1)[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][NH:29][CH:30]2[C:39]3[N:38]=[CH:37][CH:36]=[CH:35][C:34]=3[CH2:33][CH2:32][CH2:31]2)=[CH:24][CH:23]=1)(=O)=O)([O-])=O.C([BH3-])#N.[Na+]>>[N:42]1[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=1[CH2:40][NH:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:28][N:29]([CH2:6][C:3]2[CH:4]=[CH:5][NH:1][N:2]=2)[CH:30]2[C:39]3[N:38]=[CH:37][CH:36]=[CH:35][C:34]=3[CH2:33][CH2:32][CH2:31]2)=[CH:26][CH:27]=1
Reactant: O=Cc1cc[nH]n1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N(Cc1ccc(CNC2CCCc3cccnc32)cc1)Cc1ccccn1
Agent: [BH3-]C#N
Agent: [Na+]
Product: c1ccc(CNCc2ccc(CN(Cc3cc[nH]n3)C3CCCc4cccnc43)cc2)nc1
Yield: 64.3 %

Procedure:
Using general procedure A: Reaction of 3-pyrazolecarboxaldehyde (85 mg, 0.88 mmol) and N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (320 mg, 0.589 mmol) with sodium cyanoborohydride (55 mg, 0.883 mmol) followed by purification of the crude material by column chromatography on silica gel (5% methanol in dichloromethane), gave the desired product (166 mg, 45%).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([NH:25][NH2:26])(=[O:24])[CH2:22][CH3:23].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:26][NH:25][C:21](=[O:24])[CH2:22][CH3:23])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CCC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (15.0 mL) were added propanehydrazide 202 (0.120 g, 1.358 mmol), 1-hydroxybenzotriazole (0.186 g, 1.358 mmol) and 1-ethyl-(3-dimethylamino propyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 203 (0.31 g, 99%) as a white foam.
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:32]=[C:31]([N+:33]([O-])=O)[CH:30]=[CH:29][C:8]=1[O:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([CH2:25][N:26]([CH3:28])[CH3:27])[CH2:21][CH2:20]2)=[O:18])[CH:11]=1.[H][H]>[C].[Pd].CO>[NH2:33][C:31]1[CH:30]=[CH:29][C:8]([O:9][C:10]2[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([N:19]3[CH2:20][CH2:21][CH:22]([CH2:25][N:26]([CH3:28])[CH3:27])[CH2:23][CH2:24]3)=[O:18])[CH:11]=2)=[C:7]([F:6])[CH:32]=1
Reactant: [H][H]
Reactant: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])cc3F)ncn2)CC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3F)ncn2)CC1
Reaction time: 9 h
Yield: 110.2 %

Procedure:
After adding tetrahydrofuran (2 ml) and methanol (2 ml) to 4-(dimethylaminomethyl)piperidine-1-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-yl]amide (88 mg) under a nitrogen atmosphere, 10% palladium-carbon (45 mg) was added, the atmosphere in the reaction vessel was replaced with hydrogen, and the mixture was stirred for 9 hours. The atmosphere in the reaction vessel was then replaced with nitrogen and the catalyst was filtered and washed with methanol. The filtrate was concentrated under reduced pressure to provide a crude product of 4-(dimethylaminomethyl)piperidine-1-carboxylic acid [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]amide (90 mg) as a pale yellow amorphous substance.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:25])[C:5]([C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1)=[CH:6][NH:7]2.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:25])[C:5]([C:16]1[CH:17]=[CH:18][C:19]([C:20]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:21])=[CH:23][CH:24]=1)=[CH:6][NH:7]2
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(C(=O)O)cc3)c[nH]c12
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(C(=O)N4CCOCC4)cc3)c[nH]c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 25.6 %

Procedure:
4-(5-Fluoro-4-oxo-8-propoxy-1,4-dihydroquinolin-3-yl)benzoic acid (260 mg, 0.76 mmol), morpholine (99.5 mg, 1.14 mmol), WSC (189 mg, 0.99 mmol) and HOBT (151 mg, 0.99 mmol) were added to DMF (10 ml), and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was then purified by silica gel column chromatography (dichloromethane:methanol=30:1). The purified product was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to thereby obtain 80 mg of powdery white 5-fluoro-3-[4-(morpholine-4-carbonyl)phenyl]-8-propoxy-1H-quinolin-4-one (yield: 26%).
Reaction SMILES: C([O:4][CH2:5][C:6]#[C:7][CH2:8][N:9]1[C:13]([CH2:16][F:17])([CH2:14][F:15])[C:12](=[O:18])[N:11]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=2)[C:10]1=[O:31])(=O)C.CO.Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:15][CH2:14][C:13]1([CH2:16][F:17])[C:12](=[O:18])[N:11]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=2)[C:10](=[O:31])[N:9]1[CH2:8][C:7]#[C:6][CH2:5][OH:4]
Reactant: CC(=O)OCC#CCN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C1(CF)CF
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N2C(=O)N(CC#CCO)C(CF)(CF)C2=O)cc1C(F)(F)F
Reaction time: 0.5 h
Yield: 86.2 %

Procedure:
1 g of the product obtained in Stage 3 above, 18 ml of methanol and 4.5 ml of 2N hydrochloric acid are introduced then left for one hour 30 minutes at 50° C. The reaction medium is then returned to ambient temperature, poured into 30 ml of sodium bicarbonate, extraction is carried out with ethyl acetate 3 times, the extracts are washed with salt water and dried. After chromatography on silica eluting with methylene chloride-acetone: 85-15, 780 mg of expected product (white crystals) is obtained. M.p.=131-132° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:23])=[C:11]([N:15]4[CH2:22][C:21]5[CH2:20][NH:19][CH2:18][C:17]=5[CH2:16]4)[C:12]=3[F:14])[C:7](=[O:24])[C:6]([C:25]([OH:27])=[O:26])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:28](I)[CH3:29].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:23])=[C:11]([N:15]4[CH2:22][C:21]5[CH2:20][N:19]([CH2:28][CH3:29])[CH2:18][C:17]=5[CH2:16]4)[C:12]=3[F:14])[C:7](=[O:24])[C:6]([C:25]([OH:27])=[O:26])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(N3CC4=C(CNC4)C3)c(F)cc2c1=O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1CC2=C(C1)CN(c1c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 52.8 %

Procedure:
To a solution of 1-cyclopropyl 6,8-difluoro-7-[3,7-diazabicyclo [3.3.0]-oct-1(5)-en-3-yl]-1,4-dihydro-4-oxoquinoline-3-carboxyl-ic acid (0.37 g) in dimethyl formamide (30 ml), which was prepared in Example 11, ethyliodide (0.17 g) and potassium carbonate (powder, 1 g) were added and stirred at room temperature for 24 hours. To the reaction mixture, water (100 ml) was added and the precipitate was filtered. The filter cake was purified by silica gel column chromatography (CHCl3 :methanol:acetic acid=6:3:1) to give the title compound (0.21 g, yield 52%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:22][CH3:23]>C(#N)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][N:12]([CH2:22][CH3:23])[CH2:11][CH2:10]1
Reactant: CCI
Reactant: Clc1cccc(C2CCNCC2)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CCC(c2cccc(Cl)c2Cl)CC1
Temperature: 140 °C

Procedure:
To a solution of 4-(2,3-dichlorophenyl)piperidine (10 mg) in acetonitrile (2 ml), was added potassium carbonate (10 mg) and 1-iodoethane (5 mg) and the mixture was heated to 140° C. in a sealed tube under microwave radiation for 400 s. MS m/z (rel. intensity, 70 eV) 258 (M+, 11), 257 (18), 256 (14), 244 (66), 242 (bp).
Reaction SMILES: Br.Cl[C:3]1[CH:4]=[C:5]([CH3:13])[C:6]2[N:7]([C:9]([NH2:12])=[N:10][N:11]=2)[N:8]=1.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.O>CN(C=O)C>[CH3:13][C:5]1[C:6]2[N:7]([C:9]([NH2:12])=[N:10][N:11]=2)[N:8]=[C:3]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:4]=1
Reactant: C1CCNC1
Reactant: Cc1cc(Cl)nn2c(N)nnc12
Agent: Br
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(N2CCCC2)nn2c(N)nnc12
Reaction time: 1.5 h

Procedure:
6-Chloro-8-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.002; 250 mg) was dissolved in DMF (2 ml) and admixed with pyrrolidine (2 ml). Thereafter, the reaction mixture was placed into the heating block at 80° C. with stirring for 1.5 h. Subsequently, the solvent was drawn off and the residue was admixed with a little water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. When the residue was dissolved in acetonitrile/water+0.05% TFA, a solid precipitated out, which was filtered off with suction and dried. 40 mg of 8-methyl-6-pyrrolidin-1-yl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine were obtained. The mother liquor was purified by means of preparative HPLC (met. A), and the clean product fractions were combined, freed of the acetonitrile under reduced pressure and freeze-dried. 11 mg of 8-methyl-6-pyrrolidin-1-yl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine were obtained as the trifluoroacetic acid salt. 8-Methyl-6-pyrrolidin-1-yl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine