Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].CO.Cl[C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=3)[CH2:16][CH2:15]2)=[CH:12][CH:13]=1>O>[CH3:1][O:2][C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=3)[CH2:16][CH2:15]2)=[CH:12][CH:13]=1
Reactant: Cc1cccc(N2CCN(c3ccc(Cl)nn3)CC2)c1
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: O
Product: COc1ccc(N2CCN(c3cccc(C)c3)CC2)nn1
Yield: 50 %

Procedure:
To a stirred sodium methoxide solution, previously prepared starting from 1.6 parts of sodium in 24 parts of methanol, were added 4 parts of 3-chloro-6-[4-(3-methylphenyl)-1-piperazinyl]pyridazine. The whole was stirred and refluxed for 40 hours. After cooling, 25 parts of water were added. The product was filtered off, washed with water and dissolved in trichloromethane. The organic layer was dried, filtered and evaporated. The residue was crystallized from a mixture of 2-propanol and 2,2'-oxybispropane. The product was filtered off and dried, yielding 2 parts (50%) of 3-methoxy-6-[4-(3-methylphenyl)-1-piperazinyl]pyridazine; mp. 137.1° C. (compound 258).
Reaction SMILES: P(CCCC)(CCCC)CCCC.Br[C:15]1[S:16][CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=1.C([O-])([O-])=O.[K+].[K+].C(=O)([S:33][CH2:34][CH2:35][C@H:36]1[C@@H:40]([O:41][S:42]([CH3:45])(=[O:44])=[O:43])[CH2:39][C@@H:38]([O:46][CH:47]2[CH2:52][CH2:51][CH2:50][CH2:49][O:48]2)[C@@H:37]1[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])C>C(O)C.O>[CH3:45][S:42]([O:41][C@@H:40]1[C@H:36]([CH2:35][CH2:34][S:33][C:15]2[S:16][CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=2)[C@@H:37]([CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])[C@H:38]([O:46][CH:47]2[CH2:52][CH2:51][CH2:50][CH2:49][O:48]2)[CH2:39]1)(=[O:43])=[O:44]
Reactant: CCCCCCCC[C@@H]1[C@@H](CCSC(C)=O)[C@@H](OS(C)(=O)=O)C[C@H]1OC1CCCCO1
Reactant: CCOC(=O)c1csc(Br)n1
Agent: CCCCP(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCCCCCCC[C@@H]1[C@@H](CCSc2nc(C(=O)OCC)cs2)[C@@H](OS(C)(=O)=O)C[C@H]1OC1CCCCO1
Temperature: 40 °C
Reaction time: 8 h
Yield: 18.2 %

Procedure:
PBu3 (20 μL, 0.08 mmol), ethyl 2-bromothiazole-4-carboxylate (6-5, 119 mg, 0.50 mmol) and K2CO3 (107 mg, 0.77 mmol) were added to a solution of 6-3 (183 mg, 0.38 mmol) in 1.6 mL ethanol. The mixture was stirred at 40° C. overnight and then 20 mL H2O was added. The resulting mixture was extracted with ethyl acetate (30 mL) and the ethyl acetate solution was washed with brine (20 mL). The solution was then dried (Na2SO4), filtered, and evaporated. Purification of the residue by flash chromatography on silica gel (Combiflash unit by Isco) gave the title compound (41 mg, 18%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]2[N:15]=[N:16][NH:17][N:18]=2)[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-])=O>CO.[Pd]>[N:18]1[NH:17][N:16]=[N:15][C:14]=1[C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=1)[NH2:1]
Reactant: O=[N+]([O-])c1cc(-c2nn[nH]n2)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cc(-c2nn[nH]n2)cc(C(F)(F)F)c1
Temperature: 20 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
A mixture of 5-(3-nitro-5-(trifluoromethyl)phenyl)-2H-tetrazole (220 mg, 0.849 mmol) in MeOH (10 mL) was added Pd/C (45.2 mg, 0.424 mmol) under N2. The mixture was stirred at 20° C. under a H2 atmosphere for 1 h. LCMS showed the reaction was finished. The mixture was filtrated, and the filtrate was concentrated to give 3-(2H-tetrazol-5-yl)-5-(trifluoromethyl)aniline (200 mg, 0.781 mmol, 92% yield): 1H NMR (400 MHz, METHANOL-d4) δ 7.96 (s, 1H), 7.71 (s, 1H), 7.32 (s, 1H). ES-LCMS (m/z) 230 (M+H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([N:18]2[C:22]([CH3:23])=[N:21][N:20]=[C:19]2[CH2:24][N:25]2C(=O)C3=CC=CC=C3C2=O)=[C:7]([CH:17]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:16])=O.O.NN>C(O)C>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[N:18]3[C:22]([CH3:23])=[N:21][N:20]=[C:19]3[CH2:24][N:25]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])[C:7]=2[CH:17]=1
Reactant: CSc1ccc(-n2c(C)nnc2CN2C(=O)c3ccccc3C2=O)c(C(=O)c2ccccc2Cl)c1
Agent: NN
Solvent: O
Solvent: CCO
Product: CSc1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(C)n1-2

Procedure:
In the manner given in Example 5, 5-methylthio-2'-chloro-2-[3-(phthalimidomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone was heated in ethanol with hydrazine hydrate to give 8-methylthio-1-methyl-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][S:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:37][Si](CC)(CC)CC)([CH3:36])[CH3:35])[CH2:12][C@@H:11]([O:45][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[OH:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][S:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:37])([CH3:36])[CH3:35])[CH2:12][C@@H:11]([OH:45])[CH2:10]1
Reactant: CC[Si](CC)(CC)OC(C)(C)CCCCSCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(O)CCCCSCC1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 85.9 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-17-(5-triethylsilyloxy-5-methylhexylthiomethyl)androsta-5,7,16-triene (313 mg, 0.396 mmol) and a 1M tetra-n-butylammonium fluoride tetrahydrofuran solution (5 ml) were subjected to reaction using a procedure similar to that of Example 5(2) (3 hours), worked up and purified by column chromatography (ethyl acetate) to give the titled compound (152 mg, 86%) as a colorless solid.
Reaction SMILES: [CH2:1]([OH:24])[C@H:2]1[O:7][C@H:6]([O:8][CH2:9][C@@H:10]([OH:20])[C@@H:11]([OH:19])[C@H:12]([OH:18])[C@@H:13]([OH:17])[C:14](O)=[O:15])[C@H:5]([OH:21])[C@@H:4]([OH:22])[C@H:3]1[OH:23].[NH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][NH2:38]>>[CH2:37]([NH:38][C:14]([C@@H:13]([C@H:12]([C@@H:11]([C@@H:10]([CH2:9][O:8][C@H:6]1[O:7][C@H:2]([CH2:1][OH:24])[C@H:3]([OH:23])[C@H:4]([OH:22])[C@H:5]1[OH:21])[OH:20])[OH:19])[OH:18])[OH:17])=[O:15])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][NH:25][C:14]([C@@H:13]([C@H:12]([C@@H:11]([C@@H:10]([CH2:9][O:8][C@H:6]1[O:7][C@H:2]([CH2:1][OH:24])[C@H:3]([OH:23])[C@H:4]([OH:22])[C@H:5]1[OH:21])[OH:20])[OH:19])[OH:18])[OH:17])=[O:15]
Reactant: NCCCCCCCCCCCCN
Reactant: O=C(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO[C@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Product: O=C(NCCCCCCCCCCCCNC(=O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO[C@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO[C@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 75.1 %

Procedure:
3.96 g of potassium melibionate (Sigma Chemie) are reacted with 1.00 g of 1,12-diaminododecane analogously to Example 3 and 3.3 g of the title compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[CH:15][CH:16]=[CH:17]3)=[C:12]([O:19][CH3:20])[C:11]=2[CH3:21])=[O:9])=[CH:4][C:3]=1[O:22][CH3:23].[CH3:24][S:25](Cl)(=[O:27])=[O:26]>>[CH3:23][O:22][C:3]1[CH:4]=[C:5]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[CH:15][CH:16]=[CH:17]3)=[C:12]([O:19][CH3:20])[C:11]=2[CH3:21])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:1][S:25]([CH3:24])(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C(=O)c2c(C)c(OC)c3ccccn23)ccc1N
Product: COc1cc(C(=O)c2c(C)c(OC)c3ccccn23)ccc1NS(C)(=O)=O

Procedure:
Obtained according to the same procedure as the compound of Example 207, by sulphonylation of (4-amino-3-methoxyphenyl)(1-methoxy-2-methylindolizin-3-yl)methanone with methanesulphonyl chloride. The product is purified by chromatography on a silica column, eluting with a toluene/ethyl acetate (7:3) mixture. A yellow powder is obtained.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Cl:7][C:8]1[CH:29]=[CH:28][C:11]2[O:12][C:13]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:14]=3[CH:15]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH2:16][C:10]=2[CH:9]=1.[CH2:30](Br)[C:31]#[CH:32]>C(O)C>[Cl:7][C:8]1[CH:29]=[CH:28][C:11]2[O:12][C:13]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:14]=3[CH:15]([N:17]3[CH2:22][CH2:21][N:20]([CH2:32][C:31]#[CH:30])[CH2:19][CH2:18]3)[CH2:16][C:10]=2[CH:9]=1
Reactant: Clc1ccc2c(c1)CC(N1CCNCC1)c1cc(Cl)ccc1O2
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C#CCN1CCN(C2Cc3cc(Cl)ccc3Oc3ccc(Cl)cc32)CC1

Procedure:
2.87 G. of sodium carbonate are added to a solution of 7.6 g. of 1-[2,8-dichloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-piperazine in 76 ml. of ethanol. Then, a solution of 1.9 ml. of propargyl bromide in 15 ml. of ethanol is added dropwise with stirring. The mixture is stirred for 20 hours at room temperature and the solvent is then evaporated under reduced pressure. The residue is partitioned between water and chloroform. The phases are separated. The aqueous solution is extracted again with chloroform. The chloroform solutions are washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue is crystallized using diisopropyl ether, and there is obtained 1-[2,8-dichloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-4-(2-propynyl)-piperazine having a melting point of 105°-107° C. The dihydrochloride, prepared in ethanol, melts at 213°-215° C. (with decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([N+:10]([O-])=O)=[CH:5][N:4]=1>CO>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([NH2:10])=[CH:7][C:8]=1[CH3:9]
Reactant: COc1ncc([N+](=O)[O-])cc1C
Solvent: CO
Product: COc1ncc(N)cc1C
Reaction time: 0.17 h
Yield: 9.3 %

Procedure:
2-Methoxy-3-methyl-5-nitropyridine (1.63 g, 9.71 mmol) was dissolved in methanol (50 ml), 10% Pd-on-carbon powder (50% water content article) (800 mg) was added, and stirred under hydrogen atmosphere for 2 hours and 10 minutes. After the reaction was completed, celite filtration was carried out, the solvent was evaporated, thereby yielding the title compound (1.25 g, 0.90 mmol, 93%) as a blue oily substance.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][CH2:17][OH:18])[C:10]=1[CH:19]([O:25]C1CCCCO1)[C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.Cl>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][CH2:17][OH:18])[C:10]=1[CH:19]([OH:25])[C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1ccn(CCO)c(C(OC2CCCCO2)c2cccs2)c1OCc1ccccc1
Agent: Cl
Solvent: CO
Product: O=c1ccn(CCO)c(C(O)c2cccs2)c1OCc1ccccc1

Procedure:
3-Benzyloxy-1-(2-hydroxy-etbyl)-2-(hydroxy-thiophen-2-yl-methyl)-1H-pyridin-4-one: 1.88 g of 3-benzyloxy-1-(2-hydroxy-ethyl)-2-[(tetrahydro-pyran-2-yloxy)-thiophen-2-yl-methyl]-1H-pyridin-4-one are boiled under reflux for 90 minutes in 7 ml of methanol and 4.25 ml of 2N hydrochloric acid. For working-up, the methanol is removed using a rotary evaporator. The residue is diluted with 20 ml of water and covered with 20 ml of ethyl acetate. Then, with stirring, 10 ml of saturated sodium hydrogen carbonate solution are added. The resulting product is filtered off and washed with water and ethyl acetate. Drying yields 3-benzyloxy-1-(2-hydroxy-ethyl)-2-(hydroxy-thiophen-2-yl-methyl)-1H-pyridin-4-one in the form of colourless crystals. M.p.: 193.8°-196° C.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][O:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]4[CH:28]=[CH:27][C:26]([S:29][CH3:30])=[CH:25][CH:24]=4)=[N:21][CH:22]=3)[CH2:11][CH2:10]2)[O:6][N:5]=1)[CH3:3].[OH:31]O>FC(F)(F)C(O)C(F)(F)F.C(Cl)Cl>[CH3:3][CH:2]([C:4]1[N:8]=[C:7]([N:9]2[CH2:10][CH2:11][CH:12]([CH2:15][O:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]4[CH:24]=[CH:25][C:26]([S:29]([CH3:30])=[O:31])=[CH:27][CH:28]=4)=[N:21][CH:22]=3)[CH2:13][CH2:14]2)[O:6][N:5]=1)[CH3:1]
Reactant: CSc1ccc(-c2ccc(OCC3CCN(c4nc(C(C)C)no4)CC3)cn2)cc1
Reactant: OO
Solvent: OC(C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1noc(N2CCC(COc3ccc(-c4ccc(S(C)=O)cc4)nc3)CC2)n1
Temperature: 8 °C
Reaction time: 2.5 h
Yield: 0.1 %

Procedure:
A solution of 5-[({1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]-2-[4-(methylthio)phenyl]pyridine (93.7 g, 221 mol) in 1,1,1,3,3,3-hexafluoro-2-propanol (300 mL) at 5° C. was treated with 30% aqueous H2O2 (29 mL, 287 mol) over a 1.5 h period at such a rate to maintain temperature between approximately 6-10° C. The reaction was stirred at 5° C. for 2.5 h. The reaction was diluted with CH2Cl2 (600 mL), quenched by the addition of saturated aqueous Na2SO3 (400 mL), allowed to warm to room temperature and stirred for 30 min. The organic layer was washed with saturated aqueous Na2SO3 (400 mL×2), brine and was dried over MgSO4 and concentrated to give a tan solid. The solid was recrystallized from MeOH to provide the title compound (83.5 g, 86%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.37 (d, 1H, J=2.7 Hz), 8.07 (d, 2H, J=8.4 Hz), 7.74-7.64 (m, 3H), 7.27 (dd, 1H, Ja=8.7 Hz, Jb=2.8 Hz), 4.30-4.15 (m, 2H), 3.92 (d, 2H, J=6.2 Hz), 3.20-3.05 (m, 2H), 2.87 (septet, 1H, J=6.9 Hz), 2.74 (s, 3H), 2.19-2.01 (m, 1H), 2.00-1.90 (m, 2H), 1.55-1.40 (m, 2H), 1.27 (d, 6H, J=7.0 Hz); LRMS (ESI), m/z 441 (M+H).
Reaction SMILES: O1C(C2C=C(N[C:13]3[N:18]=[C:17]([C:19]4[C:20]([C:28]5[CH:29]=[C:30]([NH:34][C:35](=[O:42])[CH2:36][C:37]6[S:38][CH:39]=[CH:40][CH:41]=6)[CH:31]=[CH:32][CH:33]=5)=[N:21][N:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=45)[CH:16]=[CH:15][N:14]=3)C=CC=2)=CN=C1.[NH2:43][C:44]1[CH:53]=[C:52]2[C:47]([CH2:48][CH2:49][CH:50]([NH:54][C:55](=[O:60])[C:56]([F:59])([F:58])[F:57])[CH2:51]2)=[CH:46][CH:45]=1>>[F:59][C:56]([F:57])([F:58])[C:55]([NH:54][CH:50]1[CH2:49][CH2:48][C:47]2[C:52](=[CH:53][C:44]([NH:43][C:13]3[N:18]=[C:17]([C:19]4[C:20]([C:28]5[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][C:35](=[O:42])[CH2:36][C:37]6[S:38][CH:39]=[CH:40][CH:41]=6)[CH:29]=5)=[N:21][N:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=45)[CH:16]=[CH:15][N:14]=3)=[CH:45][CH:46]=2)[CH2:51]1)=[O:60]
Reactant: Nc1ccc2c(c1)CC(NC(=O)C(F)(F)F)CC2
Reactant: O=C(Cc1cccs1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(-c4cnco4)c3)n2)c1
Product: O=C(Cc1cccs1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CC(NC(=O)C(F)(F)F)CC4)n2)c1
Yield: 40.8 %

Procedure:
N-{3-[3-(2-Chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2-(2-thienyl)acetamide (99 mg, 0.22 mmol) (see Example 2, Step B) and N-(7-amino-1,2,3,4-tetrahydro-2-naphthalenyl)-2,2,2-trifluoroacetamide (69 mg, 0.26 mmol) following the protocol outlined in Example 54, Step C. Purification provided 60 mg (41%) of the coupled adduct as an oil. ES-LC/MS m/z=668 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:39].[CH3:40][N:41]([CH3:46])[CH2:42][CH2:43][NH:44][CH3:45]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:44]([CH2:43][CH2:42][N:41]([CH3:46])[CH3:40])[CH3:45])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:39]
Reactant: CNCCN(C)C
Reactant: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(S(C)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(N(C)CCN(C)C)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 24.6 %

Procedure:
To a solution of 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide (50 mg, 0.09 mmol) in DCM (10 mL) was added N,N,N′-trimethyl-1,2-ethanediamine (0.057 mL, 0.44 mmol). The resultant mixture was stirred at room temperature overnight. The mixture was concentrated under vacuo. Flash chromatography (90% CH2Cl2/7% MeOH/3% NH4OH) then provided the title compound (13 mg, 25%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[Br:1][C:2]1[C:10]([N+:12]([O-:14])=[O:13])=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cc(Br)ccc1Br
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(Br)cc([N+](=O)[O-])c1Br
Temperature: 100 °C
Reaction time: 5 h

Procedure:
The procedure described in R. K. Bentley and F. G. Holliman, J. Chem. Soc. (c), 2447 (1970) was used. A mixture of 2,5-dibromobenzoic acid (50 g, 0.18 mol) in concentrated sulfuric acid was vigorously stirred as fuming nitric acid (62.5 mL) was added dropwise at a rate to keep the temperature below 70° C. The reaction mixture was vigorously stirred, heated to 100° C. and then kept at 100° C. for 5 hours. The cooled reaction was cautiously poured into 2 liters of ice and vigorously stirred, the precipitate was filtered through a sintered glass funnel and the solid was washed well with water. Crystallization was achieved by dissolving the solid in acetic acid (150 mL) and after concentration to a half of the volume, crystals separated (16.72 g); mp 225°-229° C. An additional crop of 7.52 g was obtained to give a total yield of 24.24 g (41%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[C:13]#[C:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1
Reactant: COc1ccc2c(c1C#CCCN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Agent: [Pd]
Solvent: CCO
Product: COc1ccc2c(c1CCCCN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 102.5 %

Procedure:
A solution of tert-butyl 4-[4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)but-3-ynyl]piperazine-1-carboxylate (0.0883 g, 0.220 mmol) synthesized in Example B49, Step 2 in ethanol (6 mL) was added with 5% palladium/carbon (wetted with 50% water, 0.100 g), and the mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl 4-[4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)butyl]piperazine-1-carboxylate (0.0912 g, quantitative).
Reaction SMILES: [CH3:1][C:2]1[NH:8][C:7](=[O:9])[C:6]2[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:5]=2[O:4][CH:3]=1.[H-].[Na+].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>CN(C)C=O>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:8]1[C:7](=[O:9])[C:6]2[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:5]=2[O:4][CH:3]=[C:2]1[CH3:1]
Reactant: CC1=COc2ccc(C)cc2C(=O)N1
Reactant: BrCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1=COc2ccc(C)cc2C(=O)N1CCCCCBr
Reaction time: 0.5 h

Procedure:
346 mg of 4,5-dihydro-3,7-dimethyl-1,4-benzoxazepin-5-one was dissolved in 20 ml of dimethylformamide, then 88 mg (1.2 equivalents) of 60% sodium hydride was added. This was agitated for 30 minutes, then 1.68 g (4 equivalents) of 1,5-dibromopentane was added and the resultant mixture was agitated at room temperature for 4 hours.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[C:10]([S:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:9]=[C:8]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]=1[OH:23])([CH3:5])([CH3:4])[CH3:3].C(N(CC)C(C)C)(C)C.[CH3:33][O:34][C:35]([C:37]1[N:38]([CH3:46])[C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:40][CH:41]=1)=[O:36]>C1COCC1.C(OCC)(=O)C>[CH3:33][O:34][C:35]([C:37]1[N:38]([CH3:46])[C:39]([S:42]([N:16]2[CH2:17][CH2:18][CH:13]([S:12][C:10]3[CH:9]=[C:8]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]([OH:23])=[C:6]([C:2]([CH3:5])([CH3:4])[CH3:3])[CH:11]=3)[CH2:14][CH2:15]2)(=[O:44])=[O:43])=[CH:40][CH:41]=1)=[O:36]
Reactant: CC(C)(C)c1cc(SC2CCNCC2)cc(C(C)(C)C)c1O
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)n1C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(S(=O)(=O)N2CCC(Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)CC2)n1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.1 %

Procedure:
To a solution of 2,6-di-tert-butyl-4-(piperidin-4-ylsulfanyl)-phenol hydrochloride (Ex. 3c, 5.4 g) in 44 mL of THF at room temperature was added N,N-diisopropylethylamine (8.8 mL), followed by 5-chlorosulfonyl-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester (4 g). The mixture was stirred at room temperature for 18 h and then diluted with ethyl acetate and washed twice with 1 N HCl (aq), and once with brine. After concentration of the organic extracts, the crude solid was triturated with 15% ethyl acetate in hexanes to give 4.5 g of 5-[4-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-piperidine-1-sulfonyl]-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester as an off-white solid, mp 181-183° C. 1H-NMR (300 MHz, CDCl3): δ 7.23 (s, 2H), 7.17 (d, 1H, J=1.5 Hz), 7.09 (d, 1H, J=1.2 Hz), 5.30 (s, 1H), 3.96 (s, 3H), 3.83 (s, 3H), 3.60-3.54 (m, 2H), 2.80-2.74 (m, 1H), 2.54-2.45 (m, 2H), 2.03-1.97 (m, 2H), 1.73-1.67 (m, 2H), 1.41 (s, 18H).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[C:8]3[S:14][CH2:13][CH2:12][N:9]32)=[CH:4][C:3]=1[F:19].[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.Cl>N1C=CC=CC=1>[F:19][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[N:9]1[CH2:12][CH2:13][S:14][C:8]1=[C:7]([C:15]([OH:17])=[O:16])[C:6]2=[O:18]
Reactant: O=C(O)c1c2n(c3cc(Cl)c(F)cc3c1=O)CCS2
Reactant: C1CNCCN1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)c1c2n(c3cc(N4CCNCC4)c(F)cc3c1=O)CCS2

Procedure:
To one gram of 8-chloro-7-fluoro-5-oxo-1,2-dihydro-5H-thiazolo(3,2-a)quinoline-4-carboxylic acid (33 mmol) were added 2.87 grams (33 mmol) of anhydrous piperazine and 30 ml of pyridine and the resulting suspension was heated to reflux for twelve hours in an oil bath. Pyridine was evaporated therefrom under reduced pressure, water was added to the residue, and the mixture was again concentrated under reduced pressure. Water was added to the resulting residue, then 4 ml of 2 N aqueous solution of sodium hydroxide was added thereto, and the mixture was warmed to prepared uniform solution. Then this was adjusted to pH nearly seven with 1 N hydrochloric acid. Crystals separated out therefrom were collected by filtration, washed with water, washed with acetone and ether, and air dried to give the title product as powdery crystals. Yield 997.8 mg (90.7 percent). Melting point 287° to 288° C. (decomposition). Elementary analysis calculated as C16H16FN3O3S.3H2O: C 47.64, H 5.50, N 10.41; Found: C 47.60, H 5.42, N 10.63.