Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([OH:14])=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:50]([N:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51]>C(Cl)(Cl)Cl.CN(C=O)C>[CH2:53]([O:52][C:50]([N:60]1[CH2:65][CH2:64][N:63]([C:12]([CH:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:16][CH2:15]2)=[O:14])[CH2:62][CH2:61]1)=[O:51])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCN(C(=O)OCc3ccccc3)CC2)CC1
Yield: 71.4 %

Procedure:
General procedure A was followed using N-Boc-isonipecotic acid (0.25 g, 1.1 mmol), HATU (0.46 g, 1.2 mmol), DIPEA (0.57 mL, 3.3 mmol), 1-Cbz-piperazine (0.21 mL, 1.1 mmol) and DMF (5 mL) to furnish the intermediate compound benzyl-4-(1-(tert-butoxycarbonyl)piperidine-4-carbonyl)piperazine-1-carboxylate as a white solid (339 mg, 72%), umax (CHCl3)/cm−1 3014, 2863, 1688, 1644, 1427, 1367, 1205, 1168.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:8][CH:7]=1)=[O:5])C.[Li+].[OH-].O.C1COCC1>C(OCC)(=O)C>[N:16]1([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCOC(=O)c1ccc(N2CCCC2)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(N2CCCC2)c2ccccc12
Yield: 67.8 %

Procedure:
154BG19 (30 mg, 0.11 mmol) was transferred to a Pyrex tube and LiOH×H2O (14 mg, 0.33 mmol) was added, followed by H2O (0.18 mL) and THF (0.37 mL). The tube was capped and the reaction tube was exposed to microwave irradiation (160° C., 5 min). The reaction mixture was transferred to a separation funnel with ethyl acetate and washed with 2 M NaOH. The aqueous phase was acidified with 2 M HCl and extracted with ethyl acetate. The organic phases were collected, dried over Na2SO4, filtered and concentrated to yield 18 mg (68%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:28][C:29]([Cl:34])([Cl:33])[C:30](Cl)=[O:31]>>[Cl:28][C:29]([Cl:34])([Cl:33])[C:30]([NH:21][C@@H:19]([CH3:20])[C@H:18]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[N:9]=[CH:10]2)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:31]
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Product: C[C@H](NC(=O)C(Cl)(Cl)Cl)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
Prepared as described in Example 1 using (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (1a, 18 mg, 50 μmol) and trichloroacetyl chloride (27 mg, 150 μmol). Yield 21 mg (84%).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]3[S:11][C:10]([C:12]#[N:13])=[C:9]([O:14][CH2:15][C:16]([O:18]C)=[O:17])[C:7]=3[S:8][C:4]=2[CH:3]=1.[OH-].[K+].O>C1COCC1.CO>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]3[S:11][C:10]([C:12]#[N:13])=[C:9]([O:14][CH2:15][C:16]([OH:18])=[O:17])[C:7]=3[S:8][C:4]=2[CH:3]=1
Reactant: COC(=O)COc1c(C#N)sc2c1sc1cc(Cl)ccc12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: N#Cc1sc2c(sc3cc(Cl)ccc32)c1OCC(=O)O
Yield: 74.1 %

Procedure:
A solution of methyl [(6-chloro-2-cyanothieno[3,2-b][1]benzothien-3-yl)oxy]acetate (100 mg, 0.3 mmol) and potassium hydroxide (39 mg, 2 eq) in THF (2 mL), MeOH, (1 mL), and water (1 mL) was stirred at room temperature for 4h. The solvents were removed by evaporation, and the resulting oil was acidified with aq. hydrochloric acid, filtered, washed with water and dried in a vacuum oven overnight to provide [(6-chloro-2-cyanothieno[3,2-b][1]benzothien-3-yl)oxy]acetic acid (72 mg). This sample was further purified by reverse phase HPLC to provide 23 mg of the product.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C@H:7]2[C@H:12]([OH:13])[C@@H:11]([OH:14])[C@H:10]([OH:15])[C@@H:9]([CH2:16][OH:17])[O:8]2)=[CH:4][C:3]=1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1.[CH2:26](Br)[C:27]#[CH:28].C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O>[Cl:1][C:2]1[S:6][C:5]([C@H:7]2[C@H:12]([OH:13])[C@@H:11]([OH:14])[C@H:10]([OH:15])[C@@H:9]([CH2:16][OH:17])[O:8]2)=[CH:4][C:3]=1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:28][C:27]#[CH:26])=[CH:21][CH:20]=1
Reactant: OC[C@H]1O[C@@H](c2cc(Cc3ccc(O)cc3)c(Cl)s2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: C#CCOc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)sc2Cl)cc1
Temperature: 50 °C
Reaction time: 20 h
Yield: 37.5 %

Procedure:
To a solution of phenol 29 (124 mg, 0.320 mmol) in acetone (10 mL) were added propargyl bromide (80 wt % in toluene, 1.7 g, 11.2 mmol) and Cs2CO3 (1.5 g, 11.2 mmol) at room temperature. The mixture was stirred at 50° C. for 20 hours. The reaction mixture was cooled to room temperature and filtered off through celite. The filtrate was concentrated in vacuo. The residue was purified by prep HPLC (C18) to provide the title compound 30 (51 mg, 38%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1.[OH:19]O.[OH-].[Na+].Cl>C(O)C.O>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([NH2:12])=[O:19])[CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1
Reactant: OO
Reactant: N#Cc1ccc2c(c1)c(Br)nn2C1CCCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NC(=O)c1ccc2c(c1)c(Br)nn2C1CCCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution of 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (2.7 g, 8.82 mmol), in ethanol (20 mL), was added 20 mL of a 30% commercial solution of hydrogen peroxide and 2.8 mL of 6.0 N aqueous NaOH solution. The reaction mixture was stirred at room temperature. After 3 hours, the reaction mixture was acidified with 6.0 N HCl aqueous solution. Water was added to aid precipitation. The solid was collected by filtration and was washed with small portions of water. The solid was dried under vacuum (2.77 g, 97% yield): ES-MS (m/z) 325 [M+H]+.
Reaction SMILES: [Na].[O:2]=[S:3]1(=[O:17])[C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]([CH2:13][C:14]([O-])=[O:15])=[N:4]1.C([O:20][C:21]([C@H:23]1[C@@H:28]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[C@H:27]2[CH2:38][C@@H:24]1[CH2:25][CH2:26]2)=O)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[O:2]=[S:3]1(=[O:17])[C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]([C:13]2[C:14](=[O:15])[N:29]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[C@@H:28]3[C@H:23]([C:21]=2[OH:20])[C@@H:24]2[CH2:38][C@H:27]3[CH2:26][CH2:25]2)=[N:4]1
Reactant: O=C([O-])CC1=NS(=O)(=O)c2cnccc2N1
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1C(C2=NS(=O)(=O)c3cnccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.7 %

Procedure:
The crude sodium-(1,1-dioxo-1,4-dihydro-1λ6-pyrido[4,3-e][1,2,4]thiadiazin-3-yl)-acetate, (1S,2R,3S,4R)-3-(4-fluoro-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 61, 0.149 g, 0.51 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.194 g, 0.51 mmol) were combined and dissolved in anhydrous N,N-dimethylformamide (1 mL). The mixture was stirred at 25° C. for 1 h. Triethylamine (0.35 mL, 2.6 mmol) was added and the mixture was stirred at 50° C. for 16 h. Upon cooling, the mixture was diluted with ethyl acetate (100 mL), washed with saturated aqueous ammonium chloride solution (2×25 mL) and saturated aqueous brine solution (25 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm, 75% to 100% ethyl acetate in hexanes) followed trituration of the resulting oil with a 1:1 mixture of hexanes and diethyl ether (2 mL) afforded the desired product, (1R,2S,7R,8S)-5-(1,1-dioxo-1,4-dihydro-1λ6-pyrido[4,3-e][1,2,4]thiadiazin-3-yl)-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (0.0184 g, 0.039 mmol, 7.7% over two steps), as a pale yellow powder. LC-MS (ESI) calculated for C23H21FN4O4S 468.13, found 469.2 [M+H+]. 1H NMR (400 MHz, DMSO-d6) δ: 1.01-1.54 (6H, m), 2.35 (1H, d, J=3.7 Hz), 2.46 (1H, s), 2.53 (1H, s), 3.26 (1H, d, J=9.5 Hz), 4.23 (1H, d, J=15.8 Hz), 4.94 (1H, d, J=15.0 Hz), 7.08-7.13 (3H, m), 7.24-7.28 (2H, m), 8.44 (1H, d, J=4.8 Hz), 8.67 (1H, s).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=O)[CH2:7][C@@:8]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)[CH3:16])[CH2:10][CH2:9]1)(=O)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>C1COCC1>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([C@@H:15]([N:11]2[CH2:10][CH2:9][C@:8]([CH2:7][C:6]3[S:40][C:1]([CH3:2])=[N:4][N:5]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:13][C:12]2=[O:14])[CH3:16])=[CH:18][CH:19]=1
Reactant: CC(=O)NNC(=O)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: Cc1nnc(C[C@]2(c3ccccc3)CCN([C@@H](C)c3ccc(Br)cc3)C(=O)O2)s1
Yield: 20.2 %

Procedure:
To a solution of N′-acetyl-2-((S)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)acetohydrazide (50 mg, 0.105 mmol) in anhydrous THF (2 mL) was added Lawesson's Reagent (50 mg, 0.126 mmol) at rt. The mixture was heated to reflux for 3 h. The mixture was concentrated to give the crude product, which was purified by preparative TLC to give (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-((5-methyl-1,3,4-thiadiazol-2-yl)methyl)-6-phenyl-1,3-oxazinan-2-one (10 mg, 20%). 1H NMR (400 MHz, CDCl3): δ=1.39 (d, 3H), 2.02 (m, 1H), 2.22 (m, 1H), 2.39 (m, 1H), 2.69 (s, 3H), 2.81 (m, 1H), 3.58 (m, 1H), 5.52 (q, 1H), 6.66 (m, 2H), 7.16 (m, 2H), 7.21 (m, 2H), 7.32 (m, 3H).
Reaction SMILES: C(OC1N=NC(C#CC2C=CC=CC=2)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.[CH2:31]([O:38][C:39]1[N:40]=[N:41][C:42](Cl)=[CH:43][C:44]=1[O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[C:54]([C:56]1[CH:61]=[CH:60][C:59]([F:62])=[CH:58][C:57]=1[F:63])#[CH:55]>>[CH2:31]([O:38][C:39]1[N:40]=[N:41][C:42]([C:55]#[C:54][C:56]2[CH:61]=[CH:60][C:59]([F:62])=[CH:58][C:57]=2[F:63])=[CH:43][C:44]=1[O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Reactant: C#Cc1ccc(F)cc1F
Agent: C(#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1)c1ccccc1
Product: Fc1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c(F)c1

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-(phenylethynyl)pyridazine (Intermediate 2) from 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1) and 1-ethynyl-2,4-difluorobenzene.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=2[CH2:13][C:14]#[N:15])=[CH:6][CH:5]=1.[CH3:20][N:21]([CH2:25][CH2:26]Cl)[CH2:22][CH2:23]Cl.Cl>CS(C)=O>[C:14]([C:13]1([C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[S:10][C:7]2[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=2)[CH2:26][CH2:25][N:21]([CH3:20])[CH2:22][CH2:23]1)#[N:15]
Reactant: CN(CCCl)CCCl
Reactant: N#CCc1ccccc1Sc1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN1CCC(C#N)(c2ccccc2Sc2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
2.3 g of 99% sodium hydride are slowly added to a mixture, under nitrogen, of 4.3 g of 2-(4-fluorophenylthio)benzyl cyanide in 30 mls of dimethylsulfoxide. After total addition, the mixture is stirred for an additional five minutes and then a mixture of 3.9 g of 95% mechlorethamine hydrochloride in 20 ml of dimethylsulfoxide is added portionwise over a 40 minute span. After this addition, the reaction is stirred for one hour in a hot water bath at 70° C. and then permitted to stand at ambient temperature for 16 hours. The cooled reaction mixture is poured onto 150 ml of crushed ice and the diluted mixture is extracted thrice with 60 ml portions of ether. The combined ether extracts are successively washed with one 25 ml portion of a saturated sodium chloride solution and dried, providing 4-cyano-4-[2-(4-fluorophenylthio)phenyl]-1-methylpiperidine.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=C[C:8]([NH:12]S(C3C=CC(C)=CC=3)(=O)=O)=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH3:23]>>[NH2:23][C:8]1[CH:9]=[CH:10][C:11]2[C:6](=[CH:5][CH:4]=[N:3][CH:2]=2)[N:12]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc3c(Cl)nccc3c2)cc1
Reactant: N
Product: Nc1ccc2cnccc2n1
Yield: 89.73 %

Procedure:
2-Chloro-1,6-naphthyridine (0.628 g, Production Example 22b) and an aqueous ammonia (40 ml) were heated at 130° C. for 11 hours in a sealed tube. After cooling, the mixture was extracted with ethyl acetate, and the extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column, to give the title compound (0.497 g, 89.73%) as pale yellow crystals.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1
Reactant: COc1ccc(O)cc1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Temperature: 150 °C
Reaction time: 6 h
Yield: 1541.4 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (103 mg) and commercially available 4-methoxyphenol (286 mg) were mixed and stirred at 150° C. for 6 hours. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate and then partitioned between water and ethyl acetate, and the ethyl acetate layer was washed with brine and dried with anhydrous sodium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by column chromatography on silica gel eluting first with hexane/ethyl acetate and then with chloroform/ethyl acetate to obtain 2.21 g of the title compound (yield: 88%).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:72])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:52]=[C:53]4[C:57](=[CH:58][CH:59]=3)[NH:56][C:55]([CH:60]([O:62][Si](C(C)(C)C)(C)C)[CH3:61])=[CH:54]4)[CH:46]([O:70][CH3:71])[CH2:45]2)[CH:7]([CH3:73])[CH:6]([OH:74])[CH2:5][C:4]1=[O:75])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:72])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:52]=[C:53]4[C:57](=[CH:58][CH:59]=3)[NH:56][C:55]([CH:60]([OH:62])[CH3:61])=[CH:54]4)[CH:46]([O:70][CH3:71])[CH2:45]2)[CH:7]([CH3:73])[CH:6]([OH:74])[CH2:5][C:4]1=[O:75])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5[nH]c(C(C)O[Si](C)(C)C(C)(C)C)cc5c4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5[nH]c(C(C)O)cc5c4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Yield: 72.2 %

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(1-t-butyldimethylsilyloxyethylindol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (0.38 gm) in CH2Cl2 (10 ml) at room temperature was added a solution of paratoluene sulfonic acid (0.05 gm) in CH3OH (10 ml). The reaction mixture was stirred for 3 hours until TLC (silica, 2:1, hexanes:ethyl acetate) verified that reaction was complete. The reaction mixture was poured into saturated NaHCO3 and extracted twice with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography (silica, 2:1 hexanes:ethyl acetate) to provide the title compound 0.245 gm. MASS (FAB) M+Li 957. Partial 1H NMR (CDCl3, 200 MHz) δ:7.18 (d, J=10 Hz, 1H); 7.16 (bs, 1H); 7.06 (d, J=4 Hz, 1H); 6.86 (dd, J=3 Hz and 10 Hz, 1H); 6.33 (d, J=4 Hz, 1H); 4.13 (t, J=6.7 Hz, 2H); 3.83 (t, J=6.7 Hz, 2H); 3.43 (s, 3H).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].CS(C)=O.[Br:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>O>[Br:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:8]=[C:9]4[C:14](=[CH:15][CH:16]=3)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]4)[CH2:2][CH2:3]2)=[O:33])=[CH:30][CH:29]=1
Reactant: O=C1CCc2cc(N3CCNCC3)ccc2N1
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C1CCc2cc(N3CCN(C(=O)c4ccc(Br)cc4)CC3)ccc2N1
Yield: 17.2 %

Procedure:
6-(1-Piperazinyl)-3,4-dihydrocarbostyril (2.6 g) and 1 g of sodium hydrogencarbonate was added to 50 ml of dimethyl sulfoxide and the mixture was stirred with ice cooling while slowly adding dropwise 20 ml of dimethyl sulfoxide solution containing 3.2 g of 4-bromobenzoyl chloride. After completion of addition the reaction mixture was stirred at room temperature for 60 minutes. The reaction mixture was poured into a large amount of water and extracted with chloroform. The extract was washed with saturated sodium hydrogencarbonate solution and subsequently with water and dried over anhydrous sodium sulfate. Chloroform was distilled off and residual crystals were recrystallized from methanol-chloroform to give 0.8 g of 6-[4-(4-bromobenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 233°-234.5° C., colorless granules.
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:7])[CH2:4][CH2:5][Br:6].C(O[CH:12]1[NH:15][C:14](=[O:16])[CH2:13]1)(=O)C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC=CC=1>[Br:1][CH2:2][CH:3]([O:7][CH:12]1[NH:15][C:14](=[O:16])[CH2:13]1)[CH2:4][CH2:5][Br:6]
Reactant: OC(CBr)CCBr
Reactant: CC(=O)OC1CC(=O)N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C1CC(OC(CBr)CCBr)N1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A mixture of 1,4-dibromo-2-butanol (5.8 ml), 4-Acetoxyazetidinone (6.46 g), Palladium acetate (450 mg), Triethylamine (7 ml) and dry Benzene (75 ml) was stirred at room temperature under nitrogen for 23 hrs. Resulting solid was filtered off and filtrate was washed with water, brine and then dried over Magnesium sulfate. The residual oil, after evaporation, was purified by column chromatography using Hexane and Ethyl acetate (2:1) and the title compound was obtained. Yield: 5.88 g (78%). NMR (CDCl3): 2.05-2.17 (2H, m), 2.87-3.27 (2H, m), 3.42-3.60 (4H, m), 3.90-4.02 (1H, m), 5.23-5.33 (1H, m), 6.53 (1H, br, s). IR (Neat), cm-1 : 3260, 1771.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH2:25][CH2:26][CH2:27][OH:28])[CH:19]=3)[CH:15]=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)=O.[NH2:29][CH2:30][CH2:31][CH2:32][NH2:33]>C(OCC)(=O)C>[NH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:3]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH2:25][CH2:26][CH2:27][OH:28])[CH:19]=3)[CH:15]=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: NCCCN
Reactant: COC(=O)c1cccc(Nc2nccc(-c3ccnc(NCCCO)c3)n2)c1
Solvent: CCOC(C)=O
Product: NCCCNC(=O)c1cccc(Nc2nccc(-c3ccnc(NCCCO)c3)n2)c1

Procedure:
100 mg (0.26 mmol) of N-[3-methoxycarbonyl-phenyl]-4-[2-(3-hydroxy-propyl-amino)-4-pyridyl]-2-pyrimidineamine and 0.5 ml of 1,3-diamino-propane are stirred for 24 h at 90° and then diluted with 20 ml of ethyl acetate and extracted with 2×10 ml of sodium chloride solution. The organic phase is dried, concentrated and crystallised from methylene chloride/diethyl ether to give N-[3-{N-(3-amino-propyl)-aminocarbonyl}-phenyl]-4-[2-(3-hydroxy-propyl-amino)-4-pyridyl]-2-pyrimidineamine;
Reaction SMILES: [F:1][CH:2]([F:20])[CH2:3][NH:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[O:18][CH3:19].[F:21][C:22]([F:37])([F:36])[C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[N:31]=1)[C:26](O)=[O:27]>>[F:20][CH:2]([F:1])[CH2:3][N:4]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[O:18][CH3:19])[C:26](=[O:27])[C:25]1[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[N:31]=[C:23]([C:22]([F:37])([F:21])[F:36])[CH:24]=1
Reactant: COc1cc(F)ccc1-c1ccncc1NCC(F)F
Reactant: O=C(O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Product: COc1cc(F)ccc1-c1ccncc1N(CC(F)F)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from (2,2-difluoro-ethyl)-[4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]amine and 2,6-bis(trifluoromethyl)isonicotinic acid (Key Organics Ltd.) after a reaction time of 68 hours. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50). Light brown solid (57%). MS (ESI): m/z=524.10 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.O>O1CCCC1>[N:13]1([C:2]2[N:11]=[C:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: C1CCNC1
Solvent: C1CCOC1
Solvent: O
Product: c1ccc2c(N3CCCC3)nc(N3CCCC3)nc2c1

Procedure:
Ten grams of 2,4-dichloroquinazoline was added carefully to a solution of 25 ml of pyrrolidine in 200 ml of tetrahydrofuran. The resulting mixture was heated at reflux overnight and then was poured into a mixture of ice and water. The resulting mixture was extracted several times with ether. The ether extracts were combined and washed with water. The ether phase then was dried over anhydrous sodium sulfate. The solvent was removed by distillation and the residue was recrystallized from a 1:1 benzene:hexane mixture to give 10.1 g of 2,4-bispyrrolidinylquinazoline; m.p. 127°-129°. The following analytical data were obtained: