Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[Br:7][C:8]1[N:12]([C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:11]([CH:19]=[O:20])=[CH:10][CH:9]=1.CC(C)=[O:23].[OH-].[Na+]>O>[Br:7][C:8]1[N:12]([C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:11]([C:19]([OH:23])=[O:20])=[CH:10][CH:9]=1
Reactant: CC(C)=O
Reactant: O=Cc1ccc(Br)n1-c1ncccn1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(Br)n1-c1ncccn1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
A solution of 2.0 g of potassium permanganate in 10 ml of water was added dropwise to a mixture of 0.76 g of 5-bromo-1-(2-pyrimidinyl)-1H-pyrrole-2-carbaldehyde and 18 ml of acetone while the mixture was maintained at 40° C. The resulting mixture was stirred at 40° C. for 4 hours. A precipitate was filtered off to obtain a filtrate. The filtrate was adjusted to pH 10-12 by an addition of a 2N aqueous sodium hydroxide solution, and then washed with chloroform two times. The aqueous layer was adjusted to around pH 3 by an addition of 2N hydrochloric acid, and then extracted with ethyl acetate two times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 0.28 g of 5-bromo-1-(2-pyrimidinyl)-1H-pyrrole-2-carboxylic acid of the formula:
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([C:10]([O:12]C)=[O:11])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][C:17]([CH:20]3[CH2:22][CH2:21]3)=[CH:18][CH:19]=2)[C:3]=1[F:23].O.O.[OH-].[Li+]>C1COCC1.CO>[NH2:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([C:10]([OH:12])=[O:11])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][C:17]([CH:20]3[CH2:21][CH2:22]3)=[CH:18][CH:19]=2)[C:3]=1[F:23]
Reactant: COC(=O)c1nc(-c2ccc(C3CC3)nc2)c(F)c(N)c1OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1c(C(=O)O)nc(-c2ccc(C3CC3)nc2)c(F)c1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.4 %

Procedure:
To a solution of methyl 4-amino-6′-cyclopropyl-3-fluoro-5-methoxy-[2,3′-bipyridine]-6-carboxylate (100 mg, 0.315 mmol) in THF (1.00 mL), MeOH (1.000 mL), and Water (0.500 mL), lithium hydroxide hydrate (65 mg, 1.549 mmol) was added as a solid. The reaction was allowed to stir at room temperature for 18 hrs. The reaction solution was then concentrated under vacuum to dryness. The resulting solid was suspended in H2O and the pH was adjusted to 4.0, forming a ppt. The suspension was extracted with EtOAc (3×25 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under vacuum to yield 4-amino-6′-cyclopropyl-3-fluoro-5-methoxy-[2,3′-bipyridine]-6-carboxylic acid (50.0 mg, 0.165 mmol, 52.3% yield). ESIMS for m/z 304 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 0.92-1.06 (m, 4H), 2.17 (tt, J=7.8, 5.1 Hz, 1H), 3.78 (s, 3H), 6.49 (s, 2H), 7.42 (dd, J=8.3, 0.9 Hz, 1H), 8.05 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 8.81 (t, J=2.0 Hz, 1H), 13.03 (s, 1H). 19F NMR (376 MHz, DMSO-d6) δ −141.73.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([O:25][CH3:26])=[O:24])=[C:17]([CH:27]([F:29])[F:28])[CH:16]=3)=[C:11]([C:30]([F:33])([F:32])[F:31])[S:10][N:9]=2)=[CH:4][CH:3]=1.CO.[BH4-].[Na+]>[Ni](Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[C:17]([CH:27]([F:28])[F:29])[CH:16]=3)=[C:11]([C:30]([F:32])([F:31])[F:33])[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)/C=C/c1ccc(OCc2c(-c3ccc(Cl)cc3)nsc2C(F)(F)F)cc1C(F)F
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)CCc1ccc(OCc2c(-c3ccc(Cl)cc3)nsc2C(F)(F)F)cc1C(F)F
Yield: 54.4 %

Procedure:
(E)-Methyl 3-(4-((3-(4-chlorophenyl)-5-(trifluoromethyl)isothiazol-4-yl)methoxy)-2-(difluoromethyl)phenyl)acrylate (55 mg, 0.109 mmol) in a mixed solvent system (MeOH (2 mL); water (0.5 mL)) was treated with sodium borohydride (8.2 mg, 0.218 mmol) and nickel chloride (1.5 mg, 0.011 mmol) for 10 min. The solvent was removed and the residue was partitioned between ethyl acetate and saturated ammonium chloride. The organic layer was dried, filtered, and the filtrate was concentrated under reduced pressure. The resultant residue was concentrated and purified by prep-HPLC, eluting with 20-80% acetonitrile in water (0.5% TFA) to give compound 267d as a white solid (30 mg, 54% yield).
Reaction SMILES: [CH3:1][C@:2]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[C:14]=3[CH:15]=2)[CH2:6][CH2:5][CH2:4][NH:3]1.[CH3:20][O:21][C:22](=[O:25])[CH2:23]Br.CCN(C(C)C)C(C)C>CC#N.C(Cl)Cl>[CH3:20][O:21][C:22](=[O:25])[CH2:23][N:3]1[CH2:4][CH2:5][CH2:6][C@@:2]1([C:7]1[NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[C:14]=2[CH:15]=1)[CH3:1]
Reactant: COC(=O)CBr
Reactant: COC(=O)c1cccc2[nH]c([C@@]3(C)CCCN3)cc12
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN1CCC[C@]1(C)c1cc2c(C(=O)OC)cccc2[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 59.7 %

Procedure:
(R)-Methyl 2-(2-methylpyrrolidin-2-yl)-1H-indole-4-carboxylate (190 mg, 0.74 mmol) was dissolved in CH3CN (25 ml) and methylbromoacetate (250 mg, 1.6 mmol). DIPEA (350 mg, 2.7 mmol) was then added. The reaction mixture was stirred at room temperature for about 20 hours. The reaction mixture was then diluted with CH2Cl2 (15 ml) and washed with water three times. The organic layer was dried with MgSO4 and concentrated to give 146 mg of (R)-methyl 2-(1-(2-methoxy-2-oxoethyl)-2-methylpyrrolidin-2-yl)-1H-indole-4-carboxylate. 1H NMR (CDCl3-d) δ 7.85 (d, 1H, J=7.8 Hz), 7.13-7.29 (m, 3H), 4.92 (s, 2H), 3.95 (s, 3H), 3.70 (s, 3H), 3.56-3.62 (m, 2H), 1.95-2.06 (m, 4H), and 1.94 (s, 3H). MS (ESI) m/e [M+1]+ 331.0.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C@H:12]([OH:14])[CH3:13])[N:6]=[C:5]2[C:15]#[N:16].N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C@H:12]([O:14][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH3:13])[N:6]=[C:5]2[C:15]#[N:16]
Reactant: C[C@@H](O)Cn1nc(C#N)c2cc(N)ccc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C[C@H](Cn1nc(C#N)c2cc(N)ccc21)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
(R)-5-amino-1-(2-hydroxypropyl)-1H-indazole-3-carbonitrile (180 mg, 0.832 mmol) was taken up in DCM (6 mL) and imidazole (227 mg, 3.33 mmol) and DMAP (10.17 mg, 0.083 mmol) were added, followed by TBS-Cl (439 mg, 2.91 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was quenched with saturated NH4Cl solution and diluted with DCM. The organic layer was collected and washed with brine, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash column chromatography eluting with 0-40% EtOAc/Hex. (R)-5-amino-1-(2-((tert-butyldimethylsilyl)oxy)propyl)-1H-indazole-3-carbonitrile (230.5 mg) was obtained as an orange solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:14][CH2:13]1)[N:8]([C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=1[O:35][CH3:36])[CH:7]2[CH2:37][C:38]([O:40]C)=[O:39].[OH-].[Na+]>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[CH2:13][CH2:14][N:15]([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH2:16][CH2:17]1)[N:8]([C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:28]=[CH:27][C:26]=1[O:35][CH3:36])[CH:7]2[CH2:37][C:38]([OH:40])=[O:39]
Reactant: COC(=O)CC1c2cccc(F)c2N=C(N2CCN(c3ccc(F)cc3)CC2)N1c1cc(C(F)(F)F)ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(C(F)(F)F)cc1N1C(N2CCN(c3ccc(F)cc3)CC2)=Nc2c(F)cccc2C1CC(=O)O

Procedure:
In 800 ml of dioxane, 15 g (26.11 mmol) of methyl {8-fluoro-2-[4-(4-fluorophenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetate (Example 30A) and 3.13 g (78.32 mmol) of sodium hydroxide are stirred at 50° C. for 4 hours. Following distillative removal of the solvent, the residue is dissolved in 500 ml of water and acidified and the precipitate is filtered off with suction. The product is washed with water and dried under reduced pressure.
Reaction SMILES: CS(Cl)(=O)=O.C[CH:7](O)[C:8](=[O:30])[C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C:23](=[CH:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:28])[CH:19]=[CH:20]2)[CH2:15][CH2:14]3)[CH2:11][C@H:10]1[CH3:29].[ClH:32]>CC1C(CC)=NC=CC=1>[Cl:32][CH2:7][C:8](=[O:30])[C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C:23](=[CH:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:28])[CH:19]=[CH:20]2)[CH2:15][CH2:14]3)[CH2:11][C@H:10]1[CH3:29]
Reactant: CC(O)C(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@@]21C
Reactant: Cl
Agent: CCc1ncccc1C
Agent: CS(=O)(=O)Cl
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)CCl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
8.8 ml of methane sulphonyl chloride is added at 10° C. to a mixture, under an inert atmosphere, of 15 g of methyl 16α-methyl-21-hydroxy-pregna-1,4,9(11)-triene-3-20-dione in 40 ml of methyl ethyl pyridine, and the whole is agitated at ambient temperature for 5 hours. It is poured into an ice+water mixture, acidified by the addition of hydrochloric acid, filtration is carried out, followed by washing and drying. 16.2 g of expected crude product is obtained which is purified by chromatography, eluting with a benzene/ethyl acetate mixture 8/2. 13.4 g of expected pure product is obtained. M.P.=154° C.
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=1)[CH2:4][CH2:5][CH3:6]>>[CH2:3]([N:7]([C:3]1[O:1][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=1)[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([C:15]([F:18])([F:16])[F:17])[CH:9]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCNc1ccc(Cl)c(C(F)(F)F)c1
Reactant: [OH-]
Agent: [Na+]
Product: CCCCN(c1ccc(Cl)c(C(F)(F)F)c1)c1nc2ccccc2o1

Procedure:
Hydrolysis of this N-(n-butyl)benzanilide (33 g., 0.093 mole) was accomplished by adding it to a solution of sodium hydroxide (10.8 g., 0.372 mole) in 200 ml. of water and 100 ml. of ethanol. The resulting solution was heated under reflux for 20 hours. The ethanol was then removed by distillation under vacuum. The remaining basic solution was extracted with diethyl ether; the ether extract was dried over magnesium sulfate and filtered. The filtrate was evaporated to dryness by distillation under vacuum. The crude product obtained was purified by addition of 6 N hydrochloric acid and separation of the water-insoluble salts thus formed. The acidic solution was then made basic by the addition of an aqueous 10% sodium hydroxide solution. The product was again extracted with ether and dried, as described above, to give 16.9 g. of N-(n-butyl)-4-chloro-3-(trifluoromethyl)aniline.
Reaction SMILES: Br[CH:2]([C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[C:3](=O)[C:4]([CH3:7])([CH3:6])[CH3:5].[NH2:15][C:16]([NH2:18])=[S:17].C(=O)([O-])O.[Na+]>C(O)C>[NH2:18][C:16]1[S:17][C:2]([C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:3]([C:4]([CH3:7])([CH3:6])[CH3:5])[N:15]=1
Reactant: CC(C)(C)C(=O)C(Br)C(=O)C(C)(C)C
Reactant: NC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)C(=O)c1sc(N)nc1C(C)(C)C
Yield: 94.8 %

Procedure:
A mixture of 4-bromo-2,2,6,6-tetramethyl-3,5-heptanedione(α-bromo-dipivaloylmethane; 1.42 g, 5.40 mmol), thiourea (451.8 mg, 5.94 mmol) and ethanol (15 mL) was refluxed for 2 hours. After cooling, the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was crystallized (dichloromethane/hexane) to give the title compound (1.23 g, 94.5%) as a white crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:30][CH3:31])=[C:6]([CH:29]=1)/[CH:7]=[C:8]1\[CH2:9][N:10]([CH3:28])[C:11](=[O:27])[CH2:12][N:13]([C:16]([NH:18][C@@H:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)C)=[O:17])[C:14]\1=[O:15].[C:32]1([C@H](N)C)C=CC=CC=1.CNCC1C=CC=CC=1>>[CH2:19]([N:18]([CH3:32])[C:16]([N:13]1[C:14](=[O:15])/[C:8](=[CH:7]/[C:6]2[CH:29]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:30][CH3:31])/[CH2:9][N:10]([CH3:28])[C:11](=[O:27])[CH2:12]1)=[O:17])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: COc1ccc(Cl)cc1/C=C1\CN(C)C(=O)CN(C(=O)N[C@H](C)c2ccccc2)C1=O
Agent: CNCc1ccccc1
Product: COc1ccc(Cl)cc1/C=C1\CN(C)C(=O)CN(C(=O)N(C)Cc2ccccc2)C1=O

Procedure:
Instead of the starting material compound of Example 27, that is, (R)-(+)-1-phenylethylamine, N-methylbenzylamine was used for the similar procedure as with Example 27 to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][C@@H:14]([C:16]#[N:17])[CH2:13][C@H:12]1[C:18]1[NH:19][CH:20]=[C:21]([C:23]2[CH:28]=[CH:27][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][CH:24]=2)[N:22]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][N:49]([C:52]2[CH:57]=[CH:56][C:55]([C:58](=[O:73])[NH:59][C:60]3[CH:65]=[C:64]([O:66][C:67]([F:70])([F:69])[F:68])[C:63](Br)=[CH:62][C:61]=3[Cl:72])=[CH:54][N:53]=2)[C@H:48]([CH3:74])[CH2:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40].C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1>[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][N:49]([C:52]2[CH:57]=[CH:56][C:55]([C:58](=[O:73])[NH:59][C:60]3[C:61]([Cl:72])=[CH:62][C:63]([C:26]4[CH:27]=[CH:28][C:23]([C:21]5[N:22]=[C:18]([C@@H:12]6[CH2:13][C@H:14]([C:16]#[N:17])[CH2:15][N:11]6[C:9](=[O:10])[C@@H:5]([NH:4][C:3]([O:2][CH3:1])=[O:38])[CH:6]([CH3:7])[CH3:8])[NH:19][CH:20]=5)=[CH:24][CH:25]=4)=[C:64]([O:66][C:67]([F:70])([F:69])[F:68])[CH:65]=3)=[CH:54][N:53]=2)[C@H:48]([CH3:74])[CH2:47]1)=[O:45])([CH3:42])([CH3:40])[CH3:41]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C(=O)Nc2cc(OC(F)(F)F)c(Br)cc2Cl)cn1
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](C#N)C[C@H]1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C#N)C[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(NC(=O)c4ccc(N5CCN(C(=O)OC(C)(C)C)C[C@H]5C)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 100 °C
Yield: 7.5 %

Procedure:
A solution of [(S)-1-((2S,4S)-4-cyano-2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.10 g, 0.19 mmol), (R)-4-[5-(4-bromo-2-chloro-5-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (113.9 mg, 0.19 mmol) and potassium carbonate (119.3 mg, 0.86 mmol) in toluene (0.46 mL) and water (0.24 mL, 13.56 mmol) was degassed with nitrogen for 20 min and then Pd(dppf)Cl2CH2Cl2 (6.27 mg, 0.0076 mmol) was added and the reaction was degassed with nitrogen for 15 min. The reaction mixture was heated at 100° C. for 12 h, concentrated under vacuum, and purified by reverse phase HPLC. The pure fractions were combined and concentrated under vacuum to afford the di-TFA salt of the title compound (13 mg, 6% yield). (m/z): [M+H]+ calcd for C44H49ClF3N9O7 908.34. found 908.7.
Reaction SMILES: [F:1][CH:2]([F:21])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[CH2:14][S:15][C:16]1[O:17][CH:18]=[CH:19][N:20]=1.[Cl:22]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:22][C:18]1[O:17][C:16]([S:15][CH2:14][C:5]2[C:6]([C:10]([F:12])([F:13])[F:11])=[N:7][N:8]([CH3:9])[C:4]=2[O:3][CH:2]([F:1])[F:21])=[N:20][CH:19]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1nc(C(F)(F)F)c(CSc2ncco2)c1OC(F)F
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(C(F)(F)F)c(CSc2ncc(Cl)o2)c1OC(F)F

Procedure:
2-({[5-(Difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl}sulfanyl)-1,3-oxazole (1.02 g, 3 mmol) is initially charged in 15 ml of dimethylformamide. N-Chlorosuccinimide (0.550 g, 4 mmol) is then added a little at a time with stirring. The mixture is stirred at 40° C. for a further 4 hours. For work-up, the reaction mixture is added to water and extracted twice with dichloromethane, and the extracts are then washed with water and finally with saturated NaCl solution. The combined organic phases are dried over magnesium sulfate, filtered off and concentrated. The crude product is purified chromatographically (heptane:ethyl acetate, gradient 10:0 to 7:3). This gives 0.45 g of product (35.9% of theory).
Reaction SMILES: Cl[C:2]1[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][C:3]=1[C:4]([NH:6][C:7](=[NH:20])[CH2:8][O:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([Cl:19])[CH:13]=1)=[O:5].CC([O-])(C)C.[K+]>CS(C)=O>[Cl:19][C:14]1[CH:13]=[C:12]([CH2:11][CH2:10][O:9][CH2:8][C:7]2[NH:6][C:4](=[O:5])[C:3]3[CH:21]=[C:22]([CH2:25][CH3:26])[CH:23]=[N:24][C:2]=3[N:20]=2)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: CCc1cnc(Cl)c(C(=O)NC(=N)COCCc2ccc(F)c(Cl)c2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCc1cnc2nc(COCCc3ccc(F)c(Cl)c3)[nH]c(=O)c2c1

Procedure:
In analogy to the procedure described in example 78.4, 2-chloro-N-{2-[2-(3-chloro-4-fluoro-phenyl)-ethoxy]-1-imino-ethyl}-5-ethyl-nicotinamide was treated with KOtBu in DMSO to obtain 2-[2-(3-chloro-4-fluoro-phenyl)-ethoxymethyl]-6-ethyl-3H-pyrido[2,3-d]pyrimidin-4-one as off-white crystals. MS: m/e=362.1 [M+H+].
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[O:5]([C:12]1[CH:28]=[CH:27][C:15]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(C(C)C)C(C)C)C>C1C=CC=CC=1>[O:5]([C:12]1[CH:28]=[CH:27][C:15]([N:16]([C:1](=[O:3])[CH3:2])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)=[CH:14][CH:13]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(=O)Cl
Reactant: c1ccc(Oc2ccc(NCc3ccc4c(c3)OCO4)cc2)cc1
Solvent: c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(Cc1ccc2c(c1)OCO2)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.2 ml of acetyl chloride dissolved in 10 ml of anhydrous benzene is added dropwise at 0°-5° C. in the course of one hour, with stirring, to a solution of 12.7 g of 4-phenoxy-N-(3,4-methylenedioxybenzyl)-aniline and 6 g of N-ethyl-diisopropylamine in 100 ml of anhydrous benzene. The whole is subsequently heated to room temperature and stirred for a further 8 hours. The precipitated N-ethyl-diisopropylamine-hydrochloride is separated by filtration; the filtrate is washed with 10% sodium carbonate solution and then with water. After drying of the organic phase by means of sodium sulphate, the benzene is distilled off in vacuo, and the residue recrystallised in hexane to obtain 4-phenoxy-N-acetyl-N-(3,4-methylenedioxybenzyl)-aniline, M.P. 75°-76° C.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[N:3]=[C:4]1[C:13]2[C:8](=[C:9]([O:14][CH3:15])[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][CH2:5]1.CN1C(=O)N(C)CCC1.C([Li])CCC.[CH3:31][O:32][CH:33]([O:36][CH3:37])[CH2:34]Br>C1COCC1.CCCCCC.O>[CH3:1][N:2]([CH3:16])[N:3]=[C:4]1[C:13]2[C:8](=[C:9]([O:14][CH3:15])[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][CH:5]1[CH2:34][CH:33]([O:36][CH3:37])[O:32][CH3:31]
Reactant: COC(CBr)OC
Reactant: COc1cccc2c1CCCC2=NN(C)C
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: O
Solvent: CCCCCC
Product: COc1cccc2c1CCC(CC(OC)OC)C2=NN(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
3.12 g of 5-methoxy-1-tetralone N,N-dimethylhydrazone and 4.15 ml of DMPU were dissolved in 70 ml of absolute THF under argon and cooled to -75°. 10.7 ml of a 1.6M solution of n-butyllithium in hexane were added dropwise. The mixture was stirred at -75° for 1 hour and thereupon treated slowly with 2.0 ml of bromoacetaldehyde dimethyl acetal. The mixture was left to warm to room temperature and stirred for 26 hours. 20 ml of water were added at about 0° and the mixture was extracted three times with ethyl acetate. After drying over sodium sulfate, the mixture was filtered, evaporated and the residue was chromatographed on silica gel with toluene, then with toluene/ethyl acetate 9:1. 1.62 g (37%) of 2-(2,2-dimethoxy-1-ethyl)-5-methoxy-1-tetralone N,N-dimethylhydrazone were obtained as an oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[C@H:3]([NH:12][C:13]1[CH2:17][S:16][C:15](=[O:18])[N:14]=1)[C:4]([N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:5].[F:20][C:21]([F:42])([F:41])[C:22]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][C:23]=1[CH2:24][N:25]1[CH2:30][CH2:29][CH:28]([CH:31]=O)[CH2:27][CH2:26]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:42][C:21]([F:20])([F:41])[C:22]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][C:23]=1[CH2:24][N:25]1[CH2:30][CH2:29][CH:28](/[CH:31]=[C:17]2/[C:13]([NH:12][C@H:3]([C:4]([N:6]3[CH2:7][CH2:8][O:9][CH2:10][CH2:11]3)=[O:5])[CH:2]([CH3:19])[CH3:1])=[N:14][C:15](=[O:18])[S:16]/2)[CH2:27][CH2:26]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: CC(C)[C@H](NC1=NC(=O)SC1)C(=O)N1CCOCC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CC(C)[C@H](NC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1)C(=O)N1CCOCC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 52.8 %

Procedure:
To a solution of 4-{[(2S)-3-methyl-1-(morpholin-4-yl)-1-oxobutan-2-yl]amino}-1,3-thiazol-2(5H)-one (371 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (441 mg) in 2-propanol (10 mL) was added piperidinium acetate (189 mg) at room temperature. The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (416 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:21]3[C:20](=[O:30])[N:19]([CH3:31])[C:18](=[O:32])[N:17]([CH2:33][C:34](OC)=[O:35])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:21]3[C:20](=[O:30])[N:19]([CH3:31])[C:18](=[O:32])[N:17]([CH:33]=[C:34]=[O:35])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)Cn1c(=O)n(C)c(=O)c2c1nc(N1CCN(C(=O)OC(C)(C)C)CC1)n2-c1ccccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(=O)c2c(nc(N3CCN(C(=O)OC(C)(C)C)CC3)n2-c2ccccc2Cl)n(C=C=O)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-[7-(2-Chlorophenyl)-3-methoxycarbonylmethyl-1-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (87 mg) was dissolved in methanol (2 ml), and 5N aqueous sodium hydroxide solution (0.2 ml) was added to the solution. Then, the mixture was stirred at room temperature for 2 hours. The mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was removed by distillation to give the title compound.