Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([C:19]([OH:21])=[O:20])[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:24])=[N-].CC1C=CC(S(N(N=O)C)(=O)=O)=CC=1.C(O)(=O)C>CCOCC>[CH3:24][O:20][C:19](=[O:21])[C@H:10]([CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[NH:11][C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13]
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: C=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
(O-benzyl) Boc Serine 2.00 g (6.8 mmoles) was dissolved in 50 ml of ether. To this solution was added an ether solution containing freshly prepared diazomethane prepared from 5 g of Diazald using the procedure from Aldrich Technical Bulletin number AL-180. After stirring the solution for 30 minutes, glacial acetic acid was added dropwise until the solution became clear. The resulting solution was concentrated in vacuo to yield 2.00 g, 95% as a clear oil. 1H: (CDCl3); 7.3 (d, 5H), 5.5 (bs, 1H), 4.5 (s, 2H), 3.8 (m, 2H), 3.7 (s, 3H), 1.4 (s, 9H)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[N:20]=[C:19]3[N:21]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:31](=[O:41])[C:32]5[CH:37]=[CH:36][CH:35]=[C:34]([N:38]([CH3:40])[CH3:39])[CH:33]=5)[CH:25]=4)[O:23][C:18]3=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:39][N:38]([CH3:40])[C:34]1[CH:33]=[C:32]([CH:37]=[CH:36][CH:35]=1)[C:31]([NH:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([C:22]2[O:23][C:18]3[C:19]([N:21]=2)=[N:20][C:15]([CH2:14][N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:16][CH:17]=3)[CH:25]=1)=[O:41]
Reactant: CN(C)c1cccc(C(=O)Nc2cccc(-c3nc4nc(CN5CCN(C(=O)OC(C)(C)C)CC5)ccc4o3)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cccc(C(=O)Nc2cccc(-c3nc4nc(CN5CCNCC5)ccc4o3)c2)c1
Reaction time: 1 h

Procedure:
4-{2-[3-(3-Dimethylamino-benzoylamino)-phenyl]-oxazolo[4,5-b]pyridin-5-ylmethyl}-piperazine-1-carboxylic acid tert-butyl ester (25 mg, 0.045 mmol) was dissolved in 1 mL of 25% TFA in CH2Cl2 and allowed to stand at room temperature for 1 hour. It was then concentrated and the resulting residue was triturated with Et2O to afford essentially quantitative yield of 3-dimethylamino-N-[3-(5-piperazin-1-ylmethyl-oxazolo[4,5-b]pyridin-2-yl)-phenyl]-benzamide as the TFA salt.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][N:11]2[C:14](=[O:30])[CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:18]([CH3:29])[CH2:17]2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].Cl>C1COCC1.CO.O>[C:25]([O:24][C:22]([N:19]1[CH2:20][CH2:21][N:16]([CH2:15][C:14]([N:11]2[C:12]3[C:8](=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:13]=3)[CH2:9][CH2:10]2)=[O:30])[CH2:17][C@H:18]1[CH3:29])=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: COC(=O)c1ccc2c(c1)N(C(=O)CN1CCN(C(=O)OC(C)(C)C)[C@H](C)C1)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CN(CC(=O)N2CCc3ccc(C(=O)O)cc32)CCN1C(=O)OC(C)(C)C
Yield: 94.6 %

Procedure:
1-[2-((R)-4-tert-Butoxycarbonyl-3-methyl-piperazin-1-yl)-acetyl]-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester (690 mg, 1.65 mmol) was dissolved in THF/MeOH/H2O (3.3/3.3/1.7 mL) and sodium hydroxide (331 mg, 8.27 mmol) was added. The reaction was stirred for 18 h and neutralised with 2 M hydrochloric acid (4.1 mL). The solvent was removed in vacuo and the residue azeoptroped with MeOH to dryness, to give the title compound (630 mg, 95%) as a red/pink solid. 1H NMR (Me-d3-OD): 8.76 (1H, s), 7.71 (1H, dd), 7.27 (1H, d), 4.39-4.28 (2H, m), 4.27-4.10 (1H, m), 3.83 (1H, d), 3.28-3.07 (3H, m), 2.93 (1H, d), 2.84 (1H, d), 2.33 (1H, dd), 2.26-2.08 (1H, m), 1.47 (9H, s), 1.34-1.27 (3H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH:35]([C:37]1[N:47]=[CH:46][CH:45]=[CH:44][C:38]=1[C:39]([O:41][CH2:42][CH3:43])=[O:40])[NH2:36].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([C:14]([NH:36][NH:35][C:37]4[N:47]=[CH:46][CH:45]=[CH:44][C:38]=4[C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:16])=[CH:17][CH:18]=3)[S:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1cccnc1NN
Reactant: O=C(O)c1ccc(Nc2nc3ccc(Cl)cc3s2)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1cccnc1NNC(=O)c1ccc(Nc2nc3ccc(Cl)cc3s2)cc1
Reaction time: 0.08 h
Yield: 52.9 %

Procedure:
A suspension of 4-(6-chlorobenzo[d]thiazol-2-ylamino)benzoic acid (117 mg, 0.38 mmol), EDC (88 mg, 0.46 mmol) and HOBt (63 mg, 0.46 mmol) in a mixed solvent of DMF (1 mL) and CH2Cl2 (1 mL) was stirred for 5 min, and then ethyl 2-hydrazinylnicotinate (4A) (70 mg, 0.38 mmol) was added, followed by triethylamine (78 mg, 0.77 mmol). The mixture was stirred at room temperature for 2 h. Analysis by LC/MS indicated the starting material was not consumed. Additional EDC (20 mg, 0.1 mmol) and HOBt (15 mg, 0.11 mmol) were added, and the mixture stirred for another 2 h before quenching with water (3 mL). The resulting precipitate was isolated by filtration and triturated with MeOH to yield the title compound as a fluffy white solid (94 mg). The methanol solution was concentrated in vacuo to collect additional product (50 mg) (total 144 mg, 87% yield). HPLC/MS (Method C): retention time=2.23 min, [M+H]+=468.4.
Reaction SMILES: BrC1C=CC(O)=C(C(=O)C)C=1.Br[C:13]1[CH:14]=[N:15][CH:16]=[C:17]([CH:23]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19].[CH:24]([NH:27][C:28]([C:30]1[C:39](=[O:40])[C:38]2[C:33](=[N:34][CH:35]=[CH:36][CH:37]=2)[N:32]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43](Br)[CH:42]=2)[CH:31]=1)=[O:29])([CH3:26])[CH3:25]>>[CH:24]([NH:27][C:28]([C:30]1[C:39](=[O:40])[C:38]2[C:33](=[N:34][CH:35]=[CH:36][CH:37]=2)[N:32]([C:41]2[CH:42]=[CH:43][CH:44]=[C:45]([C:13]3[CH:14]=[N:15][CH:16]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:23]=3)[CH:46]=2)[CH:31]=1)=[O:29])([CH3:26])[CH3:25]
Reactant: CCOC(=O)c1cncc(Br)c1
Reactant: CC(C)NC(=O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Agent: CC(=O)c1cc(Br)ccc1O
Product: CCOC(=O)c1cncc(-c2cccc(-n3cc(C(=O)NC(C)C)c(=O)c4cccnc43)c2)c1

Procedure:
Following the procedure of Example 23 but substituting N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide for 5′-bromo-2′-hydroxyacetophenone and ethyl 5-bromonicotinate for N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide the title compound was obtained as a beige solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([NH:12][CH2:13][C@:14]2([F:27])[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]2)[N:3]=1.[CH3:28][O:29][CH2:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.[OH-].[K+]>COCCOC.O.C(O)C>[F:27][C@@:14]1([CH2:13][NH:12][C:4]2[N:3]=[C:2]([C:34]3[CH:33]=[N:32][N:31]([CH2:30][O:29][CH3:28])[CH:35]=3)[CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][CH:8]=[N:9]3)[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@](F)(CNc2nc(Cl)cc3ncccc23)C1
Reactant: COCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [K+]
Agent: [OH-]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: COCn1cc(-c2cc3ncccc3c(NC[C@]3(F)CCCN(C(=O)OC(C)(C)C)C3)n2)cn1
Temperature: 130 °C
Yield: 105 %

Procedure:
To 1,1-dimethylethyl (3R)-3-{[(7-chloro-1,6-naphthyridin-5-yl)amino]methyl}-3-fluoro-1-piperidinecarboxylate (650 mg, 1.646 mmol) in DME (5 ml), water (2.5 ml), ethanol (5.00 ml) was added 1-[(methyloxy)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.03 g 4.33 mmol), potassium hydroxide (3.95 ml, 3.95 mmol, 1M aqueous solution) and PEPPSI (112 mg, 0.165 mmol). The reaction was refluxed at 130° C. under nitrogen for 4 nights. LCMS showed main peak as product. The reaction mixture was filtered through celite and the solvent removed. The residue was dissolved in DCM and loaded onto a 25 g silica column and purified on the SP4 eluting with a 50-100% ethyl acetate in cyclohexane gradient. Appropriate fractions were combined and the solvent removed to give a yellow oil which was dried under high vacuum overnight to give the title compound as a yellow solid/film (813 mg).
Reaction SMILES: [C@@H:1]1([N:10]2[C:18]3[CH:17]=[CH:16][N:15]=[C:14](N)[C:13]=3[N:12]=[CH:11]2)[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].C(O)(=[O:22])C.N([O-])=O.[Na+].NC(N)=O>O>[C@@H:1]1([N:10]2[C:18]3[CH:17]=[CH:16][NH:15][C:14](=[O:22])[C:13]=3[N:12]=[CH:11]2)[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3]
Reactant: Nc1nccc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: CC(=O)O
Agent: NC(N)=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=c1[nH]ccc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O

Procedure:
A solution of 1.5 g of 1-β-D-arabinofuranosyl-1H-imidazo[4,5-c]pyridin-4-amine, 6 ml of acetic acid, 150 ml of water, and 2.67 g of sodium nitrite is kept at ambient temperature for 8 hours, treated with 2.4 g of urea, and then with 50 ml of wet Dowex 50 1×8 (H+), and concentrated to dryness in vacuo. The residue is coevaporated several times with xylenes and then recrystallized from water to provide 1-β-D-arabinofuranosyl-1,5-dihydro-4H-imidazo[4,5-c]pyridin-4-one.
Reaction SMILES: [CH2:1]([SiH:19]([Cl:21])[Cl:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C(O)(C)C>[CH2:22]([Si:19]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])([Cl:21])[Cl:20])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCC
Reactant: CCCCCCCCCCCCCCCCCC[SiH](Cl)Cl
Solvent: CC(C)O
Product: CCCCCCCCCCCCCCCCCC[Si](Cl)(Cl)CCCCCC
Temperature: 50 °C
Reaction time: 25 h

Procedure:
Resultant n-octadecyldichlorosilane in an amount of 176.5 g (0.5 mol), 50.4 g of 1-hexane (0.6 mol) and 0.05 mol % of a H2PtCl2 ·6H2O solution in isopropanol (relative to n-octadecyldichlorosilane) were reacted in a flask with stirring at 50° C. for 25 hours to give n-hexyloctadecyldichlorosilane [(n--C6H13)(n--C18H37)SiCl2 ].
Reaction SMILES: [N:1]1([CH:7]([CH3:16])[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Mg].Br[C:19]1[C:24]([O:25][CH3:26])=[C:23]([CH3:27])[CH:22]=[C:21]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:20]=1.BrCCBr.Cl.N>C(OCC)C>[CH3:26][O:25][C:24]1[C:23]([CH3:27])=[CH:22][C:21]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:20][C:19]=1[C:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([OH:9])[CH:7]([N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[CH3:16]
Reactant: COc1c(C)cc(C(C)(C)C)cc1Br
Reactant: CC(C(=O)c1ccccc1)N1CCCCC1
Agent: Cl
Agent: N
Agent: [Mg]
Solvent: CCOCC
Solvent: BrCCBr
Product: COc1c(C)cc(C(C)(C)C)cc1C(O)(c1ccccc1)C(C)N1CCCCC1
Reaction time: 4 h
Yield: 78.7 %

Procedure:
15 g of α-piperidinopropiophenone were added to a Grignard solution of 7.3 g of magnesium, 38.5 g of 6-bromo-2-methyl-4-tert-butylanisole and 28.2 g of 1,2,-dibromethane in 300 ml of diethyl ether. After boiling for 4 hours under reflux, the reaction mixture was poured on to ice and acidified with hydrochloric acid. The acidic aqueous solution and the oily intermediate layer were both separated, together made alkaline with a concentrated aqueous ammonia solution, and the base which separated therefrom was dissolved in diethyl ether. After evaporation of the diethyl ether, 26.5 g of viscous brown oil were obtained from which, upon trituration of dilution with isopropanol, 21.5 g of 1-(2'-methoxy-3'-methyl-5'-tert-butylphenyl)-1-phenyl-2-piperidino-propan-1-ol, having a melting point of 86° C. to 87° C., crystallized out. The product was recrystallized from isopropanol and then had a melting point of 87° C. to 88° C.
Reaction SMILES: C(OC([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[C:36]([Cl:37])=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][N:29]=2)[CH2:24][CH:23]1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.Cl.O1CCOCC1>>[ClH:37].[Cl:37][C:36]1[C:28]([N:25]2[CH2:26][CH2:27][CH:22]([CH2:21][NH:8][C@@H:9]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=[CH:13][CH:12]=3)[CH3:10])[CH:23]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:24]2)=[N:29][CH:30]=[C:31]([CH:35]=1)[C:32]([OH:34])=[O:33]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCN(c2ncc(C(=O)O)cc2Cl)CC1c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](NCC1CCN(c2ncc(C(=O)O)cc2Cl)CC1c1ccccc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 141 mg of the crude product of 6-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]-5-chloronicotinic acid was added 2.0 mL of a 4 M hydrogen chloride/1,4-dioxane solution. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure, and to the obtained residue were added ethanol, followed by crystallization to obtain 49.8 mg of 5-chloro-6-[4-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]nicotinic acid hydrochloride as a white solid.
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[CH3:6][N:7](C)[C:8](C1C=CC=CC=1)=CC=[N+](C)C.[CH3:21][N:22]([CH3:35])[CH:23]=[CH:24][C:25](=O)[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27].F[B-](F)(F)F.C([O+](CC)CC)C.CNC>ClCCl>[F:1][B-:2]([F:5])([F:4])[F:3].[CH3:6][N:7]([CH3:8])[C:25]([C:26](=[O:27])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:24][CH:23]=[N+:22]([CH3:35])[CH3:21]
Reactant: CN(C)C=CC(=O)C(=O)c1ccccc1
Reactant: CN(C)C(=CC=[N+](C)C)c1ccccc1
Agent: CC[O+](CC)CC
Agent: CNC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CN(C)C(=CC=[N+](C)C)C(=O)c1ccccc1

Procedure:
The procedure is as in Example 24 for the preparation of N-(3-dimethylamino-3-phenylpropenylidene)-N-methylmethanaminium tetrafluoroborate, starting with 4-dimethylamino-1-phenyl-3-butene-1,2-dione (9.3 g), triethyloxonium tetrafluoroborate (10.3 g) and dimethylamine (3.2 cc) in dichloromethane (140 cc). After precipitation in ethyl acetate (30 cc), N-(3-dimethylamino-3-benzoylpropenylidene)-N-methylmethanaminium tetrafluoroborate (5 g), m.p. 140° C., is obtained.
Reaction SMILES: [CH2:1]([NH:8][NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CC[O:18][CH:19]=[C:20]([C:26](OCC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>O>[CH2:1]([N:8]1[C:19](=[O:18])[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNCc1ccccc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1c[nH]n(Cc2ccccc2)c1=O

Procedure:
Benzyl hydrazine (324 mg, 2.65 mmol) in water (15 ml) containing potassium carbonate (368 mg, 2.65 mmol) was treated with diethyl ethoxymethylene malonate (575 μl, 2.65 mmol) and the whole refluxed for 3 hours. The reaction mixture was allowed to cool and then washed with ethyl acetate. The aqueous solution was then acidified (HCl) to pH 2 and extracted with ethyl acetate. The ethyl acetate extraction was dried (MgSO4) and evaporated to give the title product as an oily solid which solidified on hexane trituration 265 mg, 41%), recrystallised from aqueous ethanol, mp 79°-81° C. νmax (CHCl3) 1720, 1659, 1575 cm-1. δ(CDCl3) 1.37 (3H, t, J8 Hz, --OCH2CH3), 4.4 (2H, q, J8 Hz, OCH2CH3), 5.23 (2H, s, --CH2N), 7.44 (5H, m, phenyl protons), 7.73 (1H, s, C3 pyrazole proton), 8.50 (1H, bs, --NH proton). Found: M+, 246.0995; C13H14N2O3 requires M, 246.1003.
Reaction SMILES: [C:1]([C:4]1[C:9]([Cl:10])=[C:8]([CH2:11][CH3:12])[CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].[BrH:13].[Br:14]C1C=C(C)C=CN=1>>[BrH:14].[Br:13][CH2:2][C:1]([C:4]1[C:9]([Cl:10])=[C:8]([CH2:11][CH3:12])[CH:7]=[CH:6][N:5]=1)=[O:3]
Reactant: Cc1ccnc(Br)c1
Reactant: CCc1ccnc(C(C)=O)c1Cl
Agent: Br
Product: CCc1ccnc(C(=O)CBr)c1Cl

Procedure:
The title compound was prepared from 2-acetyl-3-chloro-4-ethylpyridine according to the procedure for preparing 2-bromo-4-methylpyridine hydrobromide described in step 2 of Example 31.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)[CH:3]=1.Cl.[NH2:18][NH:19][C:20]([NH2:22])=[O:21].O.O.O.C([O-])(=O)C.[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[N:18][NH:19][C:20]([NH2:22])=[O:21])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: O=Cc1ccc(Oc2cc(Cl)ccn2)cc1
Reactant: NNC(N)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=O)NN=Cc1ccc(Oc2cc(Cl)ccn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
To a solution of 4-(4-chloro-2-pyridinoxy)benzaldehyde (330 mg, 1.41 mmol) in ethanol (10 mL) was added a solution of semicarbazide hydrochloride (213 mg, 1.84 mmol) and sodium acetate trihydrate (224 mg, 1.65 mmol) in water (5 mL). The mixture was stirred at room temperature for 30 min., and the resulting solid was collected by filtration, washed with water and dried in vacuo to yield the title compound as a white solid (400 mg, 1.36 mmol, 96%), mp: 231-233° C. 1H NMR (DMSO-d6): δ 10.22 (s, 1H), 8.22 (d, J=2.5, 1H), 7.97 (dd, J=2.5, 8.7, 1H), 7.85 (s, 1H), 7.77 (d, J=8.7, 2H), 7.15 (d, J=8.7, 2H) 7.12 (d, J=8.7, 1H), 6.47 (s, 2H).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[K+].[O:11]1[CH2:26][CH:12]1[CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19][CH2:18]2>CO>[OH:11][CH:12]([CH2:26][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19][CH2:18]2
Reactant: Sc1ccccc1
Reactant: O=C1CCc2cc(OCC3CO3)ccc2N1
Agent: C[O-]
Agent: [K+]
Solvent: CO
Product: O=C1CCc2cc(OCC(O)CSc3ccccc3)ccc2N1
Reaction time: 8 h

Procedure:
4.11 gm (0.04 mol) of thiophenol were added to a suspension of 2.10 gm (0.03 mol) of potassium methylate in 40 ml of methanol, whereby a clear solution was obtained. Then, 4.38 gm of 6-(2,3-epoxy-propoxy)-3,4-dihydro-carbostyril (m.p. 125°-128° C.) were added while stirring, which also dissolved, accompanied by slight generation of heat. After 5 minutes the separation of a white crystal slurry started. After standing overnight, the crystals were suction-filtered off and recrystallized from a little methanol. White crystals with a melting point of 148°-149° C. were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([OH:7])=O.Cl.[CH3:13][O:14][C:15](=[O:26])[C@H:16]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[NH2:17].ON1C2C=CC=CC=2N=N1.C(N1CCOCC1)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH3:13][O:14][C:15](=[O:26])[C@H:16]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=1)[NH:17][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([OH:11])[CH:10]=[C:2]([OH:1])[CH:3]=1
Reactant: O=C(O)c1cc(O)cc(O)c1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)c1cc(O)cc(O)c1
Temperature: 25 °C

Procedure:
231.2 g of 3,5-dihydroxybenzoic acid are dissolved in 4 l of dimethyl formamide. 313 g of L-tyrosine-methyl ester hydrochloride, 202 g of 1-hydroxybenzotriazole and 346 ml of N-ethyl morpholine and subsequently 297 g of dicyclohexyl carbodiimide are added. The mixture is stirred over night at room temperature, and the precipitated dicyclohexyl urea is filtered off. The solvent is distilled off in vacuo, the residue is taken up in 4 l of ethyl acetate, the ethyl acetate solution is washed 4 times each with saturated sodium bicarbonate solution, 3 times with 400 ml portions of a solution of 5% KHSO4 and 10% K2SO4 and twice with 200 ml portions of water, dried over sodium sulfate and subsequently brought to dryness. Yield: 360 g of resin.
Reaction SMILES: [F:1][C:2]1[C:10]2[C:9]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=3)=[N:8][C:7]([NH:21][C:22]3[CH:26]=[CH:25][N:24]([CH3:27])[N:23]=3)=[N:6][C:5]=2[N:4]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:3]=1.[Cl-].[NH4+].O>CCOC(C)=O.C([O-])(O)=O.[Na+].[Zn]>[NH2:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[O:11][C:9]1[C:10]2[C:2]([F:1])=[CH:3][N:4]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:34])[CH3:35])[C:5]=2[N:6]=[C:7]([NH:21][C:22]2[CH:26]=[CH:25][N:24]([CH3:27])[N:23]=2)[N:8]=1
Reactant: Cn1ccc(Nc2nc(Oc3cccc([N+](=O)[O-])c3)c3c(F)cn(COCC[Si](C)(C)C)c3n2)n1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1ccc(Nc2nc(Oc3cccc(N)c3)c3c(F)cn(COCC[Si](C)(C)C)c3n2)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 80.7 %

Procedure:
A reaction vial was charged with 5-fluoro-N-(1-methyl-1H-pyrazol-3-yl)-4-(3-nitrophenoxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (520 mg, 1.04 mmol), zinc dust (340 mg, 5.2 mmol), ammonium chloride (279 mg, 5.2 mmol), water (4 mL) and EtOAc (20 mL). The reaction mixture was capped and stirred at rt for 20 hrs. The reaction was diluted with EtOAc (100 mL) and saturated aqueous NaHCO3 (15 mL). The insoluble material was removed by filtration through Celite. The filtrate was separated, and the organic layer was washed with brine (10 mL), dried over Na2SO4 and evaporated to afford the title compound (394 mg, 81% yield) as a foam. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.52 (s, 1H) 7.45 (s, 1H) 7.26 (d, J=2.27 Hz, 1H) 7.14 (t, J=7.93 Hz, 1H) 6.49-6.59 (m, 2H) 6.46 (dd, J=7.93, 1.38 Hz, 1H) 6.30-6.43 (m, 1H) 5.50 (s, 2H) 5.32 (s, 2H) 3.75 (s, 3H) 3.56-3.67 (m, 2H) 0.89-0.98 (m, 2H) 0.00 (s, 9H). m/z (APCI+) for C22H28FN7O2Si 470.1 (M+H)+.
Reaction SMILES: [OH:1]O.[F:3][C:4]([F:29])([CH:26]([F:28])[F:27])[CH2:5][O:6][C:7]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10](B2OC(C)(C)C(C)(C)O2)=[CH:9][N:8]=1>CO>[F:3][C:4]([F:29])([CH:26]([F:28])[F:27])[CH2:5][O:6][C:7]1[N:8]=[CH:9][C:10]([OH:1])=[CH:11][C:12]=1[C:13]([F:16])([F:15])[F:14]
Reactant: OO
Reactant: CC1(C)OB(c2cnc(OCC(F)(F)C(F)F)c(C(F)(F)F)c2)OC1(C)C
Solvent: CO
Product: Oc1cnc(OCC(F)(F)C(F)F)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.2 %

Procedure:
Hydrogen peroxide (1.29 mL, 13.33 mmol, 35% solution) was added to a solution of 2-(2,2,3,3-tetrafluoropropoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridine (Preparation 261, 4.45 g, 11.04 mmol) in methanol (50 mL) at 0° C. (ice-bath) and the reaction mixture was allowed to warm to room temperature. After 3 hours, the reaction was quenched with 1M solution of sodium thiosulfate and then methanol was removed in vacuo. The residue was partitioned between ethyl acetate and water, the organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with 30% heptane in ethyl acetate to give the title compound as a oil (2.95 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.Br[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.[Cu]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=1
Reactant: Oc1ccc(Cl)cn1
Reactant: Cc1ccc(Br)nc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2cc(Cl)ccc2=O)nc1

Procedure:
5-Chloro-2-pyridinol (2.26 g, 17.4 mmol), 2-bromo-5-methylpyridine (3.00 g, 17.4 mmol), copper (0.022 g, 0.35 mmol) and K2CO3 (2.66 g, 19.2 mmol) were heated at 180° C. for 16 hrs. The brown reaction mixture was cooled, diluted with EtOAc and washed with saturated NaHCO3. The aqueous layer was extracted with EtOAc (2×) and the combined organic extracts were washed with brine, dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed (silica gel, EtOAc: CH2Cl2 20:80 to 50:50 gradient elution) to afford the title compound as a white solid.