Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CCCCC1.C([N-]C(C)C)(C)C.[Li+].[C:15]([O:26][CH:27]([CH3:29])[CH3:28])(=[O:25])[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20].[CH:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl>O1CCCC1>[OH:37][CH:30]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH:18]([C:19]([O:21][CH:22]([CH3:23])[CH3:24])=[O:20])[CH2:17][CH2:16][C:15]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25]
Reactant: O=Cc1ccccc1
Reactant: CC(C)OC(=O)CCCC(=O)OC(C)C
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CC(C)OC(=O)CCC(C(=O)OC(C)C)C(O)c1ccccc1
Reaction time: 0.5 h
Yield: 51.8 %

Procedure:
38 ml of a 1.5M lithium diisopropylamide cyclohexane solution was dissolved in 400 ml of tetrahydrofuran, and 20 ml of a tetrahydrofuran solution containing 10.3 g of diisopropyl glutarate was dropwise added at -78° C. in a nitrogen atmosphere. After stirring at the same temperature for 30 minutes, 10 ml of a tetrahydrofuran solution containing 3.9 g of benzaldehyde was dropwise added thereto, followed by stirring at -78° C. for 1.5 hours. 2N hydrochloric acid was added to the reaction solution, and the temperature was brought to room temperature. Then, the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1→3/1) to obtain 6.14 g of the above-identified compound as a colorless oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[CH:17]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:32]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=2)=[O:33])=[C:18]([CH3:23])[CH:17]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: COc1cc2ncnc(Oc3ccc(N)c(C)c3)c2cc1OC
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(C)c3)c2cc1OC

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-methylaniline (50 mg) was dissolved in chloroform (3 ml), and p-fluorophenyl isocyanate (22 μl) was then added to the solution. The mixture was heated under reflux overnight. The precipitated crystal was collected by filtration and was washed to quantitatively give the title compound.
Reaction SMILES: Cl.[CH3:2][NH:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6].C([BH3-])#N.[Na+].[CH2:13]([CH:20]1[C:24]2[CH:25]=[C:26]([CH:29]=O)[CH:27]=[CH:28][C:23]=2[O:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CO>[CH2:13]([CH:20]1[C:24]2[CH:25]=[C:26]([CH2:29][NH:6][CH:5]([CH3:7])[C:4]([NH:3][CH3:2])=[O:8])[CH:27]=[CH:28][C:23]=2[O:22][CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=Cc1ccc2c(c1)C(Cc1ccccc1)CO2
Reactant: CNC(=O)[C@H](C)N
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CNC(=O)C(C)NCc1ccc2c(c1)C(Cc1ccccc1)CO2
Reaction time: 12 h
Yield: 49.7 %

Procedure:
To a solution of (S)-N-methyl-alaninamide hydrochloride (0.50 g, 3.6 mmol) in methanol (10 ml), in the presence of molecular sieves (1.00 g), sodium cyanoborohydride (0.44 g, 6.9 mmol) and a solution of 3-benzyl-2,3-dihydro-1-benzofuran-5-carbaldehyde (0.75 g, 3.6 mmol) in methanol (10 ml) were added at room temperature. The reaction mixture was kept under stirring and an argon atmosphere for 12 h. Then, the solvent was evaporated under vacuum and the residue was purified by flash chromatography on silica gel (ethyl acetate) affording 0.58 g of title compound (50% yield).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=O)[CH2:3]1.[CH3:7][C:8](O)([CH:10]=C)[CH3:9].CC([O-])C.CC([O-])C.CC([O-])C.[Al+3]>>[CH3:9][C:8](=[CH:7][CH2:4][CH2:3][C:2](=[O:6])[CH3:1])[CH3:10]
Reactant: C=C1CC(=O)O1
Reactant: C=CC(C)(C)O
Agent: CC(C)[O-]
Agent: [Al+3]
Product: CC(=O)CCC=C(C)C
Yield: 83 %

Procedure:
Apart from the improvements according to the present invention, this process has been disclosed by Teisseire et al. "Recherches," June 1956, page 31. The yield is only about 56%, which is entirely inadequate for industrial syntheses. If, instead of an alkyl acetoacetate, diketene is reacted with 2-methyl-3-buten-2-ol in the presence of aluminum triisopropylate, 2-methyl-2-hepten-6-one is obtained in a yield of 83% (cf. "Advances in Organic Chemistry," Volume II, 1960, page 246). It is to be deduced from the last-mentioned publication that for the manufacture of 2-methyl-2-hepten-6-one, diketene is to be preferred over an alkyl acetoacetate as the starting material. This is undoubtedly true on a laboratory scale, but unacceptable for the industrial manufacture of methylheptenone. For safety reasons alone, the instability of diketene demands the use of expensive apparatus. In addition, in order to achieve high yields and smooth operation of the plant, measures are required which substantially cancel out the advantage of the good yield. Further, German Pat. No. 1,068,696 discloses the preparation of 2-methyl-2-hepten-6-one by passing 2-methyl-3-buten-2-ol into a reaction mixture which has been preheated to 160°-250° C. and comprises an alkyl acetoacetate, a mixture of an alkyl acetoacetate and an inert solvent, or a mixture of 2-methyl-3-buten-2-ol, an alkyl acetoacetate and a solvent. However, this process also gives yields of only from 63 to 66% of theory, based on alkyl acetoacetate converted.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.[Li]CCCC.CN([CH:21]=[O:22])C.O>C1COCC1>[CH3:10][C:7]1([CH3:11])[C:6]2[CH:12]=[C:2]([CH:21]=[O:22])[CH:3]=[CH:4][C:5]=2[O:9][CH2:8]1
Reactant: CN(C)C=O
Reactant: CC1(C)COc2ccc(Br)cc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)COc2ccc(C=O)cc21
Temperature: -50 °C
Reaction time: 0.08 h
Yield: 106.6 %

Procedure:
To a solution of 5-bromo-3,3-dimethyl-2,3-dihydro-benzofuran (example 1f) (15.90 g, 70.01 mmol) in dry THF (100 mL) at −78° C., under argon, was added dropwise n-BuLi (1.6 M in hexane, 105 mmol, 42 mL). The mixture was stirred for 5 minutes then DMF (16.3 mL, 210 mmol) was added and the mixture was quickly warmed up to −50° C. and then to 0° C. for 3 hrs. Water was added slowly and the solution extracted with ethyl acetate. The organic layer was further washed with water, brine, dried (MgSO4), filtered and evaporated to give 13.15 g of 3,3-dimethyl-2,3-dihydro-benzofuran-5-carbaldehyde use as this in the next step. 1H NMR (300 MHz; CDCl3): 1.38 (s, 6H), 4.36 (s, 2H), 6.89 (d, J=7.8 Hz, 1H), 7.68 (m, 2H), 9.85 (s, 1H).
Reaction SMILES: [CH3:1][NH:2][S:3](/[CH:6]=[CH:7]/[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1)(=[O:5])=[O:4].Cl.[H][H]>[Pd].CN(C)C=O>[CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1)(=[O:4])=[O:5]
Reactant: [H][H]
Reactant: CNS(=O)(=O)/C=C/c1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Agent: [Pd]
Agent: Cl
Solvent: CN(C)C=O
Product: CNS(=O)(=O)CCc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 73.9 %

Procedure:
A solution of the product of stage (i) (5.78 g) in a mixture of ethanolic hydrogen chloride [prepared by adding acetyl chloride (1.71 g, 21.8 mmol) to IMS ethanol (400 ml) with stirring] and dimethylformamide (300 ml; added to the above to dissolve the starting material) was hydrogenated at room temperature and atmospheric pressure, using 10% palladium on carbon (5.00 g, 50% w/w with water) as the catalyst until uptake of hydrogen ceased. The mixture was filtered and the filtrate was evaporated to give a solid. The solid was partitioned between 2N sodium carbonate (60 ml) and ethyl acetate (200 ml) and the mixture was heated until the solid had dissolved. The phases were separated, the aqueous phase was extracted with ethyl acetate (200 ml) and the combined organic phases were washed with saturated brine (100 ml), dried (Na2SO4) and evaporated to give a gum. The gum was crystallised from ethyl acetate (60 ml) to give the title compound (4.30 g) as crystals, with m.p. 170°-171°
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[N:10]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH2:17](O)[CH3:18]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[N:10]=1)[C:5]([O:7][CH2:17][CH3:18])=[O:6]
Reactant: CCO
Reactant: COc1cc(C(=O)O)cc(Cl)n1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc(Cl)nc(OC)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a previously sonicated suspension of 2-chloro-6-methoxyisonicotinic acid (4.0 g, 21 mmol) in ethanol (50 mL) was added thionyl chloride (4.64 mL, 64.0 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 h and then at room temperature for 18 h. Thionyl chloride (4.64 mL, 64.0 mmol) was slowly added and the mixture was stirred at room temperature for 4 h. The reaction mixture was quenched by slowly pouring into a saturated aqueous solution of sodium bicarbonate (200 mL). Ice was added to the mixture to lower the temperature. The mixture was extracted with diethyl ether (150 mL×2). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford a clear syrup as crude product. The crude product was dried for 2 h under high vacuum while heating to 80° C. The resulting residue was concentrated from toluene (500 mL) to afford ethyl 2-chloro-6-methoxyisonicotinate as an off white solid (3.205 g). 1H NMR (400 MHz, CDCl3) δ 1.40 (s, 3H), 3.98 (s, 3H), 4.39 (s, 2H), 7.22 (s, 1H), 7.44 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1([CH3:15])[CH2:14][CH2:13][C:6]2([NH:10]C(=O)N[C:7]2=[O:12])[CH2:5][CH2:4]1.[OH-:16].[K+].[ClH:18]>>[ClH:18].[NH2:10][C:6]1([C:7]([OH:12])=[O:16])[CH2:5][CH2:4][C:3]([O:2][CH3:1])([CH3:15])[CH2:14][CH2:13]1
Reactant: [OH-]
Reactant: COC1(C)CCC2(CC1)NC(=O)NC2=O
Agent: Cl
Agent: [K+]
Product: COC1(C)CCC(N)(C(=O)O)CC1

Procedure:
169.5 g of the compound from Example 13A in 970 ml of 30% strength aqueous potassium hydroxide solution were heated under reflux for 20 hours. After cooling, the reaction mixture was adjusted to pH 2 by addition of 670 ml of concentrated aqueous hydrogen chloride solution, the precipitate was filtered off with suction and the filtrate was concentrated. This gave 110.7 g of a crude product as a mixture of diastereomers which still contains salts and was reacted without further purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1.O[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]([O:49][CH3:50])=[O:48])=[CH:43][CH:42]=1>C1COCC1>[N:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[O:32][CH2:40][C:41]1[CH:42]=[CH:43][C:44]([C:47]([O:49][CH3:50])=[O:48])=[CH:45][CH:46]=1
Reactant: Oc1ccccn1
Reactant: COC(=O)c1ccc(CO)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(COc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.3 %

Procedure:
Triphenyl phosphine (614 mg) and a THF solution (1 mL) of diethyl azodicarboxylate (408 mg) were added in that order to a THF solution (20 mL) of 2-hydroxypyridine (149 mg) and methyl 4-hydroxymethylbenzenecarboxylate (260 mg), and stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=9/1 to 2/3 to ethyl acetate alone) to obtain the entitled compound (85 mg).
Reaction SMILES: C(O)C.C(O)(=O)C.[Cl:8][C:9]1[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][N:30]([C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[CH2:29][CH2:28]2)[C:24]([N+:41]([O-])=O)=[CH:23][C:10]=1[C:11]([NH:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][C:18]1=[O:22])=[O:12]>[Fe]>[NH2:41][C:24]1[C:25]([N:27]2[CH2:28][CH2:29][N:30]([C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[CH2:31][CH2:32]2)=[CH:26][C:9]([Cl:8])=[C:10]([CH:23]=1)[C:11]([NH:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][C:18]1=[O:22])=[O:12]
Reactant: Cc1ccc(F)cc1N1CCN(c2cc(Cl)c(C(=O)NCCCN3CCCC3=O)cc2[N+](=O)[O-])CC1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc(F)cc1N1CCN(c2cc(Cl)c(C(=O)NCCCN3CCCC3=O)cc2N)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
In a 50 ml round bottom flask equipped with a magnetic stir bar and fitted with a septum and a nitrogen inlet, the iron powder (377 mg, 6.75 mmol) was suspended in clean, dry, reagent-grade ethanol (12 ml, 205.52 mmol) and allowed to stir at room temperature under nitrogen. To this was added the acetic acid (1.20 ml, 20.96 mmol) and the reaction was allowed to stir to ensure homogeneity. The 2-chloro-4-[4-(5-fluoro-2-methyl-phenyl)-piperazin-1-yl]-5-nitro-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-benzamide 16f (140.10 mg, 0.27 mmol) was added in one portion and the reaction was warmed to 75° C. and allowed to stir for 3 h. After 3 h, the reaction was cooled to room temperature and filtered through Celite, washing heavily with methanol. The collected organic solution was then concentrated under reduced pressure and the resultant red oil was taken up in 50 ml of ethyl acetate and was washed with 50 ml of saturated NaHCO3 (aq) solution. The product was then extracted from the aqueous using ethyl acetate (3×20 ml) and the organic phases were combined, washed with brine (1×50 ml) and dried over Na2SO4. The solution was then decanted, and the solvent was removed under reduced pressure. The product, 5-amino-2-chloro-4-[4-(5-fluoro-2-methyl-phenyl)-piperazin-1-yl]-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-benzamide 16g (130 mg, 0.27 mmol), was isolated as a brown solid and carried forward without further purification. LCMS (m/e)=488 (M+H).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:12][N:7]2[CH2:8][CH2:9][NH:10][CH2:11][C@@H:6]2[CH2:5][CH2:4]1.F[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22].C(=O)([O-])[O-].[Na+].[Na+].Cl>CS(C)=O>[OH:1][CH2:2][C@H:3]1[CH2:12][N:7]2[CH2:8][CH2:9][N:10]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[N+:21]([O-:23])=[O:22])[CH2:11][C@@H:6]2[CH2:5][CH2:4]1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: OC[C@@H]1CC[C@H]2CNCCN2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(F)ccc1N1CCN2C[C@H](CO)CC[C@H]2C1
Temperature: 25 °C
Yield: 77.6 %

Procedure:
A solution of 4.38 g (25.8 mmol) of (7R,9aS)-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (preparation 1), 4.19 mL (38.7 mmol) of 2,5-difluoronitrobenzene, and 5.46 g (51.5 mmol) of sodium carbonate in 25 mL of DMSO was heated at 95° C. for 16 h. The mixture was cooled to room temperature, acidified with 1M HCl, and washed with ethyl ether (3×). The aqueous layer was made basic with conc. ammonium hydroxide and extracted with ethyl acetate (3×). The combined organic layers were washed with water (3×), dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 90:10 chloroform: methanol gave 6.19 g (78%) of (7R,9aS)-7-hydroxymethyl-2-(4-fluoro-2-nitrophenyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:18])[NH:4][C:5](=[O:17])[N:6]([CH:16]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9].N1C=CN=C1.[C:24]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])([CH3:26])[CH3:25]>>[Si:28]([O:14][CH2:13][C@H:12]1[O:15][C@@H:7]([N:6]2[CH:16]=[C:2]([CH3:1])[C:3](=[O:18])[NH:4][C:5]2=[O:17])[C@H:8]([OH:9])[C@@H:10]1[OH:11])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]c1=O
Agent: c1c[nH]cn1
Product: Cc1cn([C@@H]2O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)[C@H]2O)c(=O)[nH]c1=O
Yield: 72.9 %

Procedure:
A solution of 5-methyluridine (1.42 g, 5.49 mmol), imidazole (0,816 g, 11.26 mmol) and tertbutyldimethylsilyl chloride (0.9 g, 6.01 mmol) was stirred at room temperature for 24 hours and then concentrated in vacuo. The residue obtained was purified by chromatography on a silica gel column using CHCl3 -methanol (30:1) as the eluent to give 1.49 g (73%) of 5'-O-tert-butyldimethylsilyl-5-methyluridine as a colorless solid: mp 209°-211° C. (ethyl acetate); 1H NMR (DMSO-d6) δ 0.0 (6H, s, (CH3)2Si), 0.81 (9H, s, (CH3)3CSi), 3.60-3.90 (5H, m, 2, 3, 4' and 5'-H), 4.97 (1H, d, J=4.39 Hz, 3'-OH, exchangeable), 5.25 (1H, d, J=5.57 Hz, 2'-OH, exchangeable), 5.71 (1H, d, J=5.57 Hz, 1'-H), 7.32 (1H, s, 6-H), 11.21 (1H, s, NH, exchangeable).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[CH:7][CH:8]=1.[OH-:10].[Cs+]>C(OCC)(=O)C.CCCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(Br)c1
Reactant: [OH-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1cccc(O)c1
Yield: 85 %

Procedure:
Following general operating mode B, 3-methoxybromobenzene (127 μL, 1.0 mmol) was reacted with cesium hydroxide to give the expected product in the form of an oil with a yield of 85% (eluent: ethyl acetate/heptane 10:90).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(Cl)Cl.C(OC([N:18]1[CH2:23][CH2:22][CH:21]([N:24]2[C:28]3[N:29]=[CH:30][N:31]=[C:32]([NH2:33])[C:27]=3[C:26]([C:34](=[O:53])[C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([NH:41][C:42]([NH:44][C:45]4[CH:50]=[C:49]([Cl:51])[CH:48]=[C:47]([Cl:52])[CH:46]=4)=[O:43])[CH:36]=3)=[CH:25]2)[CH2:20][CH2:19]1)=O)(C)(C)C>C(Cl)Cl>[NH2:33][C:32]1[C:27]2[C:26]([C:34]([C:35]3[CH:36]=[C:37]([NH:41][C:42]([NH:44][C:45]4[CH:50]=[C:49]([Cl:51])[CH:48]=[C:47]([Cl:52])[CH:46]=4)=[O:43])[CH:38]=[CH:39][CH:40]=3)=[O:53])=[CH:25][N:24]([CH:21]3[CH2:20][CH2:19][NH:18][CH2:23][CH2:22]3)[C:28]=2[N:29]=[CH:30][N:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(C(=O)c3cccc(NC(=O)Nc4cc(Cl)cc(Cl)c4)c3)c3c(N)ncnc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc2c1c(C(=O)c1cccc(NC(=O)Nc3cc(Cl)cc(Cl)c3)c1)cn2C1CCNCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.3 %

Procedure:
A solution of TFA/CH2Cl2 (0.49 mL/3.5 mL) was added to a solution of 4-(4-amino-5-{3-[3-(3,5-dichloro-phenyl)-ureido]-benzoyl}-pyrrolo[2,3-d]pyrimidin-7-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.2 g, 0.32 mmol) in CH2Cl2 (1 mL) at 0 C. The reaction mixture was warmed to room temperature, stirred for 12 h, and concentrated in vacuo. The crude reaction mixture was quenched with H2O (5 mL) and Na2CO3 (5 mL) and extracted with CH2Cl2 (4×5 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo to provide the title compound as a yellow solid (0.16 g, 93%). MS: 525.5 (MH+); HPLC Rf: 5.35 min. (HPLC method 4); HPLC purity: 84%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:13]2[C:17]([CH3:18])=[C:16]([C:19]([OH:21])=O)[C:15]([CH3:22])=[N:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N:23]1([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:13]2[C:17]([CH3:18])=[C:16]([C:19]([N:31]3[CH2:32][CH2:33][CH:28]([N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH2:29][CH2:30]3)=[O:21])[C:15]([CH3:22])=[N:14]2)[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: COc1cc(-n2nc(C)c(C(=O)O)c2C)cc(C(F)(F)F)c1
Product: COc1cc(-n2nc(C)c(C(=O)N3CCC(N4CCCC4)CC3)c2C)cc(C(F)(F)F)c1
Yield: 63 %

Procedure:
In analogy to the procedure described in Example 18], 1-(3-methoxy-5-trifluoromethyl-phenyl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid and 4-pyrrolidine-1-yl-piperidine gave, after purification on a flash isolute NH2-column (EtOAc), the title compound in 63% yield as light brown foam. MS: 451.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1.[Br:21]Br>C(Cl)(Cl)(Cl)Cl>[Br:21][CH:9]1[CH:8]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:6]2[CH:20]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[NH:11][C:10]1=[O:12]
Reactant: O=C1CC=C(c2ccccc2Cl)c2cc(Cl)ccc2N1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1Nc2ccc(Cl)cc2C(c2ccccc2Cl)=CC1Br
Yield: 65.3 %

Procedure:
A suspension of 0.78 g (2.56 mmole) of 7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1-benzazepin-2-one in 100 mL of carbon tetrachloride was heated to reflux, yielding a clear solution. Bromine (0.19 mL, 3.69 mmole) was added in one portion and the solution was, heated at reflux, under a sunlamp, for 15 minutes. Without cooling, the reaction solution was washed with 5% aqueous sodium thiosulfate and water, dried (sodium sulfate), and concentrated. The residue was triturated with ether. The solid was collected on a filter, washed with ether and dried yielding 0.64 g (65%) of the title compound. This crude material (shown by NMR to have a ratio of product to starting material of 85:15) was used as is in the next step.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:13]=[C:14]([N+:18]([O-])=O)[CH:15]=[CH:16][CH:17]=1>Cl.[Fe]>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[NH2:18]
Reactant: O=[N+]([O-])c1cccc(OCc2nc3ccccc3s2)c1
Agent: [Fe]
Agent: Cl
Product: Nc1cccc(OCc2nc3ccccc3s2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
To a suspension of 3-[(2-benzothiazolyl)methoxy]nitrobenzene (18.6 g) in ethanolic hydrochloric acid is added powdered iron. The reaction is stirred overnight at room temperature. After neutralization with saturated aqueous sodium bicarbonate, the mixture is extracted three times with methylene chloride. The extract is dried over magensium sulfate and concentrated to give 15.1 g (90% yield) of product, m.p. 117°-120° C.
Reaction SMILES: [OH:1][C:2]1([CH2:15][C:16]2([CH3:19])[CH2:18][CH2:17]2)[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:19][C:16]1([CH2:15][C:2]2([OH:1])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]2)[CH2:17][CH2:18]1
Reactant: CC1(CC2(O)CCN(C(=O)OC(C)(C)C)CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(CC2(O)CCNCC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound 12C (1 eq.) in DCM, was added TFA (10 eq.), the reaction mixture was stirred at room temperature for about 2 hours, when TLC detected no s.m. The reaction mixture was concentrated to afford the desired product 12D. The crude product was used for the next step directly without further purification. LC-MS: m/z 170.3 (M+H)+
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:30])[S:9][CH2:8][CH2:7][N:6]2[C:10]([C:13]3([C:16]4[CH:21]=[CH:20][C:19]([C:22]5[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][N:23]=5)=[CH:18][CH:17]=4)[CH2:15][CH2:14]3)=[N:11][N:12]=[C:5]2[CH2:4]1.CO.C(=O)([O-])[OH:34].[Na+]>Cl.O1CCOCC1>[OH:1][CH2:2][C:3]1([CH3:30])[S:9][CH2:8][CH2:7][N:6]2[C:10]([C:13]3([C:16]4[CH:21]=[CH:20][C:19]([C:22]5[CH:29]=[CH:28][C:25]([C:26]([NH2:27])=[O:34])=[CH:24][N:23]=5)=[CH:18][CH:17]=4)[CH2:15][CH2:14]3)=[N:11][N:12]=[C:5]2[CH2:4]1
Reactant: CC1(CO)Cc2nnc(C3(c4ccc(-c5ccc(C#N)cn5)cc4)CC3)n2CCS1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: CC1(CO)Cc2nnc(C3(c4ccc(-c5ccc(C(N)=O)cn5)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 38 %

Procedure:
A solution of the compound (9.14 g, 17.2 mmol) obtained in Example 60-5) in 2 N hydrochloric acid-1,4-dioxane (200 mL) was stirred at 50° C. for 2 h. The reaction mixture was cooled to room temperature, methanol (40 mL) was added to the reaction mixture, and insoluble substances were dissolved by sonication. Saturated aqueous sodium hydrogencarbonate (400 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane and purified by silica gel column chromatography (ethyl acetate:methanol=3:2) to obtain the title compound (2.74 g, 38%) as a white solid.