Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]([F:10])[CH:4]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH:20]2[CH2:25][CH2:24][N:23]([S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH2:22][CH2:21]2)=[O:19])=[CH:14][CH:13]=1.[Cl-].[NH4+]>O1CCCC1>[F:10][C:5]1[CH:4]=[C:3]([C:18]([C:15]2[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=2)([CH:20]2[CH2:25][CH2:24][N:23]([S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[OH:19])[CH:8]=[CH:7][C:6]=1[F:9]
Reactant: Fc1ccc(Br)cc1F
Reactant: O=C(c1ccc(F)cc1)C1CCN(S(=O)(=O)c2ccccc2)CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)N1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)c(F)c2)CC1
Reaction time: 1 h
Yield: 98.2 %

Procedure:
A three-necked round bottom flask, equipped with a mechanical stirrer, flushed with nitrogen, and containing 3.74 g (0.154 mole) of magnesium turnings, was dried with a Bunsen burner. After the flask had cooled, 600 ml of tetrahydrofuran was added. To this mechanically stirred mixture was slowly added a solution of 29.4 g (0.152 mole) of 4-bromo-1,2-difluorobenzene in 50 ml of tetrahydrofuran. The mixture was stirred for 1 hour, and 45.11 g (0.13 mole) of (4-fluorophenyl)[1-(phenylsulfonyl)-4-piperidinyl]methanone was added as a solid. The solution was stirred at ambient temperatures for 3 hours and was poured into an icy aqueous solution of ammonium chloride. The aqueous mixture was extracted with methylene chloride, dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was recrystallized from methylene chloridehexane to give 58.89 g (82.9%) of the title compound. A small sample was recrystallized from a mixture of methylene chloride-ether-hexane to give an analytically pure sample of the title compound, mp 97°-99° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C@@H:7]2[O:20][C@H:19]([CH2:21][O:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@@H:9]([O:10][C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C@@H:8]2[F:31])[CH:5]=[N:4][C:3]=1[C:32](=[O:37])[CH2:33][N:34]=[N+]=[N-].Cl.CO.[H][H]>CO.[Pd]>[NH2:1][C:2]1[N:6]([C@@H:7]2[O:20][C@H:19]([CH2:21][O:22][C:23](=[O:30])[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@@H:9]([O:10][C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C@@H:8]2[F:31])[CH:5]=[N:4][C:3]=1[C:32](=[O:37])[CH2:33][NH2:34]
Reactant: [H][H]
Reactant: [N-]=[N+]=NCC(=O)c1ncn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@@H]2F)c1N
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCC(=O)c1ncn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@@H]2F)c1N

Procedure:
Compound (17) obtained in step (8) above (567 mg) was dissolved in methanol (23 ml), to which was then added a 2.2M hydrogen chloride-methanol solution (0.75 ml). The resulting solution was subjected to a catalytic reduction by blowing hydrogen into the solution at room temperature in the presence as catalyst of palladium black for 1 hour (for the reduction of the azido group). The reaction solution so obtained was filtered and the filtrate was concentrated to leave a solid, which was then washed with diethyl ether, to afford the titled compound (18) as a solid (508 mg) which was insoluble in ethyl ether.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:30])[CH:12]([NH:13][C:14](=[O:29])[C:15](=[N:24][O:25][CH2:26][C:27]#[CH:28])[C:16]3[N:17]=[C:18]([NH:21]C=O)[S:19][CH:20]=3)[C@H:4]2[S:3]1.Cl>CO>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:30])[CH:12]([NH:13][C:14](=[O:29])[C:15](=[N:24][O:25][CH2:26][C:27]#[CH:28])[C:16]3[N:17]=[C:18]([NH2:21])[S:19][CH:20]=3)[C@H:4]2[S:3]1
Reactant: C#CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: C#CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.5 %

Procedure:
To a suspension of 2-methyl-7-[2-(2-propynyloxyimino)-2-(2-formylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer) (2.1 g) in methanol (42 ml) was added concentrated hydrochloric acid (0.97 ml), and the mixture was stirred for 2 hours at ambient temperature. The methanol was distilled off from the reaction mixture, and the residue was dissolved in water (50 ml) and then filtered. The filtrate was adjusted to pH 3 with a saturated aqueous solution of sodium bicarbonate, and the precipitates were collected by filtration and then dried to give 2-methyl-7-[2-(2-propynyloxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer) (0.6 g).
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=2[C:7]=1[C:8](Cl)=[O:9])[CH3:2].[Br:15][C:16]1[C:25]([O:26][CH:27]([C:35]([O:37][CH3:38])=[O:36])[CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][C:20]([CH2:39][NH3+:40])=[CH:21]2.[Cl-].C(N(CC)CC)C>C(Cl)Cl>[CH3:38][O:37][C:35](=[O:36])[CH:27]([O:26][C:25]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:39][NH:40][C:8]([C:7]3[C:6]4[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=4[O:4][C:3]=3[CH2:1][CH3:2])=[O:9])[CH:21]=2)[C:16]=1[Br:15])[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCc1oc2ccccc2c1C(=O)Cl
Reactant: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(C[NH3+])ccc2c1Br
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1oc2ccccc2c1C(=O)NCc1ccc2c(Br)c(OC(Cc3ccccc3)C(=O)OC)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
2-Ethyl-benzofuran-3-carbonyl chloride (0.444 mmol), prepared in step 2 of Example 21, was added under nitrogen to a suspension of 5-bromo-6-(1-methoxycarbonyl-2-phenyl-ethoxy)-naphthalen-2-ylmethyl-ammonium; chloride (0.200 g, 0.444 mmol), prepared in step 3 of Example 53, in 20 mL of methylene chloride. Triethylamine (0.124 mL, 0.888 mmol) was then added to the mixture. The reaction was stirred at room temperature for 18 h (overnight). The reaction was diluted with methylene chloride, extracted one time with 1N HCl and two times with 5% sodium bicarbonate. The organic layer was separated, dried (MgSO4) and the solvent removed under reduced pressure to give 2-(1-bromo-6-{[(2-ethyl-benzofuran-3-carbonyl)-amino]-methyl}-naphthalen-2-yloxy)-3-phenyl-propionic acid methyl ester (0.27 g, 100%) as a tan solid, mp 139-143° C.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH3:10])=[CH:5][C:6]=1[C:7]([OH:9])=O.S(Cl)(Cl)=O.[NH:15]([C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=1[OH:31])C1C=CC=CC=1>>[OH:31][C:23]1[CH:24]=[CH:25][C:26]([N+:28]([O-:30])=[O:29])=[CH:27][C:22]=1[NH:15][C:7]([C:6]1[CH:5]=[C:4]([CH3:10])[S:3][C:2]=1[Br:1])=[O:9]
Reactant: Cc1cc(C(=O)O)c(Br)s1
Reactant: O=[N+]([O-])c1ccc(O)c(Nc2ccccc2)c1
Solvent: O=S(Cl)Cl
Product: Cc1cc(C(=O)Nc2cc([N+](=O)[O-])ccc2O)c(Br)s1

Procedure:
In the same manner as in Starting Material Synthesis Example 67 and using 2-bromo-5-methyl-3-thiophenecarboxylic acid, thionyl chloride and 2-amiino-4-nitrophenol, N-(2-hydroxy-5-nitrophenyl)-2-bromo-5-methyl-3-thiophenecarboxamide is obtained.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].Br[CH2:27][C:28]([CH3:30])=[CH2:29]>C1COCC1>[CH3:29][C:28](=[CH2:27])[CH2:30][Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C=C(C)CBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C=C(C)C[Sn](CCCC)(CCCC)CCCC
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 97.7 %

Procedure:
n-Butyllithium (16.5 mL of a 2.5 M hexanes solution, 41.2 mmol)was added to a 0° C. solution of diisopropylamine (5.4 mL, 41.3 mmol) in THF (40 mL). After stirring for 5 minutes, tributyltin hydride (10 g, 34.4 mmol) was added. After stirring for 15 minutes at 0° C., the reaction mixture was cooled to −78° C. and 3-bromo-2-methylpropene (4.0 mL, 39.7 mmol) was added dropwise. After stirring for an additional hour, the cold reaction mixture was quenched with dilute ammonium chloride solution and extracted with ethyl acetate. The ethyl acetate layer was dried (MgSO4), filtered and concentrated to afford a colorless liquid, 2-methylallyl tributyltin (11.6 g, 98%) which was used without purification for the next step.
Reaction SMILES: S(C)C.[C:4]([O:8][C:9]([N:11]1[CH2:16][CH:15]([N:17]2[C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:27])[C:21]=3[C:20]3=[N:28][O:29][C:30]([CH3:31])=[C:19]3[C:18]2=[O:32])[CH2:14][CH:13]([C:33](O)=[O:34])[CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>C1COCC1>[C:4]([O:8][C:9]([N:11]1[CH2:12][CH:13]([CH2:33][OH:34])[CH2:14][CH:15]([N:17]2[C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:27])[C:21]=3[C:20]3=[N:28][O:29][C:30]([CH3:31])=[C:19]3[C:18]2=[O:32])[CH2:16]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: Cc1onc2c1c(=O)n(C1CC(C(=O)O)CN(C(=O)OC(C)(C)C)C1)c1cccc(Cl)c21
Solvent: C1CCOC1
Solvent: CSC
Product: Cc1onc2c1c(=O)n(C1CC(CO)CN(C(=O)OC(C)(C)C)C1)c1cccc(Cl)c21
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
Add BH3.SMe2 (3.2 mL, 6.4 mmol, 2.0 M in THF) to a solution of 5-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester (1.5 g, 3.2 mmol) in THF (20 mL) at 0° C. Remove the ice bath and stir for 30 min. Quench dropwise with MeOH and concentrate to dryness. Partition between 20% iPrOH/CHCl3 and water. Wash 2× sat. aq NaHCO3, wash 2× brine, dry over Na2SO4, filter and concentrate to dryness. Purify by radial chromatography using MeOH/CHCl3 as eluant and concentrate to dryness to afford the title compound (0.95 g, 66%) as a white foam as a mixture of cis isomers. MS(IS) 448.2 (M+); HPLC (40% IPA 60% heptane on a Chiralpak AD (0.46×25 cm) 1.5 mL/min flow; 25 μL Inj.; 225 nM) Rt=3.28 min (72.1%), 4.48 min (27.8%).
Reaction SMILES: CO[C:3]([C:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:8]2[CH:23]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:25]=[C:7]2[C:6]=1[OH:32])=[O:4].[NH2:33][CH2:34][C:35]([O-:37])=[O:36].[Na+]>>[OH:32][C:6]1[C:7]2[N:8]([CH:23]=[C:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:25]=2)[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][CH:14]=2)[C:10](=[O:11])[C:5]=1[C:3]([NH:33][CH2:34][C:35]([OH:37])=[O:36])=[O:4]
Reactant: NCC(=O)[O-]
Reactant: COC(=O)c1c(O)c2cc(-c3ccccc3)cn2n(Cc2ccc(C(F)(F)F)cc2)c1=O
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c(O)c2cc(-c3ccccc3)cn2n(Cc2ccc(C(F)(F)F)cc2)c1=O

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 4-hydroxy-2-oxo-6-phenyl-1-(4-trifluoromethyl-benzyl)-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid methyl ester (1.0 eq.) and sodium glycinate (5 eq.). ESI (m/z): 486 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:19][C:13]2([CH2:16][S:15](=[O:18])(=[O:17])[CH2:14]2)[CH2:12]1)(=[O:10])=[O:9].[F:20][C:21]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:22]=1[C:36]1[CH:37]=[N:38][C:39]([NH2:42])=[N:40][CH:41]=1>>[NH2:42][C:39]1[N:40]=[CH:41][C:36]([C:22]2[CH:23]=[CH:24][C:25]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8]([N:11]3[CH2:19][C:13]4([CH2:16][S:15](=[O:18])(=[O:17])[CH2:14]4)[CH2:12]3)(=[O:10])=[O:9])=[CH:26][C:21]=2[F:20])=[CH:37][N:38]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: O=S1(=O)CC2(CN(S(=O)(=O)c3ccccc3Br)C2)C1
Product: Nc1ncc(-c2ccc(-c3ccccc3S(=O)(=O)N3CC4(C3)CS(=O)(=O)C4)cc2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 6 utilizing 6-((2-bromophenyl)sulfonyl)-2-thia-6-azaspiro[3.3]heptane 2,2-dioxide and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C21H19FN4O4S2, 474.08; m/z found, 474.8 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.56-8.50 (d, J=1.4, 2H), 8.05-7.99 (dd, J=8.0, 1.3, 1H), 7.80-7.73 (m, 1H), 7.69-7.60 (m, 2H), 7.48-7.43 (dd, J=7.6, 1.3, 1H), 7.38-7.32 (dd, J=11.8, 1.8, 1H), 7.31-7.26 (dd, J=7.9, 1.7, 1H), 6.90 (s, 2H), 4.32 (s, 4H), 3.76 (s, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH:5]2[CH3:27].B(Br)(Br)[Br:29].ClCCl>C(=O)(O)[O-].[Na+]>[Br:29][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:5]([CH3:27])[C:4]3[C:13](=[CH:14][CH:15]=[C:2]([F:1])[CH:3]=3)[C:12]=2[CH:11]=1
Reactant: BrB(Br)Br
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccc(F)cc3C2C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1c2cc(F)ccc2-c2cc(Br)ccc2N1S(=O)(=O)c1ccc(O)cc1
Temperature: 25 °C

Procedure:
8-Fluoro-5-(4-methoxyphenylsulfonyl)-6-methyl-5,6-dihydrophenanthridine (0.64 g, 1.7 mmol) was treated with 1 M boron tribromide in dichloromethane (6.6 mL, 6.6 mmol) and stirred at room temperature for twelve hours. A solution of saturated, aqueous, sodium bicarbonate (50 mL) was added slowly to the reaction, followed by extraction of the mixture with dichloromethane (6×20 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a crude material. The crude material was filtered through a short column of silica gel, eluted with a mixture of ethyl acetate-hexane (1:4), and the filtrate concentrated in vacuo to a solid. After trituration with dichloromethane and filtration, the title compound was obtained as a homogeneous solid (0.23 g, 37%), m.p. 237-239° C.;
Reaction SMILES: C([C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6]([CH3:19])[CH:5]=1)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.ClC1C=CC=[C:34]([C:38]([O:40]O)=[O:39])C=1.[I-].[K+]>ClCCl>[C:38]([O:40][C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]([CH3:15])([CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6]([CH3:19])[CH:5]=1)(=[O:39])[CH3:34]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C(C)=O)cc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)Oc1ccc(OC(C)=O)cc1C
Temperature: 40 °C
Reaction time: 19 h

Procedure:
A solution of ethyl 2-(4-acetyl-2-methylphenoxy)-2-methylpropanoate (intermediate 8, 37.33 g) in dichloromethane (650 ml) was treated with 4-toluenesulphonic acid (2.75 g) followed by m-chloroperbenzoic acid (60.5 g) and the mixture warmed to 40° C. and stirred under nitrogen for 19 hours. The cooled mixture was treated with dichloromethane (350 ml) and the resulting mixture added to aqueous potassium iodide (1000 ml, 10% solution). The organic layer was collected and washed twice with water and brine, then dried over sodium sulfate, filtered and the filtrate concentrated to give the title compound as an orange oil.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:14][CH2:15][C:16](=[O:19])[NH:17][N:18]=2)=[CH:9][CH:8]=1)=[O:5].[C:20]1([CH2:26][CH2:27][NH2:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[C:20]1([CH2:26][CH2:27][NH:28][CH2:2][CH2:3][C:4]([NH:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH2:14][CH2:15][C:16](=[O:19])[NH:17][N:18]=3)=[CH:9][CH:8]=2)=[O:5])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCCc1ccccc1
Reactant: O=C1CCC(c2ccc(NC(=O)CCCl)cc2)=NN1
Solvent: CCO
Product: O=C1CCC(c2ccc(NC(=O)CCNCCc3ccccc3)cc2)=NN1
Yield: 36.4 %

Procedure:
11.18 g (40 millimoles) of 6-[p-(3-chloropropionylamino)-phenyl]-4,5-dihydro-3(2H)-pyridazinone in 250 ml of ethanol were initially taken and 26.5 g (220 millimoles) of 2-phenylethylamine were added dropwise, after which the mixture was refluxed for 6 hours. Insoluble material was filtered off, the solvent was stripped off and the mother liquor was then crystallized by adding acetone. The product was recrystallized twice from methanol to give 5.3 g of 6-{p-[3-(2-phenylethylamino)-propionylamino]-phenyl}-4,5-dihydro-3(2H)-pyridazinone.HCl of melting point 269°-270° C.
Reaction SMILES: C(C1C=C(C(C)C)C=C(C(C)C)C=1S(NN=[C:21]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:22][CH2:23][N:24]([CH2:27]C)[CH2:25]C)(=O)=O)(C)C.[CH:35](=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH:36]1([CH:35]([OH:42])[C:21]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:22][CH2:23][N:24]([CH3:25])[CH3:27])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: O=Cc1ccccc1
Reactant: CCN(CC)CCC(=NNS(=O)(=O)c1c(C(C)C)cc(C(C)C)cc1C(C)C)c1ccccc1
Product: CN(C)CC=C(c1ccccc1)C(O)C1CCCCC1

Procedure:
By using a method similar to that described in Example 22, but starting from β-diethylaminopropiophenone 2,4,6-triisopropylbenzenesulphonylhydrazone (30 g) and benzaldehyde (6.9 cc), 4-diethylamino-1,2-diphenyl-2-buten-1-ol (Z) hydrochloride (3.2 g) is obtained, after recrystallisation from acetone, in the form of white crystals melting at 140° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:17]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[C:16](=O)[C:15]3[C:14]([C:25]([O:27]CC)=O)=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1.O.[NH2:31][NH2:32]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[NH:9][C:10]3[C:15]4[C:16](=[N:31][NH:32][C:25](=[O:27])[C:14]=4[CH:13]=[CH:12][CH:11]=3)[CH:17]2[C:18]2[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=2)=[CH:6][CH:7]=1
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1nccn1C)C(c1ccc(F)cc1)N2
Solvent: CO
Solvent: O
Product: Cn1ccnc1C1c2n[nH]c(=O)c3cccc(c23)NC1c1ccc(F)cc1
Temperature: 45 °C
Reaction time: 8 h
Yield: 19 %

Procedure:
A mixture of ethyl 2-(4-fluorophenyl)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (210 mg) in 85% hydrazine monohydrate (10 mL) and methanol (10 mL) was stirred at 45° C. for overnight. Methanol was removed under reduced pressure. The mixture was filtered and washed with water to give 8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one 36 mg, yield 19%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.42 (s, 3H), 4.66 (d, J=8.0 Hz, 1H), 4.95 (d, J=8.0 Hz, 1H), 6.72 (s, 1H), 6.89 (s, 1H), 7.11-7.17 (m, 3H), 7.30 (s, 1H), 7.40 (d, 1H), 7.43-7.44 (m, 2H), 7.58 (d, 1H), 12.17 (s, 1H); 19F-NMR (400 MHz, DMSO-d6) δ (ppm): −114.58; LC-MS (ESI) m/z: 362 (M+1)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].C(#N)C.[C:10](OC(=O)C)(=[O:12])[CH3:11]>C([O-])(O)=O.[Na+]>[C:10]([NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: NCCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)NCCC(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of β-alanine (2.25 g, 25 mmol) in aq. NaHCO3 (15 mL) was added acetonitrile (15 mL) and acetic anhydride (2.55 g, 25 mmol). The reaction mixture was stirred at room temperature for 3 h. Acetic anhydride (2.55 g, 25 mmol) was added and after 2 h and pH was adjusted to 4-5 by addition of NaH2PO4.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])[CH3:2].[N:35]1[CH:40]=[CH:39][CH:38]=[C:37](B(O)O)[CH:36]=1.[F-].[Cs+].C(Cl)Cl>C(#N)C>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:15]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3[C:37]3[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=3)[CH:17]=[C:18]([CH3:20])[CH:19]=2)=[CH:9][C:8]=1[CH3:33])[CH3:2]
Reactant: CCOC(=O)CCc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Reactant: OB(O)c1cccnc1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3-c3cccnc3)c2)cc1C
Temperature: 100 °C
Reaction time: 5 h
Yield: 79.5 %

Procedure:
A mixture of 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-5-methyl-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester (0.112 g, 0.209 mmol), pyridine-3-boronic acid (0.077 g, 0.626 mmol), and cesium fluoride (0.111 g, 0.731 mmol) in dry ACN (7 mL) is purged with N2 and then treated with 1,1′-bis(diphenylphophino)-ferrocene palladium (II) chloride complex with DCM (0.031 g, 0.042 mmol). The mixture is heated to 100° C. and stirred for 5 hours under N2. The reaction is cooled, and the crude mixture is absorbed on silica gel and purified by flash chromatography using 2/1 hexanes/ethyl acetate to afford 0.089 g (79%) of the title compound. Rf=0.33 (1/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C31H28O4NF3 535, found 536 (M+1, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[C:8](Cl)=[N:9]2)=[CH:4][CH:3]=1.[NH2:16][CH:17](C)[CH2:18][CH2:19][OH:20]>ClCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:16][CH2:17][CH2:18][CH2:19][OH:20])=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(N)CCO
Reactant: O=[N+]([O-])c1cc2ccc(Br)cc2nc1Cl
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2cc(Br)ccc2c1NCCCO
Temperature: 0 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 7-bromochloro-3-nitroquinoline (10.00 g, 34.78 mmol) in dichloromethane (140 mL) was added triethylanine (10.2 mL, 73.1 mmol). The solution was cooled to 0° C., and 3-amino-1-butanol (2.80 mL, 36.5 mmol) was added. The solution was stirred overnight at ambient temperature and then filtered to collect a precipitate. The precipitate was washed with dichloromethane and water. The filtrate was washed with saturated aqueous sodium bicarbonate and then added to the precipitate. The mixture was concentrated under reduced pressure. Methanol and toluene were added several times and removed under reduced pressure. The resulting solid was dried under high vacuum to provide 11.34 g of 3-[(7-bromo-3-nitroquinolin-4-yl)amino]propan-1-ol as a yellow solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[CH3:22][C:23]1([CH3:31])[CH2:27][NH:26][CH:25]([C:28]([NH2:30])=[O:29])[CH2:24]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:26]3[CH2:27][C:23]([CH3:31])([CH3:22])[CH2:24][CH:25]3[C:28]([NH2:30])=[O:29])=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: CC1(C)CNC(C(N)=O)C1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC(C(N)=O)N(C(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)C1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 4,4-dimethylpyrrolidine-2-carboxamide hydrochloride (Example 90 d) in the presence of TBTU and DIEA. The mixture of enantiomers was separated by chiral HPLC (Reprosil Chiral NR). The (+) enantiomer was isolated as yellow solid; MS (EI): m/e=409.6 [MH+]; αD20 (DMSO)=+19.3°.