Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)=[N:8][N:7]([CH2:17][CH3:18])[C:6](=[O:19])[C:5]=1[N+:20]([O-])=O)(=[O:3])[CH3:2].N[C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][N:28]=[CH:29]2>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)=[N:8][N:7]([CH2:17][CH3:18])[C:6](=[O:19])[C:5]=1[NH:20][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][N:28]=[CH:29]2)(=[O:3])[CH3:2]
Reactant: CCn1nc(-c2cccc(Cl)c2)c(C(C)=O)c([N+](=O)[O-])c1=O
Reactant: Nc1cccc2cnccc12
Solvent: CCO
Product: CCn1nc(-c2cccc(Cl)c2)c(C(C)=O)c(Nc2cccc3cnccc23)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.5 %

Procedure:
To a stirred solution of 100 mg (0.311 mmol) of 5-acetyl-2-ethyl-4-nitro-6-(3-chlorophenyl)pyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in ethanol (4 mL), 5-amino-isoquinoline (67 mg, 0.467 mmol) was added. The resulting mixture was stirred at room temperature for two hours. The solvent was evaporated and the residue purified by column chromatography (silica gel, hexane/ethyl acetate 1:2) to yield the title compound (28 mg, 21.5% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14](=[O:23])[NH:13][C:12]=12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:43]([N:45]1[C:49]([CH2:50]O)=[N:48][CH:47]=[N:46]1)[CH3:44].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:43]([N:45]1[C:49]([CH2:50][O:23][C:14]2[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:16][N:11]3[N:10]=[N:9][C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])=[C:12]3[N:13]=2)=[N:48][CH:47]=[N:46]1)[CH3:44]
Reactant: CCn1ncnc1CO
Reactant: O=c1[nH]c2c(-c3ccccc3F)nnn2cc1-c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCn1ncnc1COc1nc2c(-c3ccccc3F)nnn2cc1-c1ccccc1
Yield: 52 %

Procedure:
3-(2-Fluorophenyl)-6-phenyl-4H-1,2,3-triazolo[1,5-α]pyrimidin-5-one (95 mg, 0.31 mmol), triphenylphosphine (203 mg, 0.78 mmol) and (2-ethyl-2H-1,2,4-triazol-3-yl)methanol (110 mg, 0.78 mmol) were suspended in dry tetrahydrofuran (1,5 ml). Diethyl azodicarboxylate (123 μl, 0.78 mmol) was added and a solution resulted immediately. The reaction was stirred at room temperature for 16 hours before purification by preparative tlc (40% EtOAc/hexanes) to give a white solid which was recrystallised from ethyl acetate/hexanes and triturated with diethyl ether to afford 5-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-6-phenyl-1,2,3-triazolo[1,5-α]pyrimidine (67 mg, 52%) as white plates, m.p. 147-148° C.; δH (400 MHz, CDCl3) 1.22 (3H, t, J=7.3 Hz, NCH2CHH3), 4.13 (2H, q, J=7.3 Hz, NCH2CH3), 5.70 (2H, s, OCH2), 7.24 (1H, t, J=29.3 Hz, ArH), 7.31 (1H, t, J=7.5 Hz. ArH), 7.41-7.48 (4H, m, ArH, 7.54-7.56 (2H, m, ArH), 7.89 (1H, s, triazole CH), 8.02 (1H, td, J=7.5 and 1.7 Hz, ArH), 8.79 (1H, s, pyrimidine CH); m/z (ES+) 416 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:31]=[CH:30][C:12]([O:13][CH2:14][C:15]([N:17]([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=3[N+:27]([O-])=O)[CH3:18])=O)=[CH:11][CH:10]=2)[S:3]1.CO.[ClH:34].[H][H]>[C].[Pd].CC(N(C)C)=O>[ClH:34].[CH3:26][O:25][C:23]1[CH:22]=[CH:21][C:20]2[N:27]=[C:15]([CH2:14][O:13][C:12]3[CH:30]=[CH:31][C:9]([CH2:8][CH:4]4[S:3][C:2](=[O:1])[NH:6][C:5]4=[O:7])=[CH:10][CH:11]=3)[N:17]([CH3:18])[C:19]=2[CH:24]=1
Reactant: COc1ccc([N+](=O)[O-])c(N(C)C(=O)COc2ccc(CC3SC(=O)NC3=O)cc2)c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CC(=O)N(C)C
Product: COc1ccc2nc(COc3ccc(CC4SC(=O)NC4=O)cc3)n(C)c2c1
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 48 %

Procedure:
To a solution of 2-{4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenoxy}-N-(5-methoxy-2-nitrophenyl)-N-methylacetamide (444.7 mg) in a mixed solvent of methanol (20 ml) and dimethylacetamide (5 ml) were added successively concentrated hydrochloric acid (0.344 ml) and a 10% wet palladium-carbon catalyst (244 mg). The atmosphere in the reaction flask was replaced with hydrogen gas (5 kg/cm2), and the resulting mixture was shaken at 50° C. for 3.5 hours. After shaking, the reaction mixture was cooled to room temperature and filtered to obtain a pale yellow filtrate. When the filtrate obtained was concentrated to about 5 g, the product crystallized out of solution. The crystals precipitated were collected by filtration and washed with methanol to afford the title compound (210 mg, yield: 48%) as a white crystalline solid.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([CH:13]=[O:14])[CH2:12][CH:7]2[CH2:6]1)=[O:4].O.O.P([O-])(O)(O)=[O:26].[Na+].Cl([O-])=O.[Na+].CC(=CC)C>O1CCCC1.O>[CH2:15]([C:11]1([C:13]([OH:26])=[O:14])[CH2:12][CH:7]2[CH2:6][N:5]([C:3](=[O:4])[N:2]([CH3:1])[CH3:22])[CH2:9][CH:8]2[CH2:10]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CN(C)C(=O)N1CC2CC(C=O)(Cc3ccccc3)CC2C1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)N1CC2CC(Cc3ccccc3)(C(=O)O)CC2C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
5-Benzyl-5-formyl-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 14b (0.729 g, 2.43 mmol) was dissolved in the solvent mixture of 28 mL of tetrahydrofuran and 14 mL of water under nitrogen atmosphere, followed by addition of sodium dihydrogenphosphate dihydrate (1.14 g, 7.29 mmol), sodium chlorite (0.66 g, 7.29 mmol) and 2-methyl-2-butene (0.513 g, 7.32 mmol) upon cooling to 0° C. The reaction mixture was stirred at 0° C. for 2 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 5-benzyl-2-dimethylcarbamoyl-octahydro-cyclopenta[c]pyrrole-5-carboxylic acid 14c (0.76 g, yield 98%) as a colorless oil.
Reaction SMILES: C(OC([N:7]1[C@:11]2([C@@H:16]([F:17])[CH2:15][C@@H:14]3[C@H:12]2[C@H:13]3[C:18]([OH:20])=[O:19])[C:10](=[O:21])[O:9]C1)=O)C=C.[C:22](=[O:36])([O:27][CH:28]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[O:23][CH:24](Cl)[CH3:25]>>[NH2:7][C@@:11]1([C:10]([OH:9])=[O:21])[C@@H:16]([F:17])[CH2:15][C@@H:14]2[C@H:12]1[C@H:13]2[C:18]([O:20][CH:24]([O:23][C:22]([O:27][CH:28]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:36])[CH3:25])=[O:19]
Reactant: CC(Cl)OC(=O)OC1CCCCCCC1
Reactant: C=CCOC(=O)N1COC(=O)[C@]12[C@H]1[C@@H](C[C@@H]2F)[C@@H]1C(=O)O
Product: CC(OC(=O)OC1CCCCCCC1)OC(=O)[C@H]1[C@@H]2C[C@H](F)[C@@](N)(C(=O)O)[C@@H]21
Yield: 18.2 %

Procedure:
(1S,2S,3S,5R,6S)-3′-((Allyloxy)carbonyl)-3-fluoro-5′-oxospiro[bicyclo[3.1.0]hexan-2,4′-oxazolidine]-6-carboxylic acid (A-1-2, 380 mg) and 1-chloroethyl cyclooctyl carbonate (A-11-1, 745 mg) were treated in the same manner as in Example A-1 (3) and (4) to give the title compound (A-11, 93 mg) as a colorless solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Br:8][CH:9]([CH3:15])[CH2:10][CH2:11][C:12](Cl)=[O:13].O>C(#N)C>[Br:8][CH:9]([CH3:15])[CH2:10][CH2:11][C:12]([N:5]1[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]1)=[O:13]
Reactant: CC(Br)CCC(=O)Cl
Reactant: CC1CCNCC1
Solvent: O
Solvent: CC#N
Product: CC(Br)CCC(=O)N1CCC(C)CC1
Reaction time: 2 h
Yield: 74.7 %

Procedure:
1.09 g of 4-methylpiperidine was dissolved in 10 ml of acetonitrile and added dropwise with 1.09 g of 4-bromovaleroyl chloride. The reaction mixture was stirred for 2 hours, then poured into water and extracted with ethyl acetate. The organic layer was washed with wafer and dried over sodium sulfate, and then the solvent was evaporated under reduced pressure to obtain 1.07 g of the title compound (yield: 82%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:16]1[S:17][CH:18]=[C:19]2[O:24][CH2:23][CH2:22][O:21][C:20]=12)CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:22]1[CH2:23][O:24][C:19]2[C:20](=[C:16]([C:2]3[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=3)[S:17][CH:18]=2)[O:21]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1scc2c1OCCO2
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(-c2scc3c2OCCO3)cc1
Reaction time: 0.33 h
Yield: 68 %

Procedure:
To a refluxing solution of 1-bromo-4-nitrobenzene (2.762 g, 13.67 mmol) in toluene (250 mL) was added tetrakis(triphenylphosphine)palladium(0) (75 mg). After 20 min, 2-(tributylstannyl) 3,4-(ethylenedioxy)thiophene (6.05 g, 14.03 mmol) was added via a syringe. After complete addition, the mixture was refluxed for a total of 20 h. After cooling, the mixture was filtered and the solvent was evaporated to afford a solid. Filtration using hot hexane gave 1-(3,4-ethylenedioxythien-2-yl)-4-nitrobenzene, 2.46 g, yield=68%, mp=184-186° C. IR (KBr; in cm-1) 3066, 2946, 1592, 1506, 1477, 1338, 1066 and 851. 1H NMR (CDCl3 ; δ in ppm): 4.285 (m, 2H), 4.376 (m, 2H), 6.468 (s, 1H), 7.852 (d, J=9.9 Hz, 2H) and 8.197 (d, J=9.9 Hz, 2H). 13C NMR (CDCl3 ; δ in ppm): 64.25, 64.94, 100.93, 115.10, 124.03, 125.61, 139.72, 140.53, 142.43 and 145.37. MS(EI) m/z (rel int): 263 [(M)+, 27%], 233 [(M+ --NO), 8%] and 166[(M+ --C5H5O2), 9%]. Anal. Calcd for C12H9NO4S: C, 54.75; H, 3.45;, N, 5.32; S, 12.18. Found: C, 55.04; H, 2.99; N, 4.05; S, 11.57.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:35][CH:36]([CH3:39])[CH2:37][OH:38]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:35][CH:36]([CH3:39])[CH2:37][OH:38])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CC(N)CO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O
Product: CC(CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-(2-oxo-1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-amino-1-propanol using methods similar to Example 563 to provide a white solid: 1H NMR (CDCl3) δ 10.28 (1H, d, J=7 Hz), 8.55 (1H, s), 8.28 (1H, s), 7.25 (2H, dd, J=6, 8 Hz), 6.99 (2H, t, J=8 Hz), 4.38 (2H, t, J=8 Hz), 4.25-4.34 (1H, m), 4.16 (2H, s), 3.80 (1H, dd, J=4, 11 Hz), 3.68 (1H, dd, J=6, 11 Hz), 3.53 (2H, t, J=7 Hz), 3.37 (2H, b), 2.36 (2H, b), 1.76 (4H, b), 1.33 (3H, d, J=7 Hz); ES+ MS: 497 (M+H+).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([O:17]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:12][CH:11]([C:27]([O:29][CH3:30])=[O:28])[CH2:10]2)=[CH:5][CH:4]=1.[NH:33]1[CH2:38][CH2:37][CH:36]([C:39]#[N:40])[CH2:35][CH2:34]1>>[C:39]([CH:36]1[CH2:37][CH2:38][N:33]([C:15]([N:13]2[CH2:14][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:31])[F:32])=[CH:8][CH:7]=3)[CH2:10][CH:11]([C:27]([O:29][CH3:30])=[O:28])[CH2:12]2)=[O:17])[CH2:34][CH2:35]1)#[N:40]
Reactant: N#CC1CCNCC1
Reactant: COC(=O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Product: COC(=O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC(C#N)CC2)C1

Procedure:
4.00 g (8.84 mmol) of 3-methyl 1-(4-nitrophenyl) 5-[4-(trifluoromethyl)phenyl]piperidine-1,3-dicarboxylate (Example 58A) and 2.92 g (26.5 mmol) of piperidine-4-carbonitrile were reacted according to the General Method 8A. Yield: 3.15 g (77% of theory)
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([I:11])[C:3]=1[CH3:12].OS(O)(=O)=O.[CH3:18][CH2:19]O>>[CH2:18]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[C:3]([CH3:12])[C:4]=1[I:11])[CH3:19]
Reactant: Cc1c(Br)ccc(C(=O)O)c1I
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(Br)c(C)c1I

Procedure:
A mixture of 4-Bromo-2-iodo-3-methyl-benzoic acid (5.43 g, 0.016 mol) and conc.H2SO4 (5 mL) in EtOH (50 mL) is refluxed overnight. After reaction, evaporated out EtOH, extracted with ethyl acetate (3×50 mL), The combined organic phase is washed with water and brine, dried over Na2SO4, concentrated in vacuo, and purified by column chromatography on silica gel eluted with petrol ether and ethyl acetate to afford the desired compound. Yield: 5.2 g (88%)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([CH3:7])(=[O:6])=[O:5].Cl[C:9]1[N:14]=[C:13]([C:15]2[S:19][C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[N:17][C:16]=2[C:25]2[CH:26]=[C:27]([NH:31][S:32]([C:35]3[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=3[F:42])(=[O:34])=[O:33])[CH:28]=[CH:29][CH:30]=2)[CH:12]=[CH:11][N:10]=1>>[F:42][C:36]1[CH:37]=[CH:38][CH:39]=[C:40]([F:41])[C:35]=1[S:32]([NH:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([C:16]2[N:17]=[C:18]([N:20]3[CH2:21][CH2:22][CH2:23][CH2:24]3)[S:19][C:15]=2[C:13]2[CH:12]=[CH:11][N:10]=[C:9]([NH:1][CH2:2][CH2:3][S:4]([CH3:7])(=[O:6])=[O:5])[N:14]=2)[CH:26]=1)(=[O:34])=[O:33]
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCCC3)sc2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: CS(=O)(=O)CCN
Product: CS(=O)(=O)CCNc1nccc(-c2sc(N3CCCC3)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)n1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using 2-aminoethyl-methyl-sulfone (923 mg, 7.49 mmol) and N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-pyrrolidinyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide (400 mg, 0.749 mmol) the title compound was obtained as a white solid (27 mg, 4% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.87-11.12 (m, 1H) 7.75 (d, J=5.4 Hz, 1H) 7.55-7.72 (m, 1H) 7.24-7.38 (m, 1H) 7.10-7.25 (m, 4H) 7.08 (d, J=7.8 Hz, 1H) 5.57-5.85 (m, 1H) 3.54-3.70 (m, 2H) 3.29-3.43 (m, 7H) 2.88-3.05 (m, 4H) 1.86-2.04 (m, 3H). MS (ESI): 621.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[NH:4][N:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+].[H][H]>[Pd].C(Cl)Cl.O>[O:8]([C:7]1[CH:6]=[N:5][NH:4][C:3](=[O:15])[CH:2]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: [H][H]
Reactant: O=c1[nH]ncc(Oc2ccccc2)c1Cl
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=c1cc(Oc2ccccc2)cn[nH]1
Reaction time: 24 h
Yield: 96.9 %

Procedure:
A pressure vial containing a mixture of 4-chloro-5-phenoxy-2H-pyridazin-3-one (1.76 g, 7.90 mmol), water (29.6 mL), and a 2N aqueous sodium hydroxide solution (4.26 mL) was treated with 10% palladium on carbon (174 mg, 10% weight of 4-chloro-5-phenoxy-2H-pyridazin-3-one). The reaction was then pressurized with hydrogen (50 psi), where it shook for 24 h. The resulting reaction mixture was diluted with methylene chloride (100 mL) and water (100 mL), filtered through a pad of diatomaceous earth, and rinsed. The layers were separated, and the organics were concentrated in vacuo. The aqueous layer was then acidified to pH 1-2 with a 2N aqueous hydrochloric acid solution. The resulting mixture was extracted with 90/10 methylene chloride/methanol (3×100 mL). These organics were combined, dried over sodium sulfate, filtered, rinsed, and concentrated in vacuo to afford 5-phenoxy-2H-pyridazin-3-one (1.44 g, 96%) as a white solid; ES+-HRMS m/e calcd for C10H8N2O2 [M+H+] 189.0659, found 189.0658.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]([CH2:17][C:18]([N:20]([CH:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1)[CH3:21])=[O:19])[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[CH3:16])[NH:12][N:11]=[CH:10]2)[CH3:2].FC(F)(F)S(O[CH2:38][CH:39]([F:41])[F:40])(=O)=O>>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[CH3:16])[N:12]([CH2:38][CH:39]([F:41])[F:40])[N:11]=[CH:10]2)[CH2:17][C:18]([N:20]([CH:22]1[CH2:23][C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:30]1)[CH3:21])=[O:19])[CH3:2]
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: CCOC(=O)CN(CC(=O)N(C)C1Cc2ccccc2C1)c1cc2cn[nH]c2cc1C
Product: CCOC(=O)CN(CC(=O)N(C)C1Cc2ccccc2C1)c1cc2cnn(CC(F)F)c2cc1C
Yield: 67.9 %

Procedure:
Using the compound (954 mg, 2.27 mmol) of step A and 2,2-difluoroethyl trifluoromethanesulfonate (607 mg, 3.12 mmol), and according to the method of Example 241, step C, the title compound (747 mg, yield 68%) was obtained as a colorless oil.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=[CH:17][C:4]=2[CH2:3]1.[N:22]1([CH2:28][CH2:29][N:30]2[CH2:34][CH2:33][O:32][C:31]2=[O:35])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.[OH-].[Na+]>>[F:13][C:10]1[CH:11]=[CH:12][C:7]2[S:6][C:5]3[CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=[CH:17][C:4]=3[CH2:3][CH:2]([N:25]3[CH2:26][CH2:27][N:22]([CH2:28][CH2:29][N:30]4[CH2:34][CH2:33][O:32][C:31]4=[O:35])[CH2:23][CH2:24]3)[C:8]=2[CH:9]=1
Reactant: Fc1ccc2c(c1)C(Cl)Cc1ccc(C(F)(F)F)cc1S2
Reactant: O=C1OCCN1CCN1CCNCC1
Agent: [Na+]
Agent: [OH-]
Product: O=C1OCCN1CCN1CCN(C2Cc3ccc(C(F)(F)F)cc3Sc3ccc(F)cc32)CC1

Procedure:
11.6 G. of 10-chloro-8-fluoro-10,11-dihydro-3-trifluoromethyl-dibenzo[b,f]thiepin are treated with 27.8 g. of 3-[2-(1-piperazinyl)-ethyl]-2-oxazolidinone and stirred at 115°-120°C. for 10 minutes. The mixture is cooled and treated with 2N sodium hydroxide. The product separating as an oil is extracted with ether. The organic solution is washed to neutrality with water and shaken out with a dilute, aqueous methanesulfonic acid solution. The aqeuous solution is made alkaline with sodium hydroxide and extracted with ether. The ether solution is washed with water, dried over magnesium sulfate and concentrated, whereby there is obtained 3-{2-[4-(8-fluoro-10,11-dihydro-3-trifluoromethyl-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl}-2-oxazolidinone as a yellow oil which is converted into the dimethanesulfonate (melting point 149°-151°C.) by the addition of methanesulfonic acid.
Reaction SMILES: C(Cl)Cl.Cl.[CH3:5][C:6]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16](=[N:20][O:21][CH3:22])[C:17]([NH2:19])=[O:18]>O>[CH3:5][C:6]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1/[C:16](=[N:20]\[O:21][CH3:22])/[C:17]([NH2:19])=[O:18]
Reactant: CON=C(C(N)=O)c1ccccc1COc1cc(C)ccc1C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CO/N=C(/C(N)=O)c1ccccc1COc1cc(C)ccc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.6 %

Procedure:
Methylene chloride (60 ml) and conc. hydrochloric acid (20 ml) were added to 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxyiminoacetamide (Z=at least 98%) (6.25 g, 0.02 mol), and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, water (150 ml) was added. The mixture was extracted with methylene chloride (100 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give crystals. The crystals were recrystallized from n-hexane/ethyl acetate to give (E)-2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxyiminoacetamide (5.41 g, Yield: 86.7%) as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([NH2:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[C:19]([NH:22][C:23]1[CH:24]=[C:25]2[C:30](=O)[O:29][C:27](=[O:28])[C:26]2=[CH:32][CH:33]=1)(=[O:21])[CH3:20]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:18]2[C:30](=[O:29])[C:25]3[C:26](=[CH:32][CH:33]=[C:23]([NH:22][C:19](=[O:21])[CH3:20])[CH:24]=3)[C:27]2=[O:28])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CC(=O)Nc1ccc2c(c1)C(=O)OC2=O
Reactant: CCOc1cc(C(N)CS(C)(=O)=O)ccc1OC
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3ccc(NC(C)=O)cc3C2=O)ccc1OC

Procedure:
2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-5-acetamidoisoindoline-1,3-dione was prepared by the procedure of Example 6 from 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine (1.0 g, 3.7 mmol) and 4-acetamidophthalic anhydride (751 mg, 3.66 mmol). The product was obtained as a yellow solid (330 mg, 20% yield): mp, 215.0-217.0° C.; 1H NMR (DMSO-d6) δ 1.32 (t, J=6.9 Hz, 3H, CH3), 2.12 (s, 3H, CH3), 2.99 (s, 3H, CH3), 3.73 (s, 3H, CH3), 4.00 (q, J=7.0 Hz, 2H, CH2), 4.12 (dd, J=4.5, 14.3 Hz, 1H, CHH), 4.35 (dd, J=10.5, 14.2 Hz, 1H, CHH), 5.76 (dd, J=4.5, 10.5 Hz, 1H, NCH), 6.90-6.98 (m, 2H, Ar), 7.08 (br s, 1H, Ar), 7.83-7.84 (m, 2H, Ar), 8.19 (br s, 1H, Ar), 10.95 (br s, 1H, NH); 13C NMR (DMSO-d6) δ 14.66, 24.22, 41.05, 47.35, 53.07, 55.47, 63.80, 111.74, 112.28, 112.72, 123.34, 124.59, 124.66, 129.74, 132.68, 145.00, 147.85, 148.84, 167.00, 167.28, 169.36; Anal Calcd for C22H24NO7S: C, 57.38; H, 5.25; N, 6.08. Found: C, 57.13; H, 5.18; N, 5.74.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.CC(C)([O-])C.[K+].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([O:30][C:31]2[CH:36]=[C:35](Cl)[N:34]=[CH:33][N:32]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>O1CCOCC1>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([O:30][C:31]2[CH:36]=[C:35]([N:7]3[C:8]4[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=4)[CH2:5][CH2:6]3)[N:34]=[CH:33][N:32]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: Brc1ccc2c(c1)CCN2
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(Cl)ncn2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCc4cc(Br)ccc43)ncn2)CC1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
5-Bromoindoline (60 mg, 0.3 mmol) and potassium tert-butoxide (0.1 g, 3 eq) were stirred for 5 minutes in dioxane (1 mL). 3a (0.1 g, 1.05 eq) was added and the mixture was stirred at 80° C. for 72 h. The solvent was removed under vacuum and the residue was dissolved in THF and purified by preparative HPLC to give 3b.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[CH3:16].CN([CH:20]=[O:21])C>[OH-].[Na+]>[F:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9]([CH:20]=[O:21])=[CH:10][N:11]2[CH3:16]
Reactant: Cn1ccc2c(F)cccc21
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1cc(C=O)c2c(F)cccc21
Temperature: 0 °C
Yield: 55 %

Procedure:
Under stirring at 0° C., phosphoryl chloride (2.07 ml, 22.1 mmol) was added dropwise to DMF (30 ml). After completion of the dropwise addition, a solution of 4-fluoro-1-methylindole (2.20 g, 14.7 mmol) in DMF (15 ml) was added dropwise and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was poured in 1N NaOH (120 ml), followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane-ethyl acetate (1:1, v/v) eluate fractions, 4-fluoro-1-methylindole-3-carbaldehyde (1.43 g, 55%) was obtained as a red solid.