Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[CH3:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[O:10].C[O-].[Na+]>CO>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9](=[O:10])[CH2:8][CH2:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[CH:12][CH:13]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: O=Cc1ccco1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(CCc1ccco1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.6 %

Procedure:
To a solution of 2-furaldehyde (4.15 ml, 50 mmol) and 4-fluoroacetophenone (6.16 ml, 50 mmol) in methanol (200 ml), sodium methoxide (2.85 g, 50 mmol) was added. After stirring at room temperature for 18 hours, the reaction mixture was concentrated, resuspended in ethyl acetate (600 ml) and diluted with water. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated. The crude solid (10.27 g) was purified by chromatography (silica gel, hexane/ethyl acetate, 7/3) to give 1-(4-fluorophenyl)-3-(2-furanyl)propan-1-one (8.9 g, 95%) as a white solid: mp (DSC) 72° C. Anal Calc'd. for C13H10FO: C, 72.22; H, 4.20. Found: C, 72.18; H, 4.38.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)[C:5]([F:18])=[CH:4][N:3]=1.C(N(C(C)C)C(C)C)C.[CH2:28]1[CH2:38][O:37][C:36]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][C:30]=2[O:29]1>C(O)CO>[CH2:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]2[C:5]([F:18])=[CH:4][N:3]=[C:2]([NH:33][C:32]3[CH:34]=[CH:35][C:36]4[O:37][CH2:38][CH2:28][O:29][C:30]=4[CH:31]=3)[N:7]=2)=[CH:10][CH:11]=1)[CH3:17]
Reactant: CCOc1ccc(Nc2nc(Cl)ncc2F)cc1
Reactant: Nc1ccc2c(c1)OCCO2
Solvent: OCCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(Nc2nc(Nc3ccc4c(c3)OCCO4)ncc2F)cc1
Temperature: 200 °C
Yield: 59.1 %

Procedure:
To a solution of 2-chloro-N4-(4-ethyloxyphenyl)-5-fluoro-4-pyrimidineamine (0.25 g, 0.93 mmol) in ethylene glycol (3 mL) under nitrogen at room temperature was added i-Pr2EtN, 0.93 mmol) followed by 3,4-ethylenedioxyaniline (0.17 g, 1.12 mmol). The reaction mixture was heated to 200° C. for 5 h and then cooled to room temperature. The mixture was partitioned between H2O (20 mL) and EtOAc (20 mL) and the aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude brown solid was purified by chromatography (2:1 CHCl3/EtOAc) to afford N4-(4-ethyloxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine (0.21 g, 60%) as a tan solid: Rf 0.42 (4:1 CHCl3/EtOAc); mp 163.8–167.2° C. (DSC); 1H NMR (300 MHz, CDCl3) δ 7.89 (d, J=2.8 Hz, 1H), 7.50–7.45 (m, 2H), 7.17 (d, J=2.5 Hz, 1H), 6.92–6.86 (m, 3H), 6.80–6.75 (m, 2H), 6.64 (bs, 1H), 4.26–4.21 (m, 4H), 4.03 (q, J=7.0, 2H), 1.42 (t, J=6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 156.1, 150.6, 143.6, 142.8, 140.3, 140.0, 139.5, 139.3, 134.0, 130.8, 123.2, 117.2, 115.1, 113.6, 109.4, 64.6, 64.0, 15.1; IR (ATR) 3403 cm−; ESI MS m/z 383 [C20H19FN4O3+H]+; HPLC (Method A) 98.1% (AUC), tR=12.0 min. Anal. Calcd for C20H19FN4O3: C, 62.82; H, 5.01; N, 14.65. Found: C, 62.06; H, 5.01; N, 14.35.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:20])[C:15]([F:19])([F:18])[CH:16]=[CH2:17])=[CH:4][CH:3]=1.I[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:20])[C:15]([F:18])([F:19])/[CH:16]=[CH:17]/[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:6][CH:7]=1
Reactant: Ic1ccccc1
Reactant: C=CC(F)(F)C(O)c1c(C)noc1-c1ccc(Br)cc1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)C(F)(F)/C=C/c1ccccc1

Procedure:
Prepared according to the procedure described in Example 39, Step 1, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2,2-difluoro-but-3-en-1-ol and iodobenzene.
Reaction SMILES: [C:1]([C:4]([C@H:6]1[N:9]([CH:10]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:8](=[O:29])[C@@H:7]1[C@H:30]([O:32][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[CH3:31])=[CH2:5])([OH:3])=[O:2].[CH2:43](Br)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:43]([O:2][C:1]([C:4]([C@H:6]1[N:9]([CH:10]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[C:8](=[O:29])[C@@H:7]1[C@H:30]([O:32][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[CH3:31])=[CH2:5])=[O:3])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: BrCc1ccccc1
Reactant: C=C(C(=O)O)[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccccc2)C(=O)N1C(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(C(=O)OCc1ccccc1)[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccccc2)C(=O)N1C(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Temperature: 25 °C

Procedure:
A solution of (3S,4S)-4-(1-carboxyethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone (3.7 g) in acetone (60 ml) was treated with benzyl bromide (1.4 g) in the presence of anhydrous potassium carbonate (1.88 g) under reflux for 2 hours. The reaction mixture was cooled down to room temperature, filtered to remove insoluble materials and concentrated in vacuo. The concentrate was diluted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo gave (3S,4S)-4-(1-benzyloxycarbonylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=2)[C:24]([O:26][CH3:27])=[O:25])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:30]([C:34]1[CH:39]=[CH:38][C:37]([C:40]#[CH:41])=[CH:36][CH:35]=1)[CH2:31][CH2:32][CH3:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.CCOCC.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH2:30]([C:34]1[CH:35]=[CH:36][C:37]([C:40]#[C:41][C:2]2[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:9])=[O:10])=[CH:6][CH:7]=2)=[CH:38][CH:39]=1)[CH2:31][CH2:32][CH3:33]
Reactant: C#Cc1ccc(CCCC)cc1
Reactant: CCCCCCN(Cc1ccc(F)c(C(=O)OC)c1)S(=O)(=O)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCCCN(Cc1ccc(F)c(C(=O)OC)c1)S(=O)(=O)c1ccc(C#Cc2ccc(CCCC)cc2)cc1
Temperature: 150 °C
Reaction time: 0.42 h
Yield: 58.5 %

Procedure:
To a solution of methyl 5-{[[(4-bromophenyl)sulfonyl](hexyl)amino]methyl}-2-fluorobenzoate (96 mg; 0.20 mmol) in DMF (5 mL) were added (Aldrich, p-butylphenylacetylene (31 mg; 0.20 mmol), bis(triphenylphosphine) palladium (II) chloride (6.9 mg; 0.01 mmol), copper(I) iodide (1.9 mg; 0.01 mmol), triphenylphosphine (10.4 mg; 0.04 mmol) and TEA (0.08 mL; 0.59 mmol). The mixture was stirred for 1500 s at 150° C. under MW. The mixture was diluted with Et2O (50 mL) and the precipitate obtained filtrated off. Filtrate was washed with HCl 1N and with brine (75 mL). The organic layer was dried over magnesium sulfate and the solvent was removed under reduced pressure. Purification by flash chromatography using silicagel (c-Hex:EtOAc, 9:1 then 1:1) gave 66 mg (63.3%) of the title compound as a white solid. HPLC: Rt=6.12 min (purity=99.6%). LC/MS: M+(ESI): 564.4. 1H NMR (CDCl3) δ: 7.79 (d, J=8.3 Hz, 3H) 7.64 (d, J=8.7 Hz, 2H), 7.56 (m, 1H), 7.46 (d, J=8.3 Hz, 2H), 7.19 (d, J=7.9 Hz, 2H), 7.15 (s, 1H), 4.33 (s, 2H), 3.92 (s, 3H), 3.11 (t, J=7.5 Hz, 2H), 2.63 (t, J=7.7 Hz, 2H), 1.61 (t, J=7.7 Hz, 2H), 1.35 (m, 5H), 1.15 (m, 5H), 0.93 (t, J=7.3 Hz, 3H), 0.81 (t, J=6.9 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][S:17](Cl)(=[O:19])=[O:18])[CH:8]=2)[N:3]=1.[Cl:21][C:22]1[CH:41]=[CH:40][CH:39]=[CH:38][C:23]=1[CH2:24][NH:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH:31]([O:34][CH2:35][O:36][CH3:37])[CH2:30][CH2:29]1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][S:17]([N:25]([CH2:24][C:23]3[CH:38]=[CH:39][CH:40]=[CH:41][C:22]=3[Cl:21])[CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][CH:31]([O:34][CH2:35][O:36][CH3:37])[CH2:30][CH2:29]3)(=[O:19])=[O:18])[CH:8]=2)[N:3]=1
Reactant: O=S(=O)(Cl)CCCCOc1ccc2nc(Cl)ccc2c1
Reactant: COCOC1CCN(CCNCc2ccccc2Cl)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCOC1CCN(CCN(Cc2ccccc2Cl)S(=O)(=O)CCCCOc2ccc3nc(Cl)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.2 %

Procedure:
1.75 g of 4-(2-chloro-6-quinolyloxy)butylsulfonyl chloride was added, at 0° C., to a solution of 1.6 g of 1-[2-(2-chlorobenzylamino)ethyl]-4-methoxymethoxypiperidine and 1 ml of triethylamine in 25 ml dichloromethane. The mixture was stirred at room temperature for 1 day. The reaction mixture was washed with water and dried with magnesium sulfate. The solvent was removed by distillation. The resulting residue was purified by a silica gel column chromatography (eluant: 3% methanol/dichloromethane) to obtain 2.63 g of 2-chloro-6-[4-{N-(2-chlorobenzyl)-N-[2-(4-methoxymethoxy-1-piperidinyl)-ethyl]aminosulfonyl}butoxy]quinoline.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[Cl:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:44]1[O:48][C:47]([C:49]2[CH:54]=[CH:53][N:52]=[C:51]([NH2:55])[CH:50]=2)=[N:46][C:45]=1[C:56]1[N:60](COCC[Si](C)(C)C)[CH:59]=[N:58][N:57]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:44]1[O:48][C:47]([C:49]2[CH:54]=[CH:53][N:52]=[C:51]([NH:55][C:1](=[O:5])[CH2:2][CH3:3])[CH:50]=2)=[N:46][C:45]=1[C:56]1[NH:60][CH:59]=[N:58][N:57]=1
Reactant: C[Si](C)(C)CCOCn1cnnc1-c1nc(-c2ccnc(N)c2)oc1-c1ccccc1Cl
Reactant: CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCC(=O)Nc1cc(-c2nc(-c3nnc[nH]3)c(-c3ccccc3Cl)o2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.6 %

Procedure:
A mixture of propanoic acid (0.0095 mL, 0.13 mmol), HATU (0.019 g, 0.051 mmol) and N-methylmorpholine (0.014 mL, 0.13 mmol) in DCM (1 mL) was allowed to stir at rt for 30 min. Solid 4-[5-(2-chlorophenyl)-4-(4-{[2-(trimethylsilyl)ethoxy]methyl}-4H-1,2,4-triazol-3-yl)-1,3-oxazol-2-yl]pyridine-2-amine (0.020 g, 0.043 mmol) and DMAP (0.016 g, 0.13 mmol) were then added and the reaction mixture was allowed to stir at 80° C. overnight. The reaction mixture was allowed to cool to rt and was diluted with DCM (3 mL) and washed with saturated aqueous NaHCO3 (2 mL). The organic solution was separated and the aqueous solution was extracted with DCM. The organic solutions were combined and concentrated. The residue was redissolved in DCM (0.5 mL) and to this solution was added TFA (0.5 mL). The reaction mixture was allowed to stir at rt for 12 h and then concentrated to dryness. The residue was purified by column chromatography to give N-{4-[5-(2-chlorophenyl)-4-(4H-1,2,4-triazol-3-yl)-1,3-oxazol-2-yl]pyridine-2-yl}propanamide (Compound I-75) (3.5 mg, 21%). LCMS (FA): m/z=395 (M+H). 1H NMR (400 MHz, DMSO) δ 10.72 (s, 1H), 8.79 (s, 1H), 8.51 (d, J=5.2 Hz, 1H), 7.79 (d, J=7.6 Hz, 1H), 7.67 (dd, J=5.2, 1.5 Hz, 1H), 7.64 (dd, J=8.1, 1.2 Hz, 1H), 7.58 (td, J=7.7, 1.7 Hz, 1H), 7.50 (td, J=7.5, 1.3 Hz, 1H), 2.44 (q, J=7.5 Hz, 3H), 1.08 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH2:17])=[CH:16][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18]Br.N.CO>CC(O)=O>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH2:17])=[C:16]([Br:18])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: Nc1ccc2c(c1)ncn2Cc1ccccc1
Agent: N
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ccc2c(ncn2Cc2ccccc2)c1Br
Yield: 60 %

Procedure:
To a solution of 1-benzyl-5-aminobenzimidazole (1.0 g, 5.0 mmol) in 40 ml of AcOH was added solution of Br2 in AcOH until it produces a precipitate. The reaction mixture was concentrated in vacuo to provide a brown solid which was subjected to column chromatography (5% NH3 sat'd MeOH/CHC13) to provide 0.90g (2.5 mmol, 60%) of the product.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[S:3]([CH2:6][CH2:7][N:8]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[C:11]([OH:18])=[C:10]([C:19](OC)=[O:20])[C:9]1=[O:23])(=[O:5])=[O:4].[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[C:28]([S:34][CH3:35])[CH:27]=1>CCO>[CH3:1][N:2]([CH3:24])[S:3]([CH2:6][CH2:7][N:8]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[C:11]([OH:18])=[C:10]([C:19]([NH:33][CH2:32][C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][C:28]=2[S:34][CH3:35])=[O:20])[C:9]1=[O:23])(=[O:5])=[O:4]
Reactant: COC(=O)c1c(O)c2ncccc2n(CCS(=O)(=O)N(C)C)c1=O
Reactant: CSc1cc(F)ccc1CN
Solvent: CCO
Product: CSc1cc(F)ccc1CNC(=O)c1c(O)c2ncccc2n(CCS(=O)(=O)N(C)C)c1=O

Procedure:
In a manner similar to that described in Example 2, methyl 1-{2-[(dimethylamino)sulfonyl]ethyl}-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.3 g, 0.84 mmol) was suspended in 8 mL of absolute EtOH and treated with 1-[4-fluoro-2-(methylthio)phenyl]methanamine (0.21 g, 1.3 mmol). The mixture was brought to reflux for 4.5 hours, cooled, and the solids collected and washed with a little cold EtOH to give the product as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[CH3:26][NH:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=1>>[CH3:25][C:22]1[CH:21]=[CH:20][C:19]([S:16]([NH:15][C:10]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:2][N:27]([CH3:26])[C:28]4[CH:33]=[CH:32][C:31]([O:34][C:35]([F:36])([F:37])[F:38])=[CH:30][CH:29]=4)=[CH:8][CH:7]=3)=[N:14][CH:13]=[CH:12][N:11]=2)(=[O:17])=[O:18])=[CH:24][CH:23]=1
Reactant: CNc1ccc(OC(F)(F)F)cc1
Reactant: Cc1ccc(S(=O)(=O)Nc2nccnc2-c2ccc(CCl)cc2)cc1
Product: Cc1ccc(S(=O)(=O)Nc2nccnc2-c2ccc(CN(C)c3ccc(OC(F)(F)F)cc3)cc2)cc1
Yield: 69 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-4-methylbenzenesulfonamide, and N-methyl-4-(trifluoromethoxy)aniline, the title compound was isolated as a yellow solid in 69% yield (94% purity by HPLC).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][P:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=O)[O:12]C2C=CC([N+]([O-])=O)=CC=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([C:39](=[O:41])[CH3:40])[N:34]=[CH:33]2.N12CCCN=C1CCCCC2>ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][P:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:12])[O:29][C:30]2[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=2)[N:35]([C:39](=[O:41])[CH3:40])[N:34]=[CH:33]3)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(OP(=O)(Oc2ccc([N+](=O)[O-])cc2)c2ccccc2)cc1
Reactant: CC(=O)n1ncc2cc(O)ccc21
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)n1ncc2cc(OP(=O)(Oc3ccc([N+](=O)[O-])cc3)c3ccccc3)ccc21
Reaction time: 2 h
Yield: 93.1 %

Procedure:
A solution of 2.36 g of phenylphosphonic acid bis-(4-nitrophenyl) ester (prepared according to procedure E) in 60 ml of dichloromethane is cooled in an ice bath. 1.041 g of 1-(5-hydroxyindazol-1-yl)ethanone and 900 mg of 1,8-diazabicyclo[5.4.0]undec-7-ene in 40 ml of dichloromethane are added thereto and the reaction is continued at 20° C. for 2 hours. The reaction medium is washed with a saturated sodium bicarbonate solution until discoloration of the organic phase. After separation by settling out, the organic extracts are dried over magnesium sulfate and then evaporated under reduced pressure. 2.4 g of phenylphosphonic acid 1-acetyl-1H-indazol-5-yl ester 4-nitrophenyl ester are isolated, which compound is used without purification in the subsequent stage.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([OH:15])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:25]=1[C:26](Cl)=[O:27].Cl>ClCCl>[Cl:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:25]=1[C:26]([O:15][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:8]=1)=[O:27]
Reactant: COc1ccc(O)cc1OC1CCCC1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(OC(=O)c2c(Cl)cccc2Cl)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
A stirred solution of 3-cyclopentyloxy-4-methoxyphenol (0.2 g) and triethylamine (1.35 mL) in dichloromethane (5 mL) is treated portionwise at 0°-5° C. with 2,6-dichlorobenzoyl chloride (0.28 g), and the solution is warmed to room temperature and stirred for a further 2 hours. The reaction mixture is poured into hydrochloric acid (50 ml; 2 N) and is extracted with diethyl ether (3×50 mL). The combined organic extracts are then washed with water (100 mL), and brine (100 mL), dried over magnesium sulfate and concentrated. The residual oil is subjected to flash chromatography on silica gel, eluting with a mixture of pentane and ethyl acetate (4:1 v/v), to give (3-cyclopentyloxy-4-methoxyphenyl) 2,6-dichlorobenzoate (0.28 g), m.p. 100°-101° C. [Elemental analysis: C,59.7; H,4.7%; calculated: C,59.9; H,4.8%].
Reaction SMILES: C(#N)C.[CH:4]1([C:7](=[O:25])[CH:8](C(OCC)=O)[C:9]([C:11]2[S:15][C:14]([CH3:16])=[C:13]([O:17][CH3:18])[C:12]=2[F:19])=[O:10])[CH2:6][CH2:5]1>O>[CH:4]1([C:7](=[O:25])[CH2:8][C:9]([C:11]2[S:15][C:14]([CH3:16])=[C:13]([O:17][CH3:18])[C:12]=2[F:19])=[O:10])[CH2:6][CH2:5]1
Reactant: CCOC(=O)C(C(=O)c1sc(C)c(OC)c1F)C(=O)C1CC1
Solvent: O
Solvent: CC#N
Product: COc1c(C)sc(C(=O)CC(=O)C2CC2)c1F

Procedure:
The above compound was also prepared in a similar manner, but using acetonitrile without addition of water, from 3-cyclopropyl-2-ethoxycarbonyl-1-(4-fluoro-3-methoxy-2-methylthiophenyl)propane-1,3-dione. In this experiment the reaction mixture was heated for 20 hours at reflux, resulting in a clean conversion to the title compound (as shown by nmr), but after this time 60% of the starting ethyl ester still remained.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:18](C(OC(C)(C)C)=O)[C:9]2=[N:10][C:11]([Cl:17])=[C:12]([O:14][CH2:15][CH3:16])[CH:13]=[C:8]2[CH:7]=1)=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH2:2]([O:3][C:4]([C:6]1[NH:18][C:9]2=[N:10][C:11]([Cl:17])=[C:12]([O:14][CH2:15][CH3:16])[CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:1]
Reactant: CCOC(=O)c1cc2cc(OCC)c(Cl)nc2n1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(OCC)c(Cl)nc2[nH]1

Procedure:
A solution of 1.0 g (2.71 mmol) 6-chloro-5-ethoxy-pyrrolo[2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester in 20 mL dichloromethane was cooled to 0° C., 10 mL (14.9 g, 0.13 mol) trifluoroacetic acid was added and then the cooling bath was removed. After 1 h the volatile components were removed and the residue was poured into 10% aqueous sodium bicarbonate solution and extracted twice with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The resulting white solid (100%) was used without further purification.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[Cl:18][C:19]1[N:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[N:24]=[CH:23][C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([F:17])[CH:3]=2)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(Cl)nc4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, light yellow solid (62 mg, 75%), MS (ISP) m/z=314.5 [(M+H)+], mp 232° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 6-chloro-pyridin-3-ylboronic acid (51.1 mg, 0.325 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[CH:3]=1.O.[NH2:11][NH2:12]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:11][NH2:12])[CH:5]=[C:4]([Cl:9])[CH:3]=1
Reactant: NN
Reactant: Clc1cc(Cl)cc(Cl)c1
Solvent: O
Solvent: c1ccncc1
Product: NNc1cc(Cl)cc(Cl)c1
Temperature: 180 °C
Yield: 60 %

Procedure:
A mixture of 1,3,5-trichlorobenzene (2.53 g), hydrazine hydrate (3.48 g, 5 molar equivalents) and pyridine (12 ml) was heated in an autoclave (purged with argon) for 6 hours at 180° C. The mixture was cooled, the excess hydrazine decanted and the organic phase evaporated in vacuo to give the title compound in 60% yield. It was shown that 65% of the starting material had been consumed, thus indicating that the reaction had occurred with high selectivity.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=1)[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18](=O)[CH3:19])[CH2:13]1.O>C1COCC1>[CH2:18]([N:14]1[CH2:15][CH2:16][CH2:17][CH:12]([CH2:11][C:10]2[CH:21]=[CH:22][CH:23]=[C:8]([F:7])[CH:9]=2)[CH2:13]1)[CH3:19]
Reactant: CC(=O)N1CCCC(Cc2cccc(F)c2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCN1CCCC(Cc2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.2 %

Procedure:
A solution of lithium aluminium hydride (2M in THF, 2.8 mL) was added dropwise to a solution of 1-[3-(3-fluorobenzyl)piperidin-1-yl]ethanone (Intermediate 224, 0.66 g) in anhydrous THF (20 mL) at 0° C. under argon. The mixture was stirred for 30 minutes then allowed to warm to room temperature and stirred for 2 hours. The mixture was recooled to 0° C. and water was added. The mixture was extracted with ether, washed with brine, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness to give 1-ethyl-3-(3-fluorobenzyl)piperidine (0.535 g).
Reaction SMILES: [CH2:1]1[O:5][CH2:4][O:3][CH:2]1[CH2:6][OH:7].N1C=CC=CC=1.Cl[C:15]([O:17][CH2:18][Cl:19])=[O:16]>CCOCC>[C:15](=[O:16])([O:7][CH:6]1[CH2:2][O:3][CH2:4][O:5][CH2:1]1)[O:17][CH2:18][Cl:19]
Reactant: OCC1COCO1
Reactant: O=C(Cl)OCCl
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=C(OCCl)OC1COCOC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 6.4 %

Procedure:
Glycerol formal (14 g) was dissolved in anhydrous ether (400 ml) and, after adding pyridine (15 g) at −10° C., a solution of chloromethyl chloroformate (25 g) in anhydrous ether (50 ml) was added dropwise over the period of 10 minutes. After the reaction solution was stirred at room temperature for 20 hours, the deposited pyridine hydrochloride was removed by filtration. The filtrate was washed with a saturated sodium chloride aqueous solution (400 ml×2), and then dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by subjecting it to silica gel chromatography (eluent: ethyl acetate/hexane=1/5→ethyl acetate/hexane=1/3) to obtain chloromethyl (1,3-dioxan-5-yl) carbonate (1.7 g) as a colorless oily product.
Reaction SMILES: [CH2:1](N1CCN(CC2C(=O)N(CC(C)C)N=C(C3C=CC(C)=CC=3)C=2)CC1)C1C=CC=CC=1.[C:33]([C:36]1[C:37](=[O:52])[NH:38][N:39]=[C:40]([C:42]2[CH:47]=[CH:46][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:44][CH:43]=2)[CH:41]=1)([OH:35])=[O:34]>>[CH3:1][O:34][C:33]([C:36]1[C:37](=[O:52])[NH:38][N:39]=[C:40]([C:42]2[CH:43]=[CH:44][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:46][CH:47]=2)[CH:41]=1)=[O:35]
Reactant: Cc1ccc(-c2cc(CN3CCN(Cc4ccccc4)CC3)c(=O)n(CC(C)C)n2)cc1
Reactant: O=C(O)c1cc(-c2ccc(C(F)(F)F)cc2)n[nH]c1=O
Product: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)n[nH]c1=O

Procedure:
Following the procedure of Example 1 (5), 4-carboxy-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-one was reacted to yield the title compound as slightly yellow crystalline powder (yield: 88.5%).