Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[Br:9][CH2:10][C:11](Cl)=[O:12].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[Br:9][CH2:10][C:11]([C:2]1[CH:3]=[C:4]([CH3:7])[CH:5]=[CH:6][C:1]=1[CH3:8])=[O:12]
Reactant: O=C(Cl)CBr
Reactant: Cc1ccc(C)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1ccc(C)c(C(=O)CBr)c1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 105.1 %

Procedure:
A mixture of 10.60 g (0.10 mol) of para-xylene and 16.53 g (0.105 mol) of α-bromoacetyl chloride in 300 mL of 1,2dichloroethane was cooled in an ice bath under an atmosphere of dry N2 and treated portionwise with 14.15 g (0.106 mol) of aluminum chloride. The reaction mixture was stirred for 30 minutes at 0-5° C. and then for 2.5 hours at room temperature. The mixture was then poured onto ice and the aqueous layer was acidified with concentrated HCL. The organic layer was separated and the aqueous layer was extracted twice with methylene dichloride. The combined organic extracts were dried with brine solution and with magnesium sulfate. The solvent was evaporated to give 23.87 g of an amber oil which was for use in the next reaction without further purification.
Reaction SMILES: N[C:2]1[C:3]([O:9][CH3:10])=[N:4][CH:5]=[CH:6][C:7]=1[Cl:8].N([O-])=O.[Na+].[ClH:15]>O.[Cu](Cl)Cl>[Cl:15][C:2]1[C:3]([O:9][CH3:10])=[N:4][CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cl
Reactant: COc1nccc(Cl)c1N
Agent: Cl[Cu]Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1nccc(Cl)c1Cl
Temperature: -5 °C
Reaction time: 0.33 h
Yield: 97 %

Procedure:
3-Amino-4-chloro-2-methoxypyridine (200 mg, 1.27 mmol), dissolved in conc. hydrochloric acid (4 mL) was stirred at −5° C. while a solution of sodium nitrite (437 mg, 6.33 mmol) in water (2 mL) was added dropwise over 10 min. The mixture was stirred for a further 10 min before copper chloride (1.25 g, 12.66 mmol) was added portionwise over 5 min. The dark effervescing mixture was stirred at −5° C. for 20 min and then the cooling bath was removed and the mixture stirred at ambient temperature for 1 h. The resultant green solution was basified by addition of 5N sodium hydroxide (aq.), diluted with water (100 mL) and extracted with diethyl ether (3×30 mL). The combined extracts were washed with brine (50 mL), dried (MgSO4) and concentrated in vacuo to yield the title compound (218 mg, 97%).
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1)=[N+]=[N-]>CO.C(O)(=O)C.[Pd]>[NH2:1][CH:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCCC(N=[N+]=[N-])C1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCCC(N)C1
Yield: 69.4 %

Procedure:
A solution of the title compound of Example 3 (37.1 g, 164 mmol) in a mixture of MeOH (100 mL) and acetic acid (25 mL) was added 10% Pd-C (3.7 g) and the reaction mixture was hydrogenated (50 psi) for 24 h at rt in a Parr apparatus. Analysis of the reaction by TLC (solvent system A) and IR (to look for presence or absence of N3 str peak at 2100 cm-1) indicated the reaction to be complete. The solution was filtered through celite to remove catalyst and the filtrate was evaporated in vacuo to give the crude product as an oily residue. The residue was dissolved in 500 mL of 10% aqueous acetic acid and the solution was extracted with Et2O (3×200 mL). The combined ethereal extract was discarded and the aqueous solution was basified by addition of excess concentrated aqueous NH3 solution. The basified mixture was extracted with Et2O (3×200 mL) and the combined organic extract was dried (Na2SO4) and evaporated to give the title compound (22.8 g, 69%) as a pale yellow oil. The fumarate salt crystallized from 2-propanol: mp 197°-198° C., 1H-NMR (CDCl3) ∂ 3.93 (br s, 1H), 3.82 (dm, Jgem =13 Hz, 1H), 1.46 (s, 9H), 1.29-1.41 (complex m, 3H), 1.24 (m, 1H); CIMS (MH+ calcd for C10H20N2O2): 201. Found (MH+): 201; Anal. (calc'd for C10H20N2O2.0.5C4H4O4):C, H, N.
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].[S:22]1[C:26]2=[N:27][CH:28]=[CH:29][CH:30]=[C:25]2[C:24](N)=[CH:23]1>>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:24]1[C:25]2[C:26](=[N:27][CH:28]=[CH:29][CH:30]=2)[S:22][CH:23]=1)(=[O:3])[CH3:2]
Reactant: Nc1csc2ncccc12
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2csc3ncccc23)c1=O

Procedure:
Obtained, (27%) from 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) and thieno[2,3-b]pyridin-3-ylamine (Klemm, L. H., Zell, R., Barnish, I. T., Klemm, R. A., J. Het. Chem, 1970, 373-379) following the procedure of Example 67.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([CH3:11])=[CH:6][CH:5]=2.CC[Mg+].[Br-].Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=2)[N:20]=[CH:19][CH:18]=1.CCOC(C)=O>C1(C)C=CC=CC=1.C1COCC1.O>[Cl:27][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[C:7]([CH3:11])[CH:8]=4)[NH:3][C:2]=3[CH3:1])=[CH:18][CH:19]=[N:20]2)=[CH:25][CH:24]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: Cc1ccc2[nH]c(C)cc2c1
Agent: CC[Mg+]
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc2[nH]c(C)c(-c3ccnc4cc(Cl)ccc34)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44.6 %

Procedure:
2,5-dimethylindole (500 mg) was dissolved in dry toluene (2 ml), and maintained under a nitrogen atmosphere. The reaction was cooled to 0° C. before adding EtMgBr (2.5 ml, 3M in Et2O) dropwise, keeping the temperature below 5° C. Allowed the mixture to warm to RT and stirred for 0.5 h. A solution of 4,7-dichloroquinoline (680 mg) in dry THF (3 ml) was added slowly to the reaction. After stirring for 30 minutes at RT the reaction was slowly heated to 90° C. and stirred overnight. The reaction was allowed to cool to RT before adding EtOAc and water to the mixture. The organic layer was separated and the organic layer was extracted with EtOAc (×3). The combined organics were washed with saturated aqueous NH4Cl, H2O and brine then dried (Na2SO4) and the solvent was evaporated under reduced pressure. Purification by chromatography eluting with 15% acetone/isohexane gave the sub-title compound (0.47 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([O:19][CH2:20][C@H:21]([CH3:22])[N:8]3[CH:7]=[C:6]([C:23]([O:25][CH:26]3[CH2:31][O:30]C(C4C=CC=CC=4)[O:28][CH2:27]3)=[O:24])[C:5]2=[O:38])[C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1>ClCCl.CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([O:19][CH2:20][C@H:21]([CH3:22])[N:8]3[CH:7]=[C:6]([C:23]([O:25][CH:26]([CH2:31][OH:30])[CH2:27][OH:28])=[O:24])[C:5]2=[O:38])[C:11]=1[N:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]1
Reactant: C[C@H]1COc2c(N3CCN(C)CC3)c(F)cc3c(=O)c(C(=O)OC4COC(c5ccccc5)OC4)cn1c23
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: C[C@H]1COc2c(N3CCN(C)CC3)c(F)cc3c(=O)c(C(=O)OC(CO)CO)cn1c23
Temperature: 25 °C
Reaction time: 16 h
Yield: 8.9 %

Procedure:
(S)-2-phenyl-1,3-dioxan-5-yl 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate (0.50 g, 9.55 mmol), was dissolved in a mixture of dichloromethane/methanol (2:1.5, 87.5 ml) under argon. Palladium catalyst (10 wt % Pd/C) (180 mg) was added, the flask was evacuated and allowed to stir 1 atm of hydrogen gas at room temperature for 16 hours. The crude reaction mixture was passed through a glass microfiber on a sintered funnel. The volatiles were removed under reduced pressure yielding 370 mg (88%) of a yellow gum.
Reaction SMILES: [CH2:1]([O:19][C@H:20]1[C@H:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:23][NH:22][CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:44]([O:48][C:49]([NH:51][CH2:52][C:53](O)=[O:54])=[O:50])([CH3:47])([CH3:46])[CH3:45].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)(Cl)Cl>[CH2:1]([O:19][C@H:20]1[C@H:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:23][N:22]([C:53](=[O:54])[CH2:52][NH:51][C:49](=[O:50])[O:48][C:44]([CH3:45])([CH3:46])[CH3:47])[CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CNC[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CN(C(=O)CNC(=O)OC(C)(C)C)C[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Compound 1 (100 mg, 0.167 mmol) obtained in Example 1 was dissolved in chloroform (2 mL), and stirred at room temperature for 4 hours after adding N-(tert-butoxycarbonyl)glycine (Tokyo Chemical Industry Co., Ltd.; 55 mg, 0.250 mmol), diisopropylethylamine (0.146 mL, 0.833 mmol), and HATU (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) (Aldrich; 127 mg, 0.333 mmol). The aqueous layer was extracted with ethyl acetate after adding a saturated sodium bicarbonate aqueous solution to the reaction mixture. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure after filtration. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 97/3) to give tert-butyl 2-((3R,4R)-3,4-bis((9Z,12Z)-octadec-9,12-dienyloxy)pyrrolidin-1-yl)-2-oxoethylcarbamate.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[CH3:21][C:22]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:23]=1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>C1C=CC=CC=1>[Br:1][CH2:21][C:22]1[CH:34]=[CH:33][C:32]([C:35]([F:36])([F:37])[F:38])=[CH:31][C:23]=1[C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25]
Reactant: Cc1ccc(C(F)(F)F)cc1C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)c1cc(C(F)(F)F)ccc1CBr
Yield: 53 %

Procedure:
N-Bromosuccinimide (1.18 g, 6.63 mmol) and 2,2′-azobis(isobutyronitrile) (20 mg) were added to a solution of tert-butyl 2-methyl-5-(trifluoromethyl)benzoate (1.57 g, 6.03 mmol) obtained in Example (2-1) in benzene (25 ml) and the mixture was heated under reflux for 60 minutes. The temperature of the reaction mixture was returned to room temperature and the residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=8/1-6/1) to give tert-butyl 2-(bromomethyl)-5-(trifluoromethyl)benzoate as a white powder (1.08, yield: 53%).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][S:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:13][CH2:14][S:15][CH2:16][CH2:17]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:28])=[CH:22][CH:21]=1
Reactant: Nn1nc(N2CCSCC2)c2ccccc2c1=O
Reactant: O=C(O)Cc1ccc(Cl)cc1
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(N2CCSCC2)c2ccccc2c1=O

Procedure:
The product from Example 91B and 2-(4-chlorophenyl)acetic acid were processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.49 (s, 1H), 8.29 (d, J=7.8 Hz, 1H), 7.93-8.03 (m, 2H), 7.89 (ddd, J=8.0, 6.2, 1.9 Hz, 1H), 7.34-7.47 (m, 4H), 3.67 (s, 2H), 2.83-2.86 (m, 4H); MS (APCI+) M/Z 415 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[C:13](OC(=O)C)(=[O:15])[CH3:14].Cl>O>[C:13]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Oc1ccc(C(=O)O)cc1
Temperature: 0 °C

Procedure:
An amount of 4-hydroxybenzoic acid (92.1 grams (g), 0.67 mole) was dissolved in a solution of sodium hydroxide (NaOH) (53.4 g, 1.33 moles) and 1.33 liters (L) of water in a 4 L beaker. The solution was stirred and cooled to a temperature of 0° C. by adding crushed ice, then acetic anhydride (102.1 g, 1.00 mole) was added. The temperature was maintained at -2° C. for 1 hour by adding one killogram (Kg) of crushed ice. A solution of concentrated hydrochloric acid (HCl) (144.7 g, 1.42 moles) in 267 milliliters (ml) of water was added. The slurry was stirred briefly and filtered. The product was washed twice by stirring it with 2 L portions of fresh water then filtered and dried in a vacuum oven at 80° C. for 16 hours. After recrystallization from methyl isobutyl ketone, the product consisted of 111 g of white crystals with a melting point (m.p.) of 192° C. to 192.5° C.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[F:19][C:20]([F:30])([F:29])[CH:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1>>[F:30][C:20]([F:19])([F:29])[CH:21]([NH:28][C:10]([C:7]1[CH:6]=[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: NC(c1ccccn1)C(F)(F)F
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Product: O=C(NC(c1ccccn1)C(F)(F)F)c1cc(OCC(F)(F)F)c(C2CC2)cn1

Procedure:
The title compound was synthesized in analogy to Example 24d, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and 2,2,2-Trifluoro-1-pyridin-2-yl-ethylamine (CAN 503173-14-6) as starting materials and isolated (17 mg, 26%) as a white solid; MS (ESI, m/z): 420.5 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[N:16]=[CH:17][C:18]([C:19]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:21])=[CH:22][CH:23]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)N2CCOCC2)cn1
Yield: 13 %

Procedure:
As described for example 105, 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (99 mg, 0.33 mmol) was converted, using morpholine instead of 2,2,2-trifluoroethylamine, to the title compound (16 mg, 13%) which was obtained as a white solid. MS: m/e=398.3 [M+H]+.
Reaction SMILES: C([O-])=O.[NH4+].[CH3:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][C:14]=1[CH3:15])[NH:11][CH:10]=[C:9]2[C:16]([O:18]CC1C=CC=CC=1)=[O:17]>CO.[Pd]>[CH3:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][C:14]=1[CH3:15])[NH:11][CH:10]=[C:9]2[C:16]([OH:18])=[O:17]
Reactant: Cc1cc2[nH]cc(C(=O)OCc3ccccc3)c2cc1C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1cc2[nH]cc(C(=O)O)c2cc1C

Procedure:
0.54 g of Pd/C 10% and 16.9 g of ammonium formate are added to a solution of 5 g of the compound obtained in step 2 in 120 ml of MeOH. It is heated under reflux for 2 hours. It is filtered on talc and the filtrate is evaporated.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][C:4]=1I)[CH3:2].[CH3:14][N:15]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:34]>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][C:4]=1[C:23]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:34])[N:15]([CH3:14])[CH:24]=1)[CH3:2]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2ccccc2c1=O
Reactant: CCc1ccc(S(C)(=O)=O)cc1I
Product: CCc1ccc(S(C)(=O)=O)cc1-c1cn(C)c(=O)c2ccccc12

Procedure:
The title compound of Example 312, step 3 was reacted with the title compound of Example 89, step 1 in a manner similar to Example 312, step 4 to give the title compound. 1H NMR (400 MHz, CDCl3): δ 1.10 (3H, t, J=8.0 Hz), 2.51-2.56 (2H, m), 3.10 (3H, s), 3.67 (3H, s), 6.97-7.02 (2H, m), 7.52-7.59 (3H, m), 7.80 (1H, s), 7.97 (1H, d, J=8.0 Hz), 8.54 (1H, d, J=8.0 Hz). LCMS: 342 (M+1)+
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH:6]=[CH:7][CH2:8][N:9]2[C:14](=[O:15])[C:13]([CH2:16]OS(C)(=O)=O)=[CH:12][C:11]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([F:30])[CH:23]=3)=[N:10]2)=[CH:4][CH:3]=1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][CH2:8][N:9]2[C:14](=[O:15])[C:13]([CH2:16][N:37]3[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]3)=[CH:12][C:11]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([F:30])[CH:23]=3)=[N:10]2)=[CH:31][CH:32]=1
Reactant: CN1CCNCC1
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC=Cc3ccc(Cl)cc3)n2)cc1F
Product: COc1ccc(-c2cc(CN3CCN(C)CC3)c(=O)n(CC=Cc3ccc(Cl)cc3)n2)cc1F
Yield: 66.3 %

Procedure:
Following the procedure of Example 1(10), 2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as pale brown neeldes (yield: 66.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][CH:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+].Cl>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][CH:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Cl)cnc1N1CC(Nc2ccc(F)cc2F)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc(Cl)cnc1N1CC(Nc2ccc(F)cc2F)C1
Temperature: 60 °C
Reaction time: 12 h
Yield: 99.1 %

Procedure:
To a solution of methyl 5-chloro-2-(3-((2,4-difluorophenyl)amino)azetidin-1-yl)nicotinate (D85) (37 mg, 0.104 mmol) in a mixture 3:1 1,4-dioxane/water (4 ml), 1M NaOH (0.157 ml) was added and the resulting mixture was stirred 12 h at 60° C. After cooling the reaction mixture was acidified to pH 1 by addition of 1M HCl. The resulting precipitate was collected by filtration and afforded the title compound (D118) (35 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[N:7][C:8]=1[CH3:9].Br[CH2:18][CH2:19][F:20]>>[F:20][CH2:19][CH2:18][O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:10][C:11](=[O:16])[C:12]([CH3:13])([CH3:15])[CH3:14])=[N:7][C:8]=1[CH3:9]
Reactant: Cc1nc(NC(=O)C(C)(C)C)ccc1CO
Reactant: FCCBr
Product: Cc1nc(NC(=O)C(C)(C)C)ccc1COCCF

Procedure:
This material was prepared in analogy to example 86 step A] from N-(5-hydroxymethyl-6-methyl-pyridin-2-yl)-2,2-dimethyl-propionamide (0.556 g, product of example 112 step B]) and 1-bromo-2-fluoro-ethane (0.475 g) as a light yellow gum (0.115 g). MS (ESI): 269.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7](=[O:8])[O:6][CH:5]([CH2:9][CH2:10][C:11](O)=[O:12])[C:4]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.ClC(OCC(C)C)=O.[BH4-].[Na+].Cl>O1CCCC1.O.C(N(CC)CC)C>[OH:12][CH2:11][CH2:10][CH2:9][CH:5]1[O:6][C:7](=[O:8])[C:3]([O:2][CH3:1])=[C:4]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC1=C(c2ccccc2)C(CCC(=O)O)OC1=O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COC1=C(c2ccccc2)C(CCCO)OC1=O
Yield: 82.7 %

Procedure:
To a solution of 3-(4-methoxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl)propionic acid (3 g) and triethylamine (1.95 ml) in tetrahydrofuran was added dropwise iso-butyl chloroformate (1.79 ml) at -20° C. with stirring and the mixture was stirred for 40 minutes at the same temperature. To this mixture was added sodium borohydride (1.11 g) at -20° C. and the mixture was stirred for 3 hours at ambient temperature. After being acidified with 10% hydrochloric acid at 0° , the solvent was removed under the reduced pressure to give a residue which was poured into water and extracted with diethyl ether. The ethereal extract was washed with lN hydrochloric acid and saturated aqueous solution of sodium bicarbonate successively and dried. Evaporation of the solvent gave an oil which was chromatographed on silica gel in chloroform to give 5-(3-hydroxypropyl)-3-methoxy-4- phenyl-2(5H)-furanone (2.35 g) as an oil.
Reaction SMILES: [CH2:1]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[NH2-].[Na+].C[N:29](C)C1C=CC=CC=1>O>[NH2:29][C:24]1[CH:25]=[C:20]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:21]=[CH:22][N:23]=1
Reactant: CCCCCCCCCCCCCCCCCCCc1ccncc1
Reactant: CN(C)c1ccccc1
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCc1ccnc(N)c1
Temperature: 150 °C
Yield: 45 %

Procedure:
A mixture of 0.5 molar portion of 4-nonadecylpyridine, 0.59 mole of sodium amide and 1.18 moles of N,N-dimethylaniline was heated at 150° C. for six hours. The reaction mixture, after cooling, was poured into water, and the dimethylaniline layer was separated and dried over anhydrous potassium carbonate. After removal of the solvent in vacuo the residue was stirred in petroleum ether and crystallized from ethyl acetate/ligroin. Yield 45%. Anal. Calcd for C24H44N2: C, 79.93; H, 12.30; N, 7.77. Found: C, 79.63; H, 12.40; N, 7.60. MS (ESIMS): m/z: 360.4.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].[C:10]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:11][C:12]([CH3:14])=O.C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:17]([O:16][C:10](=[O:15])/[CH:11]=[C:12](/[NH:4][C:3]1[CH:5]=[C:6]([F:9])[CH:7]=[CH:8][C:2]=1[F:1])\[CH3:14])[CH3:18]
Reactant: Nc1cc(F)ccc1F
Reactant: CCOC(=O)CC(C)=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C(\C)Nc1cc(F)ccc1F

Procedure:
A mixture of 2,5-difluoroaniline (7.5 ml) and ethyl acetoacetate (9.6 ml) were combined in toluene (15 ml) containing acetic acid (1.5 ml). The mixture was boiled under Dean-Stark azeotrope conditions, cooled and solvent removed at reduced pressure to give crude (E)-3-(2,5-difluoro-phenylamino)-but-2-enoic acid ethyl ester (16.17 g). (E)-3-(2,5-Difluoro-phenylamino)-but-2-enoic acid ethyl ester (2 g) was refluxed in Dowtherm-A (40 ml) for 3 h. After cooling the Dowtherm was diluted with pentane (40 ml) and the precipitated title compound isolated by filtration. (Method A). 1H NMR δ: 2.34 (3H, s), 5.91 (1H, s), 6.96 (1H, m), 7.53 (1H, m), 11.48 (1H, brs).