Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:34])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:32][CH3:33])=[C:16]([CH2:19][N:20]([CH3:31])[C:21]4([C:28](O)=[O:29])[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.F[P-](F)(F)(F)(F)F.[N:42]1(OC(N(C)C)=[N+](C)C)[C:46]2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN>CN(C)C=O>[Cl:1][C:2]1[C:3]([F:34])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:32][CH3:33])=[C:16]([CH2:19][N:20]([CH3:31])[C:21]4([C:28]([NH:42][CH3:46])=[O:29])[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(=O)O)CCN(C)CC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)C1(N(C)Cc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN(C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
4-[({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]-1-methylpiperidine-4-carboxylic acid (50 mg, 0.1 mmol) was dissolved in N,N-dimethylformamide (2 ml) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (59 mg, 0.15 mmol) and N,N-diisopropylethylamine (89 μl, 0.51 mmol) were added. After a few minutes methylamine hydrochloride (10 mg, 0.15 mmol) was added and the mixture stirred for 1 hour at room temperature. The mixture was absorbed onto an Isolute SCX column, washed with methanol and eluted with ammonia in methanol. Appropriate fractions were combined and concentrated. The residue was purified by column chromatography on silica, eluting with 5% 7N ammonia in methanol/dichloromethane, to give the title product (40 mg, 77%) as a white solid; 1H NMR Spectrum: (DMSO d6) 1.82 (m, 2H); 2.02 (m, 2H); 2.13 (m, 8H); 2.65 (m, 5H); 3.60 (s, 2H); 3.94 (s, 3H); 7.18 (s, 1H); 7.30 (t, 1H); 7.50 (m, 1H); 7.58 (m, 2H); 8.32 (s, 1H); 8.73 (s, 1H); 9.68 (s, 1H). Mass Spectrum: (M+H)+ 501.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]2[CH:9]=[CH:10][N:11]=[C:5]2[CH:4]=1.O=P(Cl)(Cl)Cl.CN(C)[CH:19]=[O:20]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]2[C:9]([CH:19]=[O:20])=[CH:10][N:11]=[C:5]2[CH:4]=1
Reactant: CN(C)C=O
Reactant: COc1ccn2ccnc2c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccn2c(C=O)cnc2c1
Temperature: 90 °C
Yield: 69 %

Procedure:
7-Methoxyimidazo[1,2-a]pyridine (621 mg, 4.2 mmol) was mixed with POCl3 (16.8 mmol) in dimethylformamide (4 mL). The reaction mixture was heated at 90° C. for 24 h and then cooled to room temperature. After the solvent was removed in vacuo, an oil was obtained. The oil was purified on a silica gel column eluting with EtOAc/Hexane (1:1) to afford 7-methoxyimidazo[1,2-a]pyridine-3-carbaldehyde (508 mg, 69%).
Reaction SMILES: [CH2:1]([CH:5]([C:11](=[O:29])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:28])[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[OH:27])[CH:13]=1)C(OCC)=O)[CH2:2][CH2:3][CH3:4].O[Li].O>C1COCC1.O>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]([NH:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([C:11](=[O:29])[CH2:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH:13]=2)=[O:28])=[C:21]([OH:27])[CH:22]=1
Reactant: CCCCC(C(=O)OCC)C(=O)c1cccc(NC(=O)c2ccc(Cl)cc2O)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC(=O)c1cccc(NC(=O)c2ccc(Cl)cc2O)c1
Yield: 60.1 %

Procedure:
A solution of ethyl α-butyl-3-[(4-chloro-2-hydroxybenzoyl)amino]-β-oxobenzenepropanoate (32.0 mg, 77.0 μmol) and LiOH.H2O (11.0 mg, 0.26 mmol) in THF (3.0 mL) and water (1.5 mL) was heated to 55° for 48 h. The mixture was partitioned between water and EtOAc. The aqueous layer was acidified with aqueous 10% citric acid then extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by reversed phase HPLC (Whatman Partisil® ODS-3 C18 10μ, 22×500 mm; 0 to 80% MeCN+0.06% TFA/water+0.06% TFA) to give the title compound (16.0 mg, 60% yield) as a white solid: mp 134-136°; identical to the product of example 2.
Reaction SMILES: [F-].C([N+:6](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:21]=[C:22]([C:27]2([CH2:38][CH2:39][O:40][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:29][C:28]2([C:34]([O:36][CH3:37])=[O:35])[C:30](OC)=[O:31])[CH:23]=[CH:24][C:25]=1[Cl:26].[NH4+].[OH-]>C1COCC1.CO>[NH2:6][C:30]([C:28]1([C:34]([O:36][CH3:37])=[O:35])[CH2:29][C:27]1([C:22]1[CH:23]=[CH:24][C:25]([Cl:26])=[C:20]([Cl:19])[CH:21]=1)[CH2:38][CH2:39][OH:40])=[O:31]
Reactant: COC(=O)C1(C(=O)OC)CC1(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ccc(Cl)c(Cl)c1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C1(C(N)=O)CC1(CCO)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tetrabutylammonium fluoride (TBAF) (5.6 mL, 1.1M/TFH) was added dropwise to a stirred solution of dimethyl 2-(3,4-dichlorophenyl)-2-(2-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}ethyl)-1,1-cyclopropanedicarboxylate (P14, 2.38 g) in THF (27 mL), at 0° C. After 4 h the ice-bath was removed and the reaction mixture was stirred for 3 h at RT. The solvent was removed under reduced pressure, the residue was treated with ether and water, the organic phase washed with brine, dried over Na2SO4 and the solvent evaporated under vacuum to give the crude lactone intermediate (2.08 g). This product was dissolved in a mixture of THF (15 mL) and methanol (10 mL), at RT, aqueous NH4OH (28%, 16 mL) was added dropwise and the reaction mixture was stirred for 4 h. The mixture was concentrated under reduced pressure, the residue was taken up with DCM and water, the organic phase was washed with brine, dried over Na2SO4 and the solvent evaporated under vacuum. The crude product was purified by FC (eluting with DCM/methanol from 1/0 to 9/1) to give the title compound (0.89 g) as a white foam.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@H:16]([O:17][CH3:18])[CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(Cl)Cl.O1CCOCC1>[CH3:18][O:17][C@@H:16]1[CH2:15][NH:14][CH2:13][C@H:12]1[NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1NC(=O)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CO[C@@H]1CNC[C@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
To a solution of (3R,4R)-tert-butyl 3-(benzyloxycarbonylamino)-4-methoxypyrrolidine-1-carboxylate (2.90 g, 8.28 mmol) in DCM (20 mL) was added 4 N HCl (20.69 mL, 82.76 mmol) in dioxane. The reaction mixture was stirred at ambient temperature for 2 hours. The solvent was removed under reduced pressure. Saturated bicarbonate (20 mL) and DCM (50 mL) were added. The organic layer was separated, dried (sodium sulfate), filtered and concentrated under reduced pressure to give benzyl (3R,4R)-4-methoxypyrrolidin-3-ylcarbamate (2.0 g, 96.6%) as oil.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[N:7]([CH:18]=1)[C@@H:8]1[O:17][C@H:12]([CH2:13][CH2:14][CH2:15]O)[C@@H:10]([OH:11])[CH2:9]1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N-:40]=[N+:41]=[N-:42].[Na+].C(Br)(Br)(Br)Br>CN(C)C=O>[N:40]([CH2:15][CH2:14][CH2:13][C@H:12]1[O:17][C@@H:8]([N:7]2[CH:18]=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]2=[O:19])[CH2:9][C@@H:10]1[OH:11])=[N+:41]=[N-:42]
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](CCCO)O2)c(=O)[nH]c1=O
Reactant: [N-]=[N+]=[N-]
Agent: BrC(Br)(Br)Br
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CCCN=[N+]=[N-])O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.6 %

Procedure:
A mixture of 1.25 g of 2',5'-dideoxy-5-ethyl-5'-(2-hydroxyethyl)uridine, 1.18 g of triphenylphosphine, 1.49 g of sodium azide and 1.55 g of carbon tetrabromide in 30 ml of dimethylformamide was stirred at room temperature overnight. The mixture was evaporated to dryness and the residue was partitioned between ethyl acetate and water. The ethyl acetate solution was evaporated to dryness and the residue was subjected to flash chromatography on a column of silica gel using 1% methanol/dichloromethane for the elution to give 0.28 g of 5'-(2-azidoethyl)-2',5'-dideoxy-5-ethyluridine in the form of a colorless oil which crystallized upon standing.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH2:12][N:13]1C(=O)C2C(=CC=CC=2)C1=O)[CH2:9][CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].O.NN>CCO.C(Cl)Cl>[C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH2:12][NH2:13])[CH2:9][CH2:10][CH3:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC[C@@H](CN1C(=O)c2ccccc2C1=O)NC(=O)OC(C)(C)C
Agent: NN
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CCC[C@@H](CN)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of [(S)-1-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-butyl]-carbamic acid tert-butyl ester (2.80 g, 8.42 mmol) and hydrazine monohydrate (3.0 mL, 60.0 mmol) in EtOH (50 mL) and DCM (75 mL) is stirred at RT for 48 h. The precipitated solid is collected by filtration and washed with DCM to afford the crude product as a white solid that is used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:13])=[C:4]([C:8]([O:10]CC)=[O:9])[S:5][C:6]=1[Br:7].[OH-].[Li+].C1COCC1.Cl>O>[Br:1][C:2]1[C:3]([Cl:13])=[C:4]([C:8]([OH:10])=[O:9])[S:5][C:6]=1[Br:7]
Reactant: CCOC(=O)c1sc(Br)c(Br)c1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1sc(Br)c(Br)c1Cl
Temperature: 25 °C
Reaction time: 32 h
Yield: 86.5 %

Procedure:
Ethyl 4,5-dibromo-3-chlorothiophene-2-carboxylate (5.52 g, 15.8 mmol) and lithium hydroxide (0.716 g, 31.7 mmol) were taken up in mixture of THF (30 mL) and water (30 mL). The reaction mixture was stirred at 25° C. for 32 hours. The aqueous layer was made acidic by the dropwise addition of conc hydrochloric acid and extracted with ether (3×50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to give the product as a white solid (4.38 g, 86%) that was used without purification: mp 209-223° C. (d); 1H NMR (CDCl3 and DMSO-d6) δ 4.15 (bs, 1H); EI/MS 320 m/e (M+).
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][CH2:4][CH2:5][CH3:6].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:35][C@H:36]([C:41]([NH:43][C@H:44]([C:52]([NH:54][C@H:55]([C:63]([O:65][CH3:66])=[O:64])[CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)=[O:53])[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:42])[CH2:37][C:38](=[O:40])[NH2:39].Br>O1CCCC1.CN(C)C=O.O1CCCC1.C(O)C>[NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7]([NH:35][C@H:36]([C:41]([NH:43][C@H:44]([C:52]([NH:54][C@H:55]([C:63]([O:65][CH3:66])=[O:64])[CH2:56][C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1)=[O:53])[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:42])[CH2:37][C:38](=[O:40])[NH2:39])=[O:9])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Agent: Br
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCO
Solvent: CN(C)C=O
Product: CCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC
Temperature: -20 °C

Procedure:
4.95 g of Z-Nle-OH dissolved in 50 ml tetrahydrofuran are cooled to -20° C. and 2.1 ml of N-methylmorpholine followed by 2.43 ml of chloroformic acid isobutylester are added to the solution with stirring. The solution is stirred for a further 10 minutes at -15° C. and a cold solution comprising 10.6 g of H-Asn-Phe-Phe-OMe. hydrobromide and 2.5 ml of N-methylmorpholine in 60 ml N,N-dimethylformamide/tetrahydrofuran (1:1) are added. The solution is stirred for 20 hours at 0° C. and for 2 hours at room temperature and subsequently stirred with aqueous ethanol. After filtration, washing with (a) methanol and (b) ether and drying, the title compound is obtained [α]D20 =-31° (c=1.0 in dimethylformamide): decomposition at 235° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[F:11])[C:5](Cl)=[O:6].ClC1C=C(C(F)(F)F)C=C(Cl)C=1F.S(=O)(=O)(O)[OH:27].ClS(O)(=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[F:11])[C:5]([OH:27])=[O:6]
Reactant: O=C(Cl)c1cc(Cl)c(F)c(Cl)c1
Reactant: O=S(=O)(O)O
Agent: Fc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: O=S(=O)(O)Cl
Product: O=C(O)c1cc(Cl)c(F)c(Cl)c1
Temperature: 80 °C
Yield: 49 %

Procedure:
3,5-dichloro-4-fluorobenzoyl chloride can be prepared as follows: To a round bottom flask with nitrogen purge through a 10% aqueous NaOH trap, was added 3,5-dichloro-4-fluorobenzotriflouride (5.00 g, 21.46 mmol, Aldrich), concentrated sulfuric acid (4.30 g, 42.92 mmol), and finally chlorosulfonic acid (5.15 g, 43.78 mmol). The reaction began to bubble immediately. After the bubbling subsided, the mixture was heated to 80° C. for 1 hr, cooled to room temperature, and added cautiously to stirred ice water. This was extracted twice with methylene chloride. The combined extracts were washed with water and brine, dried over magnesium sulfate, filtered, and evaporated to give a white solid (2.19 g) of 3,5-dichloro-4-fluorobenzoic acid in 49% yield. 1H-NMR (CD3COCD3, 300 MHz) δ (ppm): 7.95 (d, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.I[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[S:27][C:26]([NH2:28])=[N:25][N:24]=2)=[C:19]([O:29][CH3:30])[CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:30][O:29][C:19]1[CH:18]=[C:17]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)[CH:22]=[CH:21][C:20]=1[C:23]1[S:27][C:26]([NH2:28])=[N:25][N:24]=1
Reactant: COc1cc(I)ccc1-c1nnc(N)s1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-c2cnn(C)c2)ccc1-c1nnc(N)s1
Temperature: 80 °C
Yield: 62.1 %

Procedure:
To a stirred suspension of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (137 mg, 0.660 mmol) and 5-(4-iodo-2-methoxyphenyl)-1,3,4-thiadiazol-2-amine (200 mg, 0.6 mmol) in dioxane (4 mL) was added Pd(PPh3)4 (35 mg, 0.03 mmol) followed by a solution of Na2CO3 (191 mg, 1.801 mmol) in water (1 mL). The reaction was purged with nitrogen then heated at 80° C. for 18 hours. The reaction mixture was diluted with MeOH (20 mL), filtered through celite, and rinsed with DCM (20 mL). The filtrate was concentrated in vacuo to afford the crude product as an orange oily residue. The crude product was pre-absorbed onto silica gel and purified by flash chromatography using a 24 g silica cartridge, running a MeOH/DCM gradient to afford the title compound as a pale yellow solid (107 mg, 62% yield). LC-MS: Rt 0.81 min; MS m/z 288.1 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.27 (s, 1H), 8.05 (d, J=8.08 Hz, 1H), 7.98 (s, 1H), 7.36 (d, J=1.52 Hz, 1H), 7.28 (dd, J=8.08, 1.52 Hz, 1H), 7.13 (s, 2H), 3.99 (s, 3H), 3.88 (s, 3H).
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:12])[CH:5]([CH3:11])[CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9].[OH:13][C:14]1[CH:23]=[C:22]2[C:17]([CH2:18][CH2:19][CH2:20][O:21]2)=[CH:16][CH:15]=1>>[CH3:12][C:4]([CH:5]([CH3:11])[CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])=[CH:3][CH2:2][O:13][C:14]1[CH:23]=[C:22]2[C:17]([CH2:18][CH2:19][CH2:20][O:21]2)=[CH:16][CH:15]=1
Reactant: CC(C)=CCC(C)C(C)=CCBr
Reactant: Oc1ccc2c(c1)OCCC2
Product: CC(C)=CCC(C)C(C)=CCOc1ccc2c(c1)OCCC2

Procedure:
Following the procedure of Example 1, 1-bromo-3,4,7-trimethyl-2,6-octadiene and 7-hydroxy-chromane are reacted to form 7-(3,4,7-trimethyl-2,6-octadienyloxy)-chromane; nD20 = 1.5368.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[C:4]([CH3:24])[N:3]=1.Cl.[NH2:26][OH:27].C([O-])(O)=O.[Na+]>>[F:1][C:2]1[CH:7]=[C:6](/[C:8](=[N:26]/[OH:27])/[CH2:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[C:4]([CH3:24])[N:3]=1
Reactant: NO
Reactant: Cc1cc(C(=O)CC(c2ccccc2)c2ccccc2)cc(F)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(CC(c2ccccc2)c2ccccc2)=N/O)cc(F)n1

Procedure:
In analogy to example 1, step 2, from 1-(2-fluoro-6-methyl-pyridin-4-yl)-3,3-diphenyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a white oil, MS (ESI+): m/z=335.1553 ([M+H]+).
Reaction SMILES: [C:1]([Cu])#[N:2].[C-]#N.[Na+].[CH2:7]([O:9][C:10]1[CH:18]=[C:17](N)[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13])[CH3:8].N([O-])=O.[Na+].[C-]#N.[Na+].C([Cu])#N.N#N>O.Cl.C(O)CCCCCCC>[CH2:7]([O:9][C:10]1[CH:18]=[C:17]([C:1]#[N:2])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13])[CH3:8]
Reactant: N#C[Cu]
Reactant: CCOc1cc(N)ccc1C(=O)O
Agent: Cl
Agent: N#N
Agent: O=N[O-]
Solvent: O
Solvent: CCCCCCCCO
Product: CCOc1cc(C#N)ccc1C(=O)O
Temperature: 0 °C
Reaction time: 4 h
Yield: 71.3 %

Procedure:
In a 1 l reactor equipped with a sealed mechanical stirrer, CuCN (12 g, 134 mmol) were suspended in 100 ml of distilled water. NaCN (18.3 g, 373 mmol) was added with vigorous stirring and the internal temperature was kept below 40° C. until all the CuCN went into solution. The suspension of 2-ethoxy-4-aminobenzoic acid (20 g, 110 mmol) in water (200 ml) and concentrated HCl (33 ml) was stirred and cooled in an ice bath. When the temperature reached 5° C., a solution of NaNO2 (9.7 g, 140 mmol) in water (30 ml) was added dropwise at such a rate as to maintain the temperature below 5° C. When all the NaNO was added, the solution was slowly introduced through an ice cooled dropping funnel into the reactor containing the NaCN/CuCN solution. A reaction took place with the vigorous formation of N2. A few drops of octanol were added to keep the foaming under control. Stirring was continued for 4 h. The resulting suspension was then extracted with ethyl acetate (3×100 ml) and the organic phase dried over MgSO4 and evaporated under vacuum obtaining 15 g of the title compound (yield 71.1%) as a light brown powder, mp=170-172° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:25]=[CH:24][C:14]([O:15][C:16]4[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=4[CH:18]=O)=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:26]3[CH2:30][CH2:29][O:28][CH2:27]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:31][O:32][CH2:33][CH2:34][NH2:35]>>[CH3:31][O:32][CH2:33][CH2:34][NH:35][CH2:18][C:17]1[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=1[O:15][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:3]3[C:2]([NH2:1])=[N:7][CH:6]=[N:5][C:4]=3[N:8]([CH:26]3[CH2:30][CH2:29][O:28][CH2:27]3)[CH:9]=2)=[CH:25][CH:24]=1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3C=O)cc1)cn2C1CCOC1
Reactant: COCCN
Product: COCCNCc1ccccc1Oc1ccc(-c2cn(C3CCOC3)c3ncnc(N)c23)cc1

Procedure:
In a similar manner to Example 10, 2-[4-(4-amino-7-(3-tetrahydrofuryl)-7H-pyrrolo[2,3-d)pyrimidin-5-yl)phenoxy]benzaldehyde (0.15 g) and 2-methoxyethylamine (56 mg) were reacted together to give 5-{4-[2-(2-methoxyethyl)aminomethylphenoxy]phenyl}-7-(3-tetrahydrofuryl)-7H-pyrrolo[2,3-d]-pyrimidin-4-ylamine m.p. 66-68° C. (glassy foam).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]([O:11]CC)=[O:10])=[CH:3][CH:2]=1.S(=O)(=O)(O)O>[OH-].[Na+]>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCc1ccncc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCc1ccncc1
Yield: 69.9 %

Procedure:
A solution of ethyl 3-(pyridin-4-yl)propionate (17.14 g, 96 mmol; synthesized according to WO, A, 01/42244) in aqueous sodium hydroxide (2N, 100 ml) was heated under reflux for 1 hour, cooled, then adjusted pH 4 to 5 with conc. sulfuric acid, filtered to give precipitates which were washed with water, and then with hexane, and dried to afford 3-(pyridin-4-yl)propionic acid (10.15 g, 70%) as crystals.
Reaction SMILES: C([O:5][NH:6][C:7]([C:9]1[C:14]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=2[F:23])=[C:13]([CH3:24])[C:12](=[O:25])[N:11]([CH3:26])[CH:10]=1)=[O:8])(C)(C)C.C(O)(C(F)(F)F)=O>>[OH:5][NH:6][C:7]([C:9]1[C:14]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=2[F:23])=[C:13]([CH3:24])[C:12](=[O:25])[N:11]([CH3:26])[CH:10]=1)=[O:8]
Reactant: Cc1c(Nc2ccc(Br)cc2F)c(C(=O)NOC(C)(C)C)cn(C)c1=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Nc2ccc(Br)cc2F)c(C(=O)NO)cn(C)c1=O

Procedure:
4-(4-Bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid hydroxyamide was prepared from 4-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid tert-butoxy-amide by TFA deprotection as described in Example 37. MS APCI (+) m/z 370, 372 (M+, Br pattern) detected; 1H NMR (400 MHz, CD3OD) δ 7.88 (s, 1H), 7.32 (dd, 1H), 7.20 (dd, 1H), 6.61 (t, 1H), 3.56 (s, 3H), 1.77 (s, 3H).
Reaction SMILES: [BH4-].[Li+].C[O:4][C:5](=O)[CH:6]([CH2:11][C:12]1([CH3:17])[S:16][CH2:15][CH2:14][S:13]1)[C:7](OC)=[O:8].Cl.[Cl-].[Na+]>O1CCCC1>[CH3:17][C:12]1([CH2:11][CH:6]([CH2:5][OH:4])[CH2:7][OH:8])[S:13][CH2:14][CH2:15][S:16]1
Reactant: COC(=O)C(CC1(C)SCCS1)C(=O)OC
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC1(CC(CO)CO)SCCS1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.8 %

Procedure:
To a solution of about 14.53 g of lithium borohydride in about 630 ml of tetrahydrofuran at about 0° C. was added about 84.0 g of dimethyl[(2-methyl-1,3-dithiolan-2-yl)methyl]propanedioate dropwise. After the exotherm ended the mixture was stirred at room temperature for about 18 hours, then about 4.15 g of lithium borohydride were added and stirring was continued for about 20 hours. The solution was cooled in an ice bath, about 400 ml of about 6N hydrochloric acid were added dropwise, the mixture was saturated with sodium chloride and then extracted with ether. The ether layer was washed with brine, then saturated sodium bicarbonate, dried and the solvent removed. Methanol was added and removed three times. The solid was recrystallized from carbon tetrachloride, giving about 56.77 g of the desired title compound, mp 72°-73° C.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[OH:5][C@H:6]1[CH2:10][CH2:9][O:8][CH2:7]1>C1(C)C=CC=CC=1>[O:8]1[CH2:9][CH2:10][C@H:6]([O:5][C:1]([Cl:4])=[O:2])[CH2:7]1
Reactant: O=C(Cl)Cl
Reactant: O[C@H]1CCOC1
Solvent: Cc1ccccc1
Product: O=C(Cl)O[C@H]1CCOC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
14.1 ml (27.24 mmol) of a 20% solution of phosgene in toluene are added dropwise to 14 ml of toluene. After the mixture has been cooled in an ice-bath, a solution of 2 g (22.7 mmol) of (S)-(+)3-hydroxy-tetrahydrofuran (JPS CHIMIE, Bevaix, Switzerland) in a small amount of toluene is added, the mixture is then stirred for 1 h at RT, and the excess phosgene is expelled with argon. After concentration in a rotary evaporator at reduced pressure, distillation is carried out for the purpose of purification. Boiling point at 12 torr: 130° C.