Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[C:17]([Cl:18])[N:11]2[N:10]=[C:9]1[CH:19]=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21]1([Mg]Br)[CH2:23][CH2:22]1>C(Cl)Cl.C1COCC1>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[C:17]([Cl:18])[N:11]2[N:10]=[C:9]1[CH:19]([CH:21]1[CH2:23][CH2:22]1)[OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Br[Mg]C1CC1
Reactant: O=Cc1nn2c(Cl)ccc2c(=O)n1Cc1ccccc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=c1c2ccc(Cl)n2nc(C(O)C2CC2)n1Cc1ccccc1
Reaction time: 1 h
Yield: 69.8 %

Procedure:
To a solution of 3-benzyl-7-chloro-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-2-carbaldehyde (1.50 g, 5.21 mmol) in anhydrous CH2Cl2 (20 mL) at −76° C. under nitrogen was added dropwise cyclopropylmagnesium bromide (Boulder Scientific, 0.76 M, 20 mL, 15.2 mmol) in THF over 15 min. The reaction mixture was stirred at −70–50° C. for 1 h, quenched with aq. NH4Cl and 1 N HCl, and extracted with EtOAc (3×70 mL). The EtOAc layers were dried and concentrated. Purification of the crude product by flash column chromatography (SiO2, EtOAc/hexane 1.5:8.5 to 1:4) gave the title compound as a pale oil (1.2 g, 70%): 1H NMR (CDCl3) δ 7.24 (m, 2H), 7.19 (m, 1H), 7.09 (m, 2H), 7.00 (d, 1H, J=4.4 Hz), 6.44 (d, 1H, J=4.4 Hz), 5.33 (q, 2H, AB), 4.10 (t, 1H, J=7.15 Hz), 2.62 (d, 1H, J=7.7 Hz), 1.40 (m, 1H), 0.51 (m, 2H), 0.32 (m, 1H), 0.14 (m, 1H); 13C NMR (CDCl3) δ 154.3, 150.5, 136.1, 129.0, 127.8, 126.2, 117.8, 117.3, 110.2, 108.6, 72.76, 44.6, 15.5, 3.0; MS (ESI+) 330.10 (M++H), 352.13, 354.13 (M++Na).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Br[CH:21]([CH3:31])[C:22]([O:29][CH3:30])=[CH:23][C:24]([O:26]CC)=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:18])([F:17])[F:19])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH:21]([CH3:31])[C:22]([O:29][CH3:30])=[CH:23][C:24]([OH:26])=[O:25])=[CH:9][CH:10]=1
Reactant: CCOC(=O)C=C(OC)C(C)Br
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=CC(=O)O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1

Procedure:
A mixture of 4-(2-chloro-4-trifluoromethylphenoxy)phenol (1.16 g), ethyl 4-bromo-3-methoxy-2-pentenoate (1.74 g) and potassium carbonate (0.73 g) in DMF (5 ml.) is heated to about 130° for 2 hours. Thereafter, DMF is removed. The residue is filtered and washed with methylene dichloride. The filtrate is washed, dried and evaporated to dryness. The oily residue is subjected to prep. thin layer chromatography using 20% ethylacetate/hexane to yield the ethyl ester of 4-[4-(2-chloro-4-trifluoromethylphenoxy)phenoxy]-3-methoxy-2-pentenoic acid, MS m/e 444 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[NH:7][C:6](=[O:15])/[C:5]/2=[CH:16]/OC.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[NH:7][C:6](=[O:15])[C:5]2=[CH:16][NH:32][C:29]1[CH:28]=[CH:27][C:26]([N:23]2[CH2:22][CH2:21][N:20]([CH3:19])[CH2:25][CH2:24]2)=[CH:31][CH:30]=1
Reactant: CO/C=C1/C(=O)NC(=O)c2cc(OC)c(Br)cc21
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: CN(C)C=O
Product: COc1cc2c(cc1Br)C(=CNc1ccc(N3CCN(C)CC3)cc1)C(=O)NC2=O
Temperature: 110 °C
Yield: 46.7 %

Procedure:
A mixture of (4E)-6-bromo-7-methoxy-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (156 mg, 0.50 mmole), N,N-dimethylformamide (1 mL) and 4-(4-Methyl-piperazin-1-yl)-phenylamine (96 mg, 0.50 mmole) is stirred and heated at 110° C. for one hour, cooled in the refrigerator. The reaction mixture is evaporated to dryness, taken up in 5% methanol in chlororform and passed through a short pad of Florisil eluting with 5% methanol in chloroform. The eluate is evaporated in vacuo and treated with acetonitrile, filtered and dried to give a brown solid 110 mg (47%), mp 274-276° C.; MS (ESI): m/z 471.1, 473.1 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:15]3/[C:16](=[O:22])[N:17]=[C:18](SC)[S:19]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:23]#[N:24])[CH3:2].[N:25]1[CH:30]=[CH:29][CH:28]=[N:27][C:26]=1[CH2:31][NH2:32].CCN(C(C)C)C(C)C>>[CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:15]3/[C:16](=[O:22])[N:17]=[C:18]([NH:32][CH2:31][C:26]4[N:27]=[CH:28][CH:29]=[CH:30][N:25]=4)[S:19]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:23]#[N:24])[CH3:2]
Reactant: NCc1ncccn1
Reactant: CCOc1c(C#N)cnc2ccc(/C=C3\SC(SC)=NC3=O)cc12
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1c(C#N)cnc2ccc(/C=C3\SC(NCc4ncccn4)=NC3=O)cc12

Procedure:
Similar procedure as described in example 14h was used, starting from 4-ethoxy-6-[2-methylsulfanyl-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile (example 14g), pyrimidin-2-ylmethylamine and DIEA to give 4-ethoxy-6-[4-oxo-2-[(pyrimidin-2-ylmethyl)-amino]-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile. LC-MS m/e 417 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[CH3:13][NH:14][C@H:15]1[CH2:19][CH2:18][NH:17][CH2:16]1>>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:17]1[CH2:18][CH2:19][C@H:15]([NH:14][CH3:13])[CH2:16]1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Reactant: CN[C@H]1CCNC1
Product: CN[C@H]1CCN(c2ccc([N+](=O)[O-])cc2OC)C1
Temperature: 130 °C

Procedure:
A mixture of 1-chloro-2-methoxy-4-nitrobenzene (200 mg, 1.066 mmol) and (S)—N-methylpyrrolidin-3-amine (153 mg, 1.528 mmol) was heated at 130° C. in a sealed tube for 5 h. After cooling down to room temperature, the obtained black solid product (Example 41A) was used for next step without further purification. LCMS (ES): m/z 252.3 [M+H]+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[S:5][C:6]=1[C:7]1[N:11]2[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]2=[N:9][C:8]=1[CH3:22].[CH3:29][O-:30].[Na+]>[Cu]I.CO>[CH2:17]([CH:16]([C:15]1[C:10]2[N:11]([C:7]([C:6]3[S:5][C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:3][C:2]=3[O:30][CH3:29])=[C:8]([CH3:22])[N:9]=2)[N:12]=[C:13]([CH3:21])[CH:14]=1)[CH2:19][CH3:20])[CH3:18]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(N4CCOCC4)nc3Br)c(C)nc12
Reactant: C[O-]
Agent: [Cu]I
Agent: [Na+]
Solvent: CO
Product: CCC(CC)c1cc(C)nn2c(-c3sc(N4CCOCC4)nc3OC)c(C)nc12
Temperature: 130 °C
Yield: 35.9 %

Procedure:
100 mg of 3-(4-Bromo-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.22 mmol), 24 mg of sodium methoxide (0.44 mmol) and 21 mg of CuI (0.11 mmol) are put into 4 ml vial with MeOH 3 ml and capped with a Teflon® lined cap. The reaction vial is heated at 130° C. overnight. The reaction mixture is concentrated and applied onto a silica-gel chromatography column (Hexane: THF=10:1) to give 32.8 mg of the title compound. Yield 36%. Mass spectrum (m/e): 416 (M+1). 1H NMR (CDCl3): δ 6.64 (s, 1H), 3.96 (s, 3H), 3.86 (t, J=4.7 Hz, 4H), 3.53 (m, 4H), 3.34 (m, 1H), 2.82 (s, 3H), 2.48 (s, 3H), 1.82 (m, 4H), 0.85 (t, J=7.4 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([OH:12])=O)[N:5]=[CH:4][C:3]=1[NH:13][C@@H:14]1[CH2:19][C@@H:18]2[CH2:20][C@@H:16]([C:17]2([CH3:22])[CH3:21])[C@H:15]1[CH3:23].O[N:25]=[C:26]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)[NH2:27].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[O:12][N:27]=[C:26]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[N:25]=2)[N:5]=[CH:4][C:3]=1[NH:13][C@@H:14]1[CH2:19][C@@H:18]2[CH2:20][C@@H:16]([C:17]2([CH3:22])[CH3:21])[C@H:15]1[CH3:23]
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)O)c(=O)c1Cl)C2(C)C
Reactant: NC(=NO)c1ccncc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(Cc3nc(-c4ccncc4)no3)c(=O)c1Cl)C2(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.3 %

Procedure:
To [5-chloro-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]acetic acid (80 mg, 0.235 mmol) in dichloromethane (3 mL), N′-hydroxypyridine-4-carboximidamide (38.6 mg, 0.281 mmol) and N,N′-dicyclohexylcarbodiimide (58.2 mg, 0.282 mmol) were added and stirred at room temperature for 18 hours. After completion of the reaction, the solid was filtered off with chloroform, and the filtrate was evaporated under reduced pressure. The resulting oil in toluene (2 mL) was stirred at 110° C. for 5 hours and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/4) to give the desired product (78 mg, 75% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([F:18])([F:17])[F:16].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:16][C:15]([F:17])([F:18])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: C1CNCCN1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccccc1CN1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
1.08 g (12.5 mmol) of piperazine are placed in the presence of 1 g (4.2 mmol) of 1-bromomethyl-2-trifluoromethyl-benzene and 0.64 mL (4.6 mmol) of triethylamine in 10 mL of toluene. The reaction medium is stirred for 30 min at room temperature and then heated to 110° C. for 6 h. After dry concentration, the obtained residue is taken up with AcOEt and washed with water. After drying on MgSO4, the organic phases are dry concentrated, the obtained residue is purified by flash chromatography on silica (CH2Cl2-MeOH—NH4OH: 90-9-1). 0.7 g of intermediate 7a are thereby isolated as a clear oil (yield 68%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@H:4]([OH:25])[C@@H:5]([NH:14]C(OCC1C=CC=CC=1)=O)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([F:13])[CH:7]=1>C(O)C>[CH3:1][O:2][C:3](=[O:26])[C@H:4]([OH:25])[C@@H:5]([NH2:14])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([F:13])[CH:7]=1
Reactant: COC(=O)[C@H](O)[C@@H](NC(=O)OCc1ccccc1)c1ccc(F)c(F)c1
Solvent: CCO
Product: COC(=O)[C@H](O)[C@@H](N)c1ccc(F)c(F)c1
Reaction time: 16 h
Yield: 75.1 %

Procedure:
(2R,3S)-N-Benzyloxycarbonyl-3-amino-3-(3,4-difluorophenyl)-2-hydroxypropionic acid methyl ester (>12.2 g, 33.3 mmol maximum) was dissolved in 750 mL ethanol. The flask was purged and filled with argon three times. Palladium on carbon (2 g, 10% wt) was added under argon and the suspension was again purged and filled with argon three times. The suspension was then purged, filled with hydrogen, and stirred 16 h. The suspension was purged, filled with argon three times, filtered through celite and concentrated in vacuo to give (2R,3S)-3-amino-3-(3,4-difluorophenyl)-2-hydroxypropionic acid methyl ester (5.8 g, 25 mmol, 75% from trans-3,4-difluorocinnamic acid methyl ester).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([NH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:5][N:4]=1>ClCCl>[C:10]([NH:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([CH:2]=[O:1])[CH:8]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)Nc1ccnc(CO)c1
Solvent: ClCCl
Product: CC(=O)Nc1ccnc(C=O)c1

Procedure:
2 g of the thus obtained 2-hydroxymethyl-4-acetylaminopyridine were suspended in 400 ml of dichloromethane, mixed with 6 g of MnO3 refluxed for 26 hours. The MnO2 was then filtered hot and the dichloromethane solution rotated n to dryness. 1.5 g of 4-acetylaminopyridine-2-aldehyde were obtained.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:23][CH2:24][C@H:25]2[CH2:30][CH2:29][C@H:28]([N:31]3[CH2:34][CH:33](O)[CH2:32]3)[CH2:27][CH2:26]2)=[N:6][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]([F:22])([F:21])[F:20])=[N:8][CH:9]=1)([O-:3])=[O:2].[C:36]1(=[O:46])[NH:40][C:39](=[O:41])[C:38]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:37]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[N+:1]([C:4]1[C:5]([NH:23][CH2:24][CH:25]2[CH2:30][CH2:29][CH:28]([N:31]3[CH2:32][CH:33]([N:40]4[C:36](=[O:46])[C:37]5[C:38](=[CH:42][CH:43]=[CH:44][CH:45]=5)[C:39]4=[O:41])[CH2:34]3)[CH2:27][CH2:26]2)=[N:6][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]([F:20])([F:21])[F:22])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnc(NCc2ccccc2OC(F)(F)F)nc1NC[C@H]1CC[C@H](N2CC(O)C2)CC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1C1CN(C2CCC(CNc3nc(NCc4ccccc4OC(F)(F)F)ncc3[N+](=O)[O-])CC2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.8 %

Procedure:
1-(trans-4-{[(5-nitro-2-{[2-(trifluoromethoxy)benzyl]amino}pyrimidin-4-yl)amino]methyl}-cyclohexyl)azetidin-3-ol (111 mg, 0.22 mmol, see Example 7), phthalimide (50 mg, 0.33 mmol) and PPh3 (127 mg, 0.48 mmol) were combined in THF (5 mL). To this mixture was added DEAD (61 mg, 0.35 mmol) and the reaction was allowed to stir at 25° C. for 18 h. The reaction was diluted with EtOAc and poured into 10% aqueous NaHCO3. The aqueous phase was separated and extracted two more times with EtOAc. The organic layers were combined, dried (Na2SO4), decanted and concentrated. The crude was purified via flash chromatography (SiO2, 1:9:90-NH4OH:CH3OH:CH2Cl2) to afford 92 mg (67%) of 2-[1-(4-{[5-nitro-2-(2-trifluoromethoxy-benzylamino)-pyrimidin-4-ylamino]-methyl}-cyclohexyl)-azetidin-3-yl]-isoindole-1,3-dione.
Reaction SMILES: C(O[C:5]([C:7]1[N:8]([N:13]([C:19](=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH:9]=[C:10]([F:12])[CH:11]=1)=[O:6])C=C.[O-]CC.[Na+].CO>C(O)C.ClCCl>[CH2:24]([O:23][C:21]([C:20]1[C:19](=[O:26])[N:13]([CH2:14][CH2:15][CH:16]([CH3:17])[CH3:18])[N:8]2[CH:9]=[C:10]([F:12])[CH:11]=[C:7]2[C:5]=1[OH:6])=[O:22])[CH3:25]
Reactant: C=CCOC(=O)c1cc(F)cn1N(CCC(C)C)C(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: CCOC(=O)c1c(O)c2cc(F)cn2n(CCC(C)C)c1=O
Temperature: 40 °C
Yield: 49.1 %

Procedure:
To a solution of 1-[(2-ethoxycarbonyl-acetyl)-(3-methyl-butyl)-amino]-4-fluoro-1H-pyrrole-2-carboxylic acid allyl ester (Example 14h, 0.318 g, 0.898 mmol) in ethanol (10 mL) was added a 21% solution of sodium ethoxide in ethanol (0.728 g, 2.245 mmol) and the mixture was heated at 40° C. for 16 h. The solvent was removed in vacuo and the residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm, 20% ethyl acetate in hexanes, then 10% methanol in dichloromethane) to afford the desired product, 6-fluoro-4-hydroxy-1-(3-methyl-butyl)-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (0.137 g, 0.441 mmol, 49.1% yield) as a yellow oil. 1HNMR (400 MHz, CDCl3) δ: 0.99 (3H, s), 1.00 (3H, s), 1.44 (3H, t, J=7.0 Hz), 1.58-1.63 (2H, m), 1.67-1.75 (1H, m), 4.18-4.22 (2H, m), 4.44 (2H, quartet, J=7.1 Hz), 6.55 (1H, m), 7.04 (1H, m).
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:18][CH:17]=2)=[N+:13]([O-])[CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(OC(=O)C)(=[O:33])C>>[CH2:1]([C:9]1[C:14](=[O:33])[NH:13][C:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCOc1ccc(-c2ccc(CCCCCCCC)c[n+]2[O-])cc1
Product: CCCCCCCCOc1ccc(-c2ccc(CCCCCCCC)c(=O)[nH]2)cc1
Reaction time: 1 h

Procedure:
2.20 g (5.4 mmol) of 5-octyl-2-(4-octyloxyphenyl)pyridine N-oxide are refluxed in 30 ml of acetic anhydride for 4 hours. The acetic anhydride is then distilled off, and the residue is taken up in 10 ml of 1:1 methylene chloride/methanol, and the mixture is stirred with methanolic potassium hydroxide solution for 1 hour. Washing with water and concentrated ammonium chloride solution, drying over sodium sulfate, filtration, removal of the solvent by distillation and recrystallization from 8:2 n-hexane/ethyl acetate give 1.79 g of 3-octyl-6-(4-octyloxyphenyl)-1H-2-pyridone. ##STR14##
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH3:11].C([O:15][C:16]([CH3:18])=[CH2:17])(=O)C.C[O-].C([Sn+](CCCC)CCCC)CCC.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>C1(C)C=CC=CC=1>[CH3:11][N:6]1[C:7]2[C:3](=[C:2]([CH2:17][C:16]([CH3:18])=[O:15])[CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: Cn1ccc2c(Cl)cccc21
Reactant: C=C(C)OC(C)=O
Agent: CCCC[Sn+](CCCC)CCCC
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[O-]
Solvent: Cc1ccccc1
Product: CC(=O)Cc1cccc2c1ccn2C
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.852 g (5.14 mmol) of 4-chloro-1-methylindole in 15 mL dry toluene, 0.85 mL (7.73 mmol) isopropenyl acetate and 2.3 mL (8 mmol) tributyltin methoxide were added. The solution was heated to 100° C. After 15 min, 0.24 g (0.61 mmol) 2-dicyclohexylphospino-2′-(N,N-dimethylamino) biphenyl and 0.14 g (0.153 mmol) tris (dibenzylidineacetone)dipalladium were added and heating was continued. After 2 h the solution was cooled, filtered through a pad of CELITE diatomaceous earth and the filtrate was concentrated to ca. 5 mL. This solution was purified on a silica column using a gradient of 5-20% EtOAc/hexane to obtain the title compound. 1H NMR: (500 MHz, CDCl3): δ 2.14 (s, 3H), 3.84 (s, 3H), 3.97 (s, 2H), 6.51 (d, 1H), 7-7.3 (m, 4H).
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[C:9]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[N+:51]([C:54]1[CH:66]=[CH:65][CH:64]=[CH:63][C:55]=1[O:56][CH:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1)([O-:53])=[O:52]>CN(C=O)C.O>[N+:51]([C:54]1[CH:66]=[CH:65][CH:64]=[CH:63][C:55]=1[O:56][CH:57]1[CH2:62][CH2:61][N:60]([C:16](=[O:18])[CH2:15][NH:14][C:12]([C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:11][N:10]=2)=[O:13])[CH2:59][CH2:58]1)([O-:53])=[O:52]
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: O=[N+]([O-])c1ccccc1OC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2[N+](=O)[O-])CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 8 h
Yield: 37.1 %

Procedure:
To a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (0.15 g, 0.0006 mol) in DMF (3 mL) was added DIPEA (0.27 g, 0.0021 mol), HOBt (0.12 g, 0.0009 mol) and EDCI.HCl (0.17 g, 0.0009 mol) at ambient temperature. After 2 minutes 4-(2-nitro-phenoxy)-piperidine hydrochloride (0.19 g, 0.00073 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The product was extracted with ethyl acetate, and the organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using neutral aluminium oxide (5% methanol in chloroform) to afford 0.1 g (44%) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-nitro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 450.17 (M+1)+, 96.5%, 1H NMR (DMSO-d6): δ 8.1 (bs, 1H), 7.9 (m, 3H), 7.6 (m, 1H), 7.5 (m, 4H), 7.1 (m, 2H), 5.0 (m, 1H), 4.2 (m, 2H), 3.8 (m, 8H), 2.0 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]([OH:8])([CH2:6][CH3:7])[C:4]#[N:5])[CH3:2].[Cl:9][CH2:10][CH2:11]O>O.[Cl-].[Zn+2].[Cl-].[Zn]>[Cl:9][CH2:10][CH2:11][O:8][C:3]([CH2:6][CH3:7])([CH2:1][CH3:2])[C:4]#[N:5]
Reactant: OCCCl
Reactant: CCC(O)(C#N)CC
Agent: [Cl-]
Agent: [Zn+2]
Agent: [Zn]
Solvent: O
Product: CCC(C#N)(CC)OCCCl
Temperature: 60 °C
Reaction time: 20 h
Yield: 39471.1 %

Procedure:
Zinc chloride (68.1 g, 0.5 mol) was fused under vacuum as described in the procedure for the synthesis of intermediate 23. The molten zinc was cooled and the evacuated flask was flushed with nitrogen. The flask was loaded with intermediate 28, 2-ethyl-2-hydroxybutanenitrile, (40.3 g, 0.5 mol) and 2-chloroethanol (50.5 mL, 0.75 mmol) then stirred at 60° C. for 20 hours. The reaction mixture was diluted with water (250 mL) and extracted with dichloromethane (1×250 mL, 4×100 mL). The combined organic layers were dried (sodium sulfate), filtered, and concentrated in-vacuo. The crude product was purified by vacuum distillation (bp 83° C., 10 mmHg) to give the title compound (52 g) containing unreacted intermediate 28. 1H NMR (500 MHz, CDCl3) δ ppm: 3.82 (2H, t, J=5.8 Hz), 3.64 (2H, t, J=5.8 Hz), 1.83 (4H, J=7.3 Hz), 1.03 (6H, t, J=7.6 Hz).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:7])[CH:5]=[O:6].[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]3[CH:26]=[CH:27]C4NC(=O)[CH2:32][CH2:31][CH2:30][C:29]=4[CH:36]=3)[CH2:19][CH2:18]2)=[N:9]1.CI>CCCCC>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([N:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][C:25]3[CH:26]=[CH:27][C:3]4[N:4]([CH3:7])[C:5](=[O:6])[CH2:32][CH2:31][CH2:30][C:29]=4[CH:36]=3)[CH2:21][CH2:22]2)=[N:9]1
Reactant: O=C1CCCc2cc(CCN3CCN(c4nsc5ccccc45)CC3)ccc2N1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CI
Product: CN1C(=O)CCCc2cc(CCN3CCN(c4nsc5ccccc45)CC3)ccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under nitrogen, sodium hydride (20 mg, 0.5 mmol, 60% oil dispersed) was washed free of oil with pentane and layered with 6 ml dimethylformamide. In one portion, 155 mg (0.38 mmol) 7-(2-(4-(1,2-benzisothiazol-3-yl)piperazinyl)ethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (the title compound of Example 54) was added and stirring was continued for 0.5 hours at 25° C. To the solution was then added methyl iodide (162 mg, 1.14 mmol) and stirring was continued overnight. After pouring over 60 ml ice/water, the product was extracted with 40 ml ethyl acetate which was washed with water (2×50 ml), dried with sodium sulfate and concentrated to an oil, 54 mg. Chromatography (32-63 micron silica gel) eluting with 2% methanol in methylene dichloride provided the pure free base, 46 mg (29%).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:36])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:34])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:35])[CH:14]=2)[CH:9]=1>C1COCC1.O>[Cl:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[S:25]([C:22]1[CH:21]=[CH:20][C:19]([C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([F:35])[CH:14]=3)[CH:9]=[C:8]([CH2:7][C:6]([OH:36])=[O:5])[C:17]=2[CH3:18])=[CH:24][CH:23]=1)(=[O:26])=[O:27]
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)c3ccccc3Cl)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1-c1ccc(S(=O)(=O)c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.5 %

Procedure:
Lithium hydroxide monohydrate (0.016 g, 0.38 mmol) was added to a stirred solution of {4-[4-(2-chloro-benzenesulfonyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.045 g, 0.09 mmol) in a 3:1 THF—H2O mixture (4 mL). The reaction mixture was stirred for 16 hours at room temperature. The THF was distilled off under reduced pressure. The crude residue was diluted with water, and acidified [pH˜2] via the drop-wise addition of an aqueous solution of hydrochloric acid (6.0 N). The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Trituration with hexanes afforded {4-[4-(2-chloro-benzenesulfonyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid (0.031 g, 71%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.42-12.50 (m, 1 H), 8.37-8.41 (m, 1 H), 8.08 (d, J=7.80 Hz, 2 H), 8.01 (dd, J=8.80, 6.40 Hz, 1 H), 7.91 (s, 1 H), 7.70-7.82 (m, 4 H), 7.53 (d, J=7.80 Hz, 2 H), 7.35-7.41 (m, 1 H), 6.62 (dd, J=11.00, 2.60 Hz, 1 H), 3.84 (s, 2 H), 2.05 (s, 3 H). MS calcd. for C25H17ClFO4S [(M−H)−] 467, obsd. 467.3.